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We have previously reported that long term daily administration of aspirin-dipyridamole significantly improved laboratory findings indicative of disease activity in patients with sickle-cell disease. The laboratory index most influenced by platelet inhibitory drug therapy was the plasma concentration of high molecular weight fibrin(ogen) complexes (HMWFC), a moiety which reflects the rate of fibrin formation in vivo. Although improvement of laboratory findings with therapy was accompanied by apparent clinical improvement, the limited clinical data then available did not reach statistical significance.This report describes extension of the trial of prophylactic platelet inhibitory drug therapy. Three patients were studied during a two year period on daily aspirin-dipyridamole therapy and during a two year control period. Plasma fibrinogen concentration was correlated with patient clinical status and the clinical findings suggested that the treatment was of modest prophylactic efficacy.In 1976, we reported a characteristic pattern of blood coagulation abnormalities accompanying painful musculoskeletal sickle-cell disease (SSD) crises (1,2). With the onset of crisis, there was an increase in plasma high molecular weight fibrin(ogen) complexes (HMWFC) and a transient fall in platelets and in plasma Factor XIII. Subsequently, plasma fibrinogen concentration rose (peak at 1 week after onset of symptoms), platelets rose (peak at 2 weeks) and plasma Factor XIII increased (peak at 3 weeks). Subsidence of crisis was associated with a fall in HMWFC and a subsequent increase in fibrinogen first derivative, which reflects the rate of fibrinogenolysis. Plasma HMWFC concentration reflects the rate of fibrin formation in vivo (3) and plasma Factor XIII concentration decreases with intravascular fibrin deposition (4). Thus these laboratory findings support the hypothesis that in the early stages of SSD crisis, fibrin deposition and/or thrombosis significantly enhance the role of sickled erythrocytes in producing vascular occlusion and/or organ infarction.We also reported that, over extended periods of observation, hemostatic findings and patient clinical status were generally correlated. Except for persistent depression of plasma Factor XIII concentration, laboratory findings during asymptomatic periods were essentially normal. Emphasis was placed on the value of hemostatic measurements as objective documentation of clinical status, and both laboratory and preliminary clinical observations were reported in three patients during a control period and during daily aspirin-dipyridamole therapy. Aspirin-dipyridamole therapy significantly improved laboratory measures of disease activity, particularly mean plasma HMWFC concentration, but insufficient data was obtained to determine whether the treatment was of clinical value.We have now observed each of the three patients at weekly intervals for a minimum of 104 weeks on daily aspirin-dipyridamole, followed by a minimum of 104 weeks off the antiplatelet prophylactic regimen. This report compares clinical and laboratory findings during platelet inhibitory drug administration and following its discontinuation. Plasma fibrinogen measurements correlated with patient clinical status and the clinical findings suggest that the treatment was of modest prophylactic benefit.

SummaryBlood platelets play a crucial role in the response of blood to vascular injury through adherence to exposed subendothelial vessel wall structures, the subsequent release of substances which trigger platelet aggregation, and release-associated changes in platelet surface properties which facilitate the interaction of coagulation factors, leading to the formation of fibrin necessary for stabilization of the initial hemostatic plug. There is substantial evidence from in vitro studies to suggest that platelets may also affect the fibrinolytic plasminogen-plasmin system thought to be one of the important hemostatic regulatory mechanisms preventing inappropriate extension of the hemostatic plug which may lead to thrombotic vessel occlusion. In this paper, the published experimental evidence concerning the effects of platelets and platelet-associated factors on the activation and function of the plasminogen-plasmin system is reviewed. The experimental findings indicate that platelets may contribute to fibrin clot stabilization through the release of substances from their storage organelles which inhibit both plasminogen activation and the action of plasmin. The physiologic and pathophysiologic significance of platelet-mediated inhibition of fibrinolysis by plasmin, as well as other potentially important plasma and cellular fibrinolytic enzymes, is still largely subject to speculation and appears to be an important area for future investigation.

SummaryBased on studies with thrombin, it has been proposed that human platelets exposed to strong release-inducing agents undergo irreversible aggregation and cannot be deaggregated without the use of proteolytic enzymes. We tested the hypothesis that irreversible human platelet aggregation occurs as a result of thrombin-specific platelet alterations rather than induction of the release reaction per se. Washed human platelets were exposed to either thrombin (THR) or the aminophospholipid N-(7-Nitro- 2,1,3-benzoxydiazol-4-yl) phosphatidylserine (NBD-PS) for 20 seconds. Both agents caused similarly extensive release of platelet dense- and α-granule contents. After neutralization of thrombin and NBD-PS, and addition of PGE1 and apyrase, the platelets were sedimented, resuspended and incubated at 37° C with gentle agitation. Single, disc-shaped, degranulated platelets which were recovered in both systems were capable of aggregation in response to a second exposure to aggregating and release- inducing stimuli. Deaggregation was more rapid, more extensive, and more reproducible with NBD-PS- than with THR-degranulated platelets. Platelets exposed to thrombin for longer than 20 seconds showed a progressive loss of deaggregability which was not observed after prolonged incubation with NBD-PS. These findings do not support the concept that extensive secretion per se causes irreversible aggregation of human platelets. Instead it appears that formation of irreversible linkages between platelets involves the specific, time-dependent interaction of THR with platelets, released fibrinogen and possibly one or more other substances secreted from platelets.

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.