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

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.

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

Blood ◽

10.1182/blood.v67.4.1148.bloodjournal6741148 ◽

1986 ◽

Vol 67 (4) ◽

pp. 1148-1153 ◽

Cited By ~ 120

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.

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

Blood ◽

10.1182/blood.v76.11.2258.2258 ◽

1990 ◽

Vol 76 (11) ◽

pp. 2258-2265 ◽

Cited By ~ 39

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.

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

Blood ◽

10.1182/blood.v76.11.2258.bloodjournal76112258 ◽

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.

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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 ◽

10.1182/blood.v74.6.1972.1972 ◽

1989 ◽

Vol 74 (6) ◽

pp. 1972-1975 ◽

Cited By ~ 69

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.

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Subcutaneous Desmopressin (DDAVP) Shortens the Prolonged Bleeding Time in Patients with Liver Cirrhosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647318 ◽

1990 ◽

Vol 64 (03) ◽

pp. 358-360 ◽

Cited By ~ 40

Author(s):

Marco Cattaneo ◽

Paola M Tenconi ◽

Ignazio Alberca ◽

Vicente Vicente Garcia ◽

Pier Mannuccio Mannucci

Keyword(s):

Liver Cirrhosis ◽

Bleeding Time ◽

Bleeding Disorders ◽

Double Blind ◽

Subcutaneous Injections ◽

Prolonged Bleeding ◽

Prolonged Bleeding Time ◽

Von Willebrand ◽

Willebrand Factor ◽

Factor Antigen

SummaryThe intravenous infusion of 1-deamino-8-D-arginine vasopressin (DDAVP) shortens the prolonged bleeding time in patients with congenital or acquired bleeding disorders, including patients with uremia or liver cirrhosis. We carried out a double-blind, placebo-controlled crossover study in ten patients with liver cirrhosis to evaluate whether or not their prolonged bleeding times could be shortened by subcutaneous injections of DDAVP (0.3 μg/kg), a more practical route of administration than intravenous infusions. One hour after DDAVP injection the bleeding time was significantly shortened (p <0.05). After 4 h, however, the bleeding time shortening was no longer statistically significant. There was no bleeding time change after placebo. Plasma levels of von Willebrand factor antigen (vWF: Ag) did not significantly increase after DDAVP or placebo. The study shows that subcutaneous DDAVP is an alternative method for shortterm shortening of the bleeding time in liver cirrhosis.

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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 ◽

10.1182/blood.v74.6.1972.bloodjournal7461972 ◽

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.

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

Blood ◽

10.1182/blood.v79.12.3130.3130 ◽

1992 ◽

Vol 79 (12) ◽

pp. 3130-3137 ◽

Cited By ~ 7

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.

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

Blood ◽

10.1182/blood.v79.12.3130.bloodjournal79123130 ◽

1992 ◽

Vol 79 (12) ◽

pp. 3130-3137 ◽

Cited By ~ 86

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

10.1055/s-0039-1689493 ◽

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.

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Is a Standardized Preoperative Questionnaire a Good Tool To Detected Coagulation Disorders In Children

Blood ◽

10.1182/blood.v122.21.4786.4786 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4786-4786

Author(s):

Susan Halimeh ◽

Hannelore Rott ◽

Guenther Kappert ◽

Manuela Siebert

Keyword(s):

Bleeding Time ◽

Postoperative Bleeding ◽

Bleeding Disorder ◽

Von Willebrand Disease ◽

Coagulation Disorders ◽

Good Tool ◽

Prolonged Bleeding Time ◽

Prolonged Aptt ◽

Von Willebrand ◽

Preoperative Examination

Introduction In our study 144 children were send to our coagulation centre with a positive anamnesis (such as haematomas or nose bleeding’s) a positive family anamnesis (p.e. Mother with Menorrhagie) or a prolonged aPTT during a standardized preoperative examination. Samples and Methods We analyzed samples of 144 children by conduction the following tests: Blood count, VWF:RCo, VWF:Ag, VWF:CB, Fibrinogen (Clauss), activities of FII, FV, FVII, FVIII (clotting and chromogenic), FIX, FX, FXI, FXII, FXIII. Results In 107 of 144 children (74.3%) a bleeding disorder could be detected. In those with a bleeding disorder the distribution was as followed: 23.6% had a von Willebrand disease, 27.8% had a prolonged bleeding time and 5.6% a factor XIII-deficiency. The remaining 43% hat other bleeding. disorders (e.g. FVIII-deficiency, FVII-deficiency and other mild factor deficiencies). Discussion A standardized preoperative questionnaire can be useful in clinical practice. In our study 74.3% children with one or more positive evidence in the anamnesis suffer from a bleeding disorder. It is specifically noticeable that we found in 68% of the children which mother has a menorrhagia a bleeding disorder. In 31.8% of the children we found a von Willebrand disease. In our more coagulation disorders could be detected if a standardized preoperative questionnaire would be used and if we pay more attention to children with would a mothers with menorrhagia. Conclusions Children from mothers with menorrhagia suffer more frequently from a bleeding disorder. In our patients in 75% of the children with a mother with menorrhagia a bleeding disorder was found. To avoid an unexpected bleeding during a planned surgery or a postoperative bleeding a standardized preoperative questionnaire should be performed. Disclosures: Halimeh: Octapharma AG: Investigator Other, Research Funding.

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