HEPARIN-INDUCED THROMBOCYTOPENIA: ASSOCIATION OF THROMBOTIC COMPLICATIONS WITH HEPARIN-DEPENDENT IgG ANTIBODY THAT INDUCES THROMBOXANE SYNTHESIS AND PLATELET AGGREGATION

Chong, Beng H.; Pitney, W. R.; Castaldi, P.A.

doi:10.1016/s0140-6736(82)90106-4

Cited by 250 publications

(103 citation statements)

References 12 publications

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“…34 Because of its net negative charge, heparin, like other glycosaminoglycans, is able to bind and concentrate growth factors and chemokines on the cell surface. 35 It has also been exploited to bind and purify numerous protein components of platelet ␣-granules, including von Willebrand factor, 36 fibronectin, 37 Pselectin, 38 thrombospondin, 39 vitronectin, 40 and PF4.…”

Section: Discussionmentioning

confidence: 99%

Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling

Gao

Boylan

Fang

et al. 2011

Blood

111

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Unfractionated heparin (UFH) is a widely used anticoagulant that has long been known to potentiate platelet responses to subthreshold doses of platelet agonists. UFH has been reported to bind and induce modest conformational changes in the major platelet integrin, ␣IIb␤3, and induce minor changes in platelet morphology. The mechanism by which UFH elicits these platelet-activating effects, however, is not well understood. We found that both human and murine platelets exposed to UFH, either in solution or immobilized onto artificial surfaces, underwent biochemical and morphologic changes indicative of a potentiated state, including phosphorylation of key cytosolic signaling molecules and cytoskeletal changes leading to cell spreading. Low molecular weight heparin and the synthetic pentasaccharide, fondaparinux, had similar plateletpotentiating effects. Human or mouse platelets lacking functional integrin ␣IIb␤3 complexes and human platelets pretreated with the fibrinogen receptor antagonists eptifibatide or abciximab failed to become potentiated by heparin, demonstrating that heparin promotes platelet responsiveness via its ability to initiate ␣IIb␤3-mediated outside-in signaling. Taken together, these data provide novel insights into the mechanism by which platelets become activated after exposure to heparin and heparin-coated surfaces, and suggest that currently used glycoprotein IIb-IIIa inhibitors may be effective inhibitors of nonimmune forms of heparin-induced platelet activation.

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Section: Discussionmentioning

confidence: 99%

Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling

Gao

Boylan

Fang

et al. 2011

Blood

111

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“…[1][2][3] HIT can be regarded as a hypercoagulability state, based upon the greatly elevated levels of thrombinantithrombin complexes 4,5 (a marker of in vivo thrombin generation) observed in patients with HIT, as well as the strong association between HIT and venous and arterial thrombosis. [1][2][3] Indeed, the most common thrombotic manifestation of HIT is lower-extremity deep-vein thrombosis (DVT). 2,3,6,7 However, previous studies have not examined whether HIT is also associated with upper-extremity DVT.…”

Section: Introductionmentioning

confidence: 99%

Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia

Hong

Cook

Sigouin

et al. 2003

Blood

156

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“…Hundreds ofcases have since been reported and HITP is now recognized as an important cause ofmorbidity and mortality in patients receiving heparin therapy (3,4). HITP differs from most other forms of drug-induced thrombocytopenia in that the responsible antibodies activate platelets in the presence of optimal concentrations of hepanin, rather than merely binding to platelets to promote their destruction (3)(4)(5). This activation can be blocked in vitro by monoclonal antibodies specific for the platelet Fc receptor (FcyRII) (6), suggesting that hepann-induced antibodies somehow interact with heparin to form platelet-activating immune complexes.…”

Section: Introductionmentioning

confidence: 99%

Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.

Visentin¹,

Ford²,

Scott³

et al. 1994

J. Clin. Invest.

550

429

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Heparin-induced thrombocytopenia/thrombosis (HITP) is thought to be mediated by immunoglobulins that activate platelets in the presence of pharmacologic concentrations of heparin, but the molecular basis for this relatively common and often serious complication of heparin therapy has not been established. We found that plasma from each of 12 patients with HITP contained high titer (. 1:200) Invest. 1994. 93:81-88.)

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HEPARIN-INDUCED THROMBOCYTOPENIA: ASSOCIATION OF THROMBOTIC COMPLICATIONS WITH HEPARIN-DEPENDENT IgG ANTIBODY THAT INDUCES THROMBOXANE SYNTHESIS AND PLATELET AGGREGATION

Cited by 250 publications

References 12 publications

Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling

Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling

Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia

Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.

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