Immune heparin-induced thrombocytopenia can occur in patients receiving clopidogrel and aspirin

Selleng, Kathleen; Selleng, Sixten; Raschke, Ricarda; Schmidt, Carsten Oliver; Rosenblood, Geoffrey S.; Greinacher, Andreas; Warkentin, Theodore E.

doi:10.1002/ajh.20305

Cited by 24 publications

(21 citation statements)

References 21 publications

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“…This limited protective effect of clopidogrel in the setting of experimental ITT is in accordance with clinical studies demonstrating incomplete protection from HIT in patients receiving both aspirin and clopidogrel. 32 Our studies may explain the limited effect of P2Y12 inhibitors in the setting of HIT/ITT. P2Y12 inhibitors affect the sustained activation of Rap1, important for stable platelet adhesion at sites of vascular injury.…”

Section: Caldag-gefi ϫ/ϫ In Immune-mediated Thrombosis 1117mentioning

confidence: 99%

CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia

Stolla

Stefanini

André

et al. 2011

Blood

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Platelet activation via Fc␥ receptor IIA (Fc␥RIIA) is a critical event in immunemediated thrombocytopenia and thrombosis syndromes (ITT). We recently identified signaling by the guanine nucleotide exchange factor CalDAG-GEFI and the adenosine diphosphate receptor P2Y12 as independent pathways leading to Rap1 small GTPase activation and platelet aggregation. Here, we evaluated the contribution of CalDAG-GEFI and P2Y12 signaling to platelet activation in ITT. Mice transgenic for the human Fc␥RIIA (hFcR) and deficient in CalDAG-GEFI ؊/؊ (hFcR/CDGI ؊/؊ ) were generated. Compared with controls, aggregation of hFcR/ CDGI ؊/؊ platelets or P2Y12 inhibitortreated hFcR platelets required more than 5-fold and approximately 2-fold higher concentrations of a Fc␥RIIA stimulating antibody against CD9, respectively. Aggregation and Rap1 activation were abolished in P2Y12 inhibitor-treated hFcR/ CDGI ؊/؊ platelets. For in vivo studies, a novel model for antibody-induced thrombocytopenia and thrombosis was established. Fc␥RIIA-dependent platelet thrombosis was induced by infusion of Alexa750-labeled antibodies to glycoprotein IX (CD42a), and pulmonary thrombi were detected by near-infrared imaging technology. Anti-GPIX antibodies dosedependently caused thrombocytopenia and pulmonary thrombosis in hFcRtransgenic but not wild-type mice. CalDAG-GEFI-deficient but not clopidogreltreated hFcR-transgenic mice were completely protected from ITT. In summary, we established a novel mouse model for ITT, which was used to identify CalDAG-GEFI as a potential new target in the treatment of ITT. (Blood. 2011;118(4): 1113-1120) IntroductionPlatelets are essential components of the hemostatic response to vascular injury. However, platelets also play a role in pathologic conditions, such as atherothrombosis, and in immune-mediated thrombocytopenia and thrombosis (ITT). Several ITT syndromes, including heparin-induced thrombocytopenia and thrombosis (HIT), 1-3 bacterial sepsis-associated thrombocytopenia and disseminated intravascular coagulation, 4,5 and the thrombotic manifestations of antiphospholipid syndromes 6 are characterized by immunemediated platelet activation through the platelet Fc␥ receptor, Fc␥RIIA. In addition, thrombotic complications have been observed with the expanded use of therapeutic IgG antibodies, such as bevacizumab. [7][8][9] One of the barriers to successful treatment of these thrombotic syndromes is that therapeutic targeting of platelet activation pathways to prevent thrombosis is either not effective or comes with an inherent risk of bleeding complications.In humans, Fc␥RIIA is expressed on platelets, neutrophils, monocytes, and macrophages and activates these cells following the binding of the Fc region of IgG-coated cells or IgG-containing immune complexes. 10 Mice lack the genetic equivalent of human Fc␥RIIA and, indeed, do not express a platelet Fc receptor. Consequently, most of the studies on the role of Fc␥RIIA in platelet activation were entirely dependent on the use of inhibitors, and they did not provide in...

