Effects of recombinant human prothrombin on thrombin generation in plasma from patients with hemophilia A and B

Hansson, Kenny M.; Gustafsson, David; Skärby, Tor; Frison, Lars; Berntorp, Erik

doi:10.1111/jth.12997

Cited by 4 publications

(4 citation statements)

References 27 publications

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“…Although this view is novel, to our knowledge, its elements are in good agreement with previous reports. All results of this study in its homogeneous model are well in line with previous reports on the sensitivity of the clotting cascade to coagulation factor deficiency (11,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). The decrease in clotting sensitivity to coagulation factor deficiency with the increase in TF activation level is also well documented (34).…”

Section: Discussionsupporting

confidence: 91%

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Kuprash

Shibeko

Vijay

et al. 2018

Biophysical Journal

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Blood coagulation is a delicately regulated space-and time-dependent process that leads to the formation of fibrin clots preventing blood loss upon vascular injury. The sensitivity of the coagulation network was previously investigated without accounting for transport processes. To investigate its sensitivity to coagulation factor deficiencies in a spatial reactiondiffusion system, we combined an in vitro experimental design with a computational systems biology model. Clot formation in platelet-free plasma supplemented with phospholipids was activated with identical amounts of tissue factor (TF) either homogeneously distributed (concentration 5 pM, homogeneous model) or immobilized on the surface (surface density 100 pmole/m 2 , spatially heterogeneous model). Fibrin clot growth and thrombin concentration dynamic in space were observed using video microscopy in plasma of healthy donors or patients with deficiencies in factors (F) II, FV, FVII, FVIII, FIX, FX, or FXI. In the spatially heterogeneous model, near-activator thrombin generation was decreased in FV-, FVII-, and FX-deficient plasma. In the homogeneous model, clotting was not registered in these samples. The simulation and experiment data showed that the coagulation threshold depended on the TF concentration. Our data indicate that the velocity of spatial clot propagation correlates linearly with the concentration of thrombin at the clot wave front but not with the overall thrombin wave amplitude. Spatial clot growth in normal plasma at early stages was neither reaction nor diffusion limited but became diffusion limited later. In contrast, clot growth was always diffusion limited in FV-, FVII-, and FX-deficient plasma and reaction limited in FVIII-, FIX-, and FXI-deficient plasma. We conclude that robustness of the spatially heterogeneous coagulation system was achieved because of the combination of 1) a local high TF surface density that overcomes activation thresholds, 2) diffusion control being shared between different active factors, and 3) an early saturated stimulus-response dependence of fibrin clot formation by thrombin.

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Section: Discussionsupporting

confidence: 91%

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Kuprash

Shibeko

Vijay

et al. 2018

Biophysical Journal

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“…ETP between hemophilia A and B was compared previously and did not appear to be significantly different. 25 Therefore, it seems plausible that PWHA and PWHB can be considered somewhat equal in this respect.…”

Section: Methodsmentioning

confidence: 99%

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance

et al. 2023

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Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are <20 IU/dL, but specific recommendations in patients with very low levels according to the different clinical situations are lacking and mainly based on the anecdotal series. For PWH with baseline clotting factor levels >20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH.

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“…56 In bleeding disorders, such as hemophilia A or B, a decrease in thrombin generation (reflected by a delay in "lag-time" and/or "time to peak thrombin" or a reduction in "peak thrombin" and/or ETP) has been shown to be significantly dependent on the degree of FVIII and FIX deficiency. [57][58][59][60] The CAT variable "time to tail start" (the time taken to full deterioration of generated thrombin) furthermore possesses a unique function in that it reveals the rate of thrombin decay (►Fig. 2E).…”

Section: Seminars In Thrombosis and Hemostasismentioning

confidence: 99%

The Clotting Trigger Is an Important Determinant for the Coagulation Pathway In Vivo or In Vitro—Inference from Data Review

Hong-Lie

Thålin

et al. 2020

Semin Thromb Hemost

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Blood coagulation comprises a series of enzymatic reactions leading to thrombin generation and fibrin formation. This process is commonly illustrated in a waterfall-like manner, referred to as the coagulation cascade. In vivo, this “cascade” is initiated through the tissue factor (TF) pathway, once subendothelial TF is exposed and bound to coagulation factor VII (FVII) in blood. In vitro, a diminutive concentration of recombinant TF (rTF) is used as a clotting trigger in various global hemostasis assays such as the calibrated automated thrombogram, methods that assess fibrin turbidity and fibrin viscoelasticity tests such as rotational thromboelastometry. These assays aim to mimic in vivo global coagulation, and are useful in assessing hyper-/hypocoagulable disorders or monitoring therapies with hemostatic agents. An excess of rTF, a sufficient amount of negatively charged surfaces, various concentrations of exogenous thrombin, recombinant activated FVII, or recombinant activated FIXa are also used to initiate activation of specific sub-processes of the coagulation cascade in vitro. These approaches offer important information on certain specific coagulation pathways, while alterations in pro-/anticoagulants not participating in these pathways remain undetectable by these methods. Reviewing available data, we sought to enhance our knowledge of how choice of clotting trigger affects the outcome of hemostasis assays, and address the call for further investigations on this topic.

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Effects of recombinant human prothrombin on thrombin generation in plasma from patients with hemophilia A and B

Cited by 4 publications

References 27 publications

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance

The Clotting Trigger Is an Important Determinant for the Coagulation Pathway In Vivo or In Vitro—Inference from Data Review

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