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The Potential of Plants as Treatments for Venous Thromboembolism
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Lilitha L. Denga, Namrita Lall
The intrinsic pathway is the amplification and propagation step of the coagulation cascade. It creates numerous positive feedback loops, which accelerate the coagulation cascade. The initial creation of thrombin (Figure 17.2) generates additional thrombin by activating factors V (FV) and VIII (FVIII), which become activated factors V (FVa) and VIII (FVIIIa), respectively (Monroe, Hoffman, and Roberts 2002). FVIIIa then forms the tenase complex with FIXa.
Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
In contrast, marked abnormalities are present in patients with Factor VIII or Factor IX deficiency representing the congenital defects in intrinsic pathway of coagulation.104,212,237 Injury of a small artery or vein leads to the formation of a platelet mass within a normal time, but the plug is unstable. Within a few minutes of the primary arrest of bleeding, it is renewed, sometimes because part of the plug is dislodged. Bleeding may again be temporarily stopped, but it may take 20 to 30 min before the hemorrhage is finally arrested. Skin wounds in patients with hemophilia A (Factor-VIII deficiency) contain platelet masses, but they are greatly deficient in fibrin. This condition represents defects in the intrinsic mechanisms of clotting; although a primary platelet mass is formed, it leads to an unstable clot. Another problem in these cases is the formation of a new clot if the old one is dislodged. In Factor- VIII deficient subjects, if the primary clot is removed 24 h after its formation, a new one does not form, and only small aggregates of loosely packed platelets adhere near the open ends of the severed vessels.237 These subjects bleed continuously until external measures are applied. Thus subjects with Factor VIII deficiency show defective formation of the primary clot and more abnormalities in the formation of the secondary plug. Since the initial platelet plug is unstable and its transformation to a fibrin mass is very slow, hemophiliacs are more vulnerable to the action of a hemostatic plug being dislodged than normal subjects.
Coagulation Theory, Principles, and Concepts
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
The relationship between factor VIII and von Willebrand factor was known long before factor VIII was characterized structurally. The relationship was so close, in fact, that for a good number of years there existed a “factor VIII-related antigen,” which in reality was the von Willebrand factor. It is now accepted that the von Willebrand factor stabilizes factor VIII by forming a noncovalent complex with factor VIII (46). The half-life of highly purified factor VIII is significantly longer (12 hr) in hemophiliacs than it is in patients with homozygous von Willebrand’s disease (2–3 hr). To function in the activation of factor X, factor VIII must be activated. This activation, which involves limited proteolysis of factor VIII, can be accomplished either by factor Xa or by thrombin (47). In this scheme, it is thought that activation of factor VIII is accomplished initially by thrombin or factor Xa that is generated by the tissue factor–factor VIIa extrinsic pathway before TFPI shuts down extrinsic coagulation. Once formed, the factor Xa generated by the intrinsic pathway is sufficient to maintain activation of factor VIII. Factor VIIIa is now known to be a heterotrimer (three different chains) which is produced when thrombin activates factor VIII, releasing it from the von Willebrand factor. The resulting trimer is unstable, dissociating and losing activity. Activated protein C hastens the loss of activity by limited proteolysis.
New pharmacotherapeutic options for oral anticoagulant treatment in atrial fibrillation patients aged 65 and older: factor XIa inhibitors and beyond
Published in Expert Opinion on Pharmacotherapy, 2023
Giovanni Santostasi, Gentian Denas, Vittorio Pengo
It has thus been speculated that the intrinsic pathway is activated by damage produced inside the vascular system, unlike the extrinsic pathway, which responds to trauma external to the blood vessels [49]. Evidence from preclinical and epidemiological studies confirms this interpretation and has prompted increasing interest and research in the pharmacological inhibition of contact phase factors. In laboratory animals, factor XI, factor XII, or kallikrein deficiency induced by antisense oligonucleotides (ASO), has been shown to protect from arterial and venous thrombosis [50]. Comparable protection from thrombosis was induced by antibodies targeting FXI and FXII [51]. In preclinical studies in primates, inhibition of FXI produced more convincing evidence of an antithrombotic effect than inhibition of FXII or kallikrein suggesting that FXI performs a greater role in thromboembolism. A prevalent role of contact phase factors in thrombosis, with a limited influence on hemostasis, was confirmed in humans by population studies, and only a small increase in bleeding risk has been described in tissues with high fibrinolytic activity (e.g. following dental surgery, tonsillectomy, and prostate surgery) [52].
Application of anti-Xa assay in monitoring unfractionated heparin therapy in contemporary antithrombotic management
Published in Expert Review of Hematology, 2023
Michael Safani, Steve Appleby, Ryan Chiu, Emmanuel J Favaloro, Emanuel T. Ferro, Jimmy Johannes, Milan Sheth
The coagulation pathways represent a cascade of events intended to provide a balance between procoagulant and anticoagulant processes and maintain hemostasis. Primary hemostasis consists of platelet activation, aggregation, and thrombus formation and aims to form a plug at the site of exposed endothelial cells due to tissue damage. Secondary hemostasis, as measured by the pathology laboratory, conventionally comprises three coagulation pathways. The intrinsic pathway is activated by endothelial damage and collagen exposure and includes factors I, II, IX, X, XI, and XII. The extrinsic pathway is activated by release of tissue factor by damaged endothelium and includes factors I, II, VII, and X. The common pathway consists of factors I, II, V, VIII, X. The intrinsic and extrinsic pathways converge to form a common pathway and at a specific point to activate fibrinogen to form fibrin polymer. In vivo, the final stages of primary and secondary hemostasis are marked by binding of fibrin polymers to platelets to secure and stabilize the platelet plug [37–41].
Phenotypic and genetic analyses of four cases of coagulation factor XII deficiency
Published in Hematology, 2022
Shanshan Li, Kuangyi Shu, Fanfan Li, Xiao Yang, Wei Yang, Manli Ye, Xiaoou Wang, Minghua Jiang
In the study, four FXII deficiency cases whose APTT was obviously prolonged had no obvious bleeding tendency. This result supports that FXII deficiency is not associated with excessive bleeding [7] and that FXII is more like a bystander in haemostasis [5,8,9]. Although FXII serves as an activator in the intrinsic pathway, FXI can initiate coagulation via the TF-FVIIα complex, which is produced by the extrinsic pathway [10–12]. Under physiological conditions, the blood vessel would release tissue factors when it was damaged. The latter participated in the formation of the TF-FVIIα complex, which could start the extrinsic pathway. In addition, a small amount of thrombin as a product of the extrinsic pathway could activate factor XI to start the intrinsic pathway [12,13]. In the APTT test, the intrinsic pathway was started by FXIIα, which was activated by kaolin and diatomite. The above factors might explain why the person had no obvious bleeding tendency when his APTT prolonged greatly. Moreover, APTT plasma mixing study of the four cases could be rectified, which could eliminate the possibility of the appearance of FXII inhibitor. This finding supports that the lack of FXII:C and FXII:Ag is the main reason for prolonged APTT.