Summary of a workshop on potency and dosage of von Willebrand factor concentrates.
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Clinical Trials as Topic↗
Biomedical subjects
M J Weinstein
Publications and source records attributed to M J Weinstein.
Considerations of pool size in the manufacture of plasma derivatives.
BACKGROUND: The pooling of human plasma from many donors for the purpose of manufacturing therapeutic proteins increases the risk of exposing recipients of these proteins to pathogens that may contaminate 1 or a few units included in the pool. STUDY DESIGN AND METHODS: This risk is estimated for a range of manufacturing scales that would derive material from a varied number of donors and for a number of hypothetical infectious agents that may exist in the donor population over a wide range of prevalence. Risk is also calculated both for recipients of single doses of a plasma protein and for those who depend on long-term treatment with plasma derivatives. RESULTS: Risk of exposure increases with pool size and the prevalence of the agent in question and accumulates with repeated treatments with material manufactured from different pools. CONCLUSION: Reducing pool size would at best decrease this risk in proportion to the reduction in manufacturing scale. However, for individuals requiring repeated or continuous treatments, the risk of exposure to all but the rarest infectious agents would be only minimally affected, even by large reductions in manufacturing scale.
Blood Proteins↗
Results of surgery and doxorubicin chemotherapy in dogs with osteosarcoma.
Thirty-five dogs with appendicular osteosarcoma were treated with 5 doses of doxorubicin (30 mg/m2 of body surface, i.v., every 2 weeks). Surgical excision of the primary tumor was performed 13 days after the second (n = 18) or third (n = 17) treatment, and the subsequent doxorubicin treatment was given the day following surgery. Resected tumors were evaluated histologically to determine response to preoperative chemotherapy (ie, percentage of the tumor that was necrotic). Survival data for the 35 dogs were compared with survival data for a historical control group, consisting of 162 dogs with appendicular osteosarcoma treated by amputation alone. Administration of doxorubicin at 2 week intervals was well tolerated. Three dogs were alive and did not have evidence of disease at the time of reporting. Of the remaining 32 dogs, 3 died or were euthanatized because of cardiomyopathy presumably caused by doxorubicin; 1 died suddenly 116 weeks after initiation of treatment; and the remaining 28 were euthanatized because of problems documented to be related to distant metastases. Thirteen dogs (40.6%) were euthanatized because of pulmonary metastases, 10 dogs (31.3%) were euthanatized because of bone metastases, and 5 dogs (15.6%) were euthanatized because of metastases in other sites. The proportion of dogs euthanatized because of bone metastases was significantly (P < 0.001) higher for the study group than for the control group. Median survival time for the 35 dogs that received doxorubicin was estimated to be 52.3 weeks, and 1- and 2-year survival rates were estimated to be 50.5 and 9.7%, respectively. Survival time was significantly (P < 0.0001) longer for these dogs than for control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
Amputation, Surgical↗
Heparin causes platelet dysfunction and induces fibrinolysis before cardiopulmonary bypass.
BACKGROUND: Platelet dysfunction and increased fibrinolysis are the most important etiologic factors in the hemostatic defect observed following the institution of cardiopulmonary bypass. This study examined the effects of heparin per se, administered before the institution of cardiopulmonary bypass, on platelet function and fibrinolysis. METHODS: Sampling was performed in 55 patients undergoing cardiac operations before and 5 minutes after the routine administration of heparin, before the institution of cardiopulmonary bypass. RESULTS: Heparin administration resulted in a significant prolongation of the bleeding time (from 6.3 +/- 2.1 to 12.6 +/- 4.9 minutes; p < 0.00001), a significant reduction in the level of shed blood thromboxane B2 (from 1,152 +/- 669 to 538 +/- 187 pg/0.1 mL; p = 0.00002), and an increase in the plasma levels of plasmin (from 11.8 +/- 9.7 to 125.4 +/- 34.8 U/L; p < 0.0001) and D-dimer (from 571.3 +/- 297.1 to 698.5 +/- 358.6 micrograms/mL; p = 0.05). There were no significant differences before and after heparin administration in the plasma levels of fibrinogen, plasminogen, tissue plasminogen activator, antiplasmin, antithrombin III, and von Willebrand factor. CONCLUSIONS: Heparin, independent of cardiopulmonary bypass, causes both platelet dysfunction and increased fibrinolysis. The use of an alternative anticoagulant or a lower dose of heparin in conjunction with heparin-coated surfaces might improve the hemostatic balance during open heart operations.