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Section: Caldag-gefi ϫ/ϫ In Immune-mediated Thrombosis 1117mentioning

confidence: 99%

CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia

Stolla

Stefanini

André

et al. 2011

Blood

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“…1,20 Thrombotic thrombocytopenic purpura associated with thienopyridine therapy is a rare phenomenon that typically occurs within the first 2 weeks of use and should be considered when thrombocytopenia occurs with hemolytic anemia, renal failure, and/or neurological changes. 4 The use of glycoprotein IIb/IIIa inhibitors has previously been associated with thrombocytopenia and should be suspected when platelet counts fall soon after drug initiation. 7 Pseudothrombocytopenia, a platelet artifact, occurs commonly in patients treated with glycoprotein IIb/IIIa inhibitors and may contribute to the incidence of thrombocytopenia in this population.…”

Section: Causes Of Thrombocytopeniamentioning

confidence: 99%

“…[1][2][3][4] Among patients with non-ST-segment elevation (NSTE) ACS, previous studies have observed a low (1% to 7%) incidence of acute thrombocytopenia. [5][6][7] These studies used a conservative threshold (Ͻ100ϫ10 9 /L) to define thrombocytopenia that is lower than the clinical definition of thrombocytopenia (Ͻ150ϫ10 9 /L).…”

mentioning

confidence: 99%

Incidence and Prognostic Significance of Thrombocytopenia Developed During Acute Coronary Syndrome in Contemporary Clinical Practice

et al. 2009

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Background-Prior studies examining thrombocytopenia among patients with acute coronary syndromes (ACS) evaluated highly selected patients in a clinical trial setting using varying definitions of thrombocytopenia. Conclusions-Thrombocytopenia, a common complication of ACS, is associated with increased mortality and bleeding risks. Even mild thrombocytopenia or a platelet count drop Ն50% in the setting of normal nadir values is clinically significant. Application of a combined definition for thrombocytopenia using both absolute and relative thresholds permits increased sensitivity for patients at high risk of adverse outcomes.

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“…On the one hand, the clinical effect of monotherapy with acetylsalicylic acid or dipyridamole is difficult to predict [54]. On the other hand, in patients receiving dual antiplatelet therapy (clopidogrel with acetylsalicylic acid), a rapid increase in platelet count has been observed [55]. Of note, receptor GPIIb/IIIa antagonists are not recommended [56,57] as they can (extremely rarely) cause HIT.…”

Section: Progression Of Venous or Arterial Thrombosis During Heparin mentioning

confidence: 99%

Małopłytkowość poheparynowa

Krzych

Nowacka²,

Knapik³

2015

Anaesthesiol Intensive Ther

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Heparin-induced thrombocytopenia (HIT) is a clinical immune-mediated syndrome; symptoms of HIT result from the development of arterial and venous thrombosis and are correlated with the severity of the thrombocytopenia. In all patients receiving heparin preparations in intensive care units, platelet counts should be monitored every 2−3 days throughout therapy, particularly during days 4−14 when HIT is most likely to develop. The major screening tests should always involve a clinical assessment of HIT probability (4Ts or HEP scoring systems) and enzymatic immunoassays (IgG antibodies) for patients with a moderate to high risk of HIT. The full possibilities of such advanced diagnostic procedures are limited in Poland because functional tests are still not widely available. If the diagnosis is questionable, all heparin preparations should be withdrawn and an alternative method of anticoagulation instituted until HIT has been conclusively excluded. The use of new-generation anticoagulants (direct thrombin or Xa factor inhibitors) is currently considered the treatment of choice. Old-generation anticoagulants should not be administered (vitamin K antagonists) as they can aggravate thrombosis. If administered, their action should be reversed by vitamin K once HIT is confirmed. Antithrombotic therapy with "new" anticoagulants should be carried out at least until platelet counts return to the baseline values; the recommended duration of therapy is 4 weeks in patients with isolated thrombocytopenia or 4 months in those with thrombotic complications. Vitamin K antagonists should not be applied until the normal platelet count is restored (usually > 150 G L -1 ). When the therapy with vitamin K antagonists is reintroduced, "old" antagonists should be administered simultaneously with a "new" anticoagulant for at least 5 days due to an initial decrease in protein C concentration concentration, provided that the therapeutic value of INR is maintained (> 2) for at least 2 days.

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Immune heparin-induced thrombocytopenia can occur in patients receiving clopidogrel and aspirin

Cited by 24 publications

References 21 publications

CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia

CalDAG-GEFI deficiency protects mice in a novel model of FcγRIIA-mediated thrombosis and thrombocytopenia

Incidence and Prognostic Significance of Thrombocytopenia Developed During Acute Coronary Syndrome in Contemporary Clinical Practice

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