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 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

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.

Von Willebrand Disease (vWd) Characterized by Increased Ristocetin Aggregation: A Study of Eleven Cases

1975 ◽  
Author(s):  
N. Ciavarella ◽  
F. I. Pareti ◽  
Z. M. Ruggeri ◽  
P. M. Mannucci
Keyword(s):  
Factor Viii ◽  
Bleeding Time ◽  
Autosomal Dominant ◽  
Von Willebrand Disease ◽  
Bleeding Tendency ◽  
Laboratory Findings ◽  
Prolonged Bleeding Time ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Antihemophilic Factor

The defective ristocetin aggregation occurring in patients with vWd is thought to depend on the decrease of a plasmatic factor related to factor VIII (Willebrand factor, VIIIVWF) 10 patients from 3 families had a mild to moderate bleeding tendency with autosomal dominant pattern of inheritance and laboratory findings suggestive for vWd (decreased levels of antihemophilic factor, and factor- VIII related antigen reduced platelet retention to glass beads columns and prolonged bleeding time). However, ristocetin aggregation in PRP was markedly increased, although VIIIVWF plasma levels were decreased. Aggregation induced in PRP by other agents (such as ADP, adrenaline and collagen), and the release of 14C serotonin was normal; the addition of purified bovine factor VIII was followed by normal aggregation in patients’ PRP and washed platelets. Patients’ washed platelets added to normal plasma aggregated to ristocetin more than normal washed platelets with patients’ plasma; the most marked aggregation response, however, was obtained when patients’ washed platelets were mixed with their own plasma. These findings suggest that a, platelet component is involved in the hyperaggregation response to ristocetin of these patients; however, the interaction of platelets with patients’ plasma is needed to produce the maximum response.Supported by a grant of the Fondazione Angelo Bianchi Bonomi.

scholarly journals Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1148-1153 ◽  
Author(s):  
PM Mannucci ◽  
V Vicente ◽  
L Vianello ◽  
M Cattaneo ◽  
I Alberca ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Bleeding Time ◽  
Controlled Trial ◽  
Randomized Study ◽  
Von Willebrand Disease ◽  
Severe Thrombocytopenia ◽  
Platelet Dysfunction ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Von Willebrand

Abstract The synthetic vasopressin derivative desmopressin (DDAVP) shortens a prolonged bleeding time (BT) in patients with uremia, congenital platelet dysfunction, and von Willebrand disease. To establish the limits of the clinical usefulness of DDAVP, a controlled randomized study was carried out in 53 patients and ten volunteers with different conditions that have in common a prolonged BT. DDAVP significantly shortened the BT in 21 cirrhotics (P less than .01), in eight patients with unclassified prolonged BT (P less than .05) and in ten volunteers taking the antiplatelet drugs aspirin (P less than .05) and ticlopidine. The BT changes were not statistically significant in 15 patients with severe thrombocytopenia nor in nine with congenital platelet dysfunction, even though a few patients with storage pool deficiency responded with a marked BT shortening. Our findings indicate that DDAVP might be given when biopsies or other surgical procedures must be carried out in patients with prolonged BT. However, the compound is often ineffective in patients with thrombocytopenia or congenital platelet dysfunction.

Is There a Need for Extensive Haemostatic Screening in Neurosurgical Patients Using Valproic Acid?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1137-1137
Author(s):  
Clara PW Klerk ◽  
Djamila E Issa ◽  
Johannes C Baayen ◽  
Sonja Zweegman
Keyword(s):  
Valproic Acid ◽  
Platelet Function ◽  
Bleeding Complication ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Repeat Testing ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Neurosurgical Patients ◽  
Von Willebrand

Abstract Abstract 1137 Introduction Various haemostatic abnormalities have been reported in association with use of the anti-epileptic drug valproic acid (VPA). When neurosurgical procedures were performed in patients on VPA, our center performed extensive haemostatic screening preoperatively. However, the clinical importance of abnormal findings is unclear. In the current report we evaluate the need for elaborate haemostatic investigations and make recommendations for clinical practice. Materials and Methods We reviewed medical records of all neurosurgical patients on VPA in our university clinic from February 2006 through May 2011 and recorded outcome of the extensive haemostatic screening, any perioperative measures to prevent extensive blood loss and the occurrence of bleeding complications during or after surgery. Results A total of 65 consecutive patients using VPA had a neurosurgical procedure performed and underwent preoperative haemostatic screening. In 34 patients persistent laboratory abnormalities were found and the proportion was similar in the 13 patients who reported a bleeding tendency as in the 52 who did not. However, 5/6 patients who reported a clear time relation between start of VPA use and their bleeding tendency were found to have lab abnormalities. Five of the 65 patients had a mild thrombocytopenia (range 100–150 *10E9/L). 17/63 patients had a prolonged bleeding time of which 5 had normalized on repeat testing. 9/65 had a decreased von Willebrand cofactor activity. Only 2 of these had a prolonged bleeding time. Twelve patients had abnormal platelet function tests but in 3 these normalized on repeat testing. CT and PT were normal in all patients and fibrinogen was marginally lowered in 14/65 (lowest 1.2 g/L). Factor XIII was tested in 57 patients and no clinically relevant lowering was perceived (lowest 0.47 IU/mL). Clinical consequences of the laboratory results were left to the treating haematologist. Additional perioperative measures were taken in 15 patients (stopping VPA in 3, administering DDAVP in 12 and tranexaminic monotherapy in one). Two of 65 patients had a bleeding complication: in one no bleeding time was performed but all other tests were normal. Despite tranexaminic acid perioperatively she developed a large subdural hematoma and seizures. None of the other patients with normal lab values had a bleeding complication. The second patient had had uncomplicated non-neurological surgery during VPA use and was found to have a mildly abnormal ATP/ADP ratio. Because of his uncomplicated history no additional measures were taken and he developed a large epidural hematoma. Conclusion In our cohort of 65 neurosurgical patients using VPA, none had clinically relevant abnormalities in PT, aPTT, thrombocyte count, fibrinogen or fXIII level. Therefore, these tests appear unnecessary in the preoperative screening of patients on VPA. However, even in the presence of a normal bleeding time, clinically relevant lowering of von Willebrand factor, and abnormalities in platelet function should actively be sought after. In these cases, we recommend treatment with DDAVP perioperatively. Unlike others (Kreuz et al, Epilepsia 1992), we found DDAVP to be safe and effective in our neurosurgical population. Whether an isolated prolonged bleeding time in absence of demonstrated platelet abnormalities necessitates additional perioperative measures should be the subject of further study. In our cohort the majority of patients with an unexplained prolonged bleeding time received DDAVP perioperatively. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Controlled trial of desmopressin in liver cirrhosis and other conditions associated with a prolonged bleeding time

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1148-1153 ◽  
Author(s):  
PM Mannucci ◽  
V Vicente ◽  
L Vianello ◽  
M Cattaneo ◽  
I Alberca ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Bleeding Time ◽  
Controlled Trial ◽  
Randomized Study ◽  
Von Willebrand Disease ◽  
Severe Thrombocytopenia ◽  
Platelet Dysfunction ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Von Willebrand

The synthetic vasopressin derivative desmopressin (DDAVP) shortens a prolonged bleeding time (BT) in patients with uremia, congenital platelet dysfunction, and von Willebrand disease. To establish the limits of the clinical usefulness of DDAVP, a controlled randomized study was carried out in 53 patients and ten volunteers with different conditions that have in common a prolonged BT. DDAVP significantly shortened the BT in 21 cirrhotics (P less than .01), in eight patients with unclassified prolonged BT (P less than .05) and in ten volunteers taking the antiplatelet drugs aspirin (P less than .05) and ticlopidine. The BT changes were not statistically significant in 15 patients with severe thrombocytopenia nor in nine with congenital platelet dysfunction, even though a few patients with storage pool deficiency responded with a marked BT shortening. Our findings indicate that DDAVP might be given when biopsies or other surgical procedures must be carried out in patients with prolonged BT. However, the compound is often ineffective in patients with thrombocytopenia or congenital platelet dysfunction.

scholarly journals DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 1972-1975 ◽  
Author(s):  
M Cattaneo ◽  
M Moia ◽  
P Delle Valle ◽  
P Castellana ◽  
PM Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Double Blind ◽  
Prolonged Bleeding ◽  
Primary Hemostasis ◽  
Prolonged Bleeding Time ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract After infusion of cryoprecipitate, the very prolonged bleeding time of patients with severe von Willebrand disease (vWD) is shortened but not always normalized in spite of normalization of plasma von Willebrand factor (vWF) levels. Therefore treatments that further improve primary hemostasis in severe vWD patients are needed. Since DDAVP shortens the bleeding time in a variety of bleeding disorders, we investigated in a double-blind, placebo-controlled crossover study the effects of the intravenous (IV) infusion of DDAVP (0.3 microgram/kg) on the bleeding times of 10 patients with severe vWD treated with cryoprecipitate. Their very prolonged bleeding times (greater than 30 minutes), partially corrected by the infusion of cryoprecipitate (14 +/- 2 minutes, mean +/- SEM), were further shortened by the administration of DDAVP (9 +/- 2 minutes, P less than .01) but not of saline (15 +/- 3 minutes, ns). Plasma vWF levels, raised from unmeasurable to normal values by cryoprecipitate, were not changed after DDAVP or saline. The defective deposition of platelets from eight patients onto human umbilical artery subendothelium was increased but not normalized by cryoprecipitate and was not significantly affected by DDAVP or saline. Therefore the infusion of DDAVP after cryoprecipitate may be of clinical benefit for management of bleeding episodes in severe vWD patients. Since severe vWD patients do not have releasable tissue stores of vWF, DDAVP must shorten their prolonged bleeding times independently of released vWF.

