HITT and stent thrombosis: A “CLINICAL” diagnosis not to be missed

Hussain, Farrukh; Philipp, R; Zieroth, Shelley

doi:10.1016/j.ijcard.2007.08.078

Cited by 5 publications

(4 citation statements)

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“…Consistently, they can present with a variety of symptoms, including dyspnea, neurologic deficiencies, chest pain, and shock. 26,27 Interestingly, antibodies to GPIX are weak agonists for Fc␥RIIA-dependent mouse platelet activation/aggregation in vitro ( Figure 4), similar to what has been described for immune complexmediated activation of these cells. 7 Consistent with this observation, it is also widely known that preactivation of low responding human platelets can produce positive Fc␥RIIA-dependent aggregation responses to HIT complexes.…”

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

confidence: 70%

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 1117supporting

confidence: 70%

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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“…Very rarely, it has been described in the setting of coronary angioplasty for an acute myocardial infarction in association with the abrupt onset of HIT, such as in this case 6)9)10)…”

Section: Discussionmentioning

confidence: 99%

Acute Stent Thrombosis and Heparin Induced Thrombocytopenia in a Patient With ST-Segment Elevation Myocardial Infarction

et al. 2012

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Heparin is an essential drug in the treatment of acute coronary syndrome and it is used during percutaneous coronary intervention (PCI). Heparin-induced thrombocytopenia (HIT), albeit a serious complication of heparin therapy characterized by thrombocytopenia and high risk for venous and arterial thrombosis, has rarely been previously reported during PCI. We report a case of an acute stent thrombosis due to an unusual cause, HIT during primary PCI, in a patient with acute myocardial infarction.

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“…The causes of early stent thrombosis are multifactorial, such as residual target lesion thrombus or dissection, stasis, stent underexpansion, unstable hemodynamics, dehydration, heparin-induced thrombocytopenia [3] and clopidogrel hyporesponsiveness [4]. Although intravascular ultrasound (IVUS) was not used, there was no thrombus or dissection and an adequate vessel diameter was obtained by angiographic evaluation.…”

Section: Discussionmentioning

confidence: 99%

Repetitive early stent thrombosis in a patient with the CYP2C193/3 genotype

Takashio

Hokimoto

Kaikita

et al. 2011

Journal of Cardiology Cases

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A 45-year-old man presented with acute inferior myocardial infarction and underwent emergent coronary angiography (CAG). CAG revealed total occlusion of both the proximal right coronary artery (RCA) and distal left circumflex artery, and two bare-metal stents were deployed in the RCA. After the procedure, dual antiplatelet therapy (DAT) with 100 mg aspirin and 75 mg clopidogrel daily were given as usual, however, stent thrombosis occurred three times and he underwent repeat interventions. To investigate the cause of repeated stent thrombosis, the platelet function during DAT was measured. The result showed that he did not achieve an adequate antiplatelet effect.Clopidogrel is a prodrug that requires biotransformation by cytochrome P450 (CYP) enzyme in the liver. Recently, the carriers of CYP2C19*2 or *3 null-of-function allele, have been shown to demonstrate an increased risk of cardiovascular events, including stent thrombosis, compared with non-carriers. This patient carried the CYP2C19*3/*3 genotype. This is the first report of repetitive stent thrombosis in a poor metabolizer carrying two loss-of-function alleles (CYP2C19*3/*3).

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HITT and stent thrombosis: A “CLINICAL” diagnosis not to be missed

Cited by 5 publications

References 5 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

Acute Stent Thrombosis and Heparin Induced Thrombocytopenia in a Patient With ST-Segment Elevation Myocardial Infarction

Repetitive early stent thrombosis in a patient with the CYP2C193/3 genotype

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HITT and stent thrombosis: A “CLINICAL” diagnosis not to be missed

Cited by 5 publications

References 5 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

Acute Stent Thrombosis and Heparin Induced Thrombocytopenia in a Patient With ST-Segment Elevation Myocardial Infarction

Repetitive early stent thrombosis in a patient with the CYP2C19*3/*3 genotype

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Repetitive early stent thrombosis in a patient with the CYP2C193/3 genotype