Gaurav Kistangari, MD, MPH

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

A 43-year-old man with no medical history presented with pain and swelling in his left arm for 2 weeks. He was a regular weight lifter, and his exercise routine included repetitive hyperextension and hyperabduction of his arms while lifting heavy weights.

He had no history of recent trauma or venous cannulation of the left arm. His family history was negative for thrombophilic disorders. Physical examination revealed a swollen and erythematous left arm and visible venous collaterals at the neck, shoulder, and chest. There was no evidence of arterial insufficiency.

Duplex ultrasonography confirmed thrombosis of the left brachial, axillary, and subclavian veins. Further evaluation with computed tomography showed no intrathoracic mass but revealed several subsegmental pulmonary thrombi in the right lung. A screen for thrombophilia was negative. Venography confirmed complete thrombotic occlusion of the subclavian, axillary, and brachial veins (Figure 1).

Catheter-directed thrombolysis with tissue plasminogen activator resulted in complete resolution of the thrombosis, but venography after 3 days of thrombolysis showed 50% residual stenosis of the left subclavian vein where it passes under the first rib (Figure 2). The redness and swelling had markedly improved 2 days after thrombolytic therapy. He was discharged home on rivaroxaban 20 mg daily.

Follow-up venography 2 months later (Figure 3), with the patient performing hyperabduction of the arms, showed a patent subclavian vein with no thrombosis, but dynamic compression and occlusion of the subclavian vein where it passes the first rib. Magnetic resonance imaging (MRI) of the neck showed no cervical (ie, extra) rib and no soft-tissue abnormalities of the scalene triangle.

Following this, the patient underwent resection of the left first rib for decompression of the venous thoracic outlet, which resulted in resolution of his symptoms. He remained asymptomatic at 6-month follow-up.

PAGET-SCHROETTER SYNDROME

Paget-Schroetter syndrome, also referred to as effort-induced or effort thrombosis, is thrombosis of the axillary or subclavian vein associated with strenuous and repetitive activity of the arms. Anatomic abnormalities at the thoracic outlet—cervical rib, congenital bands, hypertrophy of scalene tendons, abnormal insertion of the costoclavicular ligament—and repetitive trauma to the endothelium of the subclavian vein are key factors in its initiation and progression.

The condition is seen primarily in young people who participate in strenuous activities such as rowing, weight lifting, and baseball pitching. It is estimated to be the cause of 40% of cases of primary upper-extremity deep vein thrombosis in the absence of an obvious risk factor or trigger such as a central venous catheter, pacemaker, port, or occult malignancy.¹

A provocative test such as the Adson test or hyperabduction test during MRI or venography helps confirm thoracic outlet obstruction by demonstrating dynamic obstruction.²

TREATMENT CONSIDERATIONS

There are no universal guidelines for the treatment of Paget-Schroetter syndrome. However, the available data^3–5 suggest a multimodal approach that involves early catheter-directed thrombolysis and subsequent surgical decompression of the thoracic outlet. This can restore venous patency and reduce the risk of long-term complications such as rethrombosis and postthrombotic syndrome.^3–5

Surgical treatment includes resection of the first rib and division of the scalene muscles and the costoclavicular ligament. MRI with provocative testing helps guide the surgical approach. Anticoagulation therapy alone—ie, without thrombolysis and surgical decompression—is inadequate as it leads to recurrence of thrombosis and residual symptoms.⁶

Paget-Schroetter syndrome should not be managed the same as lower-extremity deep vein thrombosis because the cause and the exacerbating factors are different.

Unanswered questions

Because we have no data from randomized controlled trials, questions about management remain. What should be the duration of anticoagulation, especially in the absence of coexisting thrombophilia? Is thrombophilia screening useful? What is the optimal timing for starting thrombolytic therapy?

A careful history and heightened suspicion are required to make this diagnosis. If undiagnosed, it carries a risk of significant long-term morbidity and death. Dynamic obstruction during venography, in addition to MRI, can help identify an anatomic obstruction.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 49-year-old woman with a history of depression, bipolar disorder, and chronic back pain was brought to the emergency department unresponsive after having taken an unknown quantity of amitriptyline tablets.

On arrival, she was comatose, with a score of 3 (the lowest possible score) on the 15-point Glasgow Coma Scale. Her blood pressure was 65/22 mm Hg, heart rate 121 beats per minute, respiratory rate 14 per minute, and oxygen saturation 88% on room air. The rest of the initial physical examination was normal.

