scholarly journals Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders [see comments]

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1449-1455 ◽  
Author(s):  
PM Mannucci
Keyword(s):  
Arginine Vasopressin ◽  
Von Willebrand Disease ◽  
Synthetic Analogue ◽  
Bleeding Disorders ◽  
Spinal Fusion Surgery ◽  
Prolonged Bleeding Time ◽  
Normal Individuals ◽  
Transfusion Requirements ◽  
Coagulant Activity ◽  
Von Willebrand

Abstract Desmopressin (1-deamino-8-D-arginine vasopressin, abbreviated DDAVP) is a synthetic analogue of the antidiuretic hormone L-arginine vasopressin. Because it can raise circulating levels of factor VIII coagulant activity (FVIII) and von Willebrand factor and shorten the prolonged bleeding time, DDAVP is established as a nontransfusional form of treatment for mild and moderate hemophilia and von Willebrand disease. Recently, DDAVP has also been purported to be useful for shortening the prolonged skin bleeding times that occur with uremia, cirrhosis, and platelet dysfunctions of various etiologies. Finally, there is evidence from controlled clinical trials that DDAVP can reduce blood loss and transfusion requirements for hemostatically normal individuals undergoing spinal fusion surgery and for patients undergoing cardiopulmonary bypass surgery. The purpose of this report is to review the therapeutic applications of DDAVP in congenital and acquired bleeding disorders and to discuss areas in which further basic and clinical research is needed.

scholarly journals Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders [see comments]

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1449-1455
Author(s):  
PM Mannucci
Keyword(s):  
Arginine Vasopressin ◽  
Von Willebrand Disease ◽  
Synthetic Analogue ◽  
Bleeding Disorders ◽  
Spinal Fusion Surgery ◽  
Prolonged Bleeding Time ◽  
Normal Individuals ◽  
Transfusion Requirements ◽  
Coagulant Activity ◽  
Von Willebrand

Desmopressin (1-deamino-8-D-arginine vasopressin, abbreviated DDAVP) is a synthetic analogue of the antidiuretic hormone L-arginine vasopressin. Because it can raise circulating levels of factor VIII coagulant activity (FVIII) and von Willebrand factor and shorten the prolonged bleeding time, DDAVP is established as a nontransfusional form of treatment for mild and moderate hemophilia and von Willebrand disease. Recently, DDAVP has also been purported to be useful for shortening the prolonged skin bleeding times that occur with uremia, cirrhosis, and platelet dysfunctions of various etiologies. Finally, there is evidence from controlled clinical trials that DDAVP can reduce blood loss and transfusion requirements for hemostatically normal individuals undergoing spinal fusion surgery and for patients undergoing cardiopulmonary bypass surgery. The purpose of this report is to review the therapeutic applications of DDAVP in congenital and acquired bleeding disorders and to discuss areas in which further basic and clinical research is needed.

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 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.

The Interaction of Botrocetin with Normal or Variant von Willebrand Factor (Types IIA and IIB) and Its Inhibition by Monoclonal Antibodies that Block Receptor Binding

1992 ◽  
Vol 68 (04) ◽  
pp. 464-469 ◽  
Author(s):  
Y Fujimura ◽  
S Miyata ◽  
S Nishida ◽  
S Miura ◽  
M Kaneda ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Von Willebrand Factor ◽  
Binding Activity ◽  
Von Willebrand Disease ◽  
Platelet Glycoprotein ◽  
Normal Individuals ◽  
Rag 1 ◽  
The One ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryWe have recently shown the existence of two distinct forms of botrocetin (one-chain and two-chain), and demonstrated that the two-chain species is approximately 30 times more active than the one-chain in promoting von Willebrand factor (vWF) binding to platelet glycoprotein (GP) Ib. The N-terminal sequence of two-chain botrocetin is highly homologous to sea-urchin Echinoidin and other Ca2+-dependent lectins (Fujimura et al., Biochemistry 1991; 30: 1957–64).Present data indicate that purified two-chain botrocetin binds to vWF from plasmas of patients with type IIA or IIB von Willebrand disease and its interaction is indistinguishable from that with vWF from normal individuals. However, an “activated complex” formed between botrocetin and IIB vWF expresses an enhanced biological activity for binding to GP Ib whereas the complex with IIA vWF has a decreased binding activity. Among several anti-vWF monoclonal antibodies (MoAbs) which inhibit ristocetin-induced platelet aggregation and/or vWF binding to GPIb, only two MoAbs (NMC-4 and RFF-VIII RAG:1) abolished direct binding between purified botrocetin and vWF. This suggests that they recognize an epitope(s) on the vWF molecule in close proximity to the botrocetin binding site.

scholarly journals Resolving Differential Diagnostic Problems in von Willebrand Disease, in Fibrinogen Disorders, in Prekallikrein Deficiency and in Hereditary Hemorrhagic Telangiectasia by Next-Generation Sequencing

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 202
Author(s):  
Réka Gindele ◽  
Adrienne Kerényi ◽  
Judit Kállai ◽  
György Pfliegler ◽  
Ágota Schlammadinger ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Von Willebrand Disease ◽  
Differential Diagnostics ◽  
Bleeding Disorders ◽  
Next Generation ◽  
Illumina Platform ◽  
Clinical Patient ◽  
Von Willebrand ◽  
Generation Sequencing

Diagnosis of rare bleeding disorders is challenging and there are several differential diagnostics issues. Next-generation sequencing (NGS) is a useful tool to overcome these problems. The aim of this study was to demonstrate the usefulness of molecular genetic investigations by summarizing the diagnostic work on cases with certain bleeding disorders. Here we report only those, in whom NGS was indicated due to uncertainty of diagnosis or if genetic confirmation of initial diagnosis was required. Based on clinical and/or laboratory suspicion of von Willebrand disease (vWD, n = 63), hypo-or dysfibrinogenemia (n = 27), hereditary hemorrhagic telangiectasia (HHT, n = 10) and unexplained activated partial thromboplastin time (APTT) prolongation (n = 1), NGS using Illumina platform was performed. Gene panel covered 14 genes (ACVRL1, ENG, MADH4, GDF2, RASA1, F5, F8, FGA, FGB, FGG, KLKB1, ADAMTS13, GP1BA and VWF) selected on the basis of laboratory results. We identified forty-seven mutations, n = 29 (6 novel) in vWD, n = 4 mutations leading to hemophilia A, n = 10 (2 novel) in fibrinogen disorders, n = 2 novel mutations in HHT phenotype and two mutations (1 novel) leading to prekallikrein deficiency. By reporting well-characterized cases using standardized, advanced laboratory methods we add new pieces of data to the continuously developing “bleeding disorders databases”, which are excellent supports for clinical patient management.

Coagulopathies

2020 ◽  
Author(s):  
Michael Levine
Keyword(s):  
Key Words ◽  
Bleeding Disorder ◽  
Von Willebrand Disease ◽  
Coagulation Cascade ◽  
Bleeding Disorders ◽  
Platelet Disorders ◽  
Von Willebrand

Coagulopathy can be caused by numerous hereditary or acquired etiologies. Although some of these conditions are known and the patient is aware of the bleeding disorder, other bleeding disorders are diagnosed only after the onset of excessive hemorrhage. This review discusses both hereditary and acquired disorders of coagulopathy. Platelet disorders are discussed elsewhere. This review contains 2 figures, 7 tables, and 72 references. Key words: Coagulopathies; Coagulopathy; Bleeding disorder; Hereditary bleeding disorder; Acquired bleeding disorder; von Willebrand disease; Hemophilia; Coagulation cascade; Hemorrhage; Anticoagulant-associated hemorrhage

scholarly journals The "Normandy" variant of von Willebrand disease: characterization of a point mutation in the von Willebrand factor gene

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 1937-1941 ◽  
Author(s):  
C Gaucher ◽  
S Jorieux ◽  
B Mercier ◽  
D Oufkir ◽  
C Mazurier
Keyword(s):  
Amino Acid ◽  
Point Mutation ◽  
Von Willebrand Factor ◽  
Binding Capacity ◽  
Von Willebrand Disease ◽  
Normal Individuals ◽  
New Variant ◽  
Functional Defect ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract We previously reported a functional defect of von Willebrand factor (vWF) in a new variant of von Willebrand disease (vWD) tentatively named vWD “Normandy.” The present work has attempted to characterize the molecular abnormality of this vWF that fails to bind factor VIII (FVIII). The immunopurified vWF from normal and patient's plasma were digested by trypsin and the resulting peptides were compared. The electrophoresis of ““vWF Normandy” showed a shift in the band corresponding to a polypeptide from amino acid 1 to 272. Consequently, we performed the molecular analysis of the portion of the vWF gene of this patient encoding this amino acid sequence. Exons 18–24 were amplified by the use of polymerase chain reaction and their nucleotide sequences corresponding to 1.8 kb were determined. Our analysis showed a point mutation C to T at codon 791, resulting in the substitution of Methionine for Threonine at position 28 of the mature vWF subunit. Because this nucleotide substitution destroyed a Mae II restriction site, this mutation was conveniently sought in various individual DNAs. The patterns obtained were consistent with the homozygous and heterozygous state of this mutation in the patient and in her son, respectively, and with its absence in 28 normal individuals. We conclude that Threonine at position 28 in plasma vWF may be crucial for the conformation and FVIII-binding capacity of its cystine-rich N- terminal domain.

scholarly journals Influence of mutations and size of multimers in type II von Willebrand disease upon the function of von Willebrand factor

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3553-3561 ◽  
Author(s):  
O Christophe ◽  
AS Ribba ◽  
D Baruch ◽  
B Obert ◽  
C Rouault ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Point Mutations ◽  
Von Willebrand Disease ◽  
Platelet Glycoprotein ◽  
Binding Assays ◽  
Normal Individuals ◽  
Binding Isotherms ◽  
Significant Difference ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract We compared the properties of plasma von Willebrand factor (vWF) from normal individuals and from two patients with type IIA (Glu875Lys) and type IIB (duplication of Met 540) von Willebrand disease (vWD) with the corresponding fully multimerized recombinant proteins. We included cryosupernatant from normal human plasma and type IIA plasma (Cys509Arg). Functions of vWF were analyzed by binding assays to platelets in the presence of ristocetin or botrocetin. Parameters of binding (number of binding sites per vWF subunit, and dissociation constant Kd) were quantitatively estimated from the binding isotherms of 125I-botrocetin or glycocalicin to vWF, independently of the size of the multimers. We found that ristocetin- or botrocetin-induced binding to platelets was correlated in all cases with the size of vWF multimers. In the absence of inducer, only type IIB rvWF Met-Met540 spontaneously bound to platelets. No significant difference of binding of purified botrocetin to vWF was found between normal and patients' plasma, or between wild-type rvWF (rvWF-WT) and rvWF-Lys875. In contrast, affinity of botrocetin for type IIB rvWF Met-Met540 was decreased. Botrocetin-induced binding of glycocalicin to vWF from all plasma and cryosupernatant was similar. Compared with rvWF-WT, binding of glycocalicin to rvWF-Lys875 was normal. In contrast, the affinity for type IIB rvWF Met-Met540 was 10-fold greater. Thus, our data suggest that, in the patients tested, the abnormal IIA phenotype results from the lack of large-sized multimers and is independent of the point mutations. In contrast, the type IIB mutation is directly involved by providing a conformation to the vWF subunits that allows the high molecular weight multimers to spontaneously interact with platelet glycoprotein Ib.

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.

Management Strategies of Stroke and Acute Coronary Syndrome In Von Willebrand Disease and Hemophilia: Experience From a Case Series and a Swiss Survey of Frequencies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1406-1406 ◽  
Author(s):  
Sara C. Meyer ◽  
Elina Armstrong ◽  
Christine Perdrizat ◽  
Hans-Rudolf Schmid ◽  
Riitta Lassila ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Ct Scan ◽  
Treatment Strategies ◽  
Case Series ◽  
Von Willebrand Disease ◽  
Bleeding Disorders ◽  
Coronary Syndrome ◽  
Federal Statistical ◽  
Swiss Population ◽  
Von Willebrand

Abstract Abstract 1406 Introduction: Thrombolysis and combined antiplatelet therapy is considered contraindicated in patients (pts) with bleeding disorders such as von Willebrand disease (VWD) and hemophilia (HP) presenting with stroke or acute coronary syndrome (ACS). Conservative treatment e.g. of stroke is often unsatisfactory in pts within the time window for thrombolysis. As stroke and ACS are common disorders, they may coincide with prevalent bleeding disorders such as VWD and HP and increase in frequency due to growing life expectancy in VWD and HP. An emergency protocol for safe management is desirable. Methods: We report on the management of 5 Caucasians with known VWD or HP suffering from stroke or ACS. In addition we screened the Swiss population of VWD and HP patients over 10y for the occurrence of stroke or ACS based on the data of the Swiss Federal Statistical Office. Case Series. Pt 1 is a 54-y-old Swiss female suffering from mild VWD 1 with a relevant bleeding history and characteristic VWF multimers (Tab 1). She presented with acute stroke with right hemiparesis (NIHSS 9) 2h after onset. CT scan excluded intracranial bleeding. Substitution of VWF/FVIII concentrate aiming at 80% of VWF activity resulted in 55% VWF ristocetin cofactor activity (RCo) and 76% VWF antigen (Ag). Concomitant thrombolysis with full-dose rtPA was performed. After 24h NIHSS improved to 6, RCo was 45%, Ag 63% and no signs of bleeding occurred. Secondary prophylaxis with aspirin was started. She fully recovered after 3 months. Pt 2, a 68-y-old Finnish female with VWD 2A presented with a minor stroke with mild left hemiparesis and a fall (NIHSS 2) 2h after onset. CT scan was normal and she was treated with dipyridamole. Symptoms regressed to NIHSS 0 after 6h. Pt 3 to 5 had ACS. Pt 3, a 73-y-old Swiss male with hemophilia B was successfully treated for unstable angina by percutaneous coronary intervention (PCI) with stenting at a subtotal stenosis of the RCA after substitution of FIX to 65%. Postinterventionally he was on clopidogrel for 2y and then switched to aspirin. Concomitant weekly substitution of FIX led to FIX peaks of ≂f55% and nadir of ≂f15%, was then reduced in frequency and stopped after 15 months. No bleeding complications occurred. Pt 4, a 67-y-old Finnish female with symptomatic VWD 3 presented with a NSTEMI and was successfully treated without PCI or platelet inhibition. Pt 5, a 70-y-old Finnish male with symptomatic VWD 2A suffered from ACS and had angiography with substitution of VWF/FVIII concentrate to 40–134% RCo and 134–252% Ag. Aortocoronary bypass surgery was planned due to 3-vessel disease. No antiplatelet therapy was started. Survey. The analysis of the Swiss Federal Statistical Office revealed 39 cases of VWD or HP with stroke or ACS over 10y (1998-2008) in the Swiss population of 7.70 millions (2008). A lower mean age at death in pts with VWD and HP (63 y) as compared to the normal population (77y), underreporting in the early years and a potential protective effect may contribute to reduced numbers. 19 pts with VWD showed 13 events of stroke and 6 of ACS while 20 hemophiliacs had 8 events of stroke and 12 of ACS. Conclusion: Our survey confirms the occurrence of stroke and ACS in pts with VWD and HP. Observed treatment strategies are very heterogeneous. Intravascular mechanical intervention such as PCI appears advantageous in pts with VWD and HP. If intravascular therapy is not timely available or not possible, we suggest substitution to ≂f80% VWF immediately followed by full-dose thrombolysis as described in pt 1. Repetitive substitution of VWF on a 12–24h basis or infusion over 48h may be adequate in severe deficiencies (Blood 2009;114:5256). A FIX level of 25% may suffice for safe PCI in hemophilia B given the clinical experience with oral anticoagulation. Generally, treatment strategies for stroke and ACS in pts with VWD and HP should be individually tailored and balanced between thrombotic and bleeding risk. Disclosures: No relevant conflicts of interest to declare.

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