Desmopressin (DDAVP) and hemostasis

Summary Desmopressin is a widely used hemostatic drug. It is a synthetic analogue of the natural hormone vasopressin, but, in contrast to vasopressin, it has no pressor activity. The effect is immediate, with two- to sixfold increases in the plasma concentrations of coagulation factor VIII, on Willebrand factor, and tissue plasminogen activator, and increases in platelet adhesiveness of comparable magnitude. Desmopressin is used in patients with mild hemophilia A, von Willebrand's disease, congenital platelet dysfunction, or acquired platelet dysfunction due to uremia or intake of such drugs as aspirin. It may also be used to reduce surgical blood loss in patients without known bleeding diathesis. Optimal hemostatic effect is achieved with a dosage of 0.3 g/kg given intravenously. Other routes of administration are subcutaneous injection or intranasal spray. The latter proved to be efficient for home treatment of patients with bleeding disorders.     

Self-treatment with desmopressin intranasal spray in patients with bleeding disorders: Effect on bleeding symptoms and socioeconomic factors

Summary Desmopressin (1-desamino-8-D-arginine vasopressin), an established hemostatic agent for the treatment of bleeding in mild hemophilia A, von Willebrand's disease, or platelet disorders, has mostly been given parenterally as intravenous or subcutaneous injections. Intranasal administration by spray has been shown to yield significant and highly reproducible increases in the plasma concentrations of factor VIII and von Willebrand factor and platelet adhesiveness, and to be suitable for self-administration at home, as it is easy to handle and does not involve the use of needles. This paper presents data from a questionnaire answered by 78 patients with mild hemophilia A, von Willebrand's disease, or platelet disorders, who had used the spray at home to treat bleeding symptoms. The patients experienced decreased blood loss and shortened duration of epistaxis, menorrhagia, tissue bleeding, and bleeding in connection with minor surgery or tooth extraction. The use of factor VIII concentrates was diminished, as were the number of visits to outpatient care and absence from school or work.     

The administration of desmopressin by nasal spray: a dose-determination study in patients with mild haemophilia A or von Willebrand's disease

Desmopressin is an important haemostatic agent in many types of bleeding disorders. The intranasal route for administration of desmopressin has attracted much interest because it is convenient and makes self-treatment possible. In the present study the effects of three doses (300, 450 and 600 μg) of desmopressin delivered by nasal spray and those of 0.3 μg/kg injected intravenously were compared in five patients with haemophilia A and 11 with von Willebrand's disease. There was no statistically significant difference in peak VIII:C concentration in the haemophilia patients and no difference in peak vWF concentration in von Willebrand patients between the four desmopressin dosages. Bleeding time response was comparable after all four dosages. We recommend a spray dosage of 300 μg for home treatment. As cover for major surgery or in connection with severe bleedings, however, intravenous administration is to be recommended.     

A study of von Willebrand's disease in Jordan

Summary This work reports on the results of a 9-year study of von Willebrand's disease and its subtypes in Jordan, a country with a predominantly Arab population. There were a total of 65 patients in 32 families. Detailed study of 61 patients including von Willebrand factor multimers was done for the purpose of subtyping them. Type I and variants were seen in 36 patients (59%). Type IIA and variants with decreased ristocetin response accounted for seven patients (11.5%), while 11 (18%) were of type IIB. The severe type (type III) accounted for seven patients (11.5%). Von Willebrand's disease was the second most commonly seen inherited bleeding disorder after hemophilia A. It is concluded that although the observed frequency of von Willebrand's disease in this study in Jordan is lower than that in Europe and the USA, the true prevalence cannot be ascertained since many of the mild cases presumably were missed because of referral patterns. Type I and its variants was the most common type found, but the observed frequency of types IIB and III was more than that reported in Europeans and Americans.     

Clinical effectiveness of desmopressin in a case of acquired von Willebrand's syndrome associated with benign monoclonal gammopathy

Summary A case of acquired von Willebrand's syndrome (avWs) secondary to benign monoclonal gammopathy, is described, in which desmopressin (DDAVP) has proven effective repeatedly in preventing bleeding after tooth extraction. The laboratory pattern was similar to that of congenital type IA von Willebrand's disease. After DDAVP, prolonged bleeding time and factor VIII/von Willebrand factor activities were normalized. The disappearance rate of the elicited activities was similar to that observed in patients with congenital disease. This report adds to the scarce data concerning the haemostatic effectiveness of DDAVP in avWs and suggests that this agent might also be used in controlling or preventing bleeding in patients with the acquired disease, selected on the basis of their biological responsiveness to a test-infusion.     