She was immediately intubated, put on mechanical ventilation, and given an infusion of a 1-L bolus of normal saline and 50 mmol (1 mmol/kg) of sodium bicarbonate. Norepinephrine infusion was started. Gastric lavage was not done.

Results of initial laboratory testing showed a serum potassium of 2.9 mmol/L (reference range 3.5–5.0) and a serum magnesium of 1.6 mmol/L (1.7–2.6), which were corrected with infusion of 60 mmol of potassium chloride and 2 g of magnesium sulfate. The serum amitriptyline measurement was ordered at the time of her presentation to the emergency department.

Arterial blood gas analysis showed:

• pH 7.15 (normal range 7.35–7.45)
• Paco₂ 66 mm Hg (34–46)
• Pao₂ 229 mm Hg (85–95)
• Bicarbonate 22 mmol/L (22–26).

The initial electrocardiogram (ECG) (Figure 1) showed regular wide-complex tachycardia with no definite right or left bundle branch block morphology, no discernible P waves, a QRS duration of 198 msec, right axis deviation, and no Brugada criteria to suggest ventricular tachycardia.

She remained hypotensive, with regular wide-complex tachycardia on the ECG. She was given an additional 1-L bolus of normal saline and 100 mmol (2 mmol/kg) of sodium bicarbonate, and within 1 minute the wide-complex tachycardia resolved to narrow-complex sinus tachycardia (Figure 2). At this point, an infusion of 150 mmol/L of sodium bicarbonate in dextrose 5% in water was started, with serial ECGs to monitor the QRS duration and serial arterial blood gas monitoring to maintain the pH between 7.45 and 7.55.

TRANSFER TO THE ICU

She was then transferred to the intensive care unit (ICU), where she remained for 2 weeks. While in the ICU, she had a single recurrence of wide-complex tachycardia that resolved immediately with an infusion of 100 mmol of sodium bicarbonate. A urine toxicology screen was negative, and the serum amitriptyline measurement, returned from the laboratory 48 hours after her initial presentation, was 594 ng/mL (reference range 100–250 ng/mL). She was eventually weaned off the norepinephrine infusion after 20 hours, the sodium bicarbonate infusion was discontinued after 4 days, and she was taken off mechanical ventilation after 10 days. Also during her ICU stay, she had seizures on day 3 and developed aspiration pneumonia.

From the ICU, she was transferred to a regular floor, where she stayed for another week and then was transferred to a rehabilitation center. This patient was known to have clinical depression and to have attempted suicide once before. She had recently been under additional psychosocial stresses, which likely prompted this second attempt.

She reportedly had no neurologic or cardiovascular sequelae after her discharge from the hospital.

AMITRIPTYLINE OVERDOSE

Amitriptyline causes a relatively high number of fatal overdoses, at 34 per 1 million prescriptions.¹ Death is usually from hypotension and ventricular arrhythmia caused by blockage of cardiac fast sodium channels leading to disturbances of cardiac conduction such as wide-complex tachycardia.

Other manifestations of amitriptyline overdose include seizures, sedation, and anticholinergic toxicity from variable blockade of gamma-aminobutyric acid receptors, histamine 1 receptors, and alpha receptors.²

In amitriptyline overdose, sinus tachycardia is the most common finding on ECG

Of the various changes on ECG described with amitriptyline overdose, sinus tachycardia is the most common. A QRS duration greater than 100 msec, right to extreme-right axis deviation with negative QRS complexes in leads I and aVL, and an R-wave amplitude greater than 3 mm in lead aVR are indications for sodium bicarbonate infusion, especially in hemodynamically unstable patients.³ Sodium bicarbonate increases the serum concentration of sodium and thereby overcomes the sodium channel blockade. It also alkalinizes the serum, favoring an electrically neutral form of amitriptyline that binds less to receptors and binds more to alpha-1-acid glycoprotein, decreasing the fraction of free drug available for toxicity.⁴

In patients with amitriptyline overdose, wide-complex tachycardia and hypotension refractory to sodium bicarbonate infusion can be treated with lidocaine, magnesium sulfate, direct-current cardioversion, and lipid resuscitation.^5,6 Treatment with class IA, IC, and III antiarrhythmics is contraindicated, as they block sodium channels and thus can worsen conduction disturbances.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

A 58-year-old-man with a history of intravenous drug abuse, chronic hepatitis C, and anxiety presented to our emergency department twice in 4 weeks with progressive dyspnea and night sweats. He was a nonsmoker and had been an electrician for 15 years.

