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a Harrison Department of Surgical Research, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
b The Sol Sherry Thrombosis Research Center, Hematology Division, Department of Medicine, Temple University, Philadelphia, Pennsylvania
* Address correspondence to Dr Edmunds, 3440 Market St, Suite 306, Philadelphia, PA 19104-3325 (Email: hank.edmunds{at}uphs.upenn.edu).
Bleeding that will not stop is often a consumptive coagulopathy, which may be defined as the simultaneous generation of thrombin—the enzyme that cleaves fibrinogen to fibrin, and plasmin, the enzyme that cleaves fibrin. This condition occurs in disseminated intravascular coagulation (DIC), which may complicate systemic sepsis or massive trauma. To varying degrees, consumptive coagulopathy also occurs in cardiac operations using cardiopulmonary bypass [1, 2].
Thrombin normally acts locally at sites of injury and does not circulate because it is rapidly inhibited by antithrombin. Antithrombin is present at relatively high concentration in plasma. However, during cardiac surgery with cardiopulmonary bypass, thrombin is steadily produced and circulated [2]. Direct measurement of thrombin is very difficult, but the cleavage of prothrombin to thrombin generates a fragment, F1.2, which can be measured in approximately 1 hour by enzyme linked immunosorbent assay (ELISA). F1.2 progressively increases during cardiac operations using cardiopulmonary bypass, and it documents the continuous generation of thrombin [2]. Heparin does not inhibit thrombin generation; it inhibits thrombin after it is formed and is not able to inhibit thrombin trapped in fibrin clots [3].
Thrombin is primarily generated in the surgical wound during cardiopulmonary bypass by the tissue factor (extrinsic) coagulation pathway [4]. Cell bound tissue factor is present on many cells, but not pericardium. Plasma tissue factor normally circulates in picomolar concentrations, but increases in a wide range of disease states including cardiac surgery, acute coronary syndromes, major trauma, sepsis, and some cancers [5]. Plasma or cellular tissue factor is an essential receptor and cofactor for activated factor VII (fVIIa). A phospholipid surface primarily provided by activated monocytes and, to lesser degree, platelets, is also necessary [6]. Factor VIIa binding to tissue factor generates modest amounts of thrombin, but this is sufficient to ignite explosive production of thrombin in the presence of other coagulation proteins.
Thrombin is a major stimulus for increasing plasmin concentration. Thrombin stimulates endothelial cells to produce and release tissue plasminogen activator (t-PA), which binds to fibrin with high affinity and to plasminogen with high specificity [7]. Plasminogen binding to fibrin greatly increases the rate of plasminogen activation to produce plasmin. Plasmin then cleaves fibrin and produces several degradation products, of which D-dimer is the smallest and occurs in the highest concentration. D-dimer, a marker of active fibrinolysis, increases progressively during cardiac surgery with cardiopulmonary bypass [1]. Aprotinin directly inhibits plasminogen activators and plasmin formation even in fibrin clots [8]. The lysine inhibitors, tranexamic acid, and 
-aminocaproic acid prevent binding of plasmin to fibrin [8]. Both mechanisms effectively inhibit fibrinolysis and the superiority of one over the other is controversial, but differences related to bleeding, if any, are small [5, 9, 10].
Cardiac surgeons often face major wound bleeding at the end of cardiopulmonary bypass in patients who require prolonged, complex procedures or procedures that require additional mechanical circulatory support for survival [11]. Although platelet dysfunction and thrombocytopenia play a major role in bleeding, platelet transfusions, fresh frozen plasma, and cryoprecipitate usually fail to expeditiously reduce diffuse wound bleeding. Increasingly, surgeons have turned to recombinant factor VIIa, which is extraordinarily expensive and may occasionally cause intravascular thrombosis. Bolus doses (90 µL/kg) of recombinant factor VIIa transiently increase circulating fVIIa from about 1% of fVII to 15% [12].
Effective management of ongoing consumptive coagulopathies requires simultaneous suppression of thrombin generation and fibrinolysis. During cardiac surgery most of the thrombin generation occurs in the wound; thus, it makes sense to avoid returning blood aspirated from the wound directly to the perfusion circuit. However, whenever possible the aspirated blood should be washed in a cell saver and returned as packed cells [5]. Theoretically, aprotinin or a lysine inhibitor could be added directly to the wound to inhibit fibrinolysis in the wound. Because wound clotting is desired, it may not be wise to topically suppress thrombin generation by adding a direct thrombin inhibitor.
Surgeons faced with a major wound that is bleeding from a consumptive coagulopathy must rely on platelet counts and functional assays of coagulation. Functional assays measure the initiation phase of coagulation and not the explosive phase, which generates 95% of the thrombin formed [13]. Thus, these measurements are relatively crude and usually not very helpful. The thromboelastograph has never been shown to be effective in managing intraoperative cardiac bleeding [14]. Timely measurements of F1.2 primarily and D-dimer secondarily would provide direct determination of circulating thrombin generation and fibrinolysis, respectively. Although these assays are expensive and require approximately 1 hour to perform, these drawbacks are minor in comparison to the problem.
Bivalirudin is a short acting (
30 minutes) direct inhibitor of circulating thrombin and thrombin bound within clots. The drug is cleared primarily by proteolysis and to a lesser degree by the kidney [15]. Theoretically simultaneous administration of bivalirudin and a plasmin inhibitor should inhibit both thrombin and plasmin. In contrast, anti-fibrinolytics alone cannot control plasmin generation because thrombin stimulates endothelial cell release of tissue plasminogen activator [16]. The dose of bivalirudin must be carefully adjusted to allow thrombin-generated, microvascular thrombosis in the open vessels within the wound. Serial measurements of F1.2 are needed to guide this titration, despite the time delay necessary for the assay.
Cardiac surgeons and anesthesiologists are not hematologists. Solution of this major problem requires new approaches and a team effort by these disciplines. Exsanguination of blood banks in the middle of the night and 50% "take back" rates for bleeding [11] should not continue.
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  J.-F. Hardy, S. Belisle, and P. Van der Linden Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients: A Review of 17 Randomized Controlled Trials Ann. Thorac. Surg., September 1, 2008; 86(3): 1038 - 1048. [Abstract] [Full Text] [PDF]
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