Drug-Induced Diseases
Drug-Induced Immune Thrombocytopenia
Journal of Pharmacy Practice 2014, Vol. 27(5) 430-439 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014546099 jpp.sagepub.com
Teresa Kam, PharmD, CPP1, and Maurice Alexander, PharmD, BCOP, CPP1
Abstract Thrombocytopenia is commonly seen in laboratory findings, especially in critically ill patients. Although the incidence is rare, druginduced immune thrombocytopenia (DITP) is a serious complication that is often overlooked as a cause of thrombocytopenia. Over the last century, extensive research and data collection have been done in an attempt to better characterize DITP. Heparininduced thrombocytopenia is the most common DITP and has distinct pathogenesis, diagnosis, and treatment options. However, other offending medications are less well known and have triggered many questions and constant search for answers. This review will discuss both drug-induced immune-mediated and nonimmune-mediated thrombocytopenias, with a focus on immunemediated processes. Thrombocytopenia caused by chemotherapy will not be discussed in this article. Keywords Drug-induced thrombocytopenia, heparin-induced thrombocytopenia, immune-mediated, antibodies
Introduction Drugs are important, sometimes common, culprits of blood dyscrasias, including agranulocytosis, anemia, and thrombocytopenia.1 Drug-induced immune thrombocytopenia (DITP), including, immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP), have been reported to account for 20% to 25% of all drug-related blood dyscrasias.1 The estimated incidence is 10 cases per million population per year.2 However, this number could be an underestimation, as DITP is often unrecognized as the cause of thrombocytopenia and may result in either a delayed diagnosis or a misdiagnosis.3 In an analysis of 29 cases with vancomycin-induced thrombocytopenia, approximately half of the cases were initially diagnosed as heparin-induced thrombocytopenia (HIT), autoimmune thrombocytopenia, or posttransfusion purpura.4 Once drugs are determined to be the cause of thrombocytopenia, the difficulty lies in identifying which medication is the culprit in patients taking multiple medications.5 Reese et al took steps to help resolve this challenge by compiling a list of 24 drugs (not including heparin) that have the most robust evidence for association with thrombocytopenia (Table 1). All of these medications have both published case reports of DITP and have drug-dependent, platelet-reactive antibodies identified by flow cytometry. Of these drugs, 23 also had reports of association with thrombocytopenia in the Adverse Event Reporting System (AERS) maintained by the US Food and Drug Administration (FDA).5 In 1998, George et al published a review of 515 case reports of drug-induced thrombocytopenia (excluding cases involving heparin), employing set criteria for definite, probable, possible,
or unlikely causality of agents associated with thrombocytopenia.6 To assess for evidence of DITP, the authors utilized criteria listed in Table 2 and assigned a numeric system to determine the causative relationship. Medications found to have a definite causal relationship with thrombocytopenia are listed in Table 1. Heparin-induced thrombocytopenia was excluded from this investigation, since its incidence, pathogenesis, diagnosis, and treatments are well known and distinct from other types of DITP.3 Since this initial publication of agents associated with DITP, many more drug compounds found to be associated with thrombocytopenia, such as abciximab, eptifibatide, furosemide, naproxen, linezolid, carbamazepine, and valproic acid, have been identified through case reports, additional antibodies discovered, and/or reports in the AERS.3,5 This review will discuss drugs associated with DITP (including heparin and non-heparin agents), underlying mechanisms and pathophysiology, and treatment strategies for the management of DITP.
Heparin-Induced Thrombocytopenia Incidence and Pathophysiology Thrombocytopenia from heparin administration can result in two syndromes that are pathophysiologically and clinically distinct 1
Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC, USA Corresponding Author: Teresa Kam, University of North Carolina Medical Center, 101 Manning Drive, Chapel Hill, NC 27514, USA. Email: [email protected]
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Table 1. Medications Found to be Associated With Thrombocytopenia. Using clinical criteria onlya
Using 3 different methods of evidenceb
Using combination of clinical and laboratory criteriac
‘‘Definite’’ evidence Quinidine Quinine Rifampin Trimethoprim–sulfamethoxazole Methyldopa Acetaminophen Digoxin Danazol Declofenac Aminoglutethimide Amphotericin B Aminosalicylic acid Oxprenolol Vancomycin Levamisole Meclofenamate
Abciximab Acetaminophen Amiodaroned Ampicillin Carbemazepine Eptifibatide Ethambutol Haloperidol Ibuprofen Irinotecan Naproxen Oxaliplatin Phyenytoin Piperacillin Quinidine Quinine Ranitidine
‘‘Definite’’ laboratory diagnosis Quinidine Quinine Trimethoprim/sulfamethoxazole Vancomycin Penicillin Rifampin Carbamazepine Ceftriaxone Ibuprofen Mirtazepine Oxaliplatin Suramin Abciximab Tirofiban Eptifibatide Heparin
Diatrizoate meglumine Amiodarone Nalidixic acid Cimetidine Chlorothiazide Interferon-alfa Sulfasalazine Ethambutol Iopanoic acid Sulfisoxazole Tamoxifen Thiothixene Naphazoline Amrinone Lithium Diazepam Haloperidol Alprenolol Tolmetin Nitroglycerin Minoxidil Diazoxide Chlorpromazine Isoniazid Cephalothin Difluoromethylornithine Piperacillin Diethylstilbestrol Methicillin Deferoxamine Novobiocin
Rifampin Simvastatin Sulfamethoxazole Tirofiban Trimethoprim–sulfamethoxazole Valproic acid Vancomycin
‘‘Probable’’ laboratory diagnosis Acetaminophen Amiodarone Amlodipine Ampicillin Cephamandole Ciprofloxacin Diazepam Ethambutol Furosemide Gold Haloperidol Lorazepam Naproxen Phyenytoin Ranitidine Rosiglitazone Roxifiban Sulfisoxazole Tranilast
a
Adapted from George et al.6 Only clinical criteria was utilized in compiling this list. Adapted from Reese et al.5 Methods included clinical criteria; reports of drug-dependent, platelet-specific antibodies; and reports from the Adverse Events Reporting System (AERS). c Adapted from Arnold et al.45 Methods included clinical criteria and author-generated laboratory criteria. d Evidence of thrombocytopenia associated with amiodarone was found through case reports and laboratory testing only. b
(Table 3). The more common scenario is thrombocytopenia that is not immune mediated. This condition was historically referred to as HIT type I but has more recently been referred to as nonimmune heparin-associated thrombocytopenia (sometimes abbreviated
HAT).7 This nonimmune-mediated condition can occur in 10% to 30% of patients. The underlying pathobiology is thought to involve the direct binding of heparin to platelets resulting in mild platelet aggregation.8
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Table 2. Clinical Criteria to Evaluate Causative Relationships in DrugInduced Immune Thrombocytopenia.a 1.
2.
3. 4.
Drug exposure must precede thrombocytopenia and complete recovery of platelets and sustained response after discontinuation of drug After discontinuation of the suspected drug, other drugs were continued without decrease in platelet count or the suspected drug was the only drug used prior to the onset of thrombocytopenia Other causes of thrombocytopenia are excluded Rechallenge of drug (if done) results in the recurrence of thrombocytopenia
a
Adapted from George et al.6
Heparin-induced thrombocytopenia type II, now commonly referred to as HIT, occurs less frequently than the nonimmunemediated process with an incidence that varies depending on the type of heparin being used, the duration and route of heparin, and the patient population. It can occur in up to approximately 5% of patients receiving treatment doses of intravenous (IV) unfractionated heparin (UFH) and 0% to 0.8% with low-molecular-weight heparin (LMWH).7,9 It is also notable to mention that HIT is more common with bovine heparin compared to porcine heparin. With regard to duration and route of heparin, Oliveira and colleagues analyzed 2420 patients treated with heparin for 4 days or longer to identify predictors of thrombocytopenia.10 Patients who developed thrombocytopenia were more frequently exposed to IV UFH and had longer exposures to UFH compared to those without thrombocytopenia. The risk of thrombocytopenia increased 4% per 1-day increment in the duration of heparin exposure.10 Orthopedic patients receiving heparin postoperatively have a heightened risk compared to medical patients with a reported incidence of up to 4.8% for patients receiving UFH and 0.6% for patients receiving LMWH.9 Cardiac transplantation patients are those at the highest risk with an incidence reported to be as high as 11%.11 However, the true incidence of HIT in the cardiac surgery population is difficult to characterize. Everett and colleagues evaluated 299 cardiac surgery patients who had heparin/platelet factor 4 (PF4) antibodies and platelet counts measured immediately before and 5 days after surgery. Although the prevalence of positive antibodies increased from 4.3% prior to surgery to 22.4% after surgery, thromboembolic complications occurred in 8.8% of patients testing negative for antibodies and only in 6.3% of patients positive for antibodies (P ¼ .77). There was a trend toward more thromboembolic events in those with thrombocytopenia compared to those without thrombocytopenia (17% vs 6.7%, respectively; P ¼ .06).12 This suggested that antibodies to the heparin/PF4 complex alone do not necessarily translate to an increased risk of thrombotic complications in this patient population.12 Heparin-induced thrombocytopenia is rare in critically ill patients, with a reported incidence of 0.4%. However, it is often difficult to distinguish HIT from other clinical syndromes, such as sepsis, that could be potential causes of thrombocytopenia in this population.13,14 Heparin-induced thrombocytopenia is pathologically distinct from nonimmune HAT because it is an immune-mediated process. The underlying pathophysiology involves the development
of antibodies to the heparin–PF4 complex.7,15 Platelet factor 4 is a CXC chemokine glycoprotein tetramer. Upon exposure to UFH, the UFH molecule wraps around the PF4 tetramer, altering its conformational structure. When the UFH and the PF4 glycoprotein are present at an optimal ratio, this structural modification creates an antigenic complex that ultimately causes the formation of HIT antibodies that bind to the heparin–PF4 complex. This antibody complex binds to and activates platelets, which then go on to release more PF4, ultimately creating more HIT antibody complexes. This cycle of platelet activation and antibody complex formation leads to platelet aggregation and the release of procoagulant substances from the platelets that stimulate coagulation pathways, ultimately inducing a procoagulable state. HIT antibodies can also stimulate tissue factor on the cellular surface of monocytes and endothelial cells, stimulating the production of thrombin, further contributing to the hypercoagulable state.7,15 Unfractionated heparin is a polysaccharide with molecular units that are much longer than LMWHs. Because of this increased molecular weight, UFH can more easily bind to the PF4 tetramer and, thus, is more likely to be associated with the development of HIT antibodies compared to LMWH.15 A meta-analysis has reported the incidence of HIT to be as much as 10-fold higher with UFH than with LMWH.16 Heparin-induced thrombocytopenia has been reported with fondaparinux, a factor Xa inhibitor, but in only a few rare cases.17 In fact, fondaparinux is a therapeutic option for the management of HIT.
