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Biomedical subjects

M E Rick

Publications and source records attributed to M E Rick.

At least 55 records · Page 3Linked to original sources
PubMed1985

Platelet von Willebrand factor: comparison with plasma von Willebrand factor.

Platelet von Willebrand factor (vWf) was compared to its plasma counterpart. The platelet vWf was different from plasma vWf in that the multimeric organization was different, larger multimers were present, and the ratio of vWf activity to antigen was higher. Platelet and plasma vWf were similar in their antigenic reactivity in the electroimmunoassay and by liquid phase radioimmunoassay. The amount of vWf activity in large platelets was significantly higher than in normal platelets while the antigen content, although somewhat higher, was not significant. These studies show differences between normal platelet and plasma vWf, and also suggest that platelet size must be considered when platelet vWf is measured in disease states.

Antigens↗
PubMed1985

Benefits of danazol treatment in patients with hemophilia A (classic hemophilia).

Danazol, an attenuated androgen, was given intermittently in three patients with hemophilia A. The rise in factor VIII activity with danazol treatment was associated with a fivefold decrease in hemorrhagic episodes and plasma concentrate product utilization when compared with similar periods without the drug. Four other patients with moderate hemophilia A who received danazol for 14 days had an increase of 400% to 850% in their factor VIII levels. Of four patients without detectable levels of factor VIII who were treated with danazol, two had elevations of the factor VIII level, to 3% and 4%, respectively. Danazol appears to be an effective treatment for patients with hemophilia A.

Adult↗
PubMed1985

In vitro correction of the abnormal multimeric structure of von Willebrand factor in type IIa von Willebrand's disease.

Type IIa von Willebrand's disease (vWd) has been characterized by the absence of the largest and a reduction in the intermediate-sized multimers of the plasma and platelet von Willebrand factor (vWf) and by the diminished response of the platelet-rich plasma of these patients to ristocetin. Other recently demonstrated abnormalities include the presence of an abnormal triplet structure of vWf. We have studied the plasma and platelets from three patients with this form of vWd and have found that both their plasma and platelets manifest the previously described abnormalities. Because of the heterogeneity of the multimeric structure of the vWf in these patients, we considered the possibility that postsynthetic events may have modified the vWf. When blood was collected in 5 mM EDTA or 5 mM EDTA/leupeptin/N-ethylmaleimide, the abnormal multimeric structure of the plasma and platelet vWf was partially normalized in that the intermediate and the largest vWf multimers were increased, the abnormal multimer structure was no longer as apparent, and the fastest migrating band (an abnormality seen only in the type IIa vWd plasma and platelets) disappeared. The enzymatic activity responsible for this degradation can be classified as a calcium-dependent protease. Studies of normal radiolabeled vWf incubated with platelet lysates from normal subjects and these patients revealed that the patients' platelets did not contain increased amounts of calcium-dependent protease activity as assessed by degradation of normal vWf. These data suggest that patients with type IIa vWd synthesize an abnormal vWf protein that is susceptible to in vitro proteolytic degradation and that proteolytic degradation can play a significant role in the phenotypic expression of vWd by modifying the plasma and platelet vWf multimeric structure.

Blood Coagulation Factors↗
PubMed1985

Degradation of factor VIII coagulant antigen by proteolytic enzymes.

The factors responsible for the lability of factor VIII coagulant activity (VIII:C) and factor VIII coagulant antigen (VIII:CAg) are poorly understood. In this study the VIII:C and VIII:CAg are studied after incubation with plasmin, trypsin or alpha-chymotrypsin. Both isolated human VIII:CAg and VIII:CAg associated with factor VIII-related antigen (VIII R:Ag) are evaluated. The antigenic sites of the VIII:CAg are somewhat more stable to the action of these enzymes than the functional activity, although both follow a generally parallel degradation. A biphasic decay curve is seen in the initial time points. No stabilization of the functional or antigenic reactivity is observed in the presence of the VIII R:Ag. Lower concentrations of each enzyme cause an initial rise in the factor VIII:C in the presence of VIII R:Ag, but not in the isolated VIII:CAg. Higher concentrations of alpha-chymotrypsin cause activation of VIII:C and a slight decrease in the VIII:CAg values in both preparations. These enzymes may play a modulating role in the coagulation cascade through the activation and degradation of VIII:C and VIII:CAg.

Antigen-Antibody Reactions↗
PubMed1985

Von Willebrand's disease with spontaneous platelet aggregation induced by an abnormal plasma von Willebrand factor.

