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Transmembrane calcium influx associated with von Willebrand factor binding to GP Ib in the initiation of shear-induced platelet aggregation.
We found that the binding of multimeric vWF to GP Ib under a shear force of 108 dynes/cm2 resulted in the transmembrane flux of Ca2+ ions with a two- to three-fold increase in their intracellular concentration ([Ca2+]i). The blockage of this event, obtained by inhibiting the vWF-GP Ib interaction, suppressed aggregation. In contrast, the blockage of vWF binding to GP IIb-IIIa, as well as the prevention of activation caused by increased intracellular cAMP levels, inhibited aggregation but had no significant effect on [Ca2+]i increase. A monomeric recombinant fragment of vWF containing the GP Ib-binding domain of the molecule (residues 445-733) prevented all effects mediated by multimeric vWF but, by itself, failed to support the increase in [Ca2+]i and aggregation. These results suggest that the binding of multimeric vWF to GP Ib initiates platelets aggregation induced by high shear stress by mediating a transmembrane flux of Ca2+ ions, perhaps through a receptor-dependent calcium channel. The increase in [Ca2+]i may act as an intracellular message and cause the activation of GP IIb-IIIa; the latter receptor then binds vWF and mediates irreversible aggregation.
Evaluation of hematologic alterations associated with daily administration of low molecular weight heparin (Mono-Embolex) for a 12-week period.
The long-term success rate of coronary angioplasty is only 50 to 70% due to restenosis. The pathophysiologic mechanism of this event is mainly mediated by smooth muscle cell proliferation. To some extent, it can be inhibited by heparin. The introduction of LMWHs allows for prophylaxis against restenosis on an outpatient basis, but no data are available on the long-term usage of LMWH. To investigate possible side effects, nonhuman primates received daily injections of LMWH (Mono-Embolex) over a 12-week period and the hematologic profile was assessed. There were no significant alterations of the red blood cell system. The overall WBC profile did not change, although a significant increase of granulocytes with a corresponding decrease of lymphocytes and monocytes occurred. Data from a control group suggest that these alterations are caused by chronic stress and are not drug related. Platelet count as well as platelet function tests were unaffected by this treatment. In conclusion, the long-term administration of Mono-Embolex as projected for the use in the prophylaxis of restenosis following angioplasty appears to be safe regarding hematologic parameters.
[Morphologic and functional changes in thrombocytes after deep freezing with DMSO].
BACKGROUND: During the past decade much work has been carried out towards establishing the optimum method for cryopreservation of platelets. Among the various cryoprotectants dimethyl sulfoxide (DMSO) has been shown to be the most effective. This report describes ultrastructural and functional changes of platelets during the deep-freezing process with DMSO. MATERIALS AND METHODS: Single-donor platelet concentrates were cryopreserved in liquid nitrogen by use of DMSO. Before, during and after the freezing process samples were taken for analysis of ultrastructure and platelet function. RESULTS: While after isolation and addition of DMSO a normal ultrastructure of platelets could be observed, clear signs of beginning cell necrosis were detected after thawing and resuspension in autologous plasma. Fibrinogen-binding capacity and platelet aggregation were significantly diminished. CONCLUSIONS: Although cryopreserved platelets are characterized by hemostatic effects in vivo, it seems conceivable that these effects could be improved by further development of platelet-freezing techniques.
Nonpeptide glycoprotein IIb/IIIa inhibitors: 14: oral antithrombotic efficacy of L-738,167 in a conscious canine model of coronary artery electrolytic injury.
BACKGROUND: A conscious dog model of left circumflex coronary artery electrolytic injury was used to assess the oral antithrombotic efficacy of L-738,167, a potent nonpeptide antagonist of platelet GP IIb/IIIa. L-738,167 was administered either as a single oral pretreatment dose 2 hours before initiation of vessel injury or as two oral doses administered 24 hours apart, 12 hours before and after initiation of vessel injury. METHODS AND RESULTS: In untreated controls, electrolytic coronary injury (50 microA, 3 hours) resulted in thrombotic occlusion and myocardial ischemia in 15 of 16 dogs, with 4 developing lethal arrhythmias. Significant reductions in thrombus mass and complete prevention of myocardial ischemia and infarction were achieved with a single 100- to 300-microg/kg dose of L-738,167 pretreatment and with two 100-microg/kg doses administered 12 hours before and after initiation of vessel injury. Delays and/or reductions in incidence of ischemia, thrombus mass, and infarct sizes also were achieved with 10- to 30-microg/kg pretreatment and with two 30-microg/kg doses administered 12 hours before and after initiation of vessel injury. None of the L-738,167-treated animals developed lethal arrhythmias. A single oral 100-microg/kg dose of L-738,167 achieved >90% inhibitions of ADP (extent)- and collagen (rate)-induced ex vivo platelet aggregation and fivefold to sixfold or greater elevations in bleeding time; a single oral 30-microg/kg dose of L-738,167 achieved sustained 40% to 70% inhibitions of ADP- and collagen-induced ex vivo platelet aggregation and modest twofold to threefold elevations in bleeding time. At 12 to 24 hours after single oral 30- and 100-microg/kg doses of L-738,167, a substantially greater L-738,167 concentration was associated with platelets than free in plasma. CONCLUSIONS: These findings are indicative of potent and sustained oral antithrombotic efficacy and suggest that L-738,167 possesses potential for the oral management of chronic thrombotic occlusive disorders.