The first time he came in, chest radiography revealed bilateral reticulonodular infiltrates in the lung bases. He was treated with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax) for presumed community-acquired pneumonia and was then sent home on a 10-day course of oral amoxicillin-clavulanate (Augmentin). The antibiotics did not improve his symptoms, and 3 weeks later he presented again to the emergency department.

On his second presentation, he was in respiratory distress (oxygen saturation 78% on room air) and was afebrile and tachypneic. Physical examination revealed numerous injection marks or “tracks” on the skin of both arms, and auscultation revealed diminished intensity of breath sounds in both lung bases.

Repeat chest radiography demonstrated that the infiltrates were still there. Computed tomography was ordered and showed mild centrilobular emphysematous changes in both lungs, bibasilar opacifications, and a mass-like lesion (3.3 × 1.9 cm) in the right lower lobe (Figure 1).

He subsequently underwent bronchoscopy, which showed no endobronchial abnormalities. Transbronchial lung biopsy was performed, and histopathologic analysis of the specimen (Figure 2) revealed rodlike, birefringent crystals under polarized light, with an extensive foreign-body giant-cell reaction outside pulmonary capillaries, suggestive of intravascular pulmonary talcosis. Blood and sputum cultures were negative for pathologic organisms. Bronchoalveolar lavage samples were negative for pathologic organisms and malignant cells.

On further questioning, the patient revealed that he intravenously injected various drugs intended for oral use, such as crushed meperidine (Demerol), methylphenidate (Ritalin), and methadone tablets.

Pulmonary function tests indicated a severe obstructive pattern. The predicted forced expiratory volume in the first second of expiration (FEV₁) was 25%, and the ratio of FEV₁ to forced vital capacity was 27%.

Transthoracic echocardiography revealed mild pulmonary hypertension with a right ventricular systolic pressure of 28 mm Hg at rest.

Based on the results of the histologic examination, a diagnosis of intravascular pulmonary talcosis was made. Antibiotics were discontinued, and treatment with albuterol and ipratropium bromide (Combivent) inhalers was started. The patient remained oxygen-dependent at the time of hospital discharge.

INTRAVASCULAR PULMONARY TALCOSIS

Intravascular pulmonary talcosis is seen predominantly in those who chronically inject intravenous drugs intended for oral use.^1,2

Many oral medications contain talc as a filler and lubricant to prevent the tablet from sticking to equipment during the manufacturing process. When oral medications containing talc are crushed, dissolved in water, and injected intravenously, the talc crystals and other particles lodge in the pulmonary vascular bed, resulting in microscopic pulmonary embolizations.

Over time, these particles migrate to the pulmonary interstitium and incite a foreign-body granulomatous reaction, which may be associated with progressive pulmonary fibrosis. The severity of this immune reaction and fibrosis may vary; hence, some patients remain asymptomatic, whereas some present with dyspnea from extensive fibrosis and pulmonary hypertension.

Persistent dyspnea along with persistent infiltrates on chest imaging in an intravenous drug abuser should prompt suspicion for intravascular pulmonary talcosis as well as consideration of other diagnoses, such as pneumonia, malignancy, and septic pulmonary emboli.

There is no established treatment for intravascular pulmonary talcosis; treatment is often supportive. A few studies and case reports have indicated varied success with systemic and inhaled corticosteroids.^3–5 In extreme cases, lung transplantation may be necessary; however, this would require a comprehensive psychiatric assessment to minimize the risk of addiction relapse after transplantation.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.

Immune thrombocytopenia (ITP), formerly known as idiopathic thrombocytopenic purpura, is an autoimmune disorder characterized by a low platelet count and increased risk of mucocutaneous bleeding. During the last decade its management has changed, with the advent of new medications and with increased awareness of treatment side effects. This article will focus on the pathophysiology, diagnosis, and management of ITP in adults.

A SLIGHT FEMALE PREDOMINANCE UNTIL AGE 65

The estimated age-adjusted prevalence of ITP in the United States is 9.5 to 23.6 cases per 100,000.¹ In a recent study in the United Kingdom, the incidence was 4.4 per 100,000 patient-years among women and 3.4 among men.² A slight female predominance was seen until age 65; thereafter, the incidence rates in men and women were about equal.

