Ristocetin Induced Platelet Factor 3 Availability, A Possible New Tool In The Diagnosis Of Von Willebrand’S Disease

1981 ◽  
Author(s):  
L Muszbek ◽  
H Losonczy ◽  
B Hársfalvi ◽  
I Nagy
Keyword(s):  
Bleeding Time ◽  
Laboratory Diagnosis ◽  
Von Willebrand Disease ◽  
Platelet Factor ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Total Inhibition ◽  
Plasma Factor ◽  
Von Willebrand ◽  
Normal Controls

Ristocetin induced platelet aggregation (RIPA) is a highly valuable technique in the laboratory diagnosis of von Willebrand’s disease (vWD) and together with the estimation of bleeding time, F VIII procoagulant activity and F VIII related antigen in most cases it makes also division of vWD into phenotypic subgroups possible. We have shown that ristocetin makes platelet factor 3 available and ristocetin induced platelet factor 3 availability (RIPF3) similarly to RIPA also depends on a plasma factor. In the present paper it was examined if RIPF3 can be applied as a laboratory test in the diagnosis of vWD. PRP from normal controls, patients with various release defects and von Willebrand patients was incubated and continuously stirred with ristocetin or phys. saline and after 20 min the RW clotting times were determined. RIPF3 activity was expressed as the ratio of the clotting times obtained following incubation with phys. saline and ristocetin.In healthy controls and patients with release defect (n=21) this ratio was higher than 1.5, and in most cases between 1.8-2.5. In patients with vWD (n=10) the ratio was well below 1.5 (with one exception it ranged between 0.95-1.2). In 9 of the lO patients the absence or strong diminution of RIPA and RIPF3 showed close paralellism. In one patient only the slope of first vawe of ristocetin aggregation was decreased while at the same time an almost total inhibition of RIPF3 could be observed. The results indicate that RIPF3 is a valuable quantitative diagnostic test in von Willebrand disease. It can be used if expensive aggregometer is not available and it may also have an importance as additional test to RIPA in the division of vWD into subgroups. An attempt was made to develop this test further by using chromogenic substrate for the measurement of RIPF3.

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.

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

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.

scholarly journals Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN)

Haemophilia ◽  
2012 ◽  
Vol 19 (1) ◽  
pp. 76-81 ◽  
Author(s):  
T. C. Abshire ◽  
A. B. Federici ◽  
M. T. Alvárez ◽  
J. Bowen ◽  
M. D. Carcao ◽  
...  
Keyword(s):  
Von Willebrand Disease ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Von Willebrand

scholarly journals DDAVP in type IIa von Willebrand's disease

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 465-468 ◽  
Author(s):  
HR Gralnick ◽  
SB Williams ◽  
LP McKeown ◽  
ME Rick ◽  
P Maisonneuve ◽  
...  
Keyword(s):  
Factor Viii ◽  
Protease Inhibitors ◽  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Time Period ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor

Abstract 1-D-Amino(8-D-arginine)-vasopressin (DDAVP) infusion in three patients with type IIa von Willebrand's disease (vWD) resulted in a normalization of the factor VIII coagulant, factor VIII-related antigen, and von Willebrand factor (vWF) (ristocetin cofactor) activities and the bleeding time. The normalization of these hemostatic parameters persisted for four hours. Over the same time period there was a marked increase in the quantity of the vWF multimers when blood was collected in the presence of protease inhibitors. The vWF multimers present were even larger than the normal. When blood was collected in the absence of protease inhibitors, a smaller increase in the plasma vWF multimers was observed and fewer of the intermediate and larger vWF multimers were seen; multimers larger than those present in normal plasma were not visualized. The platelet vWF multimers and activities did not change with or without inhibitors. These studies suggest that there is a subgroup of patients with type IIa vWD who respond to DDAVP with complete normalization of their hemostatic abnormalities and whose vWF is sensitive to proteolysis.

scholarly journals Platelet von Willebrand factor: an important determinant of the bleeding time in type I von Willebrand's disease

Blood ◽  
1986 ◽  
Vol 68 (1) ◽  
pp. 58-61 ◽  
Author(s):  
HR Gralnick ◽  
ME Rick ◽  
LP McKeown ◽  
SB Williams ◽  
RI Parker ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Time Factors ◽  
Type I ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen ◽  
Ristocetin Cofactor

Abstract We studied 17 patients with moderate to mild type I von Willebrand's disease (vWd) and correlated the bleeding time with the plasma von Willebrand factor antigen (vWf Ag), the plasma vWf activity (ristocetin cofactor), the platelet vWf Ag, and the platelet vWf activity. We found an excellent correlation between the bleeding time and the platelet vWf activity and, to a lesser extent, between the bleeding time and the platelet vWf Ag. The length of the bleeding time was inversely proportional to the level of the platelet vWf (P less than .001) or, to a lesser extent, the platelet vWf Ag (P less than .05). The plasma vWf Ag and activity did not correlate significantly with the bleeding time. These studies indicate that the platelet vWf is one of the important bleeding time factors in type I vWd and that the platelet vWf plays an important role in the early steps of hemostasis.

