Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management
TL;DR: The most important aspects of patient management are a high index of suspicion and a careful history of drug exposure in an individual who presents with acute, often severe thrombocytopenia of unknown etiology.
About: This article is published in Journal of Thrombosis and Haemostasis.The article was published on 2009-06-01 and is currently open access. It has received 280 citations till now.
Citations
More filters
TL;DR: From the Division of Vascular and Interventional Radiological, Jefferson Radiology, Hartford Hospital, 85 Seymour St, Ste 200, Hartford, CT 06106, Received November 18, 2008; accepted November 24, 2008.
611 citations
TL;DR: It is not yet clear what fraction of IDRs have a strong HLA dependence, and most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug.
Abstract: Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs.
259 citations
Cites background from "Drug-induced immune thrombocytopeni..."
...Virtually all idiosyncratic drug-induced thrombocytopenia appears to be immune mediated, but there are several different immune mechanisms (Aster, 2009; Aster et al., 2009)....
[...]
...The b-lactams act as haptens to produce antibodies that recognize modified platelet proteins, whereas quinine induces a conformation change in proteins that induces antibodies that only recognize the proteins in the presence of soluble drug (Aster et al., 2009)....
[...]
TL;DR: Recovery from DITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week, and it is important that the drug etiology be confirmed and the drug be avoided thereafter.
Abstract: Although drugs are a common cause of acute immune-mediated thrombocytopenia in adults, the drug etiology is often initially unrecognized. Most cases of drug-induced thrombocytopenia (DITP) are caused by drug-dependent antibodies that are specific for the drug structure and bind tightly to platelets by their Fab regions but only in the presence of the drug. A comprehensive database of 1301 published reports describing 317 drugs, available at www.ouhsc.edu/platelets, provides information on the level of evidence for a causal relation to thrombocytopenia. Typically, DITP occurs 1 to 2 weeks after beginning a new drug or suddenly after a single dose when a drug has previously been taken intermittently. However, severe thrombocytopenia can occur immediately after the first administration of antithrombotic agents that block fibrinogen binding to platelet GP IIb-IIIa, such as abciximab, tirofiban, and eptifibatide. Recovery from DITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week. Drug-dependent antibodies can persist for many years; therefore, it is important that the drug etiology be confirmed and the drug be avoided thereafter.
221 citations
Cites background from "Drug-induced immune thrombocytopeni..."
...Nadir platelet counts are often less than 20,000/μL, clinically important bleeding is common, and deaths from bleeding have been reported.(1;3) The expected course is that recovery of thrombocytopenia begins within 1 to 2 days after the drug is discontinued and recovery is usually complete within a week....
[...]
...154 American Society of Hematology drug.(2,3,11) Drug-dependent antibodies are very specific for the drug structure....
[...]
...0% of patients may have severe thrombocytopenia within several hours of their first exposure to abciximab, tirofiban or eptifibatide, and as many as 12% of patients may become acutely thrombocytopenic after a second exposure to abciximab.(2,3) The immediate reactions are the result of naturally occurring antibodies that recognize the murine structural elements of abciximab or structural changes in GP IIb-IIIa caused by binding of tirofiban or eptifibatide....
[...]
TL;DR: A microfluidic human platelet bioreactor is developed that recapitulates bone marrow stiffness, extracellular matrix composition, micro-channel size, hemodynamic vascular shear stress, and endothelial cell contacts, and supports high-resolution live-cell microscopy and quantification of platelet production.
165 citations
TL;DR: In the review, the differential diagnosis of thrombocytopenia in pregnancy, and the pathogenesis of selected throm bocytopenic disorders are discussed.
Abstract: Thrombocytopenia is a common hematologic problem in pregnant women. The most common cause of thrombocytopenia is gestational thrombocytopenia, which is usually mild, is not associated with bleeding or neonatal thrombocytopenia, and resolves spontaneously postpartum. Gestational thrombocytopenia, however, may be hard to discern from immune thrombocytopenia (ITP), another cause of isolated thrombocytopenia during pregnancy, although thrombocytopenia due to ITP is often more severe and occurs earlier in pregnancy. Preeclampsia is the most common medical disorder of pregnancy and is associated with a constellation of symptoms including hypertension and proteinuria; thrombocytopenia is generally mild, but reflects the severity of underlying preeclampsia. The syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP) is thought by some to be a variant of preeclampsia as it shares some manifestations but also displays unique ones, particularly liver involvement and microangiopathic hemolytic anemia. HELLP may be difficult to discern from primary thrombotic microangiopathies such as thrombotic thrombocytopenic purpura (TTP) and the atypical hemolytic uremic syndrome (aHUS), which are not unique to pregnancy but occur with increased frequency in this setting. Accurate diagnosis of the cause of thrombocytopenia during pregnancy is important, as treatment varies depending on the etiology. Careful consideration of the timing of onset of thrombocytopenia, and associated hematologic and other manifestations, needs to be considered in the differential diagnosis. Though thrombocytopenic disorders may severely compromise the outcomes of some pregnancies, prompt diagnosis and appropriate therapy often lead to successful pregnancy outcomes.
142 citations
References
More filters
TL;DR: The aim of this article is to review the most recent advances in the field and to give critical guidelines for the clinical diagnosis and treatment of HIT II, the most frequent and dangerous side-effect of heparin therapy.