INCREASED PLATELET DESTRUCTION AND DECREASED PRODUCTION

ITP is a complex immune process in which cellular and humoral immunity are involved in the destruction of platelets³ as well as impaired platelet production. Several theories have emerged in the last decade to explain this autoimmune process.

Autoantibodies form against platelets

The triggering event for antibody initiation in ITP is unknown.³ Autoantibodies (mostly immunoglobulin G [IgG] but sometimes IgM and IgA) are produced against the platelet membrane glycoprotein GPIIb-IIIa. The antibody-coated platelets are rapidly cleared by the reticuloendothelial system in the spleen and liver, in a process mediated by Fc-receptor expression on macrophages and dendritic cells. Autoantibodies may also affect platelet production by inhibiting megakaryocyte maturation and inducing apoptosis.^4,5

Patients with ITP also have CD4+ T cells that are autoreactive to GPIIb-IIIa and that stimulate B-cell clones to produce antiplatelet antibodies. Although autoreactive T cells are present in healthy individuals, they appear to be activated in patients with ITP by exposure to fragments of GPIIb-IIIa rather than native GPIIb-IIIa proteins.⁶ Activated macrophages internalize antibody-coated platelets and degrade GPIIb-IIIa and other glycoproteins to form “cryptic” epitopes that are expressed on the macrophage surface as novel peptides that induce further proliferation of CD4+ T-cell clones. Epitope spread thereby sustains a continuous loop that amplifies the production of GPIIb-IIIa antibodies.⁷

Defective T-regulatory cells appear to be critical to the pathogenesis of ITP by breaking self-tolerance, allowing the autoimmune process to progress.⁸ This, together with several other immune mechanisms such as molecular mimicry, abnormal cytokine profile, and B-cell abnormalities, may lead to enhanced platelet clearance.⁹

In addition to destroying platelets, antibodies may impair platelet production.¹⁰ Good evidence for platelets being underproduced in patients with ITP is that treating with thrombopoietin agonists results in increased platelet counts.

A DIAGNOSIS OF EXCLUSION

ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.¹¹ No diagnostic criteria currently exist, and the diagnosis is established only after excluding other causes of thrombocytopenia.

A recent report¹² from an international working group established a platelet count threshold of less than 100 × 10⁹/L for diagnosing ITP, down from the previous threshold of 150 × 10⁹/L. The panel also recommended using the term “immune” rather than “idiopathic” thrombocytopenia, emphasizing the role of underlying immune mechanisms. The term “purpura” was removed, because many patients have no or minimal signs of bleeding at the time of diagnosis.¹²

The 2011 American Society of Hematology’s evidenced-based guidelines for the treatment of ITP present the most recent authoritative diagnostic and therapeutic recommendations.¹³

ITP is considered to be primary if it occurs in isolation, and secondary if it is associated with an underlying disorder. It is further classified according to its duration since diagnosis: newly diagnosed (< 3 months), persistent (3−12 months), and chronic (> 12 months).

In adults, ITP tends to be chronic, presenting with a more indolent course than in childhood, and unlike childhood ITP, infrequently following a viral infection.

Clinical features associated with ITP are related to thrombocytopenia: petechiae (pinpoint microvascular hemorrhages that do not blanch with pressure), purpura (appearing like large bruises), epistaxis (nosebleeds), menorrhagia, gum bleeding, and other types of mucocutaneous bleeding. Other common clinical features include fatigue, impaired quality of life, and treatment-related side effects (eg, infection).¹⁴

A low platelet count may be the sole initial manifestation. The patient’s history, physical examination, blood counts, and findings on blood smear are essential to rule out other diagnoses. Few diagnostic tests are useful in the initial evaluation (Table 1). Abnormalities in the blood count or blood smear may be further investigated with bone marrow biopsy but is not required if the patient has typical features of ITP, regardless of age.

Because there are no specific criteria for diagnosing ITP, other causes of thrombocytopenia must be excluded. The differential diagnosis can be further classified as ITP due to other underlying disease (ie, secondary ITP) vs nonautoimmune causes that are frequently encountered in clinical practice.

