Clotting factor inhibitors

Use of clotting-factor concentrates to check for the development of inhibitors, especially in patients with severe disease and poor treatment responders... 

Another concern in infants of mothers with epilepsy is a serious hemorrhagic disorder that is associated with a high (25-35%) mortality. This probably results from the finding that many AEDs can act as competitive inhibitors of vitamin K-dependent clotting factors. The competitive inhibition can be overcome by the administration of oral vitamin K supplements to the mother during the last week or 10 days of pregnancy. 

Treatment of classic hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor FVIII (Compared to Kogenate, some patients who developed inhibitors on study with Kogenate-FS continued to manifest a clinical response when inhibitor titers were less than 10 Bethesda units (BU) per ml). 

Inhibitors of the blood clotting factor thrombin would in principle prove useful in preventing inappropriate clot formation that potentially leads to stroke and heart attack. Reaction of the carboxylic acid (56-2) with thionyl chloride leads to the corresponding acid chloride (56-3). Treatment of that intermediate with the substituted pyridyl amine (56-1) leads to the amide (56-4). Catalytic hydrogenation of (56-4) reduces the nitro group to the primary amine (56-5). Condensation of that ortho-diamine with the carboxyhc acid (56-6) in the presence of carbonyl diimidazole... 

Immunoglobulins, oq-trypsin inhibitor and a2-macroglobulin,k ten or more blood clotting factors and proteins of the complement system all have protective functions that are discussed elsewhere in this book. Hormones, many of them proteins, are present in the blood as they are carried to their target tissues. Many serum proteins have unknown or poorly understood functions. Among these are the acute phase proteins, whose concentrations rise in response to inflammation or other injury. 

One of the goals of synthetic medicinal chemistry is to design potent inilibitors of clinically important proteases. Elastase inhibitors may be useful for treatment of emphysema, pancreatitis, and arthritis,a/b while inhibitors of the angiotensinogen-converting enzyme or of renin (Box 22-D) can help control blood pressure. Inhibition of thrombin, factor Xa, or other blood clotting factors (Fig. 12-17) may prevent blood clots and inhibition of the cytosolic tryptase may provide a new treatment for asthma. Inhibition of the cysteine protease cathepsin K may help combat osteoporosis and inhibition of cysteine proteases of corona viruses may fight the common cold. Cysteine proteases of schistosomes are also targets for protease inhibitors.c... 

Lynch, C. M., Israel, D. I., Kaufman, R. J. and Miller, A. D. (1993). Sequences in the coding region of clotting factor VIII act as dominant inhibitors of RNA accumulation and protein production. Hum. Gene Ther. 4, 259-272. 

Heparin acts by binding to anti thrombin III, which serves as a major inhibitor of serine protease clotting enzymes. Abruptly ending heparin treatment can be hazardous because of reduced levels of antithrombin III. Coumarins, typified by warfarin, are structurally similar to vitamin K, which plays an important role in blood coagulation. By interfering with the function of vitamin K, vitamin K-dependent proteins such as clotting factors VII, IX, X and prothrombin are reduced. 

Morita, T., Nakamura, T., Miyata, T., Iwanaga, S. Biochemical characterisation of Limulus clotting factors and inhibitors which interact with bacterial endotoxin. In Cate, J.W., Buller, H.R., Sturk, A., Levin, J. (eds). Bacterial endotoxin, structure, biomedical significance, and detection with the limulus amoebocyte lysate test. Alan R Liss Inc, NY (1985a) pp. 53-64. 

Recent experimental evidence (3, 4) has demonstrated that heparin s anticoagulant effect results from its ability to catalyse the deactivation of several of the clotting factors. Of particular importance and the primary reason for heparin s anticoagulant effect is the drug s ability to deactivate thrombin by catalysing the reaction between thrombin and its inhibitor antithrombin III (AT-III). Because it acts directly to deactivate clotting factors, heparin has a very fast anticoagulant effect. 

The cereal dual function a-amylase/trypsin inhibitor proteins are cysteine-rich, disulphide-rich, double-headed, 13-16 kDa, dual function inhibitor proteins that inhibit both of the digestion enzymes a-amylase and trypsin [290-325] (Table 11). Thus the Zea (com) member of this family, com Hageman factor inhibitor (CHFI), is a double-headed 14 kDa protein that inhibits a-amylase and the serine proteases trypsin and blood clotting Factor Xlla [323-324] (Table 11). The structures of the bifunctional a-amylase/trypsin inhibitor proteins from Eleusine (ragi) (RBI) [292-295] and Zea (com) (CHFI) [325] have been determined. These proteins are structurally similar to the lipid transfer proteins, being composed of a bundle of 4 a-helices together with a short [3-sheet element connected by loops, the a-amylase- and protease-inhibitory domains being separately located [325]. 

The mustard family (Brassicaceae) PIPs are 7 kDa proteins with 8 cysteines in highly conserved positions that form 4 disulphide linkages in a particular pattern of connectivity. The mustard PIPs are variously potent inhibitors of serine proteases such as trypsin, chymotrypsin, thrombin, plasmin and blood clotting factors Xa and Xlla [515, 520] (Table 15). 

Allergenic extracts Antitoxins, antivenoms, venoms Blood, blood components, plasma-derived products (e.g., albumin, immunoglobulins, clotting factors, fibrin sealants, proteinase inhibitors), recombinant and transgenic versions of plasma derivatives... 

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