Rate-limiting roles of the tenase complex of factors VIII and IX in platelet procoagulant activity and formation of platelet-fibrin thrombi under flow

Swieringa, Frauke; Kuijpers, Marijke J. E.; Lamers, Moniek M. E.; Meijden, Paola E. J. van der; Heemskerk, Johan W. M.

doi:10.3324/haematol.2014.116863

Cited by 46 publications

(50 citation statements)

References 55 publications

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“…Similarly, in perfusion studies at 100 s À1 of hemophilia A blood over TF-rich surfaces, severe deficiency (1%) was associated with defective platelet and fibrin deposition, while moderate deficiency (1-5%) had partially defective fibrin production and mild (5-30%) deficiency had relatively normal platelet and fibrin production [32]. F8 À/À and F9 À/À hemophilic mouse blood displays marked deficits in platelet deposition and fibrin production when perfused over a TF-rich surface [33]. These studies confirm that for healthy blood under flow conditions, TF surfaces generate (via TF/FVIIa) triggering levels of FXa and thrombin (< 1 nmol L À1 ) sufficient to activate platelets, but the transition to and engagement of the 'intrinsic' tenase (FIXa/VIIIa) are required for the ample production of thrombin (calculated to be > 10 nmol L À1 in the clot [32]) to make fibrin under flow conditions.…”

Section: Failure To Achieve Hemostasis Under Flow Conditionsmentioning

confidence: 94%

Transport physics and biorheology in the setting of hemostasis and thrombosis

Brass

Diamond²

2016

Journal of Thrombosis and Haemostasis

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SUMMARY The biophysics of blood flow can dictate the function of molecules and cells in the vasculature with consequent effects on haemostasis, thrombosis, embolism, and fibrinolysis. Flow and transport dynamics are very distinct for: (1) haemostasis vs. thrombosis and (2) venous vs. arterial episodes. Intraclot transport changes dramatically the moment haemostasis is achieved or the moment a thrombus becomes fully occlusive. With platelet concentrations that are 50–200-fold greater than platelet rich plasma, clots formed under flow have very different composition and structure compared to blood clotted statically in a tube. The platelet-rich, core/shell architecture is a prominent feature of self-limiting hemostatic clots formed under flow. Importantly, a critical threshold concentration of surface tissue factor is required for fibrin generation under flow. Once initiated by wall-derived tissue factor, thrombin generation and its spatial propagation within a clot can be modulated by: γ′-fibrinogen incorporated into fibrin, engageability of FIXa/VIIIa tenase within the clot, platelet-derived polyphosphate, transclot permeation, and reduction of porosity via platelet retraction. Fibrin imparts tremendous strength to a thrombus to resist embolism up to wall shear stresses of 2400 dyne/cm2. Extreme flows, as found in severe vessel stenosis or in mechanical assist devices, can cause von Willebrand Factor self-association into massive fibers along with shear induced platelet activation. Pathological VWF fibers are ADAMTS13-resistant, but are a substrate for fibrin generation due to FXIIa capture. Recently, microfluidic technologies have enhanced the ability to interrogate blood in the context of stenotic flows, acquired von Willebrand’s disease, hemophilia, traumatic bleeding, and drug action.

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Section: Failure To Achieve Hemostasis Under Flow Conditionsmentioning

confidence: 94%

Transport physics and biorheology in the setting of hemostasis and thrombosis

Brass

Diamond²

2016

Journal of Thrombosis and Haemostasis

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“…Microscopy studies indicated a near complete colocalization of the constituents of the tenase (FVIIIa and FIXa, activating FX) and prothrombinase (FVa and FXa, activating prothrombin) complexes with PS‐exposing platelets . Of note, for FVIII(a) only sparse colocalization was observed, with the majority of FVIII costaining with von Willebrand factor (VWF), likely acting there as a supply pool . Kinetic studies have shown that PS‐containing membranes enhance the activities of tenase and prothrombinase complexes by up to 1000‐fold .…”