Monitoring platelet GP IIb/IIIa [corrected] antagonist therapy.
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[von Willebrand disease type 1].
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Evaluation of the abnormal platelet function in von Willebrand disease by the blood filtration test.
We have evaluated platelet function in different subtypes of von Willebrand disease (vWD) by pushing blood through the capillary-sized channels of a glass filter. Patients, including those with type IIB vWD, showed lower than normal platelet retention and increased cumulative number of blood drops passing through the filter as a function of time. In contrast, shear-induced platelet aggregation, measured in the cone-and-plate viscometer, was paradoxically increased in type IIB patients. Treatment with 1-desamino-8-D-arginine vasopressin (DDAVP) tended to normalize the filter test in patients with type I-platelet normal and type I-platelet low vWD, but infusion of a factor VIII/von Willebrand factor (vWF) concentrate lacking the largest vWF multimers was without effect in type 3 patients. Experiments with specific monoclonal antibodies demonstrated that the A1 and A3 domains of vWF, as well as the glycoproteins Ib alpha and IIb-IIIa on platelets, are required for platelet retention in the filter. Thus, the test may reflect vWF function with regard to both platelet adhesion and aggregation under high shear stress, and provide relevant information on mechanisms involved in primary hemostasis.
Disorders of platelet function: mechanisms, diagnosis and management.
Platelets play an important role in hemostasis, and alterations in platelet function may be the cause of abnormal bleeding in a wide variety of congenital and acquired clinical disorders. Platelet dysfunction may be classified as disorders of (1) substrate connective tissue, (2) adhesion, (3) aggregation and (4) platelet-release reaction. The congenital defects of platelet function, although uncommon, have provided important insights into platelet physiology and pathophysiology and, as a group, are less common, better characterized and more readily classified than the acquired defects. The severity of bleeding resulting from platelet dysfunction varies greatly and is substantially increased when another defect of hemostasis coexists. A disorder of platelet function is suspected on the basis of the history and physical examination and is confirmed by the finding of a prolonged bleeding time in the presence of an adequate number of platelets. A specific diagnosis often requires measurements of the factor VIII and von Willebrand factor complex and other tests of platelet function. Some of these tests may be available only in specialized laboratories. Therapy for bleeding episodes resulting from platelet dysfunction is directed at (1) removing or treating the underlying cause of the platelet disorder; (2) replacing the missing plasma cofactors needed to support normal platelet function (such as by the transfusion of cryoprecipitate in patients with von Willebrand disease, and (3) transfusing functional platelets in the form of platelet concentrates in patients with disorders of intrinsic platelet dysfunction.
Variability in clinical laboratory practice in testing for disorders of platelet function: results of two surveys of the North American Specialized Coagulation Laboratory Association.
Disorders of platelet function are important causes of abnormal bleeding that require laboratory tests for diagnosis. Currently there are limited guidelines on how to perform clinical testing for these disorders. The goal of our study was to obtain information on how disorders of platelet function are currently evaluated in clinical laboratories. Two patterns-of-practice surveys were distributed to laboratories of the North American Specialized Coagulation Laboratory Association (NASCOLA). The information collected was analyzed to determine practices and common problems. Forty-seven NASCOLA laboratories participated and 54% completed both surveys. The majority of the laboratories that responded performed more than 50 aggregation tests per year, mainly using platelet rich plasma based methodologies. A minority performed testing for platelet secretion and dense granule abnormalities. While platelet aggregation results were reviewed in various ways, laboratories most commonly issued a combined report containing quantitative values (% aggregation and/or slope) and a qualitative interpretation. Although laboratories used similar agonists for aggregation testing, the final agonist concentrations varied widely. Several approaches were also used to obtain reference intervals. Comments offered by the participants indicated that performing, and interpreting platelet function tests were challenging for many clinical laboratories. Although common practices have evolved, there is considerable variability in the diagnostic test procedures used by clinical laboratories to evaluate disorders of platelet function. These patterns-of-practice surveys illustrate a need for guidelines and recommendations for clinical laboratories performing tests of platelet function.
