Sherrill J. Slichter

The bleeding time as a screening test for evaluation of platelet function.

Abstract 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...

Platelet and Fibrinogen Consumption in Man

Abstract 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 destru...

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

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.)

Studies of Platelet and Fibrinogen Kinetics in Patients with Prosthetic Heart Valves

Abstract Kinetic studies of platelet and fibrinogen in 18 patients with artificial heart valves indicate that platelets are selectively consumed by interaction with the prosthetic valves in an amount directly related to the surface area of the valve. Dipyridamole effectively prevents the valve-related consumption. Although acetylsalicylic acid itself has little capacity to correct the consumption of platelets in this setting, it has a potentiating effect on dipyridamole.

Leukemia of large granular lymphocytes: association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia

Three patients had leukocytosis of large granular lymphocytes and chronic neutropenia. Clonal chromosomal abnormalities (trisomy 8 and trisomy 14) and lymphocytic infiltration of splenic red pulp, hepatic sinusoids, and bone marrow indicated the neoplastic nature of the large granular lymphocytes. Demonstration of a T3+, T8+, HNK-1 + phenotype and low natural killer cell activity that was augmented by interferon treatment showed the leukemic cells to be immature natural killer cells. Multiple autoantibodies were present and included rheumatoid factor and antinuclear, antineutrophil, antiplatelet, and antierythrocyte antibodies, suggesting a defect of B-cell immunoregulation. In addition, in-vitro studies showed impaired suppression of immunoglobulin biosynthesis by abnormal cells from one patient. Antineutrophil antibodies and absence of direct cell-mediated inhibition of granulocyte-macrophage colony formation supported a humoral immune mechanism for the neutropenia. In these patients the syndrome of splenomegaly, multiple autoantibodies with neutropenia, and lymphocytosis of large granular lymphocytes is due to a neoplastic proliferation of immature natural killer cells.

Preparation and storage of platelet concentrates. II. Storage variables influencing platelet viability and function.

Summary. Factors affecting the viability and function of stored platelet concentrates have been investigated in a blood component programme. It was found that platelets could be maintained for up to 72 h without bacterial contamination under the following conditions: (1) surgical skin preparation at venipuncture site; (2) blood collection in CPD or ACD anticoagulant in a closed bag system; (3) centrifugation of PRP at 3000 g for 20 min; (4) storage in Fenwal PL‐146, Cutter CL‐2383, or McGaw plastic bags; (5) resuspension of the platelet pellet in 70 ml residual plasma; (6) storage at 22± 2°; and (7) constant gentle mixing throughout storage. Platelet viability as determined by recovery and survival is largely maintained, as is platelet function measured by template bleeding time. Both viability and function of concentrated platelets stored at 4° are severely compromised.

Platelet consumption by arterial prostheses: the effects of endothelialization and pharmacologic inhibition of platelet function.

AbstractThe thrombogenic mechanism of arterial grafts has been studied by determining the relative utilization of platelets, fibrinogen and plasminogen by human arterial prostheses, and by direct examination of arterial grafts in a baboon model. Forty-one survival and turnover measurements of 51Crplatelets, 131I-fibrinogen and 125I-plasminogen in ten patients with aortofemoral knitted Dacron prostheses demonstrated platelet consumption after graft placement (platelet survival 4.2 days × 0.5 and turnover 68,000 plat/ul/day × 10,000 compared with 8.2 days × 0.3 and 35,000 plat/ul/day × 5,000 respectively for control subjects with stable vascular disease, p < 0.01). In vitro platelet function test results were normal. Platelet consumption was interrupted by dipyridamole or a combination of dipyridamole and acetylsalicylic acid, and platelet survival normalized spontaneously during nine months postoperatively. No significantly increased consumption of fibrinogen or plasminogen was found in these patients with arterial grafts.Placement of impervious knitted Dacron velour aortic grafts in baboons reproduced platelet consumption that progressively normalized over six weeks postoperatively. Platelet survival measurements correlated directly with endothelial cell coverage of the graft luminal surface in these animals implying that endothelialization of the graft surface was also occurring postoperatively in patients.

Mechanisms of response to treatment in autoimmune thrombocytopenic purpura

To determine the mechanisms of an increase in the platelet count after therapy for autoimmune thrombocytopenic purpura, we determined the survival time and localization of radiolabeled autologous platelets and measured platelet-associated immunoglobulin levels before and after prednisone therapy or splenectomy in 19 patients with the disease. Eleven of 12 patients (92 percent) responded to prednisone with a mean threefold increase in the platelet count, resulting from increased platelet production (P less than 0.005); platelet survival was unchanged. Treatment with steroids failed in only one patient, whose pretreatment platelet production was already above normal. After splenectomy, 6 of 10 patients had a mean fourfold rise in the platelet count that correlated with increased platelet survival (P less than 0.005), together with improved platelet recovery (the percentage of platelets circulating in the blood immediately after the injection). Platelet production was unchanged. Base-line 111In-labeled platelet localization in the liver was normal in five patients in whom splenectomy was effective and increased to above normal in two of three in whom it was ineffective. Total platelet localization in the liver and spleen decreased by more than half after successful splenectomy (P less than 0.001), whereas it decreased by less than 25 percent after unsuccessful splenectomy. Platelet-associated immunoglobulin levels neither predicted nor correlated with treatment responses to prednisone or splenectomy. We conclude that prednisone improves platelet counts primarily by increasing platelet production, whereas the effect of splenectomy is to prolong platelet survival. Baseline measurements of platelet turnover and of platelet localization in the liver may be helpful in predicting the response to prednisone or splenectomy, respectively.

Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production.

Chronic immune thrombocytopenia (ITP) is a haematological disorder in which patients predominantly develop skin and mucosal bleeding. Early studies suggested ITP was primarily due to immune‐mediated peripheral platelet destruction. However, increasing evidence indicates that an additional component of this disorder is immune‐mediated decreased platelet production that cannot keep pace with platelet destruction. Evidence for increased platelet destruction is thrombocytopenia following ITP plasma infusions in normal subjects, in vitro platelet phagocytosis, and decreased platelet survivals in ITP patients that respond to therapies that prevent in vivo platelet phagocytosis; e.g., intravenous immunoglobulin G, anti‐D, corticosteroids, and splenectomy. The cause of platelet destruction in most ITP patients appears to be autoantibody‐mediated. However, cytotoxic T lymphocyte‐mediated platelet (and possibly megakaryocyte) lysis, may also be important. Studies supporting suppressed platelet production include: reduced platelet turnover in over 80% of ITP patients, morphological evidence of megakaryocyte damage, autoantibody‐induced suppression of in vitro megakaryocytopoiesis, and increased platelet counts in most ITP patients following treatment with thrombopoietin receptor agonists. This review summarizes data that indicates that the pathogenesis of chronic ITP may be due to both immune‐mediated platelet destruction and/or suppressed platelet production. The relative importance of these two mechanisms undoubtedly varies among patients.

Preparation and storage of platelet concentrates. I. Factors influencing the harvest of viable platelets from whole blood

Summary. Factors affecting the yield and viability of concentrated platelets have been investigated in a blood component programme. It was found that 86± 1% of the platelets from a unit of whole blood can be concentrated without loss of viability by processing ACD or CPD anticoagulated blood at room temperature. The steps are initial centrifugation at 1000 g for 9 min to harvest platelet‐rich plasma; centrifugation of the platelet‐rich plasma at 3000 g for 20 min to pack the platelets; and resuspension of the platelet pellet in residual plasma after 11/2 h.