Aged↗
Fibrin sealant: summary of a conference on characteristics and clinical uses.
The 2-day conference clearly outlined the formulations of products that are being developed or are commercially available in Europe. The major difference between products in the United States and those in Europe is that US manufacturers are preparing fibrin sealant that does not contain aprotinin, epsilon amino caproic acid, or any other type of antifibrinolytic agent, whereas antifibrinolytic agents are included in all such preparations used in Europe. The conference provided no clear consensus that such agents are essential to the efficacy of the product. Although many investigators believe in the clinical benefit of fibrin sealant, most of the studies to demonstrate efficacy have not been performed in a well-controlled fashion. However, fibrin sealant, if found in a controlled trial to have clinical efficacy, could be approved by the FDA for a narrow indication. Opportunities remain for greater exploration of different forms of the product, not only as a hemostatic agent, but as an adjunct to wound healing and as a matrix for delivery of drugs and proteins with other biologic activities.
Animals↗
Disease Prevention Research at NIH: An Agenda for All. Workshop J: Prevention strategies, economic realities, and identification of prevention research needs.
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Cost-Benefit Analysis↗
M(r) 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 ATA's beneficial anti-thrombotic effect on vWF-mediated platelet responses, and should be considered when analyzing results of experiments that utilize unfractionated ATA.
Aurintricarboxylic Acid↗
Adventures in hemostasis. Desmopressin in cardiac surgery.
Desmopressin acetate (1-deamino-8-D-arginine vasopressin [DDAVP]) improves hemostasis in hemophilia A and von Willebrand's disease and in some platelet disorders. In complex cardiac operations, excluding simple coronary artery bypass graft procedures, we found that desmopressin reduced blood loss by 40% and the need for transfusion by 34%. Conflicting reports followed. Future trials should emphasize patients with excessive bleeding. A possible post-desmopressin prothrombotic state was studied after hip replacement surgery. The incidence of deep vein thrombosis associated with warfarin sodium therapy was the same as that associated with desmopressin plus warfarin therapy. No desmopressin-induced thrombotic tendency was detected. A trend toward reduced blood loss with desmopressin was not significant. During cardiac catheterization, the plasma von Willebrand factor level was correlated with hemodynamic variables, including pulmonary vascular resistance, pulmonary arterial pressure, and (inversely) with cardiac index. von Willebrand factor concentration was highest in mitral stenosis. The relationship of these factors to the response to desmopressin remains to be defined.
Aged↗
Treatment of dogs with osteosarcoma by administration of cisplatin after amputation or limb-sparing surgery: 22 cases (1987-1990).
Twenty-two dogs with appendicular osteosarcoma were treated by amputation (n = 17) or limb-sparing surgery (n = 5). All dogs were given cisplatin (60 mg/m2 of body surface, IV) at 3-week intervals, beginning 1 week after surgery. Number of cisplatin treatments ranged from 1 to 6. Survival data for the 22 dogs were compared with survival data from a historical control group consisting of 162 dogs with appendicular osteosarcoma treated by amputation alone. Median survival time for the 22 dogs given cisplatin was estimated to be 46.4 weeks, and 1- and 2-year survival rates were estimated to be 45.5 and 20.9%, respectively. Survival time was significantly (P less than 0.0001) longer for treated dogs than for control dogs. Statistically significant relation was not found between survival time and number of cisplatin treatments. Three dogs were alive with no evidence of disease at the time of reporting. Of the remaining 19 dogs, 14 (73.4%) were euthanatized for problems documented to be related to metastases. Nine (47.4%) dogs were euthanatized because of bone metastases, and 5 (26.3%) were euthanatized because of pulmonary metastases. The proportion of dogs euthanatized because of bone metastases was significantly (P less than 0.0001) higher for treated than for control dogs. Median survival times for dogs developing bone and lung metastases were estimated to be 51.2 weeks and 21.2 weeks, respectively; however, this difference was not statistically significant. One local tumor recurrence was observed among dogs that had limb-sparing surgery. Significant difference in survival time was not observed between dogs that had limb-sparing surgery and dogs that underwent amputation.
