Heparin‐induced thrombocytopenia and thrombosis

Davoren, Anne; Aster, Richard H.

doi:10.1002/ajh.20490

Cited by 69 publications

(57 citation statements)

References 89 publications

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“…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][2][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.…”

Section: Introductionmentioning

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: Introductionmentioning

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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“…2 These reactions could culminate in life-threatening venous and/or arterial thromboembolic events. 3,10,11 Type II HIT is diagnosed by the combination of clinical presentation and laboratory studies. The American College of Chest Physicians recommends that the diagnosis of HIT be considered if a patient's platelet count decreases by 50% or more from baseline or if a thrombotic event occurs within 4 to 14 days after the initiation of heparin.…”

Section: Discussionmentioning

confidence: 99%

84-Year-Old Woman With Hemodialysis-Associated Shortness of Breath

Kapa

Qian

2009

Mayo Clinic Proceedings

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A n 84-year-old woman was admitted to the hospital for evaluation of shortness of breath, hypoxia, and hypotension occurring during hemodialysis. She had recently been diagnosed as having end-stage renal failure due to membranous nephropathy and had started dialysis treatment 3 weeks previously. She had a history of hypertension, and an echocardiogram obtained 2 weeks before admission showed mild concentric left ventricular hypertrophy. Her medications included a β-blocker and oral phosphate binder. She denied smoking cigarettes or drinking alcohol.Review of her outpatient records revealed that dialysis via a tunneled catheter placed in the right internal jugular vein had been tolerated well initially. In the middle of the second week of treatment, she began to experience shortness of breath associated with hypoxia and hypotension a few minutes after the start of each dialysis, and elevated pressure was noted in the dialysis line at each session. On one occasion, the entire dialyzer was clotted. She had no chest pain, fever, chills, or electrocardiographic changes during these episodes. Although most of her treatments had to be terminated within an hour because the symptoms became intolerable, they abated within 15 to 30 minutes after each session. Fearful of such dialysis-related episodes, the patient was seriously contemplating discontinuing her dialysis treatment.On admission 1 day after the most recent dialysis attempt, physical examination revealed the following: blood pressure, 180/96 mm Hg; pulse rate, 78 beats/min and regular; respiratory rate, 18 breaths/min; and temperature, 36.8°C. Her oxygen saturation was 92% while receiving oxygen at 2 L/min via nasal cannula. Bilateral rales were audible in two-thirds of the lung field bilaterally, and 3+ pitting edema was noted in both lower extremities. . Reaction to the dialyzer or a medication given during dialysisDialysis line infection could be associated with episodic sepsislike illness. In such cases, each dialysis through the infected line results in a transient shower of bacteria from the line into the bloodstream, leading to episodes of fever, chills, and, less frequently, hypotension. For the entire duration of our patient's recurrent dialysis-associated illness, fever and chills were not observed. Therefore, although the possibility of line infection should be ruled out, her presentation is atypical.Fluid overload with pulmonary congestion could cause shortness of breath and hypoxia but should not repeatedly cause hypotension. Dialysis is a well-known efficacious method for removal of excess fluid. In our patient, the removal of excess fluid through dialysis had been curtailed because of the development of hypotension. Thus, fluid overload was a consequence, rather than the cause, of her symptoms.Large-volume uremia-associated pericardial effusion could cause intradialytic hypotension due to tamponade and be associated with shortness of breath and hypoxia. However, this scenario is unlikely in our patient because echocardiography obtained at the onse...

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“…heparininduced thrombocytopenia -HIT) yra gyvybei grės-minga klinikinė būklė, kurią sukelia dėl autoimuninių procesų atsiradusi trombocitopenija, dažnai paradoksiškai besikomplikuojanti tromboze (angl. HITTSheparin-induced thrombocytopenia with thrombosis syndrome) (1)(2)(3)(4)(5)(6). Tai svarbi patologija, nes heparinas tapo vienu iš dažniausiai vartojamų vaistų pasaulyje ir indikacijos heparino vartojimui plečiasi (7,8).…”

Section: Tęstinės Medicinos Studijosunclassified

“…Krešulys negali įtraukti fibrino į trombo formavimąsi. Nebevartojamas, nes yra efektyvesnių vaistų (2)(3)(4)(5)(6)(7)(8).…”

Section: Imuniniai Tyrimaiunclassified