Mark J. Weinstein

Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura

A platelet-agglutinating factor has been detected in the plasma of some patients during episodes of thrombotic thrombocytopenic purpura (TTP).1 , 2 Agglutination induced in vitro by this plasma fac...

Treatment of the Bleeding Tendency in Uremia with Cryoprecipitate

We gave cryoprecipitate to six patients with uremia and bleeding times prolonged to more than 15 minutes. After the infusion, all patients had shortened bleeding times; the times of five became normal. In four patients control of major bleeding episodes was attained, and five underwent major surgical or invasive procedures, with good hemostasis. After infusion the time before the nadir of the bleeding time was reached was between one and 12 hours. The bleeding time returned to pretreatment levels by 24 hours after infusion in five patients, and by 36 hours in the other patient. Platelet-aggregation studies before infusion gave normal results in three patients and abnormal results in three. There wasno change after infusion. Before infusion, levels of Factor VIII coagulant activity and Factor VIII von Willebrand activity were normal, Factor VIII-related antigen was increased, and crossed immunoelectrophoresis of Factor VIII-related antigen was normal. Our findings suggest that cryoprecipitate can temporarily correct the bleeding tendency in patients with uremia.

Fetal and neonatal von Willebrand factor (vWF) is unusually large and similar to the vWF in patients with thrombotic thrombocytopenic purpura

Summary. We have investigated the distribution of vWF multimers in blood from the umbilical cord of infants delivered vaginally and by caesarean section, from heel‐stick blood collected 1 d post‐partum, and from fetuses undergoing evaluation for Rh compatibility. To examine vWF multimers. plasma was separated by electrophoresis on SDS‐agarose gels, overlaid with 125I‐anti‐vWF, and analysed by densitometry of autoradiographs. Neonatal and fetal plasma contained unusually large von Willebrand factor multimers (ULvWFM), not present in normal adult plasma, in shed blood from adults, in maternal plasma at the time of birth, or in plasma from adults deficient in vitamin K‐dependent coagulation proteins. We conclude that ULvWFM, similar in size to vWF present in the Weibel Paladie bodies of endothelial cells, the alpha granules of platelets, and the plasma of patients with TTP, is present in the fetal circulation, at birth, and shortly after delivery.

Case Report: Von Willebrand Factor Abnormalities and Endothelial Cell Perturbation in a Patient with Acute Thrombotic Thrombocytopenic Purpura

ABSTRACT The plasma of a 63-year-old patient with an initial acute, fatal episode of thrombotic thrombocytopenic purpura (TTP) contained agglutinated platelets and a factor VIII-related von Willebrand factor (vWF) antigen level that was elevated sevenfold above normal. Unusually large vWF multimers derived from endothelial cells were detected in her plasma at the on-set of the TTP episode. This is the first patient in whom vWF abnormalities indicative of in vivo endothelial cell damage or perturbation have been found during an acute episode of TTP.

Mr 6,400 aurin tricarboxylic acid directly activates platelets

ATA is a novel anticoagulant polymeric anionic aromatic compound that inhibits von Willebrand factor binding to platelet glycoprotein Ib and thereby prevents ristocetin- and shear stress-induced platelet aggregation. To investigate its mechanism of action, ATA fractions of homogeneous M(r) have been prepared by size exclusion chromatography. ATA fractions of M(r) > or = 2,500 are most effective at inhibiting vWF-mediated platelet aggregation, and ATA of M(r) = 2,500 also inhibits thrombin-induced platelet activation. Paradoxical results were observed in studies of ATA with M(r) = 6,400. This fraction of ATA stimulates aggregation of washed platelets or platelet-rich-plasma. The dose/response of aggregation shows a bell-shaped curve with maximal aggregation at approximately 2 micrograms/ml. Platelet aggregation is associated with phosphoinositide turnover and protein kinase C- and calcium-dependent protein phosphorylation. Platelet signalling responses to ATA are inhibited by platelet pretreatment with PGI2 or dibutyryl-cyclic AMP, but are unaffected by inhibiting platelet cyclooxygenase with aspirin. These results suggest that M(r) 6,400 ATA directly activates platelet phospholipase C to initiate platelet aggregation. This effect, unique to M(r) 6,400 ATA, could potentially mitigate ATAs beneficial anti-thrombotic effect on vWF-mediated platelet responses, and should be considered when analyzing results of experiments that utilize unfractionated ATA.

Desmopressin, Von Willebrand Factor and Surgery

The synthetic vasopressin analogue desmopressin acetate (DDAVP) can induce a broad spectrum of physiological reactions that have hematological consequences. These include release of tissue plasminogen activator, depletion of plasminogen activator inhibitor, and activation of plasminogen1-3. Also, DDAVP can benefit hemostasis by stimulating the secretion of factor VIII coagulant protein (FVIII: C)/von Willebrand factor (vWF) from endogenous storage sites1. The latter hemostatic property forms the basis for the widespread therapeutic use of DDAVP to treat mild hemophilia and mild von Willebrand’s disease4, 5. DDAVP also benefits hemostasis by an unknown mechanism in many hematological and nonhematological diseases, including congenital and acquired platelet defects6,7-8, and surgical bleeding9,10, where FVIII: C/vWF concentrations are in the normal range.