Amputation, Surgical↗
In vitro assay of nuclear uptake of doxorubicin hydrochloride in osteosarcoma cells of dogs.
A rapid, simple chemosensitivity assay, assessing tumor cell nuclear uptake of doxorubicin hydrochloride, was evaluated in 16 dogs with appendicular osteosarcoma. Doxorubicin was administered to dogs in 5 biweekly treatments, and surgical resection was performed after the second or third treatment. The chemosensitivity assay was performed on biopsy specimens from all dogs before chemotherapy. It was repeated on tissue from resected tumors, and tumors were evaluated histologically to determine the degree of necrosis resulting from chemotherapy. Disease-free and total survival time correlated significantly (P less than 0.05 in both cases) with the degree of postchemotherapy necrosis of the primary tumors. Significant correlation was not apparent between the percentage of tumor cells with nuclear uptake of doxorubicin (in either biopsy or resection samples) and disease-free or total survival time. The percentage of cells with nuclear uptake of doxorubicin in surgically resected tumors correlated significantly (P less than 0.05) with percentage of necrosis.
Animals↗
Nonangiogenic and nonlymphomatous sarcomas of the canine spleen: 57 cases (1975-1987).
The case records of and histopathologic findings in 57 dogs with nonangiogenic and nonlymphomatous splenic sarcomas were reviewed. Splenic neoplasms in these dogs included leiomyosarcoma, fibrosarcoma, undifferentiated sarcoma, liposarcoma, osteosarcoma, chondrosarcoma, myxosarcoma, rhabdomyosarcoma, and fibrous histiocytoma. The clinical signs associated with splenic sarcoma included anorexia or decreased appetite, abdominal distention, polydipsia, lethargy, vomiting, weight loss, and weakness. An abdominal mass was detected in 86% of the dogs by use of abdominal palpation (63%), and/or abdominal radiography (74%). The diagnosis was based on histopathologic findings in the spleen. Abdominal exploratory surgery was performed on 43 of the 57 dogs. Twenty-seven dogs were treated by splenectomy, and 16 were euthanatized at the time of surgery because of widespread metastatic lesions. Of the 14 dogs on which surgery was not performed, 11 were euthanatized on the basis of results of preoperative diagnostic tests, and the remaining 3 dogs had splenic neoplasms that were incidental findings at necropsy. Of the 27 surgically treated dogs, 5 died in the immediate postoperative period, 12 died or were euthanatized within 1 year after splenectomy, and only 5 dogs survived greater than or equal to 1 year. Three dogs were lost to follow-up evaluation, and 2 were still alive 6 and 7 months after surgery. The median survival time of the 22 dogs for which survival was known was 2.5 months. The median survival time for 11 dogs with no obvious metastasis at the time of splenectomy was 9 months.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Relationship between human development and disappearance of unusually large von Willebrand factor multimers from plasma.