Clinical Presentation and Diagnosis Thrombocytopenia resulting from heparin therapy can be difficult to diagnose, given several other factors that often contribute to patients being thrombocytopenic. Patients may be on medications other than heparin that also cause thrombocytopenia (eg, antimicrobials, nonsteroidal anti-inflammatory drugs [NSAIDs], etc). Patients may also have conditions associated with thrombocytopenia including sepsis, hematologic malignancies, platelet autoantibodies, surgically related thrombocytopenia, and so forth. The diagnosis of both nonimmunemediated HAT and HIT involve a thorough review to rule out these other potential offending agents and/or conditions.7,18 In the case of nonimmune HAT, the thrombocytopenia typically occurs within the first few days (prior to day 5) of heparin therapy (Table 3). It is usually mild and without major clinical consequence. The platelet count often remains above 80 to 100 109 cells/L and spontaneously resolves to baseline levels in a few days, even without discontinuation of heparin products. Patients do not experience any bleeding or thrombotic complications and do not require initiation of therapy.7,19 While less frequent, HIT has a much different clinical presentation and much more severe clinical consequences (Table 3). Unlike the nonimmune-mediated process, thrombocytopenia from HIT can be moderate to severe. Both the degree of drop in platelet count and the absolute platelet count should be considered when evaluating a patient for HIT. HIT should be included in the differential diagnosis if platelets drop below a threshold of 150 109 cells/L or drop by 50% with the initiation of heparin.7,18 Timing of the drop
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Table 3. Comparison of Immune-Mediated and Nonimmune-Mediated Heparin-Induced Thrombocytopenia.a
Incidence Antibody mediated Platelet count nadir Onset of thrombocytopenia after heparin initiation Thrombotic sequelae Management
Nonimmune heparin-associated thrombocytopenia (previously HIT type I)
Immune-mediated heparin-induced thrombocytopenia (previously HIT type II)
10%-30% No Mild (100 109/L) 4.0 to ensure therapeutic levels of warfarin after DTI discontinuation.44
Novel Anticoagulants Newer anticoagulants including the oral DTI dabigatran and the oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban have no cross-reactivity with HIT antibodies.7 Although efficacious for the treatment of venous thromboembolic events, there are no data for their use in the management of HIT.
Other Drug-Induced Thrombocytopenia Mechanisms and Pathophysiology The pathogenesis of thrombocytopenia caused by medications can be categorized into immune-mediated and nonimmunemediated mechanisms.45 Nonimmune-mediated mechanisms of thrombocytopenia result from decreased platelet production due to dysfunctional megakaryocytes within the bone marrow. Antineoplastic agents commonly cause thrombocytopenia because many of these compounds are directly toxic to the hematopoietic stem cells that are precursors to platelets. Linezolid, an oxazolidinone antibiotic, has been shown to cause thrombocytopenia, but the mechanism for which this occurs is still unknown.46 No antibodies have been discovered with linezolid administration, suggesting that the etiology is likely nonimmune mediated. A published summary of clinical experiences with linezolid at 1 institution reported that an increase in thrombocytopenia was only seen in patients with treatment duration of >2 weeks. In an observational report, 1 institution found that of patients with linezolid treatment duration of >10 days, the incidence of thrombocytopenia was 32%, compared to the overall incidence reported in initial clinical trials of 3%.47 Immune-mediated reactions cause increased platelet destruction due to the formation of antibodies.48 This typically occurs
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about 1 to 2 weeks after starting a new medication and is characterized by an acute decrease in platelet counts, which can result in severe and major bleeding events.3,48 Within immunemediated etiologies, there are 5 distinct mechanisms (excluding HIT) that explain the root cause of thrombocytopenia caused by various drugs.48
Drug-Specific Antibodies One of the more common mechanisms is the formation of drug-specific antibodies.2 Abciximab, a chimeric (human/mouse) monoclonal antibody, has been found to cause DITP in this manner. It is an antiplatelet agent that works by binding to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor site on platelets, which inhibits the binding of fibrinogen to the activated GPIIb/IIIa. This ultimately causes inhibition of platelet aggregation and thrombus formation.48 However, in 1% to 2% of patients exposed to abciximab for the first time and 10% to 12% of patients exposed to the agent a second time, antibodies already in circulation seek out abciximab-bound platelets, causing an acute onset of severe thrombocytopenia.48 Less frequently, the onset of thrombocytopenia may not appear for 6 to 8 days after drug administration due to subsequent formation of antibodies after exposure to abciximab.48 The TARGET study randomized 4809 patients undergoing PCIs to either abciximab or tirofiban.49 Tirofiban-induced thrombocytopenia is described later in this review. Along with efficacy data, incidence and risk factors for thrombocytopenia were also reported. The overall incidence of thrombocytopenia was 2.9%, with characteristics of these patients being older, weighed less, and having had a recent CABG or a previous stroke or transient ischemic attack. The occurrence of thrombocytopenia was significantly higher in patients who had received abciximab compared to tirofiban (2.4% vs 0.5%, P < .001). Abciximab was also associated with a lower mean platelet nadir (60 109 cells/L vs 67 109 cells/L, P ¼ not reported), a higher rate of profound thrombocytopenia (19% vs 0%, P ¼ not reported), and longer mean days to platelet recovery compared to tirofiban (4.5 vs 2.1 days, P ¼ not reported). By 30 days postprocedure, there was no difference seen in rate of myocardial infarction, death, or target vessel revascularization in patients who developed thrombocytopenia.49
