Growth hormone (GH) therapy in GH-deficient patients, the plasma Factor VIII-von Willebrand factor complex, and capillary fragility. A double-blind, placebo-controlled crossover study

The present studies were undertaken to determine whether factor VIII/von Willebrand factor (vWF) present in the vessel wall (in addition to that in plasma) may mediate the attachment of platelets to subendothelium. Subendothelium from everted rabbit aorta was exposed to human citrated blood flowing through an annular perfusion chamber at 40 mL/min (wall shear rate of 2,600 s-1 for five minutes). The vessel segments were incubated at 37 degrees C for one hour with various dilutions of either goat-anti-rabbit factor VIII/vWF serum or an IgG fraction prepared from the serum. Control segments were incubated with serum or IgG from a nonimmunized goat. Values of platelet contact (C), platelet adhesion (C + S), and thrombus formation (T) on the subendothelium were evaluated by a morphometric technique. Compared with vessels incubated with fractions prepared from a normal goat, a significant decrease in platelet adhesion (C + S), ranging from 45% to 65%, was observed on vessels incubated with various dilutions (1:5 to 1:50) of either serum or IgG fractions of goat-anti-rabbit factor VIII/vWF. A similar decrease in platelet adhesion was observed with vessels incubated with an F(ab')2 fragment against rabbit factor VIII/vWF prepared in the goat. When goat-anti-rabbit factor VIII/vWF IgG was added to rabbit blood (1:75 dilution), platelet adhesion was reduced to the same extent (65%) on normal rabbit vessels and on vessels pre-incubated with goat-anti-rabbit factor VIII/vWF. Immunofluorescence studies revealed the presence of rabbit factor VIII/vWF in the subendothelium of rabbit aorta and the continued binding of the goat-anti-factor VIII/vWF antibodies on subendothelium during the perfusion studies. No uptake of human factor VIII/vWF on the rabbit subendothelium was observed by this immunologic technique; human factor VIII/vWF was found to be entirely associated with the attached human platelets. Thus, factor VIII/vWF in the vessel wall may mediate platelet attachment to subendothelium in a manner similar to that of plasma factor VIII/vWF.

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Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand's disease subtypes

Blood ◽

10.1182/blood.v59.6.1272.1272 ◽

1982 ◽

Vol 59 (6) ◽

pp. 1272-1278 ◽

Cited By ~ 241

Author(s):

ZM Ruggeri ◽

PM Mannucci ◽

R Lombardi ◽

AB Federici ◽

TS Zimmerman

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Resting State ◽

Bleeding Time ◽

Type I ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

Abstract We have studied the modifications in the multimeric composition of plasma factor VIII/von Willebrand factor and the bleeding time response following administration of 1-Deamino-[8-D-arginine]-Vasopressin (DDAVP) to patients with different subtypes of von Willebrand's disease. In type I, all multimers were present in plasma in the resting state, though they were decreased in concentration. Administration of DDAVP resulted in an increased concentration of these forms as well as the appearance of larger forms than were previously present. There was concomitant correction of the bleeding time. In type IIA, large multimers were absent in the resting state, and although DDAVP induced an average threefold increase in the plasma concentration of factor VIII/von Willebrand factor, the larger multimers did not appear and the bleeding time, although shortened, was not corrected. In contrast, the larger multimers that were also absent from type IIB plasma in the resting state rapidly appeared following DDAVP administration. However, their appearance was transitory and the bleeding time, as in IIA patients, was shortened but not corrected. The characteristic multimeric composition of platelet factor VIII/von Willebrand factor in given subtypes predicted the alteration in plasma factor VIII/von Willebrand factor induced by DDAVP. These studies provide evidence that the different subtypes of von Willebrand's disease represent distinct abnormalities of factor VIII/von Willebrand factor. They also suggest that complete hemostatic correction following DDAVP can be routinely expected only in type I von Willebrand's disease, and only if factor VIII/von Willebrand factor can be raised to normal levels.