We have investigated and characterized the abnormalities in four unrelated patients with von Willebrand's disease (vWd) who have (a) enhanced ristocetin-induced platelet aggregation (RIPA) at low ristocetin concentrations, (b) absence of the largest plasma von Willebrand factor (vWf) multimers, and (c) thrombocytopenia. The platelet-rich plasma of these patients aggregates spontaneously without the addition of any agonists. When isolated normal platelets are resuspended in patient plasma spontaneous aggregation occurs; however, the patients' plasmas did not induce platelet aggregation of normal washed formalinized platelets. When the patients' platelets are suspended in normal plasma, spontaneous aggregation is not observed. The spontaneous platelet aggregation (SPA) is associated with dense granule secretion as measured by ATP release and alpha granule release as measured by beta-thromboglobulin and platelet factor 4 release. The SPA is totally inhibited by 5 mM EDTA, prostaglandin I2, and dibutryl cyclic AMP, while it is only partially inhibited by 1 mM EDTA, acetylsalicylic acid, or apyrase. A monoclonal antibody directed against glycoprotein Ib (GPIb) and/or a monoclonal antibody against the glycoprotein IIb/IIIa (GPIIb/IIIa) complex totally inhibits the SPA. The vWf was isolated from the plasma of one of these patients. The purified vWf induced platelet aggregation of normal platelets resuspended in either normal or severe vWd plasma, but the vWf did not induce platelet aggregation of normal platelets resuspended in afibrinognemic plasma. Sialic acid and galactose quantification of the patient's vWf revealed approximately a 50% reduction compared with normal vWf. These studies indicate that a form of vWd exists, which is characterized by SPA that is induced by the abnormal plasma vWf. The SPA is dependent on the presence of plasma fibrinogen, and the availability of the GPIb and the GPIIb/IIIa complex. In this variant form of vWd the abnormal vWf causes enhanced RIPA, SPA, and thrombocytopenia.

Antigens↗
PubMed1985

Effect of calcium on the availability of platelet von Willebrand factor.

The binding of a polyclonal immune-purified rabbit anti-human von Willebrand factor (VWF) antibody to activated and nonactivated normal human platelets was studied in the presence and absence of extracellular calcium. Extracellular Ca++ in the incubation buffer results in no increase in the amount of antibody bound to the surface of unstimulated platelets when compared with that bound in the absence of Ca++. Alpha thrombin stimulation of the platelets increases antibody binding to the platelets in both the presence and absence of extracellular Ca++; however, the increase is approximately four times as great in the presence of extracellular Ca++. The amount of VWF detected in the incubation supernatants of unstimulated platelets is similar in either the presence or absence of Ca++, and this amount is increased without demonstrating a Ca++ dependency after thrombin stimulation. Measurement of thrombin-induced beta thromboglobulin (beta TG) release reveals some parallel between anti-VWF antibody binding and beta TG release. However, the amount of beta TG release after thrombin stimulation is independent of extracellular Ca++, whereas the amount of bound anti-VWF is markedly increased in the presence of Ca++. These studies demonstrate that thrombin induces an increase in the surface exposure of platelet VWF even in the absence of extracellular Ca++. The data also suggest that there may be a quantity of platelet VWF that can become exposed on the platelet surface by an action of thrombin that is independent of the Ca++-dependent granule release reaction induced by thrombin.

Animals↗
PubMed1984

Circulating heparan sulfate anticoagulant in a patient with a fatal bleeding disorder.

We have identified a circulating, heparin-like anticoagulant in a patient with multiple myeloma (IgG4 lambda) who had serious clinically evident bleeding that contributed to his death. Purification of the patient's circulating coagulation inhibitor was accomplished by ammonium sulfate concentration, anion exchange chromatography, and affinity chromatography on protamine sulfate. Analysis of the purified inhibitor showed that it was a proteoglycan that comigrated with heparan sulfate on lithium acetate-agarose-gel electrophoresis and that it contained 39 per cent L-iduronic acid. Control samples of heparan sulfate and heparin contained 29 and 68 per cent L-iduronic acid, respectively. Functional coagulation studies revealed that the purified inhibitor had cofactor activity with antithrombin III that could be abolished by prior incubation with protamine sulfate or platelet factor 4. Recognition of the existence of this or of other similar inhibitors in bleeding patients is important because of the potential for treatment with agents such as protamine sulfate and platelet factor 4, which neutralize the anticoagulant effects of proteoglycans.

Blood Coagulation↗
PubMed1984

Changes in coagulation parameters with exercise in patients with classic hemophilia.

Vigorous exercise is known to increase VIII:C and VIIIR:Ag levels transiently in normal individuals. Although exercise programs are frequently advocated in the management of hemophilia, the effects of exercise on coagulation parameters in these patients have not been well studied. Eleven hemophiliacs were exercised on a bicycle ergometer to maximum voluntary effort as evidenced by an increase in pulse, blood pressure, and plasma catecholamine (norepinephrine and epinephrine) levels. The effects of this exercise on coagulation parameters, including functional and antigenic components of the factor VIII molecule, were determined. The entire group demonstrated a decrease in mean prothrombin time (11.7 to 11.2 sec). Four mild hemophiliacs demonstrated an increase in mean VIII:C (14.5% to 17.3%), and VIII:CAg (12% to 17.8%). Changes in VIII:C and VIII:CAg were not noted in the seven severe hemophiliacs. Both severe and mild patients demonstrated significant changes in fibrinogen, factor II, and factor VII after exercise. This study indicates that submaximal exercise modifies coagulation parameters in patients with hemophilia.