SECONDARY ITP

The differential diagnosis of thrombocytopenia due to known underlying immune disease includes the following:

Drug-induced ITP

Recurrent episodes of acute thrombocytopenia not explained by other causes should trigger consideration of drug-induced thrombocytopenia. ¹¹ Patients should be questioned about drug use, especially of sulfonamides, antiepileptics, and quinine. Thrombocytopenia usually occurs 5 to 7 days after beginning the inciting drug for the first time and more quickly when the drug is given intermittently. Heparin is the most common cause of drug-related thrombocytopenia among hospitalized patients; the mechanism is unique and involves formation of a heparin-PF4 immune complex.

Human immunodeficiency virus infection

Approximately 40% of patients with human immunodeficiency virus (HIV) infection develop thrombocytopenia at some time.¹⁵ HIV infection can initially manifest as isolated thrombocytopenia and is sometimes clinically indistinguishable from chronic ITP, making it an important consideration in a newly diagnosed case of thrombocytopenia.

The mechanism of thrombocytopenia in early HIV is similar to that in primary ITP: as the disease progresses, low platelet counts can result from ineffective hematopoiesis due to megakaryocyte infection and marrow infiltration.¹⁶

Hepatitis C virus infection

Hepatitis C virus (HCV) infection can also cause immune thrombocytopenia. A recent study demonstrated the potential of the HCV core envelope protein 1 to induce antiplatelet antibodies (to platelet surface integrin GPIIIa49-66) by molecular mimicry.¹⁷ Other causes of thrombocytopenia in HCV infection may be related to chronic liver disease, such as portal hypertension-related hypersplenism, as well as decreased thrombopoietin production.¹⁸ Antiviral treatment with pegylated interferon may also cause mild thrombocytopenia.¹⁹

Helicobacter pylori

The association between H pylori infection and ITP remains uncertain. Eradication of infection appears to completely correct ITP in some places where the prevalence of H pylori is high (eg, Italy and Japan) but not in the United States and Canada, where the prevalence is low.²⁰ The different response may be due not only to the differences in prevalence, but to different H pylori genotypes: most H pylori strains in Japan express CagA, whereas the frequency of CagA-positive strains is much lower in western countries.²⁰

In areas where eradication therapy may be useful, the presence of H pylori infection should be determined by either a urea breath test or stool antigen testing.

Lymphoproliferative disorders

Secondary forms of ITP can occur in association with chronic lymphocytic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma. These diagnoses should especially be considered in patients presenting with thrombocytopenia accompanied by systemic illness. ITP occurs in at least 2% of patients with chronic lymphocytic leukemia and is usually difficult to distinguish from thrombocytopenia secondary to marrow infiltration or from fludarabine (Fludora) therapy.²¹

It is especially important to determine if a lymphoproliferative disorder is present because it changes the treatment of ITP. Treatment of ITP complicating chronic lymphocytic leukemia is challenging and includes corticosteroids and steroid-sparing agents such as cyclosporine (Gengraf, Neoral, Sandimmune), rituximab (Rituxan), and intravenous immunoglobulin.²²

Systemic lupus erythematosus and other autoimmune diseases

Thrombocytopenia is a frequent clinical manifestation of systemic lupus erythematosus, occurring in 7% to 30% of patients,²³ and is an independent risk factor for death.²⁴ Lupus should be suspected in patients with ITP who have multiorgan involvement and other clinical and laboratory abnormalities. A small percentage of patients with ITP (about 2%−5%) develop lupus after several years.²¹

Thrombocytopenia can also result from other autoimmune disorders such as antiphospholipid antibody syndrome²⁵ and autoimmune thyroid diseases as well as immunodeficient states such as IgA deficiency and common variable immunodeficiency with low IgG levels.

NONAUTOIMMUNE THROMBOCYTOPENIA

Thrombocytopenia can also be caused by a number of nonautoimmune conditions.

Pseudothrombocytopenia

Pseudothrombocytopenia can occur if ex-vivo agglutination of platelets is induced by antiplatelet antibodies to EDTA, a standard blood anticoagulant. Automated counters cannot differentiate the agglutinated platelet clumps from individual cells such as red cells. This can frequently be overcome by running the counts in a citrate or ACD reagent tube. A peripheral blood smear can demonstrate whether platelet clumps are present.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura presents with thrombocytopenia, purpura, and anemia. Associated clinical abnormalities (fever, neurologic symptoms, and renal failure) and the presence of fragmented red cells on blood smear help to distinguish it from ITP. Plasma exchange is the treatment of choice.