DDAVP shortens the prolonged bleeding times of patients with severe von Willebrand disease treated with cryoprecipitate. Evidence for a mechanism of action independent of released von Willebrand factor

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 1972-1975
Author(s):  
M Cattaneo ◽  
M Moia ◽  
P Delle Valle ◽  
P Castellana ◽  
PM Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Double Blind ◽  
Prolonged Bleeding ◽  
Primary Hemostasis ◽  
Prolonged Bleeding Time ◽  
Bleeding Episodes ◽  
Von Willebrand ◽  
Willebrand Factor

After infusion of cryoprecipitate, the very prolonged bleeding time of patients with severe von Willebrand disease (vWD) is shortened but not always normalized in spite of normalization of plasma von Willebrand factor (vWF) levels. Therefore treatments that further improve primary hemostasis in severe vWD patients are needed. Since DDAVP shortens the bleeding time in a variety of bleeding disorders, we investigated in a double-blind, placebo-controlled crossover study the effects of the intravenous (IV) infusion of DDAVP (0.3 microgram/kg) on the bleeding times of 10 patients with severe vWD treated with cryoprecipitate. Their very prolonged bleeding times (greater than 30 minutes), partially corrected by the infusion of cryoprecipitate (14 +/- 2 minutes, mean +/- SEM), were further shortened by the administration of DDAVP (9 +/- 2 minutes, P less than .01) but not of saline (15 +/- 3 minutes, ns). Plasma vWF levels, raised from unmeasurable to normal values by cryoprecipitate, were not changed after DDAVP or saline. The defective deposition of platelets from eight patients onto human umbilical artery subendothelium was increased but not normalized by cryoprecipitate and was not significantly affected by DDAVP or saline. Therefore the infusion of DDAVP after cryoprecipitate may be of clinical benefit for management of bleeding episodes in severe vWD patients. Since severe vWD patients do not have releasable tissue stores of vWF, DDAVP must shorten their prolonged bleeding times independently of released vWF.

scholarly journals Comparison of four virus-inactivated plasma concentrates for treatment of severe von Willebrand disease: a cross-over randomized trial

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3130-3137 ◽  
Author(s):  
PM Mannucci ◽  
PM Tenconi ◽  
G Castaman ◽  
F Rodeghiero
Keyword(s):  
Plasma Levels ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Prolonged Bleeding Time ◽  
Randomized Design ◽  
Coagulant Activity ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity

Abstract Until recently, cryoprecipitate has been the treatment of choice in patients with severe von Willebrand disease (vWD) because it can transiently correct low plasma levels of factor VIII coagulant activity (FVIII:C) and shorten or normalize the prolonged bleeding time (BT), the two laboratory hallmarks of the disease. However, cryoprecipitate may still transmit blood-borne viruses, whereas the development of virucidal methods have rendered plasma concentrates containing FVIII:C and von Willebrand factor (vWF) safer. To establish their potential usefulness in the treatment of vWD, we compared the effect of four virus-inactivated concentrates on FVII:C and vWF plasma levels and the BT (template method) in 10 patients with severe vWD using a crossover randomized design. The concentrates were an intermediate-purity, pasteurized FVIII-vWF concentrate; an intermediate-purity, dry-heated FVIII-vWF concentrate; a solvent/detergent-treated vWF concentrate, containing little FVIII; and a high-purity solvent/detergent-treated FVIII-vWF concentrate. All concentrates were equally effective in attaining normal and sustained levels of FVIII:C postinfusion, although peak levels were more delayed after the vWF concentrate. The effect of concentrates on the BT, however, was less uniform and satisfactory. The pasteurized FVIII-vWF concentrate transiently corrected, completely or partially, the BT in 8 of 10 patients, the dry-heated and solvent/detergent FVIII/vWF concentrates in five, whereas in no patient did the vWF concentrate correct the BT according to the criteria used in this study. These effects on the BT were not related to the plasma levels of ristocetin cofactor activity-attained postinfusion (100 U/dL or more in the majority of patients) or to the multimeric structure of vWF in concentrates (defective in larger multimers in all cases). In conclusion, even though virus-inactivated concentrates can be used to increase FVIII:C levels in patients with severe vWD, none of the concentrates studied by us consistently normalizes the BT in a sustained fashion.