Effect Of Prednisone On Platelet Function In Patients With Bleeding Disorders

1981 ◽  
Author(s):  
R McKenna ◽  
F Bachmann ◽  
O Pichairut ◽  
B Whittaker
Keyword(s):  
Platelet Count ◽  
Platelet Function ◽  
Bleeding Time ◽  
Platelet Factor ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Before And After ◽  
History Of ◽  
The Mean ◽  
One Year

There is considerable controversy regarding the effect of Prednisone on the hemostatic mechanism of normal people versus patients with bleeding diatheses. We administered Prednisone 15 mg TID to patients with a positive history of a bleeding disorder, and evaluated the bleeding time and other in-vitrc tests of platelet function prior to and between the 5th and 7th day after Prednisone.Eleven patients were admitted into this study over a one year period. All patients had a history of excessive bruising, epistaxis, bleeding after dental extractions, and gastrointestinal or other bleeding in various combinations. Two out of the eleven had template bleeding times of greater than 15 minutes both before and after the Prednisone. These two patients were subsequently proven to have von Willebrand’s disease by the washed platelet ristocetin assay. In the remaining 9 patients, the pre-Prednisone bleeding time was 9.3 ±3.7 minutes (x ± 1 S.D.) whereas the post-Prednisone bleeding time was 5.8 ±3.6 minutes (x ±1 S.D.). These results were significant(td=3.83;df:7;p=0.007).Platelet aggregation in response to exogenous ADP (1 μM, 3 μM) Sigma bovine tendon collagen (1.8 mg/ml F) and epinephrine (5.5 × 104M), platelet retention in a glass bead column or platelet factor 3 availability did not improve or worsen after Prednisone therapy. The mean platelet count of 328,000±94,000 (x ±1 S.D.) was significantly (p=0.05) higher than the mean pre-Prednisone platelet count of 268,000±77,000 (x ±1 S.D.).In conclusion, we have shown that large doses of Prednisone appear to shorten the bleeding time in patients with significant defects in the primary hemostatic mechanism. However the bleeding time improvement is not evident in patients with von Willebrand’s disease.

scholarly journals The RIIIS/J inbred mouse strain as a model for von Willebrand disease

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2258-2265 ◽  
Author(s):  
JD Sweeney ◽  
EK Novak ◽  
M Reddington ◽  
KH Takeuchi ◽  
RT Swank
Keyword(s):  
Bleeding Time ◽  
Inbred Mouse ◽  
Inbred Mouse Strain ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Serotonin Content ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Plasma Factor ◽  
Von Willebrand

Abstract Mice of the RIIIS/J inbred strain have prolonged bleeding times (greater than 15 minutes) after experimental injury when compared with normal C57BL/6J mice (1.8 minutes) and other strains of mice. The prolonged bleeding time was accompanied by normal platelet counts. Platelet aggregation with collagen and agglutination with ristocetin were not significantly altered in RIIIS/J mice. Also, platelets from RIIIS/J mice had normal serotonin content and normal numbers of dense granules by electron microscopy. Thus, the bleeding abnormality is not due to platelet storage pool deficiency as has been found in several other mouse mutants. The activated partial thromboplastin time (APTT) which plasma from RIIIS/J mice was prolonged compared with normal mice, and factor VIII:C activity and von Willebrand antigen levels were one half to one third that of normal mouse plasma. Factor XI activity was also significantly deficient (levels at 42% to 64% of normal). Plasma of RIIIS/J mice contained the full complement of multimers of von Willebrand factor, although each multimer was lower in concentration compared with that in normal mice. Platelet alpha-granule von Willebrand antigen levels were similar to those of normal mice. The prolonged bleeding time of RIIIS/J mice was corrected by treatment with desmopressin. Heterozygous C57BL/6J x RIIIS/J F1 animals had low plasma von Willebrand antigen levels like the RIIIS/J parent and had variable bleeding times. Inheritance of the bleeding tendency was as an incomplete dominant, autosomal trait. These data indicate the RIIIS/J strain is a suitable animal model for type IA von Willebrand disease.

