Phenotyping the clotting system.

The combined research efforts in our field over the last hundred years made that we now recognise dozens of plasma proteins with a function in the clotting system and a set of platelet components that is of the same order. Progress in molecular biology is such as to have identified some one hundred genes that may influence haemostasis and thrombosis and a new one comes about every month. Nevertheless the phenotype of the clotting system cannot be adequately established. There is no simple method that gives us a clear picture of the net result of the activity of all those genes, together with non-genetic influences (e.g. drugs), on the over-all clotting function of blood at a given moment. For over a century we make do with clotting times that we know to be marginally – if at all – sensitive to hypercoagulability and mild bleeding disorders. We are used to employing different variants for the control of oral anticoagulants and of heparin. Some anticoagulants do not significantly influence any type of clotting time and for convenience are assumed not to require control. Standardisation is a constant problem. But we are so used to clotting times as to almost forget that they do not actually serve the purpose of a simple adequate indicator of clotting function, that we lack a test that is equivalent to blood sugar in diabetes or blood pressure in hypertension. Conceivably measuring thrombin generation could be such a test. Thrombin is at a focal point in haemostasis and thrombosis. The whole “clotting” mechanism is engaged in its generation and subsequent inactivation. During its active life it exerts a multitude of actions on the blood and the vessel wall, among which the clotting of fibrinogen. The sum of these actions is haemostatic and/or thrombotic. The part played by thrombin has always been evident in haemophiliac bleeding and venous thrombosis. It becomes more and more clear that it is also pivotal in arterial thrombosis (1-4). Anticoagulant therapies that decrease thrombin formation by completely different mechanisms, such as oral anticoagulation and heparin, are effective in both venous and arterial thrombosis (5, 6). Even “antiplatelet” drugs do influence thrombin generation (see below).