Thrombocytopenia is usually defined as a platelet count below 100,000 cells/mm3 (100 × 109/L) or greater than 50% reduction from baseline values.
The annual incidence of drug-induced thrombocytopenia is about 10 cases per 1,000,000 population (excluding cases associated with heparin).82,83 Although numerous epidemiologic studies have been reported, none of them have identified patient-specific risk factors that are associated with an increased risk for the development of drug-induced thrombocytopenia.82
HIT has garnered much attention. Certain patient populations have a higher risk for developing HIT than others; patients who have had recent, major surgery are one of the highest risk groups.84 The next highest risk groups include patients receiving heparin for thrombosis prophylaxis after peripheral vascular surgery, cardiac surgery, and orthopedic surgery.85 A lower incidence is seen in medical, obstetric, and pediatric patients, especially those receiving low molecular weight heparin (LMWH) instead of unfractionated heparin (UFH).84 The most recent practice guidelines by the American College of Chest Physicians recommend varying degrees of platelet monitoring based on the relative risk of developing HIT.86
Drug-induced thrombocytopenia typically presents 1 to 2 weeks after a new drug is initiated, but may present immediately after a dose when an agent has been used intermittently in the past.87 Rapid onset may also occur with the GPIIb/IIIa inhibitor class of drugs.88 Development of thrombocytopenia may be associated with the systemic drug concentration, as is the case with linezolid.89 This condition may be overlooked or misdiagnosed as idiopathic thrombocytopenia purpura (ITP); clinicians may distinguish between the two by the severity of thrombocytopenia (platelets <20,000 cells/mm3[<20 ×109/L]), timing in relation to medication administration, and the presence of bleeding which almost always accompanies drug-induced thrombocytopenia.88,90
HIT causes paradoxical increases in thrombotic rather than bleeding complications.91 It is caused by the development of antibodies against platelet factor-4 (PF-4) and heparin complexes(Fig. e103-1).91 LMWH binds less well to PF-4 than UFH, and therefore antibody formation is less common. However, antibodies developed by patients receiving UFH react against LMWH; thus, LMWH should not be used in patients with HIT.84 After the antibodies bind to the complexes, platelet activation and aggregation occur, with subsequent release of more circulating PF-4 to interact with heparin. In addition, procoagulant microparticles are also released that increase the risk of thrombosis.84
Proposed explanation for the presence of both thrombocytopenia and thrombosis in heparin-sensitive patients who are treated with heparin. Injected heparin reacts with PF-4, which is normally present on the surface of endothelial cells (ECs) or released in small quantities from circulating platelets, to form PF-4–heparin complexes (1). Specific IgG antibodies react with these conjugates to form immune complexes (2) that bind to crystallizable fragment (Fc) receptors on circulating platelets. Fc-mediated platelet activation (3) releases PF-4 from a-granules in platelets (4). Newly released PF-4 binds to additional heparin, and the antibody forms more immune complexes, establishing a cycle of platelet activation. PF-4 released in excess of the amount that can be neutralized by available heparin binds to heparin-like molecules (glycosaminoglycans) on the surface of ECs to provide targets for antibody binding. This process leads to immune-mediated EC injury (5) and heightens the risk of thrombosis and disseminated intravascular coagulation. (Used with permission from Aster RH. Heparin-induced thrombocytopenia and thrombosis. N Engl J Med 1995; 332:1374-1376. Copyright © 1995 Massachusetts Medical Society. All rights reserved.)
