An antiplatelet monoclonal antibody, PMI-1, reacts with glycoproteins (GP) GPIIb, free GPIIb, and the GPIIb-HIa complex. This antibody binds to 40,900 sites per platelet, with a Kd = 0.95 gM, and its binding is inhibited by the presence of magnesium or calcium in the suspending medium (50% suppression at -0.5 mM divalent cation). Regulation of the PMI-1 epitope is independent of disassembly of the GPIIb-IIIa heterodimer, because it occurred at 220C and in response to mM magnesium as well as calcium. PMI-1 binding inversely correlated with fibrinogen binding. In addition, we identified a variant of Glanznn's thrombasthenia with near-normal platelet content of the GPIIbIIIa heterodimer as judged by crossed immunoelectrophoresis and surface labeling. Binding of PMI-1 to these patients' platelets was not dependent on reduction of the divalent cation concentration. These data suggest that the surface orientation of GPIIb is important in the capacity of platelets to bind fibrinogen.
Cerebrovascular accidents are one of the life-threatening complications of diabetic ketoacidosis (DKA) in children and adolescents. Our objective was to evaluate the effect of DKA and its treatment on factors known to affect thrombotic activity (protein C; protein S; von Willebrand factor, fibrinogen; homocysteine; and folate) by comparing seven adolescents with DKA prior to treatment and at 6, 24, and 120 hours after initiation of treatment. We found that protein C activity was significantly decreased by DKA, but normalized slowly following treatment. Free protein S was low throughout the study. Protein C antigen and protein S antigen showed varying degrees ofchange within the first 24 hours, but remained in the normal range, with the exception of the initial value of protein C antigen, which was elevated. von Willebrand factor (vWF) antigen and vWF activity were both significantly increased prior to treatment, but decreased with treatment. However, vWF activity remained elevated at 120 hours. Fibrinogen concentrations showed no significant changes throughout the study. Homocysteine was significantly decreased prior to treatment and increased with the initiation of treatment Folate was significantly increased prior to treatment, and decreased to high normal levels. The increased vWF and the decreased levels of protein C activity and of free protein S support the hypothesis that DKA and its treatment results in a prothrombotic state and activation of the vascular endothelium, which, in turn, predispose to cerebrovascular accidents.
The optimal treatment of patients with von Willebrand's disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety-nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF-containing FVIII product, type 3 patients with vWF-containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.
A method for the measurement of immunoglobulin G associated with gel- filtered platelets is described and finding in 70 control subjects and 37 patients with immune thrombocytopenic purpura (ITP) are reported. Control platelet-associated IgG (PAIgG) levels (nanograms IgG per 10(9) platelets) averaged (+/-SD) 1231+/-424; samples studied after 24 and 48 hr remained within the control range. PAIgG values of 19 adult and 12 childhood patients with chronic ITP averaged 4711+/-3025 and 4923+/- 3955, respectively, and differed significantly from controls (p less than 0.001). There was an inverse correlation between PAIgG values and the chronic ITP patient's platelet count. Six patients with childhood acute ITP had PAIgG levels ranging from 5588 to 56,250 and appeared to represent a different statistical population from those with chronic ITP. In chronic ITP patients responding to splenectomy, there was an immediate normalization of PAIgG levels; however, a certain percentage of patients studied several months after splenectomy evidenced elevated PAIgG levels in association with normal platelet counts. These data showed that the direct measurement of platelet associated antibody is a useful technique in the diagnosis and follow-up of patients with chronic ITP. Preliminary studies in patients with acute ITP have suggested that this method may be useful in differentiating acute and chronic childhood ITP.
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