Factor , clotting

BLOOD CLOTTING. The formation of blood clots is the result of a series of zymogen activations (Figure 15.5). The amplification achieved by this cascade of enzymatic activations allows blood clotting to occur rapidly in response to injury. Seven of the clotting factors in their active form are serine proteases ... 

An example of a biological Friedel-Crafts reaction occurs during the biosynthesis of phylloquinone, or vitamin Kl( the human blood-clotting factor. Phylloquinone is formed by reaction of 1,4-dihydroxynaphthoic acid with phytyl diphosphate. Phytyl diphosphate first dissociates to a resonance-stabilized allylic carbocation, which then substitutes onto the aromatic ring in the typical way. Several further transformations lead to phylloquinone (Figure 16.10). 

The protein-C pathway is one of the most important anticoagulant mechanisms. It is activated by thrombin. Thrombin binds to a cofactor in the membrane of endothelial cells, thrombomodulin (TM). TM bound thrombin no longer activates clotting factors or platelets but becomes an effective protein C (PC) activator. Activated PC (APC) forms a complex with Protein S, which inactivates FVIIIa and FVa. Hereby generation of Flla by the prothrombinase complex is inhibited (Fig. 9). Thus, the PC-pathway controls thrombin generation in a negative feedback manner. 

Binding calcium ions (Ca2+) is a prerequisite for the activation of seven clotting factors in the coagulation cascade that are dependent on vitamin K. The term cascade indicates, that the factois involved depend from... 

All anticoagulants interfere with the clotting mechanism of the blood. Warfarin and anisindione interfere with the manufacturing of vitamin K-dependent clotting factors... 

Blood plasma is the liquid part of blood, containing water, sugar, electrolytes, fats, gases, proteins, bile pigment, and clotting factors. Human plasma, also called... 

Blood platelets are key players in the blood-clotting mechanism. These tiny fragments of cytoplasm are shed into the circulation from the surface of megakaryocytes located in the bone marrow. When the lining of a blood vessel is injured, activated platelets release clotting factors, adhere to each other and to damaged surfaces, and send out numerous filopodia. The shape changes that occur in activated platelets are the result of actin polymerization. Before activation, there are no microfilaments because profilin binds to G-actin and prevents its polymerization. After activation, profilin dissociates from G-actin, and bundles and networks of F-actin filaments rapidly appear within the platelet. 

In the case of prothrombin and related clotting factors, interruption of the vitamin K cycle leads to the production of nonfunctional, undercarboxylated proteins, which are duly exported from hepatocytes into blood (Thijssen 1995). They are nonfunctional because there is a requirement for the additional carboxyl residues in the clotting process. Ionized carboxyl groups can establish links with negatively charged sites on neighboring phospholipid molecules of cell surfaces via calcium bridges. 

Vitamin E (tocopherol) is the most important antioxidant in the body, acting in the lipid phase of membranes and protecting against the effects of free radicals. Vitamin K functions as cofactor to a carboxylase that acts on glutamate residues of clotting factor precursor proteins to enable them to chelate calcium. 

Glucose Hexose Glc UDP-GIc Present during the biosynthesis of N-linked glycoproteins but not usually present in mature glycoproteins. Present in some clotting factors. 

Fucose Deoxyhexose Fuc GDP-Fuc May be external in both N- and 0-linked glycoproteins or internal, linked to the GIcNAc residue attached to Asn in N-linked species. Can also occur internally attached to the OH of Ser (eg, in t-PA and certain clotting factors). 

Xylose Pentose Xyl UDP-Xyl Xyl is attached to the OH of Ser in many proteoglycans. Xyl in turn is attached to two Gal residues, forming a link trisaccharide. Xyl is also found in t-PA and certain clotting factors. 

We shall first describe the coagulation pathway leading to the formation of fibrin. Then we shall briefly describe some aspects of the involvement of platelets and blood vessel walls in the overall process. This separation of clotting factors and platelets is artificial, since both play intimate and often mutually interdependent roles in hemostasis and thrombosis, but it facifitates description of the overall processes involved. 

Table 51-1. Numerical system for nomenclature of blood clotting factors. The numbers indicate the order in which the factors have been discovered and bear no relationship to the order in which they act.

The intrinsic pathway (Figure 51-1) involves factors XII, XI, IX, VIII, and X as well as prekallikrein, high-molecular-weight (HMW) kininogen, Ca, and platelet phospholipids. It results in the production of factor Xa (by convention, activated clotting factors are referred to by use of the suffix a). 

Solberg and co-workers have applied discriminate analysis of clinical laboratory tests combined with careful clinical and anatomic diagnoses of liver disease in order to determine which combinations of the many dozen liver diagnostic tests available are the bes t ( ). These authors found that the measurement of GPT, GMT, GOT, ALP and ceruloplasmin were the most useful enzymatic tests, when combined with other non-enzymatic tests such as the measurement of bilirubin, cholesterol, hepatitis-B associated Australian antigen, etc. Another group of highly useful enzymes, not discussed in this review, are those clotting factors and the enzyme cholinesterase which are synthesized by the liver cells. 

Strancar, A., Barut, M., Podgomik, A., Koselj, P, Schwinn, H., Raspor, P, and Josic, D., Application of compact porous tubes from preparative isolation of clotting factor VII from human plasma, /. Chromatogr. A, 760, 117, 1997. 

FIGURE 8-3. The physiologic clotting cascade. Clot formation beginning with vessel or tissue injury. Tissue injury starts the complex process involving clotting factors and resulting in cross-linked fibrin. This is a schematic of the factors and steps involved in the process. 

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