Factor VIII excess

Hypercoagulable states include malignancy activated protein C resistance deficiency of protein C, protein S, or antithrombin factor VIII or XI excess antiphospholipid antibodies and other situations. Estrogens and selective estrogen receptor modulators have been linked to venous thrombosis, perhaps due in part to increased serum clotting factor concentrations. Although a thrombus can form in any part of the venous circulation, the majority of thrombi begin in the lower extremities. Once formed, a venous... 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Excessive bleeding hemophilia due to failed coagulation path interactions VWF mutations and hemophilia A (factor VIII) B (factor IX) and C (factor XI) and... 

It is supposed that each autosomal locus (the von Willebrand genes) and the X-chromosome locus (the hemophilia gene) create products at the same rate, molecule for molecule, and that these are polypeptide chains (designated A and B, respectively), which subsequently combine (in the cytoplasm of the synthesizing cells ) to form factor VIII. Since two A-chains are formed for each B-chain, an excess of free A-chains remains. In hemophilia all the B-chains are abnormal (Bi ), and thus the completed molecules (A+ + B ) are all abnormal, despite the normal A+ component the excess consists entirely of normal A-chains (A" "). In von Willebrand s disease some (heterozygote) or all (homozygote) of the completed molecules are abnormal because they contain abnormal A-chains (A ). The excess will contain free A -chains. 

Hemophilia has been observed in a small number of females. This can occur if both factor VIII or IX genes are defective, if a female patient has only one X chromosome, as in Turner s syndrome, or if the normal X chromosome is excessively inactivated through a process called lyonization. 

Excessive factor VIII activity in vulnerable arterial beds, for example atherosclerotic vessels, could lead to thrombotic events, such as venous thrombosis or myocardial infarction. In patients with hemophilia A... 

The procoagulant factors produced by endothelial cells are the coagulation factors von Willebrand factor (WF), F-V, F-VIII, tissue factor (TF), and plasminogen activator inhibitor (PAI), which blocks the activators u-PA and t-PA and counteracts fibrinolysis (G21, FI6). It has been shown that under the influence of complement activation (C9), in response to endotoxin in vitro (C24), in experimental E. coli sepsis in baboons (D30), and after stimulation with TNF (Al, N6), endothelial cells up-regulate the expression of TF, down-regulate TM and inhibit the production of t-PA and PAF. Thus, the balance may shift in the procoagulant direction with a large excess of PAI-1. 

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