The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity

Dörmann, Dagmar; Clemetson, Kenneth J.; Kehrel, Beate E.

doi:10.1182/blood.v96.7.2469

Cited by 165 publications

(95 citation statements)

References 71 publications

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“…(d) Percentage surface coverage with annexin V binding platelets prior to thrombin (Control) and 10 min after the start with the thrombin/annexin V solution (þ thrombin). that SFLLRN desensitizes the thrombin-induced procoagulant response of platelets [11].…”

Section: Resultsmentioning

confidence: 94%

von Willebrand factor stimulates thrombin-induced exposure of procoagulant phospholipids on the surface of fibrin-adherent platelets

Briedé

Wielders

Heemskerk

et al. 2003

Journal of Thrombosis and Haemostasis

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Summary. Studies from our laboratory have demonstrated that von Willebrand factor (VWF) stimulates thrombin generation in platelet-rich plasma. The precise role of VWF and fibrin in this reaction, however, remained to be clarified. In the present study we utilized thrombin-free planar fibrin layers and washed platelets to examine the relationship between platelet-fibrin interaction and exposure of coagulation-stimulating phosphatidylserine (PS) under conditions of low and high shear stress. Our study confirms that platelet adhesion to fibrin at a shear rate of 1000 s À1 requires fibrin-bound VWF. ), but only a minority of the platelets (11 AE 8%) exposed PS. The essential role of VWF in this thrombin-induced procoagulant response became apparent from low shear rate perfusion studies over fibrin that was incubated with VWF and botrocetin. After treatment with thrombin, the majority of the adherent platelets (57 AE 23%) exposed PS and had peak values of [Ca 2þ ] i of about 0.6 mmol L À1 . Taken together, these results demonstrate that thrombin-induced exposure of PS and high calcium response on fibrin-adherent platelets depends on shear-or botrocetin-induced VWF-platelet interaction.Keywords: fibrin, platelet procoagulant activity, von Willebrand factor.Thrombus formation at an injured vessel wall involves platelet adhesion, platelet activation and fibrin formation. Previous studies have provided evidence that fibrin, besides physically entrapping platelets [1], may also be involved in signal pathways that result in the exposure of anionic phospholipids (PS) at the plasma membrane of platelets [2,3]. The presence of PS in the outer leaflet of the platelet plasma membrane is of physiological importance because of its critical role in maintaining thrombin generation at the surface of a developing thrombus [4]. Platelets adhere to fibrin by molecular mechanisms that vary with the surface shear rate [5,6]. At low shear rates, platelet adhesion is mediated by integrin a IIb b 3 whereas at high shear rates an interaction between platelet glycoprotein (GP) Ib and fibrin-bound von Willebrand factor (VWF) tethers the platelets as a prerequisite for an irreversible, integrin a IIb b 3 -mediated, adhesion to fibrin [7][8][9][10].Recently, conflicting reports appeared on the role for GPIb in the development of procoagulant platelets. Studies in plateletrich plasma revealed that VWF supports thrombin generation by two mechanisms: one that involves integrin a IIb b 3 but not fibrin and another one that depends on both fibrin and GPIb [3]. Other investigators studied the thrombin-dependent expression of procoagulant activity in suspensions of gel-filtered platelets and found that the GPIb binding site for thrombin, but not that for VWF, has a key role in the exposure of procoagulant phospholipids on the platelet surface, implying that VWF does not function in this response [11]. Earlier studies, however, indicated that PAR1 is the primary mediator of thrombin-stimulated platelet procoagulant activity, implicating that GPIb doe...

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Section: Resultsmentioning

confidence: 94%

von Willebrand factor stimulates thrombin-induced exposure of procoagulant phospholipids on the surface of fibrin-adherent platelets

Briedé

Wielders

Heemskerk

et al. 2003

Journal of Thrombosis and Haemostasis

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“…Thrombin generation initiated in platelet-rich plasma with tissue factor and Ca 21 and measured by calibrated automated thrombography has been reported to be reduced in BSS [51], and we found that P2's endogenous thrombin potential was half that of controls (data not shown) (P1 was not available for investigation). Clearly, other defects occur as a result of the reduction of GPIba that lead to the decreased prothrombin consumption/thrombin generation observed in BSS; these could include impaired binding of factor XI, thrombin and/or fibrin [51][52][53][54].…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

et al. 2010

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In the Bernard-Soulier syndrome (BSS), the giant platelets are said to have increased phosphatidylserine (PS) surface exposure in the resting state and shortened survival in the circulation. When normal platelets are activated, they undergo many biochemical and morphological changes, some of which are apoptotic. Herein, we investigated apoptotic-like events in BSS platelets upon activation, specifically, PS exposure, microparticle (MP) formation, cell shrinkage, and loss of mitochondrial inner membrane potential (DC m ). Platelets from two unrelated BSS patients were examined in whole blood; agonists used were collagen, thrombin, PAR1-or PAR4-activating peptides (APs), or combinations of collagen with thrombin, and the PAR-APs. Flow cytometry was used to measure PS exposure (annexin A5 binding), platelet-derived MPs (forward scatter; events <0.75 lm size), and DC m (TMRM fluorescence). PS exposure was increased on resting and activated BSS platelets, and this was independent of the platelet size. MP formation by BSS platelets was generally enhanced. Cell shrinkage occurred on activation to form smaller, PS-exposing platelets in BSS and controls. A proportion of PS-exposing BSS and control platelets exhibited DC m loss, but unlike controls, there was also loss of DC m in the BSS platelets not exposing PS. Thus, BSS platelets undergo apoptotic-like events upon activation, with PS exposure and MP formation being enhanced. These events may play a role in the shortened survival in BSS, as well as affecting thrombin generation. Am. J. Hematol. 85:584-592, 2010. V

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“…Thrombin is a very potent PLT activator and binds to protease activating receptor-1 and -4 (PAR-1 and PAR-4) as well as to glycoprotein Iba. [19][20][21][22][23] TRAP-6 binds to PAR-1, but in contrast to thrombin no inhibition of fibrinogen polymerization with GPRP is required in the assay, further enhancing its feasibility.…”

Section: Discussionmentioning

confidence: 99%

In vitro platelet function of platelet concentrates prepared using three different apheresis devices determined by impedance and optical aggregometry

Jilma‐Stohlawetz¹,

Eichelberger²,

Horvath³

et al. 2009

Transfusion

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The GPIb thrombin-binding site is essential for thrombin-induced platelet procoagulant activity

Cited by 165 publications

References 71 publications

von Willebrand factor stimulates thrombin-induced exposure of procoagulant phospholipids on the surface of fibrin-adherent platelets

von Willebrand factor stimulates thrombin-induced exposure of procoagulant phospholipids on the surface of fibrin-adherent platelets

Phosphatidylserine exposure and other apoptotic‐like events in Bernard‐Soulier syndrome platelets

In vitro platelet function of platelet concentrates prepared using three different apheresis devices determined by impedance and optical aggregometry

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