Blood, 1 July 2002, Vol. 100, No. 1, pp. 1-1
Clotting in whole blood: analysis of a biochemical
reaction network
The coagulation cascade is a complex biochemical
network replete with regulatory reactions and cellular contributions.
The behavior of the system cannot necessarily be predicted intuitively from the existing state-of-the-art biochemical knowledge of the individual reactions. Knowledge of the reaction kinetics of the components in this complex system has major implications for an understanding of the regulation of coagulation and its effective control by therapeutic agents.
Brummel and colleagues (page 148) describe an analysis of thrombin
formation and function following the addition of tissue factor to
initiate coagulation in whole blood in which the contact pathway is
inhibited. They present results observed in samples from 20 healthy individuals describing the time course of thrombin formation as well as its procoagulant activation products: activated platelets, fibrinopeptides A and B, factor Va, and factor XIIIa. Each
of these products accumulate in an initial slow phase (initiation) followed by an explosive phase of product formation (propagation). They
observe clot formation to coincide with the onset of the propagation
phase for thrombin-antithrombin III formation. But the transition points for the other thrombin activation products occur much earlier at very low concentrations of thrombin. Crucial activation of the different procoagulant thrombin substrates occurs in
a graded fashion before the clot is visible and is catalyzed by 0.2%
or less of the possible thrombin that can be formed. The bulk of
thrombin formation (96%) occurs well after overt clot formation.
Their quantitative analyses raise interesting questions regarding
the significance of the high concentrations of thrombin available after
the clot has already formed. Experimental and computational approaches
pioneered by the Mann laboratory that also incorporate the protein C
pathway might shed light on this interesting finding. From a clinical
standpoint, their findings also highlight the complexities of using
direct thrombin inhibitors as antithrombotic agents. Such therapeutics
would need to effectively inhibit the low levels of thrombin activity
necessary for the initiation phase even when the maximum concentrations
of thrombin can vastly exceed those necessary for the activation of its
procoagulant substrates.
Sriram Krishnaswamy
Children's Hospital of Philadelphia and University of
Pennsylvania