Drug-Dependent Antibodies In this type of immune-mediated reaction, drug-specific antibodies are derived from preexisting antibodies that have a weak affinity to platelet epitopes when drug is not present.48 The epitopes targeted are typically on the GPIIb/IIIa or Ib/V/IX complexes.2 Once the sensitizing drug is introduced into the body, the drug binds to glycoproteins on the surface of platelets and causes conformational changes that increase the affinity of antibodies to platelet membrane glycoproteins. The end result is a tight conglomeration of drug in between platelet and antibody. However, more recent discussion has questioned whether the drug first binds to the glycoproteins or the antibodies, or perhaps the order in which binding occurs depends on the degree of affinity of drug to either glycoprotein or
antibody.48 The bigger question yet to be answered is why platelet glycoproteins tend to be more common targets for antibodies compared to other blood cells.3 Quinine was one of the first drugs found over a century ago to cause thrombocytopenia, although its proposed mechanism has evolved over decades of research with drug-dependent antibodies being a consistent theme.48 Other drugs that cause DITP in this manner include ranitidine, quinidine, NSAIDs, and various antibiotics, including sulfamethoxazole, vancomycin, rifampin, and beta-lactams.48 The usual onset of drug-dependent antibodies is approximately 1 to 2 weeks after initiation of the new drug. Furthermore, antibodies can also appear after a long period of intermittent drug usage.3 Of the long list of medications that have been reported to activate drug-dependent antibodies, many are antibiotics.48 A retrospective analysis of patients with suspected vancomycininduced thrombocytopenia was published in 2007. Serum samples from these patients were tested against a group of control samples for vancomycin-specific antibodies.4 Vancomycindependent platelet-reactive antibodies were found in 34 samples, which accounted for approximately 20% of the samples tested. Clinical and laboratory data were available for 29 antibodypositive patients. The average decline in platelet count was 93%, and median time to platelet nadir was 7.0 days. Of the 14 patients who received platelet transfusions during the period of acute thrombocytopenia, there was no increase in platelets in 11 patients and unknown response for the remaining 3 patients. Despite receiving treatments for assumed autoimmune thrombocytopenia or posttransfusion purpura, the only successful intervention was discontinuation of vancomycin.4
Fiban-Type Drug Reaction Arginine–glycine–aspartic acid-mimetic platelet inhibitors, or fibans, are used to prevent restenosis after coronary angioplasty. The medications in this class, tirofiban and eptifibatide, bind to GPIIb/IIIa and produce a conformational change that prevents interactions between platelets and fibrinogen. This inhibits formation of platelet thrombi. Thrombocytopenia from these agents is likely caused by naturally occurring antibodies that recognize the newly formed drug–platelet complex in the presence of fibans. Thus, the onset of thrombocytopenia can occur within a few hours of drug initiation.2 Although this mechanism of DITP is very similar to the drug-specific antibodies that bind to abciximab, the reported incidence of DITP with fibans is relatively lower at 0.1% to 2%.48
Autoantibodies In 1% of patients receiving gold salts and an even smaller percentage of patients receiving other drugs, such as procainamide and levodopa, thrombocytopenia closely resembles autoimmune idiopathic thrombocytopenia.2 The exact mechanism is not clearly understood. However, clinical and laboratory data suggest that autoantibodies specific to platelets are produced in the presence of these medications. One proposed thought is that the drug interferes with platelet surface glycoproteins
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Table 4. The 4T’s Scoring Scale for Pretest Clinical Probability of Heparin-Induced Thrombocytopenia.a,b Score 2
1
>50% decline AND nadir 20 109/L >50% decline, but surgery in previous 3 Thrombocytopenia (compare highest AND no surgery in previous 3 days days; any combination of platelet platelet value to decline and nadir not meeting criteria lowest platelet value) for score 2 or 0 (eg, 30%-50% platelet decline or nadir 10-19 109/L) Timing (of platelet count Platelet decline 5-10 days after heparin Platelet decline 5-10 days after heparin initiation but not clear (eg, missing initiation; platelet decline within 1 decline after heparin counts); platelet decline within 1 day day of heparin initiation AND initiation; day 0 ¼ day of start of heparin AND heparin heparin exposure within past 5-30 of heparin initiation) exposure within past 31-100 days; days platelet decline after day 10 Thrombosis (or other Confirmed new thrombosis (venous or Recurrent venous thrombosis in patient receiving anticoagulants; suspected clinical sequelae) arterial); skin necrosis at injection thrombosis (awaiting confirmational site; anaphylactoid reaction to IV imaging); erythematous skin lesions at heparin bolus; adrenal hemorrhage heparin injection sites OTher causes of No alternative explanation for platelet Potential alternatives (culture negative thrombocytopenia decline sepsis, thrombocytopenia associated with initiation of ventilator, other)
0
Drug-Induced Immune Thrombocytopenia
Journal of Pharmacy Practice 2014, Vol. 27(5) 430-439 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014546099 jpp.sagepub.com
Teresa Kam, PharmD, CPP1, and Maurice Alexander, PharmD, BCOP, CPP1
Abstract Thrombocytopenia is commonly seen in laboratory findings, especially in critically ill patients. Although the incidence is rare, druginduced immune thrombocytopenia (DITP) is a serious complication that is often overlooked as a cause of thrombocytopenia. Over the last century, extensive research and data collection have been done in an attempt to better characterize DITP. Heparininduced thrombocytopenia is the most common DITP and has distinct pathogenesis, diagnosis, and treatment options. However, other offending medications are less well known and have triggered many questions and constant search for answers. This review will discuss both drug-induced immune-mediated and nonimmune-mediated thrombocytopenias, with a focus on immunemediated processes. Thrombocytopenia caused by chemotherapy will not be discussed in this article. Keywords Drug-induced thrombocytopenia, heparin-induced thrombocytopenia, immune-mediated, antibodies
