Coagulation inhibitors

The antithrombotic factors produced by endothelial cells are thrombomodulin (TM) and protein S (PS), components of the vitamin K-dependent protein C (PC) anticoagulant pathway, inhibiting F-Va-F-Villa (E15) tissue plasminogen activator (tPA), responsible for fibrinolysis (N2, LI8) and the lipoprotein-associated coagulation inhibitor (LACI), which inhibits F-VIIa-TF complex and F-Xa (B51). 

B51. Broze, G. J., Warren, L. A., Novotny, W. F., Higuchi, D. A., Girard, J. J., and Miletich, J. P The lipoprotein-associated coagulation inhibitor which inhibits the factor Vll-tissue factor complex also inhibits factor Xa Insight into its possible mechanism of action. Blood 71,335-343 (1988). 

F14. Fourrier, F., Jourdain, M., Tournois, A., Caron, C., Goudemand, J and Chopin, C., Coagulation inhibitor substitution during sepsis. Intensive Care Med. 21(Suppl 2), S264-268 (1995). 

Novotny W. F Girard T. J., Miletich J. P., Broze G. J. Platelets secrete a coagulation inhibitor functionally and antigenically similar to the lipoprotein associated coagulation inhibitor. Blood 1988 72,2020-5. 

In hormone replacement therapy, the risk of deep vein thrombosis is increased by a factor of 2-4 (35-37). The absolute increase in the treated population as a whole is low, with about one case of venous thromboembolism in 5000 women-years of use of hormone replacement therapy. However, in the subgroup with pre-existing risk factors, such as obesity, varicose veins, smoking, and a prior history of venous thromboembolism or superficial thrombophlebitis, the increase in risk from hormone replacement therapy can be substantial among these women are those with a genetic predisposition to thrombosis, generally due to some form of thrombophilia, such as deficiency of the coagulation inhibitors protein S, protein C, or anti thrombin III. In any of these subjects thrombosis can occur early in hormone replacement therapy. However, this tendency to early occurrence of deep vein thrombosis also seems to be present in all those who take hormone replacement therapy. 

Girard TJ, Warren LA, Novotny Wp Likert KM, Brown SG, Miletich JR et al. Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 1989 338 518-520. 

I 10 Day KC, Hoffman LC, Palmier MO, et al, Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit. Blood 1990 76 1538-1545. 

Three proteins, for which I did not have structural data, should also be mentioned, namely the so-called minibody [147-149] a Kunitz inhibitor domain of the human lipoprotein associated coagulation inhibitor (LACI-D1 Refs. 89 and 90) which resembles BPTI and CP-1, a designed scaffold zinc-finger [150], The minibody is a 61 aa designed... 

Coagulation factors Coagulation inhibitors Fibrinolytic system ... 

Tab. 35.4 Abnormal coagulation factors, coagulation inhibitors and fibrinolytic system values in hepatic cirrhosis (TPT = thromboplastin time PTT = partial thromboplastin time HRGP = histidine-rich glycoprotein t-PA = tissue plasminogen activator)...

Patients with bleeding disorders are at risk of developing antibodies against the protein that is absent, present in reduced amounts, or present in an inactive form in their blood. Such coagulation inhibitors make treatment very difficult. Inhibitors of factor VIII are the most common and develop in 5-20% of patients with hemophiha A. Inhibitors of factor IX develop in 1-4% of patients with hemophilia B (3,4). Patients with factor VIII inhibitors present clinically either as high responders who show a strong anamnestic response and a sharp rise in inhibitor concentrations after exposure to factor VIII, or low responders, who show little or no anamnestic response (5). 

Patients with bleeding disorders are at risk of developing antibodies against the coagulation protein that is absent, present in reduced amounts, or present in an inactive form in their blood. Such coagulation inhibitors make treatment very difficult. 

If thrombin and factor Xa, the major activated blood coagulation factors (Fig. 11.6), escape into healthy blood vessels, blood clots will develop and occlude capillaries throughout the body. Direct inhibition of these activated enzymes in the blood flow utilizes serine protease inhibitors, of which there are two common types a Kunitz inhibitor and a serpin. The former possess a Kunitz domain, a convex antiparallel (1-sheet that exactly fits into the concave active site of a serine protease, directly blocking it (lock and key mechanism). By contrast, serpins undergo complex interactions with other proteins to cause conformational changes that bait and block the catalytic action (Fig. 11.12 shows the bait). Table 11.3 fists the major coagulation inhibitors and cofactors, their targets and mechanisms of action. 

McFarland was the first to report the development of hemophilia in a 45-year-old patient who had received repeated transfusions. Several case reports have appeared. At first it was believed that the hemorrhagic diathesis resulted from the accumulation of coagulation inhibitors heparin was often incriminated. Only in the 1950 s was the immunological pathogenesis of the disease accepted. Inhibitors of factors VIII (hemophilia A) and IX (hemophilia B) have been reported. The acquired inhibitors to factor VIII have been studied most extensively. In fact, the inhibitors have been purified. They are believed to be y-globulins with a sedimentation constant of 7 S. 

Nar, H., Bauer, M., Schmid, A., et al (2001) Structural basis for inhibition promiscuity of dual specific thrombin and factor Xa blood coagulation inhibitors. 

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