Gestational thrombocytopenia

Five percent of pregnant women develop mild thrombocytopenia (platelet counts typically > 70 × 10⁹/L) near the end of gestation.²⁶ It requires no treatment and resolves after delivery. The fetus’ platelet count remains unaffected.

Gestational thrombocytopenia should be differentiated from the severe thrombocytopenia of preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which requires immediate attention.

Myelodysplastic syndrome

Myelodysplastic syndrome is common among elderly patients and should be considered in cases of unexplained cytopenia and abnormalities in the peripheral blood smear suggestive of dysplastic cytologic features. It can be diagnosed by bone marrow biopsy. Thrombocytopenia occurs in about 40% to 65% of cases of myelodysplastic syndrome.²⁷

MANAGE ITP TO KEEP PLATELET COUNT ABOVE 30 × 10⁹/L

ITP does not necessarily require treatment, and the initial challenge is to determine whether treatment or observation is indicated. Treatment is based on two major factors: the platelet count and degree of bleeding. The goals of management are to achieve a safe platelet count to prevent serious bleeding while minimizing treatment-related toxicity.⁷

Adults with platelet counts of less than 30 × 10⁹/L are usually treated. In multiple large cohort studies, patients with platelet counts above that level have been safely observed without treatment.^11,28

Table 2 outlines a comprehensive approach to therapy.

INITIAL TREATMENT: STEROIDS AND IMMUNOGLOBULINS

Oral corticosteroids are the initial agents of choice

Oral prednisone 1 mg/kg/day in tapering doses for 4 to 6 weeks is the most common initial regimen. Other regimens, such as high-dose dexamethasone (Decadron) (40 mg daily for 4 days per month) for several cycles, have been reported to be more effective²⁹ but have not been studied in head-to-head trials with oral prednisone.

Due to their effectiveness, low cost, and convenience of use, corticosteroids have been the backbone of initial treatment in ITP. However, in most patients the platelet count decreases once the dose is tapered or stopped; remission is sustained in only 10% to 30% of cases.³⁰ Continuation of corticosteroids is limited by long-term complications such as opportunistic infections, osteoporosis, and emotional lability.³¹

Intravenous immunoglobulin and anti-D immunoglobulin are alternatives

Intravenous immunoglobulin is recommended for patients who have not responded to corticosteroids and is often used in pregnancy. It is thought to act by blocking Fc receptors in the reticuloendothelial system. Intravenous immunoglobulin rapidly increases platelet counts in 65% to 80% of patients,³² but the effect is transient and the drug requires frequent administration. It is usually well tolerated, although about 5% of patients experience headache, chills, myalgias, arthralgias, and back pain. Rare, serious complications include thrombotic events, anaphylaxis (in IgA-deficient patients), and renal failure.

Anti-D immunoglobulin, a pooled IgG product, is derived from the plasma of Rh(D)-negative donors and can be given only to patients who are Rh(D)-positive. Response rates as high as 70% have been reported, with platelet effects lasting for more than 21 days.³³ Studies have shown better results at a high dose (75 μg/kg) than with the approved dose of 50 μg/kg.³⁴

Anti-D immunoglobulin can also be given intermittently whenever the platelet count falls below a specific level (ie, 30 × 10⁹/L). This allows some patients to avoid splenectomy and may even trigger long-term remission.³²

Common side effects of anti-D immunoglobulin include fever and chills; these can be prevented by premedication with acetaminophen or corticosteroids. Rare but fatal cases of intravascular hemolysis, renal failure, and disseminated intravascular coagulation have been reported, precluding its use for ITP in some countries, including those of the European Union.