scholarly journals Patients with a prolonged bleeding time and normal aggregation tests may have storage pool deficiency: studies on one hundred six patients

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 620-623 ◽  
Author(s):  
HK Nieuwenhuis ◽  
JW Akkerman ◽  
JJ Sixma
Keyword(s):  
Platelet Count ◽  
Bleeding Time ◽  
Bleeding Tendency ◽  
Von Willebrand's Disease ◽  
Common Disorder ◽  
Storage Pool ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time ◽  
Platelet Serotonin

Abstract One hundred six patients with storage pool deficiency (SPD) were studied with respect to platelet count, bleeding time, total platelet ATP and ADP, platelet serotonin, and in vitro aggregation. The diagnosis of SPD was made on basis of a prolonged bleeding time, a decreased total platelet ADP, and a diminished level of serotonin. Fifty-one patients from 34 unrelated families had congenital SPD, and 55 patients had acquired SPD. Congenital SPD was a common disorder in patients with a lifelong bleeding tendency and a prolonged bleeding time. The frequency in this group of patients was 18%, about one-half the frequency of von Willebrand's disease (vWd). Twenty-three percent of all patients had normal aggregation responses to ADP, epinephrine, and collagen; 33% had aggregation tracings typical for a secretion defect; and 44% had miscellaneous aggregation abnormalities. These findings indicate that SPD is common, heterogeneous, and not necessarily associated with in vitro aggregation abnormalities.

scholarly journals Comparison of four virus-inactivated plasma concentrates for treatment of severe von Willebrand disease: a cross-over randomized trial

Blood ◽  
1992 ◽  
Vol 79 (12) ◽  
pp. 3130-3137 ◽  
Author(s):  
PM Mannucci ◽  
PM Tenconi ◽  
G Castaman ◽  
F Rodeghiero
Keyword(s):  
Plasma Levels ◽  
Bleeding Time ◽  
Von Willebrand Disease ◽  
Prolonged Bleeding Time ◽  
Randomized Design ◽  
Coagulant Activity ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Ristocetin Cofactor ◽  
Ristocetin Cofactor Activity

Until recently, cryoprecipitate has been the treatment of choice in patients with severe von Willebrand disease (vWD) because it can transiently correct low plasma levels of factor VIII coagulant activity (FVIII:C) and shorten or normalize the prolonged bleeding time (BT), the two laboratory hallmarks of the disease. However, cryoprecipitate may still transmit blood-borne viruses, whereas the development of virucidal methods have rendered plasma concentrates containing FVIII:C and von Willebrand factor (vWF) safer. To establish their potential usefulness in the treatment of vWD, we compared the effect of four virus-inactivated concentrates on FVII:C and vWF plasma levels and the BT (template method) in 10 patients with severe vWD using a crossover randomized design. The concentrates were an intermediate-purity, pasteurized FVIII-vWF concentrate; an intermediate-purity, dry-heated FVIII-vWF concentrate; a solvent/detergent-treated vWF concentrate, containing little FVIII; and a high-purity solvent/detergent-treated FVIII-vWF concentrate. All concentrates were equally effective in attaining normal and sustained levels of FVIII:C postinfusion, although peak levels were more delayed after the vWF concentrate. The effect of concentrates on the BT, however, was less uniform and satisfactory. The pasteurized FVIII-vWF concentrate transiently corrected, completely or partially, the BT in 8 of 10 patients, the dry-heated and solvent/detergent FVIII/vWF concentrates in five, whereas in no patient did the vWF concentrate correct the BT according to the criteria used in this study. These effects on the BT were not related to the plasma levels of ristocetin cofactor activity-attained postinfusion (100 U/dL or more in the majority of patients) or to the multimeric structure of vWF in concentrates (defective in larger multimers in all cases). In conclusion, even though virus-inactivated concentrates can be used to increase FVIII:C levels in patients with severe vWD, none of the concentrates studied by us consistently normalizes the BT in a sustained fashion.

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