Abstract: BACKGROUND AND OBJECTIVE: There are two types of heparin-induced thrombocytopenia (HIT). HIT I is characterized by a transitory, slight and asymptomatic reduction in platelet count, occurring in the first 1-2 days of therapy, that resolves spontaneously; in contrast, HIT II, which has an immunologic origin, is characterized by a significant thrombocytopenia generally after the fifth day of therapy that usually resolves in 5-15 days only after therapy withdrawal. HIT II is the most frequent and dangerous side-effect of heparin therapy; in fact, in spite of thrombocytopenia, it can be complicated by venous and arterial thrombosis. Therefore, the recognition of HIT II may be difficult due to the underlying thrombotic symptoms for which heparin is administered. The aim of this article is to review the most recent advances in the field and to give critical guidelines for the clinical diagnosis and treatment of HIT II. STATE OF THE ART: The prevalence of HIT II, as confirmed by laboratory tests, seems to be about 2% in patients receiving unfractionated heparin (UH), while it is much lower in those receiving low molecular weight heparin (LMWH). The immunologic etiology of HIT II is largely accepted. Platelet factor 4 (PF4) displaced from endothelial heparan sulphate or directly from the platelets, binds to the heparin molecule to form an immunogenic complex. The anti-heparin/ PF4 IgG immunocomplexes activate platelets and provoke an immunologic endothelial lesion with thrombocytopenia and/or thrombosis. The IgG anti-heparin/PF4 immunocomplex activates platelets mainly through binding with the FcgRIIa (CD32) receptor. The onset of thrombocytopenia is independent of the dosage, schedule and route of administration of heparin. Orthopedic and cardiovascular surgery patients receiving post-surgical prophylaxis or treatment for deep venous thrombosis are at higher risk of HIT II. Besides thrombocytopenia, cutaneous allergic manifestations and skin necrosis may be present. Hemorrhagic events are not frequent, while the major clinical complications in 30% of patients are both arterial and venous thromboses which carry a 20% mortality. The diagnosis of HIT II should be formulated on the basis of clinical criteria and in vitro demonstration of heparin-dependent antibodies. Functional tests, such as platelet aggregation and (14)C-serotonin release assay and immunologic tests, such as the search for anti-PF4/heparin complex antibodies by an ELISA method are available. If HITT II is probable, heparin must be immediately suspended and an alternative anticoagulant therapy should be initiated before resolution of thrombocytopenia and the following treatment with a vitamin K antagonist. The general opinion is to administer low molecular weight heparin (in the absence of in vitro cross-reactivity with the antibodies), heparinoids such as Orgaran or direct thrombin inhibitors such as hirudin. PERSPECTIVES: Further studies are required to elucidate the pathogenesis of HIT II and especially to discover the clinical and immunologic factors that induce the occurrence of thrombotic complications. The best therapeutic strategy remains to be confirmed in larger clinical trials.
751 citations
TL;DR: Observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-inducedThrombocytopenia.
467 citations
TL;DR: The current understanding of pathogenesis is summarized and a guide for diagnosis and management of thrombocytopenia is provided.
Abstract: Drug-induced thrombocytopenia should be suspected in any patient with acute thrombocytopenia of unknown cause Although the incidence is low, more than 100 drugs have been implicated in thrombocytopenia, including quinine, sulfonamides, abciximab, carbamazepine, and vancomycin, as well as herbal remedies and several nonprescription drugs This review summarizes the current understanding of pathogenesis and provides a guide for diagnosis and management of this potentially dangerous disorder
459 citations
TL;DR: This systematic review analyzed all published reports of drug-induced thrombocytopenia by using explicit, a priori criteria for establishing levels of evidence of a causal relation to help clinicians better understand the likelihood that a drug will cause throm bocy topenia.
Abstract: Purpose To determine the strength of clinical evidence for individual drugs as a cause of thrombocytopenia. Data sources All English-language reports on drug-induced thrombocytopenia. Study selection Articles describing thrombocytopenia caused by heparin were excluded from review. Of the 581 articles reviewed, 20 were excluded because they contained no patient case reports. The remaining 561 articles reported on 774 patients. Data extraction Two of the authors used a priori criteria to independently review each patient case report. Two hundred fifty-nine patient case reports were excluded from further review because of lack of evaluable data, platelet count of 100000 cells/microL or more, use of cytotoxic or nontherapeutic agents, occurrence of drug-induced systemic disease, or occurrence of disease in children. For the remaining 515 patient case reports, a level of evidence for the drug as the cause of thrombocytopenia was assigned. Data on bleeding complications and clinical course were recorded. Data synthesis The evidence supported a definite or probable causal role for the drug in 247 patient case reports (48%). Among the 98 drugs described in these reports, quinidine was mentioned in 38 case reports, gold in 11, and trimethoprim-sulfamethoxazole in 10. Of the 247 patients described in the case reports, 23 (9%) had major bleeding and 2 (0.8%) died of bleeding. Conclusions Many reports of drug-induced thrombocytopenia do not provide evidence supporting a definite or probable causal relation between the disease and the drug. Future patient case reports should incorporate standard criteria to clearly establish the etiologic role of the drug.
412 citations
TL;DR: Fab fragments of certain antibodies against LIBS on integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa) block platelet aggregation, and changes in the conformation of this integrin modulate both the specificity and affinity of ligand recognition.
352 citations