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Presence Of Receptor For Activated Factor VIII On The Surface Of Released Platelets

10.1055/s-0038-1652900 ◽

1981 ◽

Author(s):

K Brodén ◽

L-O Andersson

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Factor X ◽

Factor Viii Activity ◽

Platelet Receptor ◽

Plasma Factor ◽

Centrifuge Tube ◽

Dilute Suspension ◽

Von Willebrand ◽

Willebrand Factor

In normal plasma Factor VIII activity is associated with a series of high molecular weight glycoprotein complexes also containing von Willebrand Factor related activities. To study the possible binding of various forms of Factor VIII to released platelets, a solution containing Factor VIII was mixed with a dilute suspension of platelets, which were released by addition of collagen. After 10 minutes of incubation the mixture was layered over 1.5 ml of 30% human serum albumin solution in a centrifuge tube and subjected to centrifugation at 7,000xg. Fractions were collected and analyzed for Factor VIII activity and phospholipid-related procoagulant activity. When purified Factor VUI/von Willebrand Factor complex was studied no significant association between the Factor VIII activity and the platelets were found. When purified Factor VUI/von Willebrand Factor complex was activated with 10-3 units/ml of thrombin and then tested, the main part of the Factor VIII activity became associated with the platelets. Even at very low platelet counts this binding was clearly detectable. The binding occurred both in the presence and in the absence of Ca2+. Thus released platelets bind thrombin-activated Factor VIII but not the Factor VUI/von Willebrand Factor complex. It is known that activation of Factor VIII by thrombin causes dissociation of the Factor VIII from the von Willebrand Factor part of the complex. The data obtained indicate that this dissociation is necessary in order to get the Factor VIII to bind to the platelet receptor. It may work as an amplification mechanism where the first traces of Thrombin formed upon initiation of coagulation dissociates Factor VIII from von Willebrand Factor, followed by binding to receptor on released platelets and formation of Factor X activator complex on the surface of the platelets.

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J.L. Moake, C.K. Rudy and J.H. Troll et al., Unusually large plasma factor VIII : von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura, New Engl. J. of Med. 307 (1982), pp. 1432–1435.

Revue Fran&#xE7 aise de Transfusion et Immuno-h&#xE9 matologie ◽

10.1016/s0338-4535(83)80059-2 ◽

1983 ◽

Vol 26 (1) ◽

pp. 105-106 ◽

Cited By ~ 1

Author(s):

E RACADOT

Keyword(s):

Factor Viii ◽

Thrombotic Thrombocytopenic Purpura ◽

Von Willebrand Factor ◽

Thrombocytopenic Purpura ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

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Effect of multimeric structure of the factor VIII/von Willebrand factor protein on binding to platelets

Blood ◽

10.1182/blood.v58.2.387.bloodjournal582387 ◽

1981 ◽

Vol 58 (2) ◽

pp. 387-397 ◽

Cited By ~ 2

Author(s):

HR Gralnick ◽

SB Williams ◽

DK Morisato

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Competitive Inhibition ◽

Human Platelets ◽

Factor Vii ◽

Variant Form ◽

Factor Binding ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

The characteristics of the intact factor VIII/von Willebrand factor protein binding to human platelets was compared to 2-mercaptoethanol- treated factor VIII/von Willebrand factor protein and to fractions of plasma factor VIII/von Willebrand factor protein that elute after the void volume. These studies indicate that the factor VIII/von Willebrand factor protein larger size oligomers bind preferentially with high affinity to low capacity sites on human platelets. The intermediate and smaller size oligomers bind with intermediate or low affinity to sites with a much greater capacity. The results from binding analysis are also paralleled by the competitive inhibition of the intact factor VIII/von Willebrand factor protein by the various 2-mercaptoethanol- treated materials. These studies indicate that the two classes of binding sites seen in previous reports of factor VII/von Willebrand factor binding reflect heterogeneity in the oligomer size of the factor VIII/von Willebrand factor protein used in these assays. This study provides a model for understanding some of the normal structure- function relationships of the normal factor VIII/von Willebrand factor protein and the defect(s) in a variant form of von Willebrand's disease. In this form of the disease, decreased factor VIII/von Willebrand factor binding to platelets is reflected in decreased von Willebrand factor activity but coagulant and/or antigen levels are normal or only slightly decreased.