Adolescent↗
PubMed1984

Collagen-factor VIII/von Willebrand factor protein interaction.

Factor VIII/von Willebrand factor (FVIII/vWF) protein interaction with collagen was studied by incubating plasma or purified FVIII/vWF with purified type I fibrillar collagen. Collagen adsorbed FVIII/vWF activities in a similar time and concentration-dependent manner from normal plasma, plasmas from classical and variant type von Willebrand's disease (vWD), and from purified FVIII/vWF. Incubation with denatured collagen or fibrin, produced in the presence or absence of fibronectin, showed no adsorption of FVIII/vWF. Examination of the multimeric structure of the remaining unadsorbed FVIII/vWF protein by agarose gel electrophoresis and autoradiography showed that the largest multimers had been adsorbed to the collagen. Studies of the adsorbed FVIII/vWF protein when eluted from collagen showed that it complemented the alterations in multimeric structure observed in the supernatants following collagen exposure. The multimeric structure of normal plasma following collagen adsorption resembled that of unadsorbed type IIb plasma; however, the collagen-adsorbed normal plasma did not produce enhanced ristocetin-induced platelet aggregation ( RIPA ). This phenomenon, therefore, must not be due solely to absence of large multimers from type IIb FVIII/vWF protein. The adsorbed multimers of FVIII/vWF protein may act as a subendothelial collagen-platelet bridge to promote primary hemostasis.

Adsorption↗
PubMed1983

Danazol increases factor VIII and factor IX in classic hemophilia and Christmas disease.

We gave danazol (600 mg per day orally for 14 days), an attenuated androgen, to four adults with classic hemophilia and one adult with Christmas disease. The levels of factor VIII in the patients with classic hemophilia ranged from 1 to 3 per cent before treatment and rose to 3 to 8 per cent during the treatment period. The level of factor IX in the patient with Christmas disease rose from 5 to 14 per cent. The rise in clotting-factor activity was usually observed within five to six days after the initiation of therapy and peaked between 7 and 13 days. The drug had no untoward effects. During the 70 patient-days of therapy, only two patients required plasma products, each on one occasion. These data suggest that danazol therapy may decrease the hemorrhagic tendency and reduce the need for transfusions of plasma products in classic hemophilia and Christmas disease. Controlled clinical trials will be required to establish its value in these applications.

Adult↗
PubMed1983

Role of carbohydrate in multimeric structure of factor VIII/von Willebrand factor protein.

The carbohydrate moiety of the factor VIII/von Willebrand (vW) factor protein is important in the expression of vW factor activity and the intravascular survival of the protein. Studies of normal human factor VIII/vW factor protein indicate that there is a requirement of a full complement of penultimate galactose for the maintenance of a normal multimeric structure. Release of penultimate galactose by beta-galactosidase or modification by galactose oxidase results in loss of the largest molecular weight multimers and increased numbers of intermediate and smaller multimers. In contrast, terminal galactose on the factor VIII/vW factor protein does not appear to play a significant role in the maintenance of the multimer organization. The abnormalities in multimeric structure and molecular size were demonstrated by NaDodSO4/polyacrylamide/agarose gel electrophoresis, NaDodSO4/glyoxyl-agarose electrophoresis, and sucrose density ultracentrifugation. These studies indicate that the penultimate galactose plays a role in the maintenance of the largest multimers of the factor VIII/vW factor protein. This may explain why, in some patients with variant forms of vW disease, a carbohydrate abnormality also may affect the multimeric structure of the plasma factor VIII/vW factor protein.

Blood Coagulation Factors↗
PubMed1982

The identification and functional significance of factor VIII components on normal platelets.

Factor VIII-related antigen (VIII R:Ag) has previously been identified on human platelets by fluorescein-labelled heterologous antibodies to factor VIII. However, it is not known whether these antibodies identify only VIII R:Ag or whether antigens associated with factor VIII coagulant activity (VIII:C Ag) are also present. The current studies utilize specific antibodies and their Fab' fragments to evaluate the presence of both VIII R:Ag and VIII:C Ag on human platelets and to study the functional role of the platelet-associated VIII R:Ag on ristocetin-induced platelet agglutination. Immunofluorescent studies demonstrate the presence of VIII R:Ag, but do not identify VIII:C Ag on platelets. The functional studies reveal that after incubation with either of the Fab' fragments, platelets retain their reactivity in the ristocetin cofactor assay. These results indicate that this population of VIII R:Ag is not essential for the ristocetin aggregation reaction and that no antigenic determinants for factor VIII coagulant activity (VIII:C) are detectable on human platelets by immunofluorescence.

Antigens↗
PubMed1982

Activation of factor VIII by factor IXa.

Thrombin causes an increase in factor VIII coagulant (VIII:C) activity, which is followed by a decay of VIII:C activity to below baseline levels. It has been suggested that a similar interaction of trace amounts of thrombin and factor VIII is a necessary prerequisite before factor VIII can participate in the coagulation cascade. In the current study, factor IXa, a serine protease with structural similarities to thrombin, is shown to cause an increase and subsequent fall in VIII:C in a manner qualitatively similar to the reaction with thrombin. The reaction is inhibited by a human inhibitor to factor IX and the interaction appears to involve only VIII:C, since factor-VIII-related protein (VIII:RP) is not changed on polyacrylamide gel electrophoresis (PAGE) or radioimmunoassay during the reaction. Phospholipid increases the activation of factor VIII by factor IXa, and high concentrations of diisopropylfluorophosphate and hirudin inhibit the reaction. The physiologic significance of the interaction of factor IXa with factor VIII is not entirely clear since the concentration of factor IXa needed for activation is much greater than the concentration of thrombin required for similar activation of factor VIII. Factor IXa is most likely to play a role in the intrinsic cascade acting as an initial activator of factor VIII, since factor IXa precedes thrombin in this clotting sequence. In addition, factor IXa may be important wherever relatively high local concentrations of factor IXa and factor VIII occur, particularly in the presence of phospholipid, which may serve to localize the coagulation factors.

Animals↗
PubMed1981

Studies on a circulating anticoagulant in procainamide-induced lupus erythematosus.

Circulating anticoagulant activity that had at least two distinct mechanisms--one directed against factor XII and one directed against blood thromboplastin (prothrombin activator complex)--developed in a patient with clinical and laboratory evidence of procainamide hydrochloride-induced systemic lupus erythematosus. The anticoagulant activity behaved as a gamma-globulin in chromatographic and electrophoretic analyses, with the majority of activity behaving as an IgM immunoglobulin. Despite markedly abnormal coagulation study results, no clinical bleeding occurred. Anticoagulant activity paralleled clinical and laboratory evidence of the inflammatory disease and improved on discontinuance of procainamide therapy.

Aged↗
PubMed1978

Pathogenesis of hypercalcemia in lymphosarcoma cell leukemia. Role of an osteoclast activating factor-like substance and a mechanism of action for glucocorticoid therapy.

The pathogenesis of hypercalcemia and mode of action of glucocorticoid therapy was examined in a patient with lymphosarcoma cell leukemia. Circulating neoplastic cells were cultured in vitro and secreted a bone-resorbing factor. The bone-resorbing factor was partially purified with the use of a bioassay for bone resorption, and was found to be chromatographically and pharmacologically similar to osteoclast activiating factor (OAF), which is produced by normal mitogen-activated peripheral blood lymphocytes. Other factors which stimulate bone resorption, such as parathyroid hormone, prostaglandins and the vitamin D metabolites, were excluded by criteria which included dose-response curves, radioimmunoassays, extraction in organic solvents and failure of glucocorticoids to inhibit bone-resorbing activity. The patient's hypercalcemia responded rapidly to prednisone therapy. The effects of the bone-resorbing factor secreted by the neoplastic cells on bone cultures to which cortisol was added were examined. Cortisol inhibited bone resorption directly at low doses (10(-8) M), which suggests that prednisone may have lowered the serum calcium in this patient by direct inhibition of bone resorption.

Aged↗
PubMed1978

Thrombin activation of factor VIII. II. A comparison of purified factor VIII and the low molecular weight factor VIII procoagulant.

The current experiments examine the reaction between purified human alpha-thrombin and purified human factor VIII and compare this with the reaction between alpha-thrombin and the low molecular weight factor VIII procoagulant activity obtained by high ionic strength dissociation. The reaction patterns of both procoagulants are similar, demonstrating in initial increase in factor VIII activity followed by a decay of procoagulant activity. The extent of activation which is observed in the initial phase decreases with lower temperatures and with lower thrombin concentrations. A pseudo-first order relationship is demonstrated for the activation phase. The labile factor VIII procoagulant activity produced by the initial action of thrombin appears to be intrinsically unstable, since the addition of hirudin or diisopropylfluorophosphate does not prevent the subsequent decay of the procoagulant activity. The similar activation and decay patterns of purified factor VIII and the dissociated low molecular weight factor VIII procoagulant support the concept that the low molecular weight procoagulant itself represents the functional coagulant moiety of the factor VIII complex.

Chemical Phenomena↗