Sherrill J. Slichter

The hemostatic alterations underlying the occasional bleeding diathesis associated with cardiopulmonary bypass surgery have been defined in 31 selected patients by simultaneously measuring the serial changes in concentration, function and kinetics of platelets, coagulation factors, and fibrinolytic components. The effects of uncomplicated bypass surgery were evaluated in 21 elective patients. Immediately upon bypass, the circulating levels of platelets, coagulation factors, and plasminogen regularly fell about 50% due to dilution with nonblood prime in the oxygenator apparatus. However, none of these components was reduced below established hemostatic levels at any time during or following the procedure. Furthermore, the functional transformation of fibrinogen to fibrin was not measurably impaired. Heparin effectively blocked both fibrinolysis and fibrinogen consumption during bypass and was consistently neutralized with protamine without rebound at the end of bypass. Circulating platelets were uniformly activated in elective patients during bypass through a process that involved release and partial depletion of α-granules, but not release of dense granule constituents. Platelet activation was associated with transient marked impairment of function as evidenced by striking prolongation of the bleeding time and defective aggregation in vitro. In uncomplicated patients, platelet function largely normalized within 1 hr after bypass. Controlled studies in baboons demonstrated that platelet dysfunction was produced by either cardiopulmonary bypass under normothermic conditions or by hypothermia alone without bypass. In the baboon model, defective platelet function was also transient and characterized by selective depletion of platelet a-granule contents without release of dense granule contents. By contrast, in all of 10 patients in whom bypass surgery was complicated by substantial abnormal bleeding, there was persistent bleeding time prolongation to greater than 25 min that persisted for hours after bypass despite platelet counts above 100,000/µl. With platelet transfusions, the bleeding time shortened rapidly, followed by cessation of bleeding. From these studies we conclude that cardiopulmonary bypass patients demonstrate abnormal clinical bleeding when there is a persistence of platelet dysfunction manifested as a bleeding time of greater than 20 min after protamine administration. Such bleeding patients with a prolonged bleeding time should receive platelet transfusions even when the platelet count is greater than 100,000/µl.

BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

The value of the standardized template bleeding time was studied in 100 normal subjects and 136 patients with various disorders. With normal platelets the bleeding time in this test is 4.5 ± 1.5 minutes (± 1 S.D.) when the circulating platelet concentration exceeds 100,000 per microliter, and is 30.5 – (platelet count per μl/3850) minutes at platelet counts between 100,000 and 10,000 per microliter. More prolonged bleeding times reflect impaired platelet function, as associated with acetylsalicylic acid ingestion, uremia, or von Willebrand's disease. In contrast, bleeding times shorter than predicted with normal platelets are due to increased hemostatic competence of young platelets, associated either with idiopathic thrombocytopenic purpura or with bone-marrow recovery after chemotherapy. The standardized bleeding time measures the overall hemostatic role of platelets in vivo, and is thus suitable for systematic screening.

Survival and turnover measurements of platelets and fibrinogen in 35 normal subjects and 104 selected patients defined three types of consumptive processes involving the hemostatic apparatus. The first, characterized by combined platelet and fibrinogen consumption, represents an exaggeration of the physiologic hemostatic response. It occurs in patients with venous thrombosis, tissue trauma, widespread cancer, obstetric complications, and bacteremia. The result of activation of the coagulation system, this process can be modified by heparin. The second, characterized by selective platelet destruction, appears to reflect platelet thrombus formation on abnormal surfaces in the arterial system, including prosthetic devices and arterial thrombosis, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, and vasculitis syndromes. This process is reversed by certain inhibitors of platelet function or adrenocortical steroid suppression of vascular inflammation. The third involves selective destruction of fibrinogen and follows the infusion of urokinase. Isolated fibrinogen destruction seems typical of primary fibrinolytic syndromes.