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Effect of multimeric structure of the factor VIII/von Willebrand factor protein on binding to platelets

Blood ◽

10.1182/blood.v58.2.387.387 ◽

1981 ◽

Vol 58 (2) ◽

pp. 387-397 ◽

Cited By ~ 65

Author(s):

HR Gralnick ◽

SB Williams ◽

DK Morisato

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Competitive Inhibition ◽

Human Platelets ◽

Factor Vii ◽

Variant Form ◽

Factor Binding ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

Abstract The characteristics of the intact factor VIII/von Willebrand factor protein binding to human platelets was compared to 2-mercaptoethanol- treated factor VIII/von Willebrand factor protein and to fractions of plasma factor VIII/von Willebrand factor protein that elute after the void volume. These studies indicate that the factor VIII/von Willebrand factor protein larger size oligomers bind preferentially with high affinity to low capacity sites on human platelets. The intermediate and smaller size oligomers bind with intermediate or low affinity to sites with a much greater capacity. The results from binding analysis are also paralleled by the competitive inhibition of the intact factor VIII/von Willebrand factor protein by the various 2-mercaptoethanol- treated materials. These studies indicate that the two classes of binding sites seen in previous reports of factor VII/von Willebrand factor binding reflect heterogeneity in the oligomer size of the factor VIII/von Willebrand factor protein used in these assays. This study provides a model for understanding some of the normal structure- function relationships of the normal factor VIII/von Willebrand factor protein and the defect(s) in a variant form of von Willebrand's disease. In this form of the disease, decreased factor VIII/von Willebrand factor binding to platelets is reflected in decreased von Willebrand factor activity but coagulant and/or antigen levels are normal or only slightly decreased.

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Precipitating antibodies to factor VIII/von Willebrand factor in von Willebrand's disease: effects on replacement therapy

Blood ◽

10.1182/blood.v57.1.25.25 ◽

1981 ◽

Vol 57 (1) ◽

pp. 25-31 ◽

Cited By ~ 41

Author(s):

PM Mannucci ◽

ZM Ruggeri ◽

N Ciavarella ◽

MD Kazatchkine ◽

JF Mowbray

Keyword(s):

Factor Viii ◽

Replacement Therapy ◽

Antibody Titer ◽

Von Willebrand Factor ◽

Factor Vii ◽

Von Willebrand's Disease ◽

Von Willebrand’S Disease ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

Abstract Precipitating antibodies to factor VII/von Willebrand factor can develop in patients with severe homozygous-like von Willebrand's disease following multiple transfusions with blood derivatives. This study of 4 patients treated with cryoprecipitate for 13 different bleeding episodes demonstrates that the occurrence of such antibodies interferes with the management of the disease. The control of mucosal bleeding was poor, whereas more favorable responses were obtained in soft-tissue hemorrhages. These findings probably relate to failure of replacement therapy to shorten the prolonged bleeding time. Immediately after treatment, measurement of plasma factor VIII/von Willebrand factor-related antigen and ristocetin cofactor showed either no increase, or very low values, depending on the pre-infusion antibody titer. Levels of the factor VIII/von Willebrand factor-related procoagulant activity in the circulation were also lower than predicted and usually there was no evidence of the delayed and sustained rise typically observed in uncomplicated von Willebrand's disease. An anamnestic rise in antibody titer appeared 6–15 days after treatment and showed no obvious relationship with the amount of cryoprecipitate infused. Replacement therapy invariably caused severe side effects during, or immediately after, concentrate infusion. The results of in vitro studies support the view that these reactions were due to the appearance of circulating immune complexes.