At least two types of HIT have been identified. The most common, type I, occurs in about 10% to 20% of patients treated with heparin.84 It is a mild, reversible, nonimmune-mediated reaction that usually occurs within the first 2 days of therapy. The platelet count slowly returns to baseline after an initial decline despite continued heparin therapy. HIT type I is usually an asymptomatic condition and is thought to be related to platelet aggregation.2 It is not antibody mediated and is not considered clinically significant.92
Patients with HIT type II usually present with a low platelet count (eg, below 150,000 cells/mm3 [150 × 109/L]) or a 50% or more decrease in platelet count from the highest platelet count value after initiation of heparin, and thrombosis may be present at diagnosis.91 The platelet count generally begins to decline 5 to 10 days after the start of heparin therapy. However, this decline can occur within hours of receiving heparin if the patient has recently received heparin (ie, within 100 days).91 Thrombocytopenia and thrombosis can develop with low-dose heparin, heparin-coated catheters, or even heparin flushes.91
The diagnosis of HIT is frequently a clinical one, supported by laboratory testing. Clinicians should use a scoring system, such as the 4T scoring system, to evaluate the probability of HIT.91 Such a system should evaluate timing and magnitude of platelet drop, thrombosis, and other potential causes of thrombocytopenia.91 If the scoring system indicates that HIT is likely, the clinician can order laboratory tests to assist in the diagnosis of HIT, including platelet activation assays, platelet aggregation studies, and enzyme-linked immunosorbent assay methods, each with varying sensitivities and specificities.7 Overall, these tests have a high negative predictive value.91
Protamine is an agent often used to neutralize heparin’s anticoagulant action. Protamine-induced thrombocytopenia may be confused with HIT, since patients may have exposure to both agents. In protamine-induced thrombocytopenia, antibodies activate platelets similar to those in HIT, but it often occurs after cardiovascular surgery and is associated with earlier onset of thrombocytopenia and thrombosis, compared with the 5 to 10 day delay usually seen with HIT.93
Drug-induced thrombocytopenia can result from immune-mediated mechanisms or through a nonimmune-mediated mechanism. Nonimmune-mediated mechanisms, such as direct-toxicity-type reactions, are associated with medications that cause bone marrow suppression. This results in suppressed thrombopoiesis and a decreased number of megakaryocytes. This type of reaction is dose-dependent and often takes weeks to manifest.88 Several mechanisms have been proposed for the development of immune-mediated drug-induced thrombocytopenia. These include hapten-type reactions, drug-dependent antibody mechanism, platelet-specific autoantibody, immune complex-induced thrombocytopenia, and drug-specific autoantibody type reaction. Although several mechanisms of drug-induced thrombocytopenia have been proposed, it is often not possible to determine the mechanism for an individual drug or patient, and more than one mechanism can be responsible for the condition.
In hapten-type reactions, the offending drug binds covalently to certain platelet glycoproteins (GP). Antibodies are generated that bind to these drug-bound GP epitopes. After the binding of antibodies to the platelet surface, lysis occurs through complement activation or through clearance from the circulation by macrophages.94,95,96 Platelets are destroyed by the autoantibodies.88 Hapten-mediated immune thrombocytopenia usually occurs at least 7 days after the initiation of the drug, although it can occur much sooner if the exposure is actually a re-exposure to a previously administered drug.
This mechanism is slightly different from the hapten-type mechanism. In this type of reaction, platelet-reactive antibodies bind platelets when the drug is present. The antibodies may occur naturally, but there is an increased affinity if the drug is present. Reactions typically occur after 5 to 10 days of therapy.88 It is thought that antibodies exist within the patient’s circulation that recognize an epitope on the platelet GP, but this recognition is too weak to result in antibody binding to the platelet surface. However, the drug contains structural elements that are noncovalently complementary to regions of the antibody and the GPs on the platelet surface. This causes an improved fit between the antibody and the platelet surface, with the drug “trapped” in between, resulting in antibody binding of platelet.94
Eptifibatide and tirofiban are platelet GPIIb/IIIa receptor antagonists that prevent platelet activation and binding of fibrinogen, thereby inhibiting platelet thrombus formation. Competitive inhibition of fibrinogen bindings causes platelet clearance and activation, so concomitant thrombosis may occur.88 In clinical trials and postmarketing studies, it was found that about 0.1% to 2% of patients treated with these medications experienced acute profound thrombocytopenia within several hours of their first exposure to the drug.94,95,97,98 This acute drop in platelets without prior drug exposure suggested initially that this reaction was mediated by a nonimmune mechanism. However, a plausible immune-mediated mechanism has since been proposed. After binding to the GPIIb/IIIa receptor, these medications cause a conformational change in the receptor that allows it to be recognized by naturally occurring antibodies already in the patient’s blood (ie, a ligand-induced binding site). In contrast to the two previously discussed immune-mediated mechanisms (hapten-type and drug dependent), the drug is not present within the binding between the antibody and the platelet surface. The drug has been removed from the platelet surface before the antibody binds, but the conformational change in the GPIIb/IIIa receptor remains.95