von Willebrand factor (vWF) multimers were examined in fetal, umbilical cord, and neonatal platelet-poor plasma (PPP) specimens. Sixty-five of 65 (100%) fetal PPP samples aged less than 35 weeks and seven of ten (70%) fetal samples aged greater than 35 weeks had unusually large vWF (ULvWF) multimers. Thirty of 46 (65%) cord PPP samples from neonates ranging in gestational age from 34 to 41 weeks had ULvWF. There was no significant relationship between either gestational age at time of delivery or birth weight and likelihood of finding ULvWF multimers in cord PPP samples. No maternal PPP sample contained ULvWF multimers. Serial heelstick samples from 16 preterm and term neonates were analyzed for 8 weeks. ULvWF multimers disappeared from the PPP of ten of the neonates during this time. The PPP of four neonates had vWF patterns similar to those in normal adult PPP throughout the sampling period. The ULvWF multimeric forms of fetal and neonatal PPP samples were similar to those constitutively released from endothelial cells. They were not as slowly migrating in a very porous 0.5% agarose gel system as the ULvWF multimers released from Weibel-Palade bodies in response to the calcium ionophore A23187. A vWF protomer was present in 97% of fetal samples, 83% of cord blood specimens, and 11% of neonatal heelstick samples, but was not found in any maternal sample. These results indicate that control mechanisms operative in older children and adults to prevent circulation of ULvWF multimers and vWF protomeric forms are normally acquired late in uterine life or during the neonatal period. ULvWF multimers, which are normal components of fetal, most cord, and some neonatal plasma samples, may contribute to in utero and postnatal hemostasis.
Autoradiography↗
Fetal and neonatal von Willebrand factor (vWF) is unusually large and similar to the vWF in patients with thrombotic thrombocytopenic purpura.
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.
Antigens↗
Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial.
Bleeding after cardiopulmonary bypass remains a cause for concern, requiring reexploration of the chest in approximately 3 percent of patients who have had operations on the heart. We examined the possibility that this problem might be alleviated by desmopressin acetate (DDAVP), which increases the plasma level of von Willebrand factor and improves hemostasis in mild hemophilia and other conditions associated with defective platelet function. In a double-blind, prospective, randomized trial, we studied the effect of intraoperative desmopressin acetate in 70 patients undergoing various cardiac operations requiring cardiopulmonary bypass. Patients undergoing uncomplicated primary coronary-artery bypass grafting were not included. The drug significantly reduced mean operative and early postoperative blood loss (1317 +/- 486 ml in the treated group vs. 2210 +/- 1415 ml in the placebo group); of the 14 patients whose 24-hour blood loss exceeded 2000 ml, 11 had received the placebo. Plasma levels of von Willebrand factor were higher after desmopressin acetate than after placebo. Patients with the most bleeding had relatively low levels of von Willebrand factor before operation, suggesting a role for this factor in the hemorrhagic tendency induced by extracorporeal circulation. There were no untoward side effects of desmopressin acetate. We conclude that the administration of desmopressin acetate can be recommended to reduce blood loss in patients undergoing complex cardiac operations. The beneficial effect of the drug on hemostasis after cardiopulmonary bypass may be related to its effect on von Willebrand factor.
Adult↗
von Willebrand factor abnormalities and endothelial cell perturbation in a patient with acute thrombotic thrombocytopenic purpura.
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 seven-fold above normal. Unusually large vWF multimers derived from endothelial cells were detected in her plasma at the onset 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.
Antigens↗
Therapy of chronic relapsing thrombotic thrombocytopenic purpura with prednisone and azathioprine.
As a 51-year-old woman recovered from an initial acute episode of thrombotic thrombocytopenic purpura (TTP), her plasma was found to contain unusually large von Willebrand factor (vWF) multimers. Clinical, hematological, and vWF studies of her siblings and children were normal. The unusually large vWF forms were presumably derived from endothelial cells, persisted in her plasma after recovery, and were associated with recurrent episodes of TTP during the subsequent 6 months. After the last episode of relapse they disappeared from her plasma following 3 1/2 weeks of therapy with prednisone and did not return during 17 months of treatment with prednisone and/or azathioprine. She is now receiving no drugs, has normal plasma vWF forms, and has not had any more episodes of TTP. We conclude that our patient had an acquired defect in the conversion of unusually large vWF multimers derived from endothelial cells to the somewhat smaller vWF forms usually present in circulation. The defect may have been immune-mediated, because it was eliminated during therapy with immunosuppressive drugs.
