Familial Clustering of Factor VIII and von Willebrand Factor Levels

1998 ◽  
Vol 79 (02) ◽  
pp. 323-327 ◽  
Author(s):  
Jeanine Houwing-Duistermaat ◽  
Hans van Houwelingen ◽  
Jeroen Eikenboom ◽  
Rogier Bertina ◽  
Frits Rosendaal ◽  
...  
Keyword(s):  
Factor Viii ◽  
Blood Group ◽  
Von Willebrand Factor ◽  
Familial Aggregation ◽  
Univariate Analysis ◽  
Clotting Factor ◽  
Thrombotic Risk ◽  
Plasma Factor ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryRecently, we found that high levels of clotting factor VIII (>150 IU/dl) are common and make an important contribution to thrombotic risk. The determinants of high factor VIII:C are unclear and might be partly genetic. Therefore, we tested the influence of age, blood group and von Willebrand factor (VWF) levels on factor VIII:C levels, and investigated whether factor VIII:C levels are genetically determined. We performed an analysis of 564 female relatives of hemophilia A patients, who had visited our center for genetic counseling. In univariate analysis, AB0 blood group, age and VWF antigen (VWF:Ag) levels all influenced factor VIII:C levels. After adjustment for the effect of VWF:Ag levels, both blood group and age still had an effect on factor VIII:C levels. In sister pairs, the Pearson correlation coefficient between factor VIII:C levels was 0.17 (p = 0.024) and this correlation remained positive (0.15, p = 0.046) after correction for the influence of VWF:Ag. In mother-daughter pairs, no correlation of factor VIII:C levels was found. The correlation of VWF:Ag levels in sisterpairs was 0.41 (p <0.001) and in mother-daughter pairs 0.44 (p <0.001), in line with the assumption that VWF:Ag levels are under control of autosomal genes. Familial influence on plasma factor VIII:C and VWF:Ag levels was investigated with a recently developed familial aggregation test. This test verifies whether familial aggregation of a particular parameter exists in a set of pedigrees. In 435 women from 168 families, factor VIII:C as well as VWF:Ag levels correlated significantly within families, which suggests a familial influence. The familial aggregation was more prominent for VWF:Ag levels than for factor VIII:C levels, possibly because the genetic effect on VWF:Ag levels is larger than on factor VIII:C levels. Our results support the presence of a familial influence on factor VIII:C as well as on VWF:Ag levels.Our results support the presence of a familial influence on factor VIII:C as well as on VWF:Ag levels.

A New Animal Model of Thrombophilia Confirms that High Plasma Factor VIII Levels Are Thrombogenic

1999 ◽  
Vol 81 (02) ◽  
pp. 306-311 ◽  
Author(s):  
Tomihisa Kawasaki ◽  
Takehiro Kaida ◽  
Jef Arnout ◽  
Jos Vermylen ◽  
Marc Hoylaerts
Keyword(s):  
Factor Viii ◽  
Intravenous Injection ◽  
Von Willebrand Factor ◽  
Clotting Factor ◽  
Dependent Manner ◽  
Elevated Plasma ◽  
Thrombotic Risk ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Thrombotic Tendency

SummaryThe thrombotic risk associated with elevated plasma levels of clotting factor VIII (FVIII) was investigated in a mouse model of thrombophilia. After the intravenous injection of recombinant human FVIII and/or of purified FVIII-free human von Willebrand factor (vWF), a controlled mild injury was inflicted on the carotid artery of FVB mice by irradiation with filtered green light in combination with intravenous injection of the dye rose bengal. Formation of a platelet-rich thrombus was continuously monitored for 40 min via transillumination and the thrombus size was measured via image analysis. Administration of recombinant human FVIII at 40 g/kg led to initial FVIII plasma activities equivalent to 250% of normal human plasma FVIII activity and significantly enhanced thrombus size. Immunohistochemical staining illustrated the accumulation of FVIII within the thrombi. Human vWF, even at 10 mg/kg, had no effect on thrombus formation. The thrombotic tendency induced by FVIII was significantly inhibited by the administration of human vWF in a dose-dependent manner. Separate plasma measurements revealed that human FVIII has comparable affinities for human and murine vWF but that human vWF does not effectively bind murine platelets. The inhibition by human vWF of the thrombotic tendency induced by human FVIII could therefore be explained by a lack of accumulation of FVIII within the developing thrombus because of the reduced affinity of human vWF for murine platelets and the reduced occupancy of murine von Willebrand factor by human FVIII after injection of human vWF. These results show that vWF actively participates in FVIII accumulation in the arterial thrombus and provide experimental evidence for epidemiological findings that elevated plasma FVIII levels are associated with an increased thrombotic risk, also in arteries.