Section: How Do Platelets Control Thrombin Generation?mentioning

confidence: 99%

Integrating platelet and coagulation activation in fibrin clot formation

Swieringa

Spronk

Heemskerk

et al. 2018

Research and Practice in Thrombosis and Haemostasis

128

110

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Platelets interact with the coagulation system in a multitude of ways, not only during the phases of thrombus formation, but also in specific areas within a formed thrombus. This review discusses current concepts of platelet control of thrombin generation, fibrin formation and structure, and anticoagulation. Indicated are how combined signalling via the platelet receptors for collagen (glycoprotein VI) and thrombin induces the secretion of (anti)coagulation factors, as well as surface exposure of phosphatidylserine, thereby catalysing thrombin generation. This procoagulant platelet response is also facilitated by the adhesive complexes glycoprotein Ib‐V‐IX and integrin αIIbβ3. In the buildup of a platelet‐fibrin thrombus, the extrinsic, tissue factor–driven coagulation pathway is predominant in early stages, while the intrinsic, factor XII pathway seems to promote at later time points. Already early generation of thrombin enforces platelet responses and stimulates intra‐thrombus heterogeneity with patches of loosely aggregated, contracted, and phosphatidylserine‐exposing platelets. Fibrin actively formed on the surface of activated platelets supports thrombus growth, but also captures thrombin. The fibrin distribution in a thrombus appears to rely on the local procoagulant trigger and the blood flow rate. Clinical studies support the importance of the platelet‐coagulation interplay, by showing beneficial effects of combination therapy in the secondary prevention of cardiovascular disease.

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“…The contribution of FXa and thrombin stemming from residual intrinsic tenase in various TF-laden backgrounds has not been studied extensively. Previous studies only assessed severe cases of human FVIII or FIX deficiency (<1%) often with FXIIa function uncontrolled or blood from mice deficient in FVIII or FIX[17,18,21]. Few have examined how milder deficiencies in FVIII or FIX levels affect platelet adherence and fibrin formation in the presence of bypass therapy and surface TF[22].…”

Section: Introductionmentioning

confidence: 99%

Recombinant factor VIIa addition to haemophilic blood perfused over collagen/tissue factor can sufficiently bypass the factor IXa/VIIIa defect to rescue fibrin generation

Panckeri

Fogarty

et al. 2017

Haemophilia

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Introduction Factor VIII or FIX-deficient hemophilic patients display deficits in platelet and fibrin deposition under flow detectable in microfluidics. Compared to fibrin generation, decreased platelet deposition in hemophilic blood flow is more easily rescued with recombinant factor VIIa (rFVIIa), whereas rFVIIa requires FXIIa participation to generate fibrin when tissue factor (TF) is absent. Aims Perfusion of hemophilic whole blood over collagen/TF surfaces was used to determine if rFVIIa/TF was sufficient to bypass poor FIXa/FVIIIa function in blood from hemophilia A and B patients. Methods Whole blood (WB) treated with high dose corn trypsin inhibitor (40 μg/ml) from 7 healthy donors and 10 patients was perfused over fibrillar collagen presenting low or high TF (TFlow or TFhigh) at wall shear rate of 100 s−1. Results With WB from healthy controls, platelet deposition and fibrin accumulation increased as TF was increased. Factor-deficient WB (1–3% of normal) displayed striking deficits in platelet deposition and fibrin formation at either TFlow or TFhigh. In contrast, mildly factor-deficient WB (14–32%) supported fibrin formation under flow on TFhigh/collagen. With either TFlow or TFhigh, exogenously added rFVIIa (20 nM) increased platelet deposition and fibrin accumulation in WB from factor-deficient patients (1–3% of normal) to levels commensurate with untreated healthy WB. Conclusion The absence of FIXa/FVIIIa in severe hemophilic patients results in deficits in fibrin formation that cannot be rescued by wall-derived TF ex vivo. The effects of rFVIIa on platelet adhesion and rFVIIa/TF can act together to reinforce thrombin generation, platelet deposition, and fibrin formation under flow.

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Rate-limiting roles of the tenase complex of factors VIII and IX in platelet procoagulant activity and formation of platelet-fibrin thrombi under flow

Cited by 46 publications

References 55 publications

Transport physics and biorheology in the setting of hemostasis and thrombosis

Transport physics and biorheology in the setting of hemostasis and thrombosis

Integrating platelet and coagulation activation in fibrin clot formation

Recombinant factor VIIa addition to haemophilic blood perfused over collagen/tissue factor can sufficiently bypass the factor IXa/VIIIa defect to rescue fibrin generation

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