Introduction Drugs are important, sometimes common, culprits of blood dyscrasias, including agranulocytosis, anemia, and thrombocytopenia.1 Drug-induced immune thrombocytopenia (DITP), including, immune thrombocytopenia (ITP) and thrombotic thrombocytopenic purpura (TTP), have been reported to account for 20% to 25% of all drug-related blood dyscrasias.1 The estimated incidence is 10 cases per million population per year.2 However, this number could be an underestimation, as DITP is often unrecognized as the cause of thrombocytopenia and may result in either a delayed diagnosis or a misdiagnosis.3 In an analysis of 29 cases with vancomycin-induced thrombocytopenia, approximately half of the cases were initially diagnosed as heparin-induced thrombocytopenia (HIT), autoimmune thrombocytopenia, or posttransfusion purpura.4 Once drugs are determined to be the cause of thrombocytopenia, the difficulty lies in identifying which medication is the culprit in patients taking multiple medications.5 Reese et al took steps to help resolve this challenge by compiling a list of 24 drugs (not including heparin) that have the most robust evidence for association with thrombocytopenia (Table 1). All of these medications have both published case reports of DITP and have drug-dependent, platelet-reactive antibodies identified by flow cytometry. Of these drugs, 23 also had reports of association with thrombocytopenia in the Adverse Event Reporting System (AERS) maintained by the US Food and Drug Administration (FDA).5 In 1998, George et al published a review of 515 case reports of drug-induced thrombocytopenia (excluding cases involving heparin), employing set criteria for definite, probable, possible,
or unlikely causality of agents associated with thrombocytopenia.6 To assess for evidence of DITP, the authors utilized criteria listed in Table 2 and assigned a numeric system to determine the causative relationship. Medications found to have a definite causal relationship with thrombocytopenia are listed in Table 1. Heparin-induced thrombocytopenia was excluded from this investigation, since its incidence, pathogenesis, diagnosis, and treatments are well known and distinct from other types of DITP.3 Since this initial publication of agents associated with DITP, many more drug compounds found to be associated with thrombocytopenia, such as abciximab, eptifibatide, furosemide, naproxen, linezolid, carbamazepine, and valproic acid, have been identified through case reports, additional antibodies discovered, and/or reports in the AERS.3,5 This review will discuss drugs associated with DITP (including heparin and non-heparin agents), underlying mechanisms and pathophysiology, and treatment strategies for the management of DITP.
Heparin-Induced Thrombocytopenia Incidence and Pathophysiology Thrombocytopenia from heparin administration can result in two syndromes that are pathophysiologically and clinically distinct 1
Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC, USA Corresponding Author: Teresa Kam, University of North Carolina Medical Center, 101 Manning Drive, Chapel Hill, NC 27514, USA. Email: [email protected]
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Table 1. Medications Found to be Associated With Thrombocytopenia. Using clinical criteria onlya
Using 3 different methods of evidenceb
Using combination of clinical and laboratory criteriac
‘‘Definite’’ evidence Quinidine Quinine Rifampin Trimethoprim–sulfamethoxazole Methyldopa Acetaminophen Digoxin Danazol Declofenac Aminoglutethimide Amphotericin B Aminosalicylic acid Oxprenolol Vancomycin Levamisole Meclofenamate
Abciximab Acetaminophen Amiodaroned Ampicillin Carbemazepine Eptifibatide Ethambutol Haloperidol Ibuprofen Irinotecan Naproxen Oxaliplatin Phyenytoin Piperacillin Quinidine Quinine Ranitidine
‘‘Definite’’ laboratory diagnosis Quinidine Quinine Trimethoprim/sulfamethoxazole Vancomycin Penicillin Rifampin Carbamazepine Ceftriaxone Ibuprofen Mirtazepine Oxaliplatin Suramin Abciximab Tirofiban Eptifibatide Heparin
Diatrizoate meglumine Amiodarone Nalidixic acid Cimetidine Chlorothiazide Interferon-alfa Sulfasalazine Ethambutol Iopanoic acid Sulfisoxazole Tamoxifen Thiothixene Naphazoline Amrinone Lithium Diazepam Haloperidol Alprenolol Tolmetin Nitroglycerin Minoxidil Diazoxide Chlorpromazine Isoniazid Cephalothin Difluoromethylornithine Piperacillin Diethylstilbestrol Methicillin Deferoxamine Novobiocin
Rifampin Simvastatin Sulfamethoxazole Tirofiban Trimethoprim–sulfamethoxazole Valproic acid Vancomycin
‘‘Probable’’ laboratory diagnosis Acetaminophen Amiodarone Amlodipine Ampicillin Cephamandole Ciprofloxacin Diazepam Ethambutol Furosemide Gold Haloperidol Lorazepam Naproxen Phyenytoin Ranitidine Rosiglitazone Roxifiban Sulfisoxazole Tranilast
a
Adapted from George et al.6 Only clinical criteria was utilized in compiling this list. Adapted from Reese et al.5 Methods included clinical criteria; reports of drug-dependent, platelet-specific antibodies; and reports from the Adverse Events Reporting System (AERS). c Adapted from Arnold et al.45 Methods included clinical criteria and author-generated laboratory criteria. d Evidence of thrombocytopenia associated with amiodarone was found through case reports and laboratory testing only. b
(Table 3). The more common scenario is thrombocytopenia that is not immune mediated. This condition was historically referred to as HIT type I but has more recently been referred to as nonimmune heparin-associated thrombocytopenia (sometimes abbreviated
HAT).7 This nonimmune-mediated condition can occur in 10% to 30% of patients. The underlying pathobiology is thought to involve the direct binding of heparin to platelets resulting in mild platelet aggregation.8
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Table 2. Clinical Criteria to Evaluate Causative Relationships in DrugInduced Immune Thrombocytopenia.a 1.