Abciximab, a GPIIb/IIIa receptor antagonist like tirofiban and eptifibatide, is also associated with thrombocytopenia. Abciximab-induced thrombocytopenia appears to occur through a different drug-specific antibody mechanism as opposed to a ligand-induced binding site mechanism with eptifibatide and tirofiban.94,95,98 Abciximab is a chimeric monoclonal antibody. Therefore, it is not surprising that this molecule may exhibit some immunogenic properties. The murine component binds platelets’ surface proteins and attracts antibodies that then destroy the platelet.88 It has been demonstrated that patients who experience thrombocytopenia after the administration of abciximab have circulating antibodies that directly recognize the drug.94,95 Because the drug is bound to platelets, thrombocytopenia results. About 2% of patients experience thrombocytopenia with the first administration and 10% to 12% with subsequent administrations.97,99 Furthermore, in patients who experience the reaction with the first administration, some experience immediate thrombocytopenia, but a few patients develop delayed thrombocytopenia about one week after drug administration. In patients who experience immediate thrombocytopenia, drug-specific antibodies are naturally occurring and present at the time of drug administration. For those with a delayed response (6-8 days later), drug-specific antibodies are produced during this time, and because abciximab remains bound to platelets for up to 2 weeks, the reaction can still occur.100 Because all three GPIIb/IIIa receptor antagonists are co-administered with heparin, it is important to distinguish between GPIIb/IIIa receptor antagonist-induced thrombocytopenia and HIT. A heparin-induced platelet aggregation study can help to determine the offending agent. Pseudothrombocytopenia, defined as in vitro platelet aggregation in blood anticoagulated with ethylenediamine tetraacetic acid (EDTA), is clinically insignificant, but it must also be differentiated from thrombocytopenia induced by GPIIb/IIIa receptor antagonists.101 This type of reaction may also occur with rituximab, and may be complicated by infusion reactions and disseminated intravascular coagulopathy (DIC).88
In this type of reaction, a drug, such as gold or procainamide, induces the production of autoantibodies that bind to platelet membranes and cause destruction, but the causative drug does not have to be present for the reaction to occur. These agents bind platelets in the absence of the drug, so can persist after discontinuation of the agent; reports of thrombocytopenia up to 39 months after exposure have been published.88 In contrast, the drug-dependent antibody reaction requires the presence of the drug to allow antibody binding.
The final type of immune-mediated thrombocytopenia has been categorized as immune complex-induced thrombocytopenia.94,95 This describes the mechanism of the most serious type of HIT, type II.HIT type II is less common but more severe than HIT type I and can be associated with more complications. In this type of reaction, heparin binds the platelet and forms an antigenic structure, which is then bound by antibodies. This complex activates the platelets.91 HIT has been reported to occur in 1 of every 5,000 hospitalized patients and 1% to 3% of patients after cardiac surgery. The risk is higher following major surgery than minor surgical procedures or medical treatment, and is about 10 times higher for those receiving UFH as compared to LMWH.91
In 1998, George et al. from the University of Oklahoma undertook the first attempt at a systematic review of the literature and case reports associated with drug-induced thrombocytopenia.102 At that time, there were 98 drugs reported to be associated with thrombocytopenia. The Oklahoma group has continued to update this systematic review nearly every 2 years since 1998.103 In 2009, 317 drugs had been implicated in 1,301 reports.87 It has also been reported with foods, such as walnuts, cranberries, milk, and sesame seed.104 One study found that only about 40% of implicated agents had a positive laboratory test, and only 10% should be considered definite causes.88 This condition is more common in adults than children, but may be unrecognized in children. Thirty-one medications have been noted as definite or probable causes of thrombocytopenia in children.90
The agents most commonly implicated in immune-mediated thrombocytopenia are quinine, quinidine, gold salts, sulfonamide antibiotics, rifampin, GPIIb/IIIa receptor antagonists, vancomycin, and heparin.88,95 A list of medications (excluding cancer chemotherapeutic agents) associated with drug-induced thrombocytopenia is provided in Table e103-8.
TABLE e103-8Drugs Associated with Thrombocytopenia