Emergency treatment: Combination therapy

Evidence-based guidelines are limited for treating patients with active bleeding or who are at high risk of bleeding. For uncontrolled bleeding, a combination of first-line therapies is recommended, using prednisone and intravenous immunoglobulin.³⁵ Other options include high-dose methylprednisolone and platelet transfusions, alone or in combination with intravenous immunoglobulin.³⁶

SECOND-LINE TREATMENTS

Splenectomy produces complete remission in most patients

Patients who relapse and have a platelet count of less than 20 × 10⁹/L are traditionally considered for splenectomy. More than two-thirds of patients respond with no need for further treatment.³⁷

Although splenectomy has the highest rate of durable platelet response, the risks associated with surgery are an important concern. Even with a laparoscopic splenectomy, complications occur in 10% of patients and death in 0.2%. Long-term risks include the rare occurrence of sepsis with an estimated mortality rate of 0.73 per 1,000 patient-years, and possible increased risk of thrombosis.^38,39

Adherence to recommended vaccination protocols and early administration of antibiotics for systemic febrile illness reduce the risk of sepsis.⁴⁰ Patients are advised to receive immunization against encapsulated bacteria with pneumococcal, Haemophilus influenzae type b, and meningococcal vaccines. These vaccines should be given at least 2 weeks before elective splenectomy.⁴¹

Treatment of patients refractory to splenectomy is challenging and requires further immunosuppressive therapy, which is associated with an increased risk of infections and infection-related deaths.⁴²

Rituximab in addition to or possibly instead of splenectomy

Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody that targets B cells. Although initially approved for treatment of lymphomas, rituximab has gained popularity in treating ITP due to its safety profile and ability to deplete CD20+ B cells responsible for antiplatelet antibody production by Fc-mediated cell lysis.

In the largest systematic review of published reports of rituximab use in ITP (19 studies, 313 patients), Arnold and colleagues⁴³ reported an overall platelet response (defined as platelet count > 50 × 10⁹/L) in 62.5% (95% confidence interval [CI] 52.6%−72.5%) of patients. The median duration of response was 10.5 months (range 3–20), and median follow-up was 9.5 months (range 2–25). Nearly all patients had received corticosteroid treatment and half of them had undergone splenectomy.

Rituximab has also been investigated as an alternative to splenectomy. In a prospective, single-arm, phase 2 trial, 60 patients with chronic ITP (platelet counts < 30 × 10⁹/L) for whom one or more previous treatments had failed received rituximab infusions and were followed for up to 2 years. A good response (defined as a platelet count ≥ 50 × 10⁹/L, with at least a doubling from baseline) was obtained in 24 (40%) of 60 patients (95% CI 28%–52%) at 1 year and 33.3% at 2 years. The authors concluded that rituximab could be used as a presplenectomy therapeutic option, particularly in patients with chronic ITP who are at increased surgical risk or who are reluctant to undergo surgery.⁴⁴ Based on these results, rituximab may spare some patients from splenectomy, or at least delay it. However, it has never been tested in randomized controlled trials to establish its role as a splenectomy-sparing agent in ITP.

Side effects include infusion reactions, which are usually mild but in rare cases can be severe. Recently, progressive multifocal leukoencephalopathy has been recognized as a complication of rituximab treatment in patients with lymphoproliferative and autoimmune disorders.⁴⁵ Although this complication is rare in patients with ITP, careful monitoring is required until additional long-term safety data are available.

Thrombopoietic receptor agonists require continuous treatment

In the early 1990s, recombinant thrombopoietin was tested in clinical studies. These were halted when antibodies developed to recombinant thrombopoietin that cross-reacted with endogenous thrombopoietin, resulting in severe thrombocytopenia.⁴⁶

This led to the development of nonimmunogenic thrombopoietin receptor agonists that mimic the effect of thrombopoietin and stimulate the production of platelets. In 2008, the US Food and Drug Administration approved two drugs of this class for treating ITP: romiplostim (Nplate) and eltrombopag (Promacta). They are mainly used to treat patients with chronic ITP who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Although well tolerated and effective in increasing platelet counts, these agents share common drawbacks. They do not modify the course of the disease, they are used only to sustain the platelet count, they require repeated administration, and they must be given for about 7 days to achieve an adequate platelet response, so they cannot be used in emergencies. Long-term adverse effects include bone marrow fibrosis and thrombosis.

Romiplostim is a synthetic peptide capable of binding to the thrombopoietin receptor c-Mpl. It has no sequence homology with endogenous thrombopoietin,⁴⁷ so does not induce cross-reacting antibodies. It has a half-life of 120 to 160 hours and is usually given subcutaneously 1 to 10 μg/kg weekly.

