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C H A P T E R 126

MOLECULAR BASIS OF BLOOD COAGULATION

Kathleen Brummel-Ziedins and Kenneth G. Mann

Blood is the principal vehicle delivering oxygen and nutrients to the primed to react to vascular injury in an explosive manner. Therefore
various tissues and organs of the body. Blood flow and the integrity following sections describe the process of blood coagulation in terms
of the vasculature are essential to life itself. The hemostatic process of the inventory, the connectivity, and then the dynamics.
has evolved to provide damage recognition and protection from blood
loss after perforation of the vasculature while at the same time pre-
venting the systemic activation of the clotting system. However, INVENTORY: PROCOAGULANT, ANTICOAGULANT, AND
pathologic occlusions are associated with dysregulation of the intra- FIBRINOLYTIC PROTEINS, INHIBITORS AND RECEPTORS
vascular system, resulting in venous or arterial thrombosis. The fine
line between vascular occlusion and hemostasis is defined by the Putting together an inventory of the blood coagulation components
complex interplay between pro- and anticoagulant materials provided is still ongoing, but what we currently know to date began from initial
by the blood, the vasculature, and subvascular elements. The appro- observations that were made in the fifth century and recorded in the
priate functions occur as a consequence of intense focal development Babylonian Talmud. It was noted that if two male children died of
1
and regulation of enzymatic activity at sites of vascular injury. bleeding after circumcision, the third should not be circumcised.
The development of the inventory of components involved in Over the centuries, many more hypotheses were made regarding what
2,3
plasma clotting were initially based on the most abundant procoagu- happens to blood when it escapes from the body. The realization
2,3
lant plasma proteins, notably prothrombin and fibrinogen, and that clots stem blood loss only occurred in the 18th century. The
extended during the past century with the identification of genetic existence of thrombin, the key enzyme in blood coagulation, was
abnormalities that led to bleeding and deviations in laboratory tests recognized in the 19th century. 2,4
that evolved as the inventory of congenital defects expanded. In some In 1905, Paul Morawitz proposed the classic theory of coagula-
5
instances, laboratory test results indicating a defect in the procoagu- tion. He hypothesized that in the presence of calcium and throm-
lant system were not mirrored by hemostatic pathology. In a similar boplastin, prothrombin was converted to thrombin, which in turn
fashion, the congenital defects associated with thrombosis led to the converted fibrinogen to the fibrin clot. These clotting factors were
discovery of anticoagulant proteins in blood and vascular counterparts subsequently assigned Roman numerals, factor I (fibrinogen), factor
associated with their presentation and activation. II (prothrombin), factor III (thromboplastin; tissue factor mem-
6
The functional connections between procoagulant “factors” were brane), and factor IV (calcium). As more coagulation factors were
developed by mixing and matching plasmas associated with different introduced, they were assigned consecutive Roman numerals. The
hemostatic disorders. This inventory and its connectivity were ratified activated forms are distinguished by a lower case “a” after their Roman
and expanded by experiments performed with transgenically mutated numeral designation. Therefore the activated form of factor V
mice. becomes factor Va.
The dynamics of the plasma coagulation process as expressed are More complex descriptions of the coagulation system were as a
7
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a consequence of the molar concentrations of the pro- and anticoagu- “cascade” or “waterfall.” Macfarlane and Davie and Ratnoff pro-
lant components in blood and the vasculature, and the kinetic pro- posed that in an intrinsic pathway, involving only plasma, blood
cesses associated with the dynamics of both the activation and coagulated by a sequence of events in which the reactions occurred
functions of the various proteins associated with the process. in a defined series leading to fibrin clot formation. Over the past six
The initial result of the activation of the procoagulant hemostatic decades, the Morawitz/Davie and Macfarlane pathways have been
process is the formation of a fibrin–platelet plug that forms the significantly expanded (Fig. 126.1). Each reaction shares a similar
temporary seal of the vascular perforation in hemostasis. The genera- mechanism in which an inactive zymogen protein is converted to an
tion of an occlusive fibrin–platelet plug blocking further flow through active enzyme and each “enzyme” is a surface-bound multiprotein
2+
an element of the vasculature is thrombosis. In both instances, the complex consisting of a surface, divalent calcium ions (Ca ), a
fibrin–platelet scaffold is ultimately removed and substituted by protease, and a cofactor. Although some facets of these initial descrip-
vascular repair, new cells, and connective tissue. In thrombosis, the tions are still valid, the emerging concept of coagulation and fibrino-
platelet–fibrin plug is removed mechanically or by biochemical lysis centers on a complex network of highly interwoven concurrent
intervention to restore flow to the flow-starved vascular bed. processes. Procoagulant and fibrinolytic events occur simultaneously
The elements of clotted fibrinogen–platelet plug are dissolved by with many positive- and negative-feedback loops regulating the
the fibrinolytic system, a tightly regulated dynamic system involving processes.
enzyme activation, feedback regulation, and blockade by a potent To fully understand the multiple simultaneous processes that
series of inhibitors. Just as there is an interplay between the pro- and occur to effect a hemostatic response, we will first inventory the key
anticoagulant components that brings about a blood clot in hemosta- procoagulant, anticoagulant, and fibrinolytic participants. The inven-
sis, similar mechanisms occur when blood clots are dissolved via the tory sections discuss vitamin K–dependent protein family, cofactor
fibrinolytic process, which is essential for tissue repair. This chapter proteins, the intrinsic accessory pathway proteins, endothelium,
describes the components of the pro- and anticoagulant system and platelets, proteinase inhibitors, clot proteins, and fibrinolysis
the pro- and antifibrinolytic system, and the interplay between these proteins.
systems. The common feature of both systems is the focal presentation
of activity that is dependent on the presentation of surface-bound
enzymatic complexes that can cleave their respective substrates. The Vitamin K–Dependent Protein Family
Blood coagulation can best be understood if viewed as a choreo-
graphed system that starts from an inventory of the key players, the Vitamin K–dependent proteins, synthesized in the liver, play a central
relationship or connectivity of these players, and the dynamic catalytic role in blood coagulation through either procoagulant or anticoagu-
processes. These processes together keep blood in a fluid state but lant mechanisms. The vitamin K–dependent protein family includes

1885