Azathioprine↗
Abnormal factor VIII coagulant antigen in patients with renal dysfunction and in those with disseminated intravascular coagulation.
Factor VIII antigen (VIII:CAg) exhibits molecular weight heterogeneity in normal plasma. We have compared the relative quantities of VIII:CAg forms present in normal individuals (n = 22) with VIII:CAg forms in renal dysfunction patients (n = 19) and in patients with disseminated intravascular coagulation (DIC; n = 7). In normal plasma, the predominant VIII: CAg form, detectable by sodium dodecyl sulfate polyacrylamide gel electrophoresis, was of molecular weight 2.4 X 10(5), with minor forms ranging from 8 X 10(4) to 2.6 X 10(5) D. A high proportion of VIII:CAg in renal dysfunction patients, in contrast, was of 1 X 10(5) mol wt. The patients' high 1 X 10(5) mol wt VIII: CAg level correlated with increased concentrations of serum creatinine, F1+2 (a polypeptide released upon prothrombin activation), and with von Willebrand factor. Despite the high proportion of the 1 X 10(5) mol wt VIII:CAg form, which suggests VIII:CAg proteolysis, the ratio of Factor VIII coagulant activity to total VIII:CAg concentration was normal in renal dysfunction patients. These results could be simulated in vitro by thrombin treatment of normal plasma, which yielded similar VIII:CAg gel patterns and Factor VIII coagulant activity to antigen ratios. DIC patients with high F1+2 levels but no evidence of renal dysfunction had an VIII:CAg gel pattern distinct from renal dysfunction patients. DIC patients had elevated concentrations of both the 1 X 10(5) and 8 X 10(4) mol wt VIII:CAg forms. We conclude that an increase in a particular VIII:CAg form correlates with the severity of renal dysfunction. The antigen abnormality may be the result of VIII:CAg proteolysis by a thrombinlike enzyme and/or prolonged retention of proteolyzed VIII:CAg fragments.
Aged↗
Effects of fresh-frozen plasma and its cryosupernatant fraction on von Willebrand factor multimeric forms in chronic relapsing thrombotic thrombocytopenic purpura.
Remission plasma samples of some patients with chronic relapsing thrombotic thrombocytopenic purpura (TTP) contain unusually large von Willebrand factor (vWF) multimers similar to those produced by normal human endothelial cells in culture. The infusion of the cryosupernatant fraction of normal plasma is as effective as normal fresh-frozen plasma (FFP) in the treatment or prevention of TTP episodes in patients with the chronic relapsing form of TTP. Three patients with chronic relapsing TTP during remission have unusually large vWF multimers present in their plasma. Two of the patients were transfused once with FFP, one of the two received cryosupernatant on three occasions, and the third patient was studied before and immediately after plasma exchange. Unusually large vWF multimers decreased or disappeared from patient plasma samples within 1/2 to 1 1/2 hours following the transfusion of FFP (on two occasions) or cryosupernatant (on two of three occasions), and immediately after plasma exchange (on one occasion). The patient who received cryosupernatant was studied serially after the infusions. Unusually large vWF multimers returned to her plasma within ten to 24 hours and persisted thereafter. Unusually large vWF multimers did not disappear from patient remission plasma samples, or from the culture medium removed from normal human endothelial cells, when these fluids were incubated in vitro with either normal FFP or cryosupernatant. We conclude that an activity in FFP, and its cryosupernatant fraction, promoted the rapid in vivo disappearance of unusually large vWF multimers from the plasma of two patients with chronic relapsing TTP in remission, and plasma exchange reversed the abnormality in a third patient who was in partial remission. Neither FFP nor cryosupernatant directly converted unusually large multimers to smaller vWF forms in vitro in the fluid phase. These results indicate that an activity in the cryosupernatant fraction of normal plasma is involved in vivo in controlling the metabolism of unusually large vWF multimers, and that this process is defective in some chronic relapsing TTP patients.
Adult↗