2.
3. 4.
Drug exposure must precede thrombocytopenia and complete recovery of platelets and sustained response after discontinuation of drug After discontinuation of the suspected drug, other drugs were continued without decrease in platelet count or the suspected drug was the only drug used prior to the onset of thrombocytopenia Other causes of thrombocytopenia are excluded Rechallenge of drug (if done) results in the recurrence of thrombocytopenia
a
Adapted from George et al.6
Heparin-induced thrombocytopenia type II, now commonly referred to as HIT, occurs less frequently than the nonimmunemediated process with an incidence that varies depending on the type of heparin being used, the duration and route of heparin, and the patient population. It can occur in up to approximately 5% of patients receiving treatment doses of intravenous (IV) unfractionated heparin (UFH) and 0% to 0.8% with low-molecular-weight heparin (LMWH).7,9 It is also notable to mention that HIT is more common with bovine heparin compared to porcine heparin. With regard to duration and route of heparin, Oliveira and colleagues analyzed 2420 patients treated with heparin for 4 days or longer to identify predictors of thrombocytopenia.10 Patients who developed thrombocytopenia were more frequently exposed to IV UFH and had longer exposures to UFH compared to those without thrombocytopenia. The risk of thrombocytopenia increased 4% per 1-day increment in the duration of heparin exposure.10 Orthopedic patients receiving heparin postoperatively have a heightened risk compared to medical patients with a reported incidence of up to 4.8% for patients receiving UFH and 0.6% for patients receiving LMWH.9 Cardiac transplantation patients are those at the highest risk with an incidence reported to be as high as 11%.11 However, the true incidence of HIT in the cardiac surgery population is difficult to characterize. Everett and colleagues evaluated 299 cardiac surgery patients who had heparin/platelet factor 4 (PF4) antibodies and platelet counts measured immediately before and 5 days after surgery. Although the prevalence of positive antibodies increased from 4.3% prior to surgery to 22.4% after surgery, thromboembolic complications occurred in 8.8% of patients testing negative for antibodies and only in 6.3% of patients positive for antibodies (P ¼ .77). There was a trend toward more thromboembolic events in those with thrombocytopenia compared to those without thrombocytopenia (17% vs 6.7%, respectively; P ¼ .06).12 This suggested that antibodies to the heparin/PF4 complex alone do not necessarily translate to an increased risk of thrombotic complications in this patient population.12 Heparin-induced thrombocytopenia is rare in critically ill patients, with a reported incidence of 0.4%. However, it is often difficult to distinguish HIT from other clinical syndromes, such as sepsis, that could be potential causes of thrombocytopenia in this population.13,14 Heparin-induced thrombocytopenia is pathologically distinct from nonimmune HAT because it is an immune-mediated process. The underlying pathophysiology involves the development
of antibodies to the heparin–PF4 complex.7,15 Platelet factor 4 is a CXC chemokine glycoprotein tetramer. Upon exposure to UFH, the UFH molecule wraps around the PF4 tetramer, altering its conformational structure. When the UFH and the PF4 glycoprotein are present at an optimal ratio, this structural modification creates an antigenic complex that ultimately causes the formation of HIT antibodies that bind to the heparin–PF4 complex. This antibody complex binds to and activates platelets, which then go on to release more PF4, ultimately creating more HIT antibody complexes. This cycle of platelet activation and antibody complex formation leads to platelet aggregation and the release of procoagulant substances from the platelets that stimulate coagulation pathways, ultimately inducing a procoagulable state. HIT antibodies can also stimulate tissue factor on the cellular surface of monocytes and endothelial cells, stimulating the production of thrombin, further contributing to the hypercoagulable state.7,15 Unfractionated heparin is a polysaccharide with molecular units that are much longer than LMWHs. Because of this increased molecular weight, UFH can more easily bind to the PF4 tetramer and, thus, is more likely to be associated with the development of HIT antibodies compared to LMWH.15 A meta-analysis has reported the incidence of HIT to be as much as 10-fold higher with UFH than with LMWH.16 Heparin-induced thrombocytopenia has been reported with fondaparinux, a factor Xa inhibitor, but in only a few rare cases.17 In fact, fondaparinux is a therapeutic option for the management of HIT.