Phase III clinical trials have shown the effectiveness of romiplostim in attaining a durable platelet response (platelet count > 50 × 10⁹/L) in splenectomized and nonsplenectomized populations. It is well tolerated, and only two uncommon serious adverse effects have been reported: bone marrow reticulin formation and thromboembolism.⁴⁸

A long-term open-label extension study of 142 patients treated with romiplostim for up to 156 weeks showed that 124 (87%) achieved a platelet count of more than 50 × 10⁹/L at some point, and 84% of patients were able to reduce or discontinue concurrent medications for ITP.⁴⁹

Kuter et al,⁵⁰ in a randomized controlled trial, confirmed the efficacy of romiplostim in attaining durable increased platelet counts. Patients treated with romiplostim at a mean weekly dose of 3.9 μg/kg ± 2.1 μg/kg demonstrated a higher rate of platelet response, lower incidence of treatment failure, and improved quality of life vs patients treated with standard care.

Eltrombopag is a nonpeptide thrombopoietin agonist that binds to the transmembrane domain of the thrombopoietin receptor and stimulates the proliferation and differentiation of megakaryocytes in bone marrow. It is given orally in doses of 25 to 75 mg daily.

Eltrombopag has been shown to be effective in increasing platelet counts in chronic ITP.⁵¹ In a phase III trial conducted by Cheng and colleagues, 197 patients were randomized to eltrombopag or placebo.⁵² Patients treated with eltrombopag were eight times more likely to achieve platelet counts of more than 50 × 10⁹/L during the 6-month treatment period (odds ratio 8.2, 95% CI 4.32–15.38, P < .001) vs placebo. Patients treated with eltrombopag had fewer bleeding episodes and were more likely to reduce or discontinue the dose of concurrent ITP medications. The only significant side effect seen was a rise in aminotransferases (seen in 7% of eltrombopag recipients vs 2% with placebo).⁵²

Additional thrombopoietin agonists under investigation include ARK-501, totrombopag, and LGD-4665. MDX-33, a monoclonal antibody against the Fc-receptor, is also being studied; it acts by preventing opsonization of autoantibody-coated platelets.⁵³

THIRD-LINE TREATMENTS FOR REFRACTORY CASES

Patients with ITP that is resistant to standard therapies have an increased risk of death, disease, and treatment-related complications.^28,42

Combination chemotherapy

Immunosuppressants such as azathioprine (Imuran), cyclosporine (Neoral, Sandimmune), cyclophosphamide (Cytoxan), and mycophenolate (CellCept) were used in the past in single-agent regimens with some efficacy, but their use was limited due to drug-related toxicity and a low safety profile.³ However, there is increasing evidence for a role of combination chemotherapy to treat chronic refractory ITP to achieve greater efficacy and fewer adverse effects.⁵⁴

Arnold and colleagues⁵⁵ reported that combined azathioprine, mycophenolate, and cyclosporine achieved an overall response (platelet count > 30 × 10⁹/L and doubling of the baseline) in 14 (73.7%) of 19 patients with chronic refractory ITP, lasting a median of 24 months.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation has provided remission in a limited number of patients. However, it is associated with fatal toxicities such as graft-vs-host disease and septicemia, and therefore it is reserved for severe refractory ITP with bleeding complications unresponsive to other therapies.^56,57

THERAPY FOR SECONDARY ITP DEPENDS ON THE CAUSE

Treatments for secondary ITP vary depending on the cause of thrombocytopenia and are often more complex than therapy for primary disease. Optimal management involves treating the underlying condition (eg, chronic lymphocytic leukemia or systemic lupus erythematosus).

Drug-induced thrombocytopenia requires prompt recognition and withdrawal of the inciting agent.

Treating ITP due to HCV infection primarily involves antiviral agents to suppress viral replication. If treating ITP is required, then intravenous immunoglobulin is preferable to glucocorticoids because of the risk of increasing viral load with the latter.⁵⁸ Eltrombopag may effectively increase platelet counts, allowing patients to receive interferon therapy for HCV.⁵⁹ However, a recent study was halted due to increased incidence of portal vein thrombosis, raising concerns about the safety of eltrombopag for patients with chronic liver disease.⁶⁰

Secondary ITP due to HIV infection should always be treated first with antivirals targeting HIV unless thrombocytopenia-related bleeding complications warrant treatment. If treatment for ITP is necessary, it should include corticosteroids, intravenous immunoglobulin, or anti-D immunoglobulin as first-line therapy.

Eradication therapy for H pylori is recommended for patients who are positive for the organism based on urea breath testing, stool antigen testing, or endoscopic biopsies.