Inflammo-coagulatory response, extrinsic pathway thrombin generation and a new theory of activated clotting time interpretation.
When blood is subjected to contact with foreign surfaces, as during cardiopulmonary bypass (CPB), the whole body inflammatory response is initiated, resulting in the expression of procoagulant molecules on the vascular endothelium and white blood cells. These surface bound procoagulants participate in the extrinsic coagulation pathway. It appears that the primary source of thrombin generation during CPB is due to extrinsic pathway activation. Thrombin not only converts fibrinogen to fibrin, it also acts as a proinflammatory agent resulting in a positive feedback loop or the inflammo-coagulatory response. Extrinsic pathway thrombin generation occurs as a membrane bound event. Membrane bound factors are resistant to heparin/ATIII inhibition. Therefore, the anticoagulant effect of heparin/ATIII is due to thrombin inhibition, not the inhibition of thrombin generation. Interpretation of the activated clotting time (ACT) must take into account the thrombin concentration [T]; this results in the coagulatory ratio, ACT is proportional to ([Hep -ATIII]/[T]). Considering this proportionality, it can be seen that the ACT cannot be used to quantitate heparin concentration. Changes in the ACT can reflect changes in [Hep - ATIII], changes in [T], or changes in both concentrations. Anti-inflammatory agents which suppress or inhibit the extrinsic pathway, such as aprotinin, result in decreased thrombin generation. As thrombin generation decreases, the ACT-heparin dose response curve is warped, resulting in a dose response curve resembling a PTT-heparin dose response curve. We can no longer assume that the disproportionate rise in the ACT relative to the [HEP - ATIII] when aprotinin is used as indicative of failure of the ACT to provide a credible indication of anticoagulation.
Gil
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West Penn Allegheny Health System, Pittsburgh, Pennsylvania, USA.
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000990:Antithrombin III / Q000502:physiology; D001779:Blood Coagulation Factors / Q000502:physiology; D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000097:blood*; D008954:Models, Biological; D013917:Thrombin / Q000096:biosynthesis* / Q000502:physiology; D019851:Thrombophilia / Q000209:etiology; D013925:Thromboplastin / Q000502:physiology; D014914:Whole Blood Coagulation Time
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D000990:Antithrombin III; D006493:Heparin; D013925:Thromboplastin; D013917:Thrombin