Clinical Presentation and Diagnosis Thrombocytopenia resulting from heparin therapy can be difficult to diagnose, given several other factors that often contribute to patients being thrombocytopenic. Patients may be on medications other than heparin that also cause thrombocytopenia (eg, antimicrobials, nonsteroidal anti-inflammatory drugs [NSAIDs], etc). Patients may also have conditions associated with thrombocytopenia including sepsis, hematologic malignancies, platelet autoantibodies, surgically related thrombocytopenia, and so forth. The diagnosis of both nonimmunemediated HAT and HIT involve a thorough review to rule out these other potential offending agents and/or conditions.7,18 In the case of nonimmune HAT, the thrombocytopenia typically occurs within the first few days (prior to day 5) of heparin therapy (Table 3). It is usually mild and without major clinical consequence. The platelet count often remains above 80 to 100 109 cells/L and spontaneously resolves to baseline levels in a few days, even without discontinuation of heparin products. Patients do not experience any bleeding or thrombotic complications and do not require initiation of therapy.7,19 While less frequent, HIT has a much different clinical presentation and much more severe clinical consequences (Table 3). Unlike the nonimmune-mediated process, thrombocytopenia from HIT can be moderate to severe. Both the degree of drop in platelet count and the absolute platelet count should be considered when evaluating a patient for HIT. HIT should be included in the differential diagnosis if platelets drop below a threshold of 150 109 cells/L or drop by 50% with the initiation of heparin.7,18 Timing of the drop
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Table 3. Comparison of Immune-Mediated and Nonimmune-Mediated Heparin-Induced Thrombocytopenia.a
Incidence Antibody mediated Platelet count nadir Onset of thrombocytopenia after heparin initiation Thrombotic sequelae Management
Nonimmune heparin-associated thrombocytopenia (previously HIT type I)
Immune-mediated heparin-induced thrombocytopenia (previously HIT type II)
10%-30% No Mild (100 109/L) 4.0 to ensure therapeutic levels of warfarin after DTI discontinuation.44
Novel Anticoagulants Newer anticoagulants including the oral DTI dabigatran and the oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban have no cross-reactivity with HIT antibodies.7 Although efficacious for the treatment of venous thromboembolic events, there are no data for their use in the management of HIT.
Other Drug-Induced Thrombocytopenia Mechanisms and Pathophysiology The pathogenesis of thrombocytopenia caused by medications can be categorized into immune-mediated and nonimmunemediated mechanisms.45 Nonimmune-mediated mechanisms of thrombocytopenia result from decreased platelet production due to dysfunctional megakaryocytes within the bone marrow. Antineoplastic agents commonly cause thrombocytopenia because many of these compounds are directly toxic to the hematopoietic stem cells that are precursors to platelets. Linezolid, an oxazolidinone antibiotic, has been shown to cause thrombocytopenia, but the mechanism for which this occurs is still unknown.46 No antibodies have been discovered with linezolid administration, suggesting that the etiology is likely nonimmune mediated. A published summary of clinical experiences with linezolid at 1 institution reported that an increase in thrombocytopenia was only seen in patients with treatment duration of >2 weeks. In an observational report, 1 institution found that of patients with linezolid treatment duration of >10 days, the incidence of thrombocytopenia was 32%, compared to the overall incidence reported in initial clinical trials of 3%.47 Immune-mediated reactions cause increased platelet destruction due to the formation of antibodies.48 This typically occurs
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Journal of Pharmacy Practice 27(5)
about 1 to 2 weeks after starting a new medication and is characterized by an acute decrease in platelet counts, which can result in severe and major bleeding events.3,48 Within immunemediated etiologies, there are 5 distinct mechanisms (excluding HIT) that explain the root cause of thrombocytopenia caused by various drugs.48
Drug-Specific Antibodies One of the more common mechanisms is the formation of drug-specific antibodies.2 Abciximab, a chimeric (human/mouse) monoclonal antibody, has been found to cause DITP in this manner. It is an antiplatelet agent that works by binding to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor site on platelets, which inhibits the binding of fibrinogen to the activated GPIIb/IIIa. This ultimately causes inhibition of platelet aggregation and thrombus formation.48 However, in 1% to 2% of patients exposed to abciximab for the first time and 10% to 12% of patients exposed to the agent a second time, antibodies already in circulation seek out abciximab-bound platelets, causing an acute onset of severe thrombocytopenia.48 Less frequently, the onset of thrombocytopenia may not appear for 6 to 8 days after drug administration due to subsequent formation of antibodies after exposure to abciximab.48 The TARGET study randomized 4809 patients undergoing PCIs to either abciximab or tirofiban.49 Tirofiban-induced thrombocytopenia is described later in this review. Along with efficacy data, incidence and risk factors for thrombocytopenia were also reported. The overall incidence of thrombocytopenia was 2.9%, with characteristics of these patients being older, weighed less, and having had a recent CABG or a previous stroke or transient ischemic attack. The occurrence of thrombocytopenia was significantly higher in patients who had received abciximab compared to tirofiban (2.4% vs 0.5%, P < .001). Abciximab was also associated with a lower mean platelet nadir (60 109 cells/L vs 67 109 cells/L, P ¼ not reported), a higher rate of profound thrombocytopenia (19% vs 0%, P ¼ not reported), and longer mean days to platelet recovery compared to tirofiban (4.5 vs 2.1 days, P ¼ not reported). By 30 days postprocedure, there was no difference seen in rate of myocardial infarction, death, or target vessel revascularization in patients who developed thrombocytopenia.49