scholarly journals Factor VIII/von Willebrand factor in subendothelium mediates platelet adhesion

Blood ◽  
1985 ◽  
Vol 65 (4) ◽  
pp. 823-831 ◽  
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

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.

scholarly journals Influence of blood group, von Willebrand factor levels, and age on factor VIII levels in non‐severe haemophilia A

2020 ◽  
Vol 18 (5) ◽  
pp. 1081-1086
Author(s):  
Judit Rejtő ◽  
Oliver Königsbrügge ◽  
Ella Grilz ◽  
Stefanie Hofer ◽  
Lisa‐Marie Mauracher ◽  
...  
Keyword(s):  
Factor Viii ◽  
Blood Group ◽  
Von Willebrand Factor ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Von Willebrand ◽  
Willebrand Factor

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

Blood ◽  
1982 ◽  
Vol 59 (6) ◽  
pp. 1272-1278 ◽  
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.

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

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.

The Relationship between ABO Groups, Factor VIII, von Willebrand Factor Levels and Platelet Function Analysis Using Cone and Plate(let) Analyzer.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4024-4024
Author(s):  
Maria Lourdes Barjas Castro ◽  
Aline Crucello ◽  
Heloise P. Fernandes ◽  
Norma C. Sousa ◽  
Joyce M. Annichino-Bizzacchi ◽  
...  
Keyword(s):  
Factor Viii ◽  
Blood Group ◽  
Platelet Function ◽  
Von Willebrand Factor ◽  
Function Analysis ◽  
World Health ◽  
Enzyme Linked Immunosorbent Assay ◽  
Abo Blood Group ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract ABO blood group has been described to influence levels of von Willebrand factor (VWF), as well as factor VIII. Individuals carrying O allele have significant lower plasma levels of these factors. Indeed, recently non-O individuals have been described to have increased risk for both, arterial and venous thrombotic disease. VWF mediate platelet interaction with areas of damage blood vessel wall. Thus, it could be interesting to evaluate the possible influence of the ABO group in this interaction, particularly in situations in which low levels of VWF are close to those found in VW disease (such in O group). Cone and plate(let) analyzer (CPA) represent a simple and fast method, that allow the evaluation of platelet function (adhesion as well aggregation) in whole blood under shear conditions, closer to physiological conditions. In this method, no platelet agonists are needed and interaction with fibrinogen and VWF is particularly evaluated. The aim of the present study was to evaluate the influence of ABO group in platelet function using CPA. Samples from 15 male blood donors with no history of drug intake, were submitted to ABO serology and molecular analysis, VWF:Ag, FVIII dosages, and CPA analysis using Impact-R (Diamed - Switzerland), according to manufacturer’s instructions. ABO phenotypes were determined by agglutination test using monoclonal and polyclonal anti-A, B and AB antibodies (Asem-NPBI, São Paulo Brazil; DiaMed SA, Suisse; DiaMed Latino América, Brazil). H antigen was determined using anti-H lectin from Ulex europaeus (DiaMed Latino América, Brazil). ABO genotyping was performed by polymerase chain reaction (PCR) amplification of exons 6 and 7 of the ABO gene, followed by diagnostic restriction enzyme digestion. Factor VIII coagulant was measured by a one stage clothing method using a factor-VIII deficient substrate. VWF:Ag was measured by an enzyme linked immunosorbent assay (ELISA) using polyclonal antiserum (Dako, Denmark). Lyophilised commercial reference preparations of VWF:Ag, and FVIII, standardized against the World Health Organization standard, were used as the standards in this study. The age of the donors ranged from 27–65 years (median = 42 years). The donors were distributed according to ABO groups: 5 = OO; 5 = AB; 5 = AO. Median levels of factor VIII, according to blood group were: OO= 79% (70–142%); AO= 87% (80–140%); AB= 112% (98–200%). Median levels of VWF, according to blood group were: OO= 79% (50–99%); AO= 82% (73–120%); AB= 169% (92–250%). CPA analysis presented the following results: median AS in μm2 (average size) - OO= 24 (23–42); AO= 33 (24–42); AB= 23 (21–24) - median SC in % (surface coverage) - OO= 7.1 (4–13); AO= 8 (5–8); AB= 6.9 (4.8–8). No significant differences using Wilcoxon’s rank sum test were found among groups, when platelet function was analyzed. In conclusion, our results suggest that, although O allele carriers present lower levels of both factor VIII and VWF, the use of platelet function analysis does not seem to predict the risk for bleeding or thrombosis, according to individual ABO blood group.

