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The Rational Basis of Thrombosis Models
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
If the clinical experience is taken into account in only a portion of thrombosis patients, between 10 and 20%, a hereditary defect of a known blood clotting factor or inhibitor may be of such an important influence, or may have substantially contributed to the development of thrombosis.3–6 Antithrombin III deficiency, caused either by the lack of or a qualitative defect in the molecule, was found in about 2% of thrombosis cases. Deficiency of protein S was estimated in 10% of cases up to 40 years of age. The frequency of factor C defects is still difficult to assess. Other hereditary defects such as dysfibrinogenemias, factor XII deficiency, and sickle cell anemia are infrequently connected with the occurrence of thrombosis. Another portion of thrombosis patients may have inherited defects of the fibrinolytic system such as deficient or defective plasminogen, deficient tissue plasminogen activator (tPA) synthesis or release, as well as increased plasminogen activator inhibitor (PAI). This particularly concerns patients with recurrent attacks of deep vein thrombosis. Of course, not all possibly important factors and their hereditary defects have been properly identified as yet. Some factors inhibiting endothelial synthesis, accumulation or release of blood clotting or fibrinolytic factors or endothelial viability may exist as well, such as in homocysteinemia.7, 8 A special kind of a hereditary predisposition in thrombosis patients is suggested by the high freqency of some HLA antigens (Cw 4)9 and the prevalence of blood group A.10–14
Acquired Circulating Anticoagulants Other than Lupus Anticoagulants
Published in E. Nigel Harris, Thomas Exner, Graham R. V. Hughes, Ronald A. Asherson, Phospholipid-Binding Antibodies, 2020
Anticoagulants may be categorized as either specific antibodies to clotting factors or nonspecific in their function. The former class can be split into slow- or fast-acting categories. Examples of specific slow-acting anticoagulants are the classic inhibitors of factor VIII found in hemophiliacs, whereas other immunoglobulins directed against specific clotting factors are usually immediate-acting. Circulating anticoagulants or acquired inhibitors of coagulation are usually defined as “pathological substances in circulating blood that directly inhibit blood clotting factors or their interactions”.4 Characteristically their effect on clotting tests is not corrected readily by the addition of normal plasma clotting factors. The majority are immunoglobulins (although this finding is not substantiated in many studies) which may usually be subdivided further into two groups: (1) those arising in patients with an initial blood clotting factor deficiency and arising as a direct immunological response to the infusion of blood products containing a “foreign” antigen and (2) those which occur spontaneously for no apparent reason in patients with previously normal hemostatic function. It is possible that the latter patients may have, or may later develop some kind of immune disorder.
Blood and immune system disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Von Willebrand disease (VWD) is a genetic disorder that afects the ability of the blood to clot properly. It is mainly characterised by prolonged bleeding and vulnerability to bruising. All types of Von Willebrand disease are caused by problems with the Von Willebrand factor (VWF) protein. The main function of VWF is to support the blood’s platelets, which therefore cannot function properly in VWD. The VWF protein also helps to protect factor VIII, a blood-clotting factor. The gene for VWF is located on the short arm of chromosome 12.
An update on novel therapies for treating patients with arterial thrombosis
Published in Expert Review of Hematology, 2023
Udaya S Tantry, Sanchit Duhan, Eliano Navarese, Bogumil Ramotowski, Parshotam Kundan, Kevin P Bliden, Paul Gurbel
Animal experiments demonstrated that inhibition of A1 domain by humanized anti-VWF-A1 blocking nanobody named caplacizumab (ALX-0081) can inhibit platelet binding to VWF under shear and acute thrombosis without any effect on hemostasis [42]. The clinical development of caplacizumab in arterial disease patients was discontinued due to severe bleeding risk. However, caplacizumab is the first humanized, bivalent nanobody approved for treatment in patients with thrombotic thrombocytopenic purpura (TTP). Caplacizumab binds to A1 domain of VWF thereby inhibits VWF-mediated platelet adhesion and aggregation and concomitant reduction of blood clotting factor VIII. In patients with TTP, the ability of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif) to cleave ultra-large multimers of VWF is inhibited by autoantibodies (enzyme activity < 10%) leading to platelet consumption in VWF-platelet aggregates and microvascular thrombosis. In the phase III HERCULES, subcutaneous administration of caplacizumab on top of current therapy in patients with TTP demonstrated faster resolution of the disease, fewer TTP-related deaths and less recurrence of the disease [43].
Chronic thromboembolic pulmonary hypertension: a review of risk factors, management and current challenges
Published in Expert Review of Cardiovascular Therapy, 2022
John E Cannon, David P Jenkins, Stephen P Hoole
Despite its association with acute PE, classical hereditary risk factors for VTE including Protein C, Protein S and antithrombin deficiencies and mutations of factor V and factor II are not risk factors for the development on CTEPH. In contrast, antiphospholipid antibody syndrome is a recognized risk factor for developing acute PE and CTEPH [18]. There are a few thrombophilic factors that are implicated in CTEPH pathogenesis including an elevated factor VIII level [19]. Von Willebrand factor (vWF) plays an important role in platelet recruitment mediating the adhesion of platelets to the endothelium and is also a carrier protein for the pro-coagulant blood clotting factor VIII. vWF is noted to be elevated in patients with CTEPH and the vWF-cleavage protein ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which regulates vWF-activity is also reduced. Together, ADAMTS13–VWF axis dysregulation appears to be important in CTEPH pathogenesis. The linkage of the ADAMTS13 gene and ABO genetic locus may also explain why CTEPH is more common in patients with non-O blood group [20,21].
Economic burden of hemophilia A and B: a case in Iran
Published in Hematology, 2020
Khosro Keshavarz, Mohammadreza Bordbar, Zeinab Hashemipoor, Farideh Sadat Jalali, Ramin Ravangard
Inherited bleeding disorders are a group of rare diseases that cause prolonged bleeding due to a defective coagulation system [1]. Hemophilia is a congenital hemorrhagic disease that occurs due to impaired production of blood clotting factors as a result of mutations in related genes. Deficiencies in the blood clotting Factor VIII (FVIII) is called ‘hemophilia A’ and deficiencies in the blood clotting Factor IX (FIX) is known as ‘hemophilia B’ [2] which are categorized in terms of the severity into severe, moderate, and mild. Hemophilia imposes enormous health care costs on the patients, society and the health system [3]. In the United States and European countries, hemophilia is one of the most expensive diseases and a costly disorder that is highly considered not only because of its high direct medical costs but also because of its indirect costs [4–7].