Drug-Dependent Antibodies In this type of immune-mediated reaction, drug-specific antibodies are derived from preexisting antibodies that have a weak affinity to platelet epitopes when drug is not present.48 The epitopes targeted are typically on the GPIIb/IIIa or Ib/V/IX complexes.2 Once the sensitizing drug is introduced into the body, the drug binds to glycoproteins on the surface of platelets and causes conformational changes that increase the affinity of antibodies to platelet membrane glycoproteins. The end result is a tight conglomeration of drug in between platelet and antibody. However, more recent discussion has questioned whether the drug first binds to the glycoproteins or the antibodies, or perhaps the order in which binding occurs depends on the degree of affinity of drug to either glycoprotein or
antibody.48 The bigger question yet to be answered is why platelet glycoproteins tend to be more common targets for antibodies compared to other blood cells.3 Quinine was one of the first drugs found over a century ago to cause thrombocytopenia, although its proposed mechanism has evolved over decades of research with drug-dependent antibodies being a consistent theme.48 Other drugs that cause DITP in this manner include ranitidine, quinidine, NSAIDs, and various antibiotics, including sulfamethoxazole, vancomycin, rifampin, and beta-lactams.48 The usual onset of drug-dependent antibodies is approximately 1 to 2 weeks after initiation of the new drug. Furthermore, antibodies can also appear after a long period of intermittent drug usage.3 Of the long list of medications that have been reported to activate drug-dependent antibodies, many are antibiotics.48 A retrospective analysis of patients with suspected vancomycininduced thrombocytopenia was published in 2007. Serum samples from these patients were tested against a group of control samples for vancomycin-specific antibodies.4 Vancomycindependent platelet-reactive antibodies were found in 34 samples, which accounted for approximately 20% of the samples tested. Clinical and laboratory data were available for 29 antibodypositive patients. The average decline in platelet count was 93%, and median time to platelet nadir was 7.0 days. Of the 14 patients who received platelet transfusions during the period of acute thrombocytopenia, there was no increase in platelets in 11 patients and unknown response for the remaining 3 patients. Despite receiving treatments for assumed autoimmune thrombocytopenia or posttransfusion purpura, the only successful intervention was discontinuation of vancomycin.4
Fiban-Type Drug Reaction Arginine–glycine–aspartic acid-mimetic platelet inhibitors, or fibans, are used to prevent restenosis after coronary angioplasty. The medications in this class, tirofiban and eptifibatide, bind to GPIIb/IIIa and produce a conformational change that prevents interactions between platelets and fibrinogen. This inhibits formation of platelet thrombi. Thrombocytopenia from these agents is likely caused by naturally occurring antibodies that recognize the newly formed drug–platelet complex in the presence of fibans. Thus, the onset of thrombocytopenia can occur within a few hours of drug initiation.2 Although this mechanism of DITP is very similar to the drug-specific antibodies that bind to abciximab, the reported incidence of DITP with fibans is relatively lower at 0.1% to 2%.48
Autoantibodies In 1% of patients receiving gold salts and an even smaller percentage of patients receiving other drugs, such as procainamide and levodopa, thrombocytopenia closely resembles autoimmune idiopathic thrombocytopenia.2 The exact mechanism is not clearly understood. However, clinical and laboratory data suggest that autoantibodies specific to platelets are produced in the presence of these medications. One proposed thought is that the drug interferes with platelet surface glycoproteins
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Table 4. The 4T’s Scoring Scale for Pretest Clinical Probability of Heparin-Induced Thrombocytopenia.a,b Score 2
1
>50% decline AND nadir 20 109/L >50% decline, but surgery in previous 3 Thrombocytopenia (compare highest AND no surgery in previous 3 days days; any combination of platelet platelet value to decline and nadir not meeting criteria lowest platelet value) for score 2 or 0 (eg, 30%-50% platelet decline or nadir 10-19 109/L) Timing (of platelet count Platelet decline 5-10 days after heparin Platelet decline 5-10 days after heparin initiation but not clear (eg, missing initiation; platelet decline within 1 decline after heparin counts); platelet decline within 1 day day of heparin initiation AND initiation; day 0 ¼ day of start of heparin AND heparin heparin exposure within past 5-30 of heparin initiation) exposure within past 31-100 days; days platelet decline after day 10 Thrombosis (or other Confirmed new thrombosis (venous or Recurrent venous thrombosis in patient receiving anticoagulants; suspected clinical sequelae) arterial); skin necrosis at injection thrombosis (awaiting confirmational site; anaphylactoid reaction to IV imaging); erythematous skin lesions at heparin bolus; adrenal hemorrhage heparin injection sites OTher causes of No alternative explanation for platelet Potential alternatives (culture negative thrombocytopenia decline sepsis, thrombocytopenia associated with initiation of ventilator, other)
0