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The Factor VIII/Von Willebrand Factor Ratio Discriminates between Reduced Synthesis and Increased Clearance of Von Willebrand Factor

Thrombosis and Haemostasis ◽

10.1055/s-0037-1612981 ◽

2002 ◽

Vol 87 (02) ◽

pp. 252-257 ◽

Cited By ~ 29

Author(s):

Giancarlo Castaman ◽

Pieter Kamphuisen ◽

Frits Rosendaal ◽

Rogier Bertina ◽

Jeroen Eikenboom

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Null Allele ◽

Genetic Defect ◽

Clinical Importance ◽

Von Willebrand Disease ◽

Plasma Factor ◽

Factor Ratio ◽

Von Willebrand ◽

Willebrand Factor

SummaryIt is often stated that a decrease in Von Willebrand factor (VWF), the carrier protein of factor VIII, results in a concordant change in factor VIII. Clinical data suggest that this is not always the case and we hypothesized that the ratio between factor VIII and VWF depends on the genetic defect that causes the VWF deficiency. We have analyzed the ratio between plasma factor VIII and VWF in several subtypes of Von Willebrand Disease and we show that the ratio is increased when VWF synthesis is reduced, but that the ratio remains one when VWF clearance is increased. These observations could be of clinical importance as an increased factor VIII/VWF ratio in combination with a borderline VWF level may indicate the presence of a true genetic defect, possibly a VWF null allele.

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Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion

Blood ◽

10.1182/blood.v65.4.823.823 ◽

1985 ◽

Vol 65 (4) ◽

pp. 823-831 ◽

Cited By ~ 106

Author(s):

VT Turitto ◽

HJ Weiss ◽

TS Zimmerman ◽

II Sussman

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Vessel Wall ◽

Platelet Adhesion ◽

Human Factor ◽

Rabbit Aorta ◽

Human Factor Viii ◽

Plasma Factor ◽

Von Willebrand ◽

Willebrand Factor

Abstract The present studies were undertaken to determine whether factor VIII/von Willebrand factor (vWF) present in the vessel wall (in addition to that in plasma) may mediate the attachment of platelets to subendothelium. Subendothelium from everted rabbit aorta was exposed to human citrated blood flowing through an annular perfusion chamber at 40 mL/min (wall shear rate of 2,600 s-1 for five minutes). The vessel segments were incubated at 37 degrees C for one hour with various dilutions of either goat-anti-rabbit factor VIII/vWF serum or an IgG fraction prepared from the serum. Control segments were incubated with serum or IgG from a nonimmunized goat. Values of platelet contact (C), platelet adhesion (C + S), and thrombus formation (T) on the subendothelium were evaluated by a morphometric technique. Compared with vessels incubated with fractions prepared from a normal goat, a significant decrease in platelet adhesion (C + S), ranging from 45% to 65%, was observed on vessels incubated with various dilutions (1:5 to 1:50) of either serum or IgG fractions of goat-anti-rabbit factor VIII/vWF. A similar decrease in platelet adhesion was observed with vessels incubated with an F(ab')2 fragment against rabbit factor VIII/vWF prepared in the goat. When goat-anti-rabbit factor VIII/vWF IgG was added to rabbit blood (1:75 dilution), platelet adhesion was reduced to the same extent (65%) on normal rabbit vessels and on vessels pre-incubated with goat-anti-rabbit factor VIII/vWF. Immunofluorescence studies revealed the presence of rabbit factor VIII/vWF in the subendothelium of rabbit aorta and the continued binding of the goat-anti-factor VIII/vWF antibodies on subendothelium during the perfusion studies. No uptake of human factor VIII/vWF on the rabbit subendothelium was observed by this immunologic technique; human factor VIII/vWF was found to be entirely associated with the attached human platelets. Thus, factor VIII/vWF in the vessel wall may mediate platelet attachment to subendothelium in a manner similar to that of plasma factor VIII/vWF.

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