Platelet count and liver function tests in proteinuric and chronic hypertension in pregnancy.
Platelet counts and plasma enzyme estimations were performed in 207 pregnant patients with proteinuric hypertension and in 60 patients with chronic hypertension. Patients with abruptio placentae were excluded. In the proteinuric hypertensive patients a low platelet count (less than 150,000/mm3) was found in 63 (30%) and elevated transaminase levels in 50 (24%) and both abnormalities were present in 47 patients (23%). The serum lactate dehydrogenase (LDH) value was mildly elevated in most proteinuric hypertensive women, but a markedly elevated LDH level (greater than 400 IU/l) was usually associated with other evidence of liver necrosis. Raised plasma alkaline phosphatase and gamma-glutamyltransferase levels were not related to the occurrence or severity of liver necrosis. In proteinuric hypertensive patients a low platelet count or elevated transaminase level was associated with deteriorating renal function, increased maternal morbidity, increased incidence of low-birth-weight babies and a raised perinatal mortality rate (149/1,000). In patients with chronic hypertension, 1 had a low platelet count but none had elevated transaminase, LDH or other enzyme levels and there was no recorded perinatal mortality.
Use of the platelet reactivity index by Grotemeyer, platelet function analyzer, and retention test Homburg to monitor therapy with antiplatelet drugs.
In 1974, Wu and Hoak described a method for determining circulating platelet aggregates. This method was modified by Grotemeyer in 1983. The platelet reactivity index (PR) is based on the ratio of platelet aggregates in blood samples obtained in different buffer solutions. Platelet aggregates are resolved when blood is sampled in EDTA-buffer, but remain fixed when EDTA-formalin-buffer is used. Generally, the PR is preferred, because in vitro manipulations of platelets are not necessary, and the results are calculated. PR values above 1.05 are suspicious for elevated platelet aggregation. PR values above 1.2 indicate pathological changes in platelet aggregation. The PR is inexpensive (4.0 euro dollars) and rapid to perform. PR values were used successfully to identify nonresponders to secondary prophylaxis with acetylsalicylic acid (ASA), that is, patients suffering from stroke (33%) and patients after cardiac ischemia (18%). Furthermore, elevated PR values correlated significantly with the incidence of arterial thromboembolic complications. The PR correlated well in our prospective study with values received from the retention test Homburg (RT-H) and the platelet function analyzer (PFA-100). The data indicate that the values of the PR seem to be highly predictive for the evaluation of the ASA therapy. However, the PR is not feasible for the determination of the ASA overdosage.
[On the blood platelet count and function test].
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[Epidural analgesia in a pregnant woman with essential thrombocythaemia].
Epidural analgesia is often considered as risk of epidural haematoma in patient with essential thrombocythaemia because of the platelet disorder. In this observation, uncomplicated epidural analgesia was performed in a pregnant woman with asymptomatic essential thrombocythaemia, because the absence of bleeding symptoms was associated with normal thrombo-elastography and time of occlusion by PFA-100 suggesting normal platelet function. PFA-100 is a biological test evaluating platelet function in whole blood, which is easy and quick to perform. This case study suggests that this test might be useful in evaluating platelet function in obstetrics but must be validated before recommending its extensive use.
Platelet function in hypertension and effect of therapy.
Platelet function was evaluated in 10 hypertensive and 11 normal subjects. In the placebo phase, the plasma beta thromboglobulin level (an index of platelet activation in vivo) was significantly (p less than 0.01) higher in the hypertensive than in the normal subjects; other tests of platelet function gave similar results in the two groups. After control of blood pressure with lofexidine (a centrally acting imidazoline derivative), plasma beta thromboglobulin levels decreased in 9 of the 10 hypertensive patients, but increased in one who showed no change in blood pressure. These studies suggest that enhanced platelet activation in primary hypertension may be associated with increased vascular resistance.
Platelet aggregation and release of ATP in patients with hepatic cirrhosis.
The purpose of this study was to assess the platelet aggregation and releasable platelet ATP in patients with alcoholic cirrhosis (n = 10) and primary biliary cirrhosis (n = 10). In patients with liver disease a significant decrease was found in both adenosine diphosphate-induced aggregation (P less than 0.01) and collagen-induced aggregation (P less than 0.001) compared with that of controls, but there was no significant difference between the two groups of patients. Patients with primary biliary cirrhosis release smaller amounts of ATP than patients with alcoholic cirrhosis, and compared with the controls there was a significant (P less than 0.001) decrease in the releasable ATP in the patient groups. These results suggest that platelets are damaged during an intravascular activation (loss of granules), which gives rise to their subsequent hypo-function when tested in vitro.
Clotting disturbances as thrombosis risk factors. Significance and diagnostic value of some tests of platelet thromboplastic function.
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