Retention of Platelet Fibrin Stabilizing Factor during the Platelet Release Reaction and Clot Retraction

Jh, Joist; Niewiarowski, Stefan

doi:10.1055/s-0038-1648110

Cited by 22 publications

(23 citation statements)

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“…Indeed, an increase in FXIII-A activity over time was observed on incorporation of intact platelets into plasma clots. 37 We show that inhibiting platelet activation or FXIIIa activity dramatically reduces stabilization of thrombi by platelets. The impact of platelet FXIII-A on thrombus stabilization suggests it may translocate from the activated membrane into the adjacent fibrin network, but the extent of diffusion requires further clarification.…”

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

“…37,38 One potential mechanism of FXIII-A transport to the membrane could be via sphingomyelin-rich lipid rafts. Sphingomyelin-rich rafts act as signaling platforms on the platelet membrane between intra-and extracellular clot retraction machinery.…”

Section: Discussionmentioning

confidence: 99%

“…FXIII has previously been detected in platelet releasates, 54,55 but these observations are not consistent with our data or other reports. 23,24,37,46 FXIII-A levels are normal in platelets derived from patients with gray-platelet syndrome 25 and plasma FXIII levels are unchanged in thrombocytopenic mice.38 Together these data indicate a very minor contribution of a-granule FXIII-A 2 B 2 to the overall TG activity derived from platelet preparations.Platelet activation is essential for FXIII-A-mediated stabilization of FXIII-depleted thrombi. FXIII-A activity assays on platelets preactivated with TRAP-6/collagen are carried out in the absence of exogenous thrombin, suggesting that FXIII-A is nonproteolytically activated by the high Ca 21 levels associated with platelet stimulation.…”

mentioning

confidence: 98%

“…32 Platelets are known to stabilize static clots, 33,34 increase high-molecular-weight a-polymers and g-g dimer formation, [33][34][35][36] and augment cross-linking of a 2 AP to fibrin. [33][34][35] However, it is unclear how platelet FXIII-A elicits these functions because it is not released during activation 37 and does not follow classical routes of secretion in platelets or other cells. 38 We have previously shown, using thrombi formed under flow, that FXIII increases resistance to fibrinolysis, 39 specifically via crosslinking of a 2 AP to fibrin.…”

Section: Introductionmentioning

confidence: 99%

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Functional factor XIII-A is exposed on the stimulated platelet surface

Mitchell

Lionikiene

Fraser

et al. 2014

Blood

105

141

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Key Points• Factor XIII-A is exposed in protruding caps on the activated platelet surface.• Platelet FXIII-A exerts antifibrinolytic function by cross-linking a 2 AP to fibrin.Factor XIII (FXIII) stabilizes thrombi against fibrinolysis by cross-linking a 2-antiplasmin (a 2 AP) to fibrin. Cellular FXIII (FXIII-A) is abundant in platelets, but the extracellular functions of this pool are unclear because it is not released by classical secretion mechanisms. We examined the function of platelet FXIII-A using Chandler model thrombi formed from FXIIIdepleted plasma. Platelets stabilized FXIII-depleted thrombi in a transglutaminase-dependent manner. FXIII-A activity on activated platelets was unstable and was rapidly lost over 1 hour. Inhibiting platelet activation abrogated the ability of platelets to stabilize thrombi. Incorporating a neutralizing antibody to a 2 AP into FXIII-depleted thrombi revealed that the stabilizing effect of platelet FXIII-A on lysis was a 2 AP dependent. Platelet FXIII-A activity and antigen were associated with the cytoplasm and membrane fraction of unstimulated platelets, and these fractions were functional in stabilizing FXIII-depleted thrombi against lysis. Fluorescence confocal microscopy and flow cytometry revealed exposure of FXIII-A on activated membranes, with maximal signal detected with thrombin and collagen stimulation. FXIII-A was evident in protruding caps on the surface of phosphatidylserine-positive platelets. Our data show a functional role for platelet FXIII-A through exposure on the activated platelet membrane where it exerts antifibrinolytic function by cross-linking a 2 AP to fibrin. (Blood. 2014;124(26):3982-3990) IntroductionFactor XIII (FXIII) plays an essential role in normal hemostasis where it contributes to the regulation of fibrinolysis, 1-3 the maintenance of pregnancy, 4 wound healing, and angiogenesis. 5 The function of FXIII in hemostasis is further emphasized in its deficiency, which results in hemorrhage 6,7 and slow wound healing. 4,7 FXIII circulates in plasma as a heterotetramer (FXIII-A 2 B 2 ) where the catalytic A (FXIII-A 2 ) subunits are almost exclusively in complex with the inhibitory carrier B (FXIII-B 2 ) subunits. 8 FXIII is activated by the combined action of thrombin and Ca 21 to form the active transglutaminase (TG) FXIIIa. 9,10 FXIIIa confers stability to the fibrin matrix by cross-linking fibrin, substantially altering its rheologic properties.11,12 TG catalyzes formation of covalent e-(g-glutamyl) lysyl bonds 13 in which the lysine e-amino group is cross-linked to the glutamine g-carboxymide group. 14The cross-linking of g-chains confers a degree of rigidity to the fibrin network, which is further stabilized by the cross-linking of a-chains 15 to generate high-molecular-weight polymers. 10,16 FXIIIa also cross-links inhibitors of fibrinolysis to fibrin, further increasing its insolubility and resistance to plasmin. These inhibitors include a 2 -antiplasmin (a 2 AP), 17 thrombin activatable fibrinolysis inhibitor, 18 and plasminogen ac...