scholarly journals Analytic Review: Von Willebrand’s Disease-Diagnostic Criteria

Blood ◽  
1968 ◽  
Vol 32 (4) ◽  
pp. 668-679 ◽  
Author(s):  
HARVEY J. WEISS
Keyword(s):  
Bleeding Time ◽  
Autosomal Dominant ◽  
Family Studies ◽  
Progressive Increase ◽  
Plasma Transfusion ◽  
Platelet Factor ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time

Abstract Our present criteria for diagnosing von Willebrand’s disease are summarized below and illustrative examples of recently studied patients are shown in Table 1. A) Prolonged bleeding time and decreased AHG: When these abnormalities, inherited as an autosomal dominant, are found in several family members, they are considered diagnostic for these patients and for their clinically affected relatives, even though the latter may now show both defects (Case 10). In the absence of family studies, the diagnosis would also be made in individual subjects if a history of bleeding in relatives was consistent with autosomal inheritance (Cases 3,13,18). When family studies are negative (sporadic cases) or no history is attainable, a diagnosis of typical von Wille-brand’s disease would also be made (Cases 1,2,4,14,15,16) unless intrinsic platelet defects were found (see below) or plasma transfusion failed to produce a progressive increase in AHG activity. B) Prolonged bleeding time, normal AHG: The diagnosis would be considered "probable" in such a patient if the following criteria were met: 1. There was no evidence of an "intrinsic" platelet abnormality, as indicated by normal values for platelet aggregation, PF-3 availability and ADP release by connective tissue and kaolin and 2. Platelet adhesiveness, by the modified Salzman test, was abnormal and/or the patient’s bleeding time was shortened by transfusion of plasma in a dosage of 13-15 ml. per Kg. body weight. C) Normal bleeding time, decreased AHG (Case 17): A diagnosis of probable von Willebrand’s disease would be made if: 1. An unequivocal pattern of autosomal dominant inheritance, by history, ruled out hemophilia. 2. The Salzman test was abnormal. 3. Transfusion of hemophiliac, as well as normal plasma resulted in a progressive increase in plasma AHG concentration. D) Normal bleeding time, normal AHG: The diagnosis would be considered as "possible" if: 1. There was no evidence of intrinsic platelet abnormality (see B 1). 2. The Salzman test was abnormal. The above criteria are tentative and, undoubtedly, will not satisfy all investigators. To confuse matters even more, some patients who appear to have the "classic" syndrome may also have abnormal platelet factor 338 or fail to "synthesize" AHG after plasma transfusion.13,38 Whether even the "classic" syndrome represents a spectrum of disorders remains to be determined.

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

Blood ◽  
1981 ◽  
Vol 57 (1) ◽  
pp. 25-31 ◽  
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.

scholarly journals Subunit composition of plasma von Willebrand factor in patients with the myeloproliferative syndrome

Blood ◽  
1986 ◽  
Vol 68 (6) ◽  
pp. 1213-1217 ◽  
Author(s):  
U Budde ◽  
JA Dent ◽  
SD Berkowitz ◽  
ZM Ruggeri ◽  
TS Zimmerman
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Polyacrylamide Gel Electrophoresis ◽  
Von Willebrand's Disease ◽  
Von Willebrand’S Disease ◽  
Prolonged Bleeding Time ◽  
Myeloproliferative Syndrome ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract In order to evaluate the role of proteolysis in acquired von Willebrand's disease (vWD) associated with the myeloproliferative syndrome, we have determined the relative quantity of von Willebrand factor (vWF) fragments as compared with the intact 225 kDa subunit in four patients. The plasma vWF of each individual lacked large multimers; each had a prolonged bleeding time; and both platelet and leukocyte counts were elevated. Plasma was obtained from blood drawn into 1 mmol/L leupeptin, 6 mmol/L N-ethylmaleimide, and 5 mmol/L EDTA to prevent in vitro proteolysis. vWF was isolated from plasma by immunoadsorbent chromatography, reduced, subjected to SDS-5% polyacrylamide gel electrophoresis, and immunoblotted with a mixture of 55 anti-vWF monoclonal antibodies. In three patients with essential thrombocytosis (ET) the 176 and 140 kDa fragments were increased in proportion to the intact 225 kDa subunit indicating increased proteolysis. Treatment of one ET patient with CCNU (Lomustine) decreased the platelet count and, to a lesser extent, the white blood cell count. This was associated with a correction of the bleeding time, a partial correction of the multimeric abnormality, and a lessening of vWF cleavage. In a patient with polycythemia rubra vera (PRV) the proportion of the 176 kDa fragment was increased to the upper limit of normal but there was no definite evidence of increased proteolysis. These studies provide evidence that proteolysis plays a role in the acquired von Willebrand's disease associated with the myeloproliferative syndrome. However, other mechanisms must also be considered.

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