Compromised Proteolytic Cleavage of Von Willebrand Factor Type 2N Variants by ADAMTS13 in the Presence of Factor VIII (and Platelets) Under Fluid Shear Stress.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 28-28
Author(s):  
Christopher G. Skipwith ◽  
Sandra L. Haberichter ◽  
Wenjing Cao ◽  
Ashley L. Gehrand ◽  
X. Long Zheng
Keyword(s):  
Shear Stress ◽  
Factor Viii ◽  
Von Willebrand Factor ◽  
Fluid Shear Stress ◽  
Proteolytic Cleavage ◽  
Binding Activity ◽  
Clotting Factor ◽  
Fluid Shear ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Abstract 28 von Willebrand Factor (VWF) is a large, multimeric adhesive glycoprotein that is involved in the formation of a platelet plug after vascular injury. In addition, VWF functions as a carrier protein for clotting factor VIII (FVIII) which prevents rapid clearance of plasma FVIII. Decreased levels of VWF or defects in VWF function are found in patients with von Willebrand disease (VWD). Quantitative defects of VWF protein in type 1 and 3 VWD affect plasma levels of both VWF and FVIII, whereas qualitative defects in type 2 VWD result in abnormal binding of VWF to platelets such as in type 2A, 2B, and 2M, or to FVIII such as in type 2N. Previous studies have demonstrated that FVIII binds VWF, which dramatically accelerates the proteolytic cleavage of multimeric VWF by ADAMTS13 under mechanically-induced shear stresses. This rate-enhancing effect of FVIII on VWF proteolysis appears to depend on the ability of FVIII to bind VWF, as a FVIII variant lacking the A3 acidic region fails to exhibit the cofactor activity that accelerates VWF proteolysis. To determine whether reduced FVIII binding in VWF type 2N variants affects VWF proteolysis, we examined the proteolytic cleavage of recombinant VWF type 2N variants in the presence of FVIII (and lyophilized platelets) for variants with a moderate VWD phenotype (Arg854Gln and His817Gln) or severe VWD phenotype (Arg763Gly, Arg782Trp, Thr791Met, and Arg782Trp + His817Gln). Recombinant VWF type 2N variants (37.5 μg/ml or 150 nM) were incubated with ADAMTS13 (25 nM) in the absence and the presence of various concentrations of FVIII (0-40 nM) with or without lyophilized platelets (0-600×103/μl) under fluid shear stress. The proteolytic cleavage products (350 kDa) were determined by 5% SDS-PAGE and Western blot under denaturing but non-reducing conditions. We show that the proteolytic cleavage of VWF type 2N variants by ADAMTS13 under these conditions was variably reduced as compared that of wild type VWF. The reduction in the cleavage rate was proportional to the degree of reduction in VWF FVIII binding activity, which was assessed with a microtiter assay, with the least cleavage by ADAMTS13 of the variants with the lowest FVIII binding activity. This reduced cleavage of the type 2N variants was not correlated with the binding affinity between the type 2N variants and ADAMTS13 protease. These results provide further evidence that binding of FVIII to VWF, which may alter VWF conformation, is necessary to accelerate VWF proteolysis by ADAMTS13 under fluid shear stress. This variability in ADAMTS13 cleavage may contribute to the heterogeneity of bleeding phenotype of type 2N VWD variants. The bleeding phenotype may be modulated not only by plasma FVIII levels, but also the extent of VWF proteolysis by ADAMTS13 under physiological fluid shear stress. Disclosures: No relevant conflicts of interest to declare.

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