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Functional factor XIII-A is exposed on the stimulated platelet surface

Mitchell

Lionikiene

Fraser

et al. 2014

Blood

105

141

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Platelets and Fibrinolysis

Colucci

Semeraro

2017

Platelets in Thrombotic and Non-Thrombotic Disorders

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When I joined Marc Verstraete's laboratory as a medical student in 1959, the emphasis was on hemophilia, vitamin K antagonists as oral anticoagulants, and the development of thrombolysis. Platelet studies were limited to platelet count, bleeding time, and clot retraction. When an otherwise healthy patient with a bleeding disorder had a normal coagulation profile, a normal platelet count, a prolonged bleeding time, and an absent clot retraction, we diagnosed Glanzmann's thrombasthenia; if, however, in the same setting the clot retraction was normal, we considered von Willebrand's disease. How times have changed! In the 1960s, aggregometry allowed the first functional platelet studies; the inhibitory effect of some anti-inflammatory agents, in particular aspirin, was discovered, and the first speculations made about a possible antithrombotic potential of these agents. In the 1970s, there was in scientific meetings a strict divide between "clotters" (studying coagulation) and "clumpers" (studying platelet aggregation); fortunately, this gap gradually narrowed when it became obvious that platelets are closely involved in physiological coagulation and that coagulation induces platelet activation. The 1980s saw confirmation of aspirin as antithrombotic agent; it became a mainstay for the prevention and treatment of arterial vascular disease. At the same time, new developments in cell biology were being applied to megakaryocytes and platelets. Since then, new pathways and receptors have been continuously discovered; the molecular bases of numerous congenital thrombocytopenias have been defined; new platelet inhibitors have been developed and evaluated in clinical studies; platelet inhibition remains crucial despite the continuing progress with vascular stents to combat arterial disease. Platelets are now recognized to play an important role in inflammation, angiogenesis, cancer, etc.So why, in this Internet age, a new book on platelets? Platelet studies are a typical area where cell biology and clinical practice meet. A book is an ideal site to bring these two separate worlds together. Cell biologists are interested in the potential clinical application of their findings; clinicians are interested in the biological basis of their treatments; this book provides all the answers in one place. It now has become impossible to possess the total knowledge on platelets; even experts will benefit from a book like this. For students entering the field, it provides them with a daunting but comprehensive "state of the art," to which they can hope to add new findings.The first edition of this book dates from 2002. When comparing the Tables of Contents, I find, besides an update of previously covered topics, many new entries such as the platelet proteome and transcriptome, CLEC, a new emphasis on neutrophil-platelet interactions, platelets as carriers of genetic material for cell delivery, or platelets in regenerative medicine, among several others.The book now contains 97 chapters. To identify and convince top scientists to contribu...

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Blutgerinnungsfaktor XIII und Fibrinstabilisierung

Rasche

1975

Klin Wochenschr

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Coagulation factor XIII (fibrin stabilizing factor, FSF) is detectable in plasma, platelets, placenta and various tissues. In the activated form FSF has the enzymatic properties of a transglutaminase and is capable of stabilizing fibrin by inducing covalent bondings between fibrin monomers. In patients with congenital factor XIII deficiency or acquired immune inhibitors of fibrin stabilization a severe bleeding tendency is evident. There is not yet enough information available concerning the significance of reduced FSF-activity as cofactor in hemorrhagic diathesis and wound healing disturbances in various disease states. There are some indications from experimental studies that there might be an influence of FSF on tumor growth and metastasis as well as arteriosclerosis. The quantitation of the enzyme by radiological and immunological techniques yield reproducible results. Fibrin in its stabilized or non stabilized form can be discriminated in polyacrylamide gel electrophoresis after reduction of fibrin clots.

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Retention of Platelet Fibrin Stabilizing Factor during the Platelet Release Reaction and Clot Retraction

Abstract: SummaryPlatelet FSF was found to be retained by rabbit, pig or human platelets during the release reaction induced by thrombin, collagen or plasmin and during a 2 hours incubation of platelet rich fibrin clots.

Cited by 22 publications

References 5 publications

Functional factor XIII-A is exposed on the stimulated platelet surface

Functional factor XIII-A is exposed on the stimulated platelet surface

Platelets and Fibrinolysis

Blutgerinnungsfaktor XIII und Fibrinstabilisierung

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