Hemophilia A or von Willebrand disease?

Summary Seven members of the same family were studied on several occasions due to a history of hemorrhages. The propositus, a 12-year-old boy, his sister, one brother, and their father all had a low plasma factor VIII (FVIII) level. Von Willebrand factor (vWF) activity, vWF multimeric analysis, and vWF factor domain for binding to FVIII were normal in all seven subjects. The sister had a normal 46XX karyotype. The study of two intragenic restriction fragment length polymorphisms (RFLPs) and two closely linked, highly polymorphic extragenic markers showed a phenotypic expression of mild hemophilia A, which suggests that the sister of the propositus is homozygous or compound heterozygous at the hemophilia A locus. She would have inherited two hemophilic genes: one from her carrier mother and the other from her father, a mild hemophiliac.     

Heamoperitoneum caused by heamorrhagic corpus luteum in a patient with type 3 von Willebrand's disease

In female patients affected by congenital coagulation disorders heamorrhagic corpus luteum must be considered for the differential diagnosis of acute abdomen. We report the complication in a 22-year-old woman with type 3 von Willebrand's disease who presented with abdominal pain and heamorrhagic shock. Along with adequate factor VIII replacement therapy oral contraceptive treatment is the key for the management of this potentially life-threatening complication and the long-term prevention of future bleeding episodes of this origin.     

Rapid mutation screening in type 2A von Willebrand's disease using universal heteroduplex generators

Patients with type 2A von Willebrand's disease (VWD) commonly have missense mutations in the A2 domain of the von Willebrand factor (VWF) protein. This domain is encoded by the 3' region of VWF gene exon 28 and the large majority of patients have heterozygous mutations clustered in the sequence between codons 742 and 909. We describe a DNA-based diagnostic technique which enables at least 10 previously described mutations to be rapidly identified. The method involves polymerase chain reaction (PCR) amplification of two exon 28 gene segments between codons 717–788 and 803–893, respectively. Each fragment is then hybridized with a synthetic complementary DNA molecule of similar size, termed a Universal Heteroduplex Generator (UHG). The UHG contains base deletions contiguous to the sites of known mutations and, following hybridization, allele-specific heteroduplexes are generated which can be detected by simple polyacrylamide gel electrophoresis and ethidium bromide staining. A small panel of UHG molecules covering the 3' region of exon 28 should enable the large majority of type 2A VWD patients to be rapidly diagnosed by genotype.     

Pharmacokinetics and hemostatic effect of different factor VIII/von Willebrand factor concentrates in von Willebrand's disease type III

Summary Four different plasma-derived concentrates composed of coagulation factor VIII (FVIII) and von Willebrand factor (vWF) of varying quality (Hemate-P, Behring; Profilate, Alpha; and FVIII-VHP-vWF, C.R.T.S Lille), or almost purified vWF (Facteur Willebrand, C.R.T.S Lille) and one recombinant FVIII concentrate (Recombinate, Baxter) were given, in doses of 30–60 IU VIII:C/kg or 70–110 IU RCof/kg, to five patients with von Willebrand's disease type III, in order to evaluate the role of the vWF in factor FVIII concentrates. All plasma concentrates except Profilate had a multimeric vWF pattern almost similar to that of normal plasma. Bleeding time (b.t.), VIII:C, vWF: Ag, ristocetin cofactor activity, and multimeric pattern of the plasma-vWF were followed for 72 h. Both Duke b.t. and the multimeric pattern in plasma normalized after infusion of Hemate-P, FVIII-VHP-vWF, and Facteur Willebrand and, to a lesser extent, after Profilate. As expected, in response to Recombinate there was no effect on primary hemostasis, and the half-life of FVIII procoagulant activity (VIII:C) was very short. Normalization of the vWF is important not only for improving the primary hemostasis, but also for maintaining the plasma FVIII concentration on a high level, both by reducing the elimination rate of infused FVIII and via a secondary release of endogenous FVIII. If a prompt hemostatic effect is required, we recommend a concentrate containing both FVIII and all vWF multimers, but for prophylactic treatment, pure vWF may be used.     

High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A.

An open-label multicentre trial was conducted to evaluate high-dose DDAVP (desmopressin acetate) intranasal spray (Stimate; 1.5 mg mL(-1)), for the control of bleeding in 333 patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease, or symptomatic carriers of haemophilia A. Overall, 278 patients received 2170 doses of high-dose DDAVP intranasal spray (1.5 mg mL(-1)). Using study-defined guidelines, patients evaluated the efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) as 'excellent' or 'good' in 743 (95%) of 784 bleeding episodes. It demonstrated 'excellent' results in 384 (93%) of 413 administrations for prophylaxis and in eight of eight uses prior to acute surgical or dental procedures. When used for the treatment of menorrhagia, the efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) was rated as 'excellent' after 655 (92%) of 721 daily uses. Of 2170 doses of high-dose DDAVP intranasal spray (1.5 mg mL(-1)), 172 (8%) were associated with adverse events. A total of 272 adverse events were reported among 80 patients. Of these, 239 (88%) were mild or moderate in intensity and only one patient was removed from the study due to an adverse event. These results demonstrate the safety and efficacy of high-dose DDAVP intranasal spray (1.5 mg mL(-1)) for control of bleeding episodes in patients with mildly decreased levels of factor VIII, von Willebrand factor, or both.     

Hyper-responsiveness to DDAVP for patients with type I von Willebrand's disease and normal intra-platelet von Willebrand factor

Desmopressin (DDAVP) has gained wide acceptance as the drug of first choice in the treatment or prevention of haemorrhages in the majority of patients with von Willebrand's disease (vWd). However, data concerning the clinical effectiveness of DDAVP refer generally to mild vWd, with factor VIII and vW factor levels usually above 20% of normal. In 14 patients with type I vWd characterized by very low plasma levels of factor VIII coagulant activity (VIII:C) and vWf, measured as ristocetin cofactor activity (lower than 20% and 3% of normal respectively), but with a normal intraplatelet content of vWf, a test infusion of DDAVP (0.4 microgram/kg) elicited a very marked increase of VIII:C and vWf and normalized the bleeding time. All these patients subsequently underwent tooth extraction after DDAVP infusion. The incidence of bleeding was remarkably low, with only two minor late bleeding episodes easily stopped by repeating DDAVP infusion. Compared to the cases of type I vWd with unknown intraplatelet vWf content reported in the literature, this subgroup of patients had a more marked, albeit short-lived, increment of VIII:C and vWf.     

Acquired von Willebrand's disease due to aberrant expression of platelet glycoprotein Ib by marginal zone lymphoma cells

A 69-year-old woman presented with splenic marginal zone lymphoma associated with acquired von Willebrand's disease (AVWD). Laboratory abnormalities included markedly decreased plasma levels of factor VIII coagulant (C) activity (VIII:C 28%), von Willebrand's factor (VWF) antigen (Ag) (vWF:Ag < 6%), and VWF ristocetin cofactor (RCo) activity (VWF:RCo, < 12%). VWF multimer analysis revealed a severe type II defect. Treatment with cryoprecipitate, high-dose gamma globulin or desmopressin given intravenously was unsuccessful. Clinical bleeding and coagulation abnormalities showed transient improvement after replacement therapy with Humate-P concentrate. The coagulation abnormalities improved partially after splenectomy and completely after subsequent chemotherapy. The neoplastic lymphocytes in the blood and spleen strongly expressed platelet glycoprotein Ib (CD42) and VWF but not other platelet-associated antigens.     

Octreotide in the treatment of gastrointestinal bleeding caused by angiodysplasia in two patients with von Willebrand's disease

Two cases of von Willebrand's disease and angiodysplasia with intractable gastrointestinal bleeding are presented. Replacement therapy with cryoprecipitate and variable purity von Willebrand factor (VWF) was ineffective, as were other treatments including steroids, immunoglobulin and hormonal replacement. Both patients required massive blood transfusion and product support. The efficacy of somatostatin and an analogue is described. In one patient, we observed a rise in von Willebrand factor activity after octreotide infusion.     

Two consecutive pregnancies and deliveries in a patient with von Willebrand''s disease type 3

Pregnancy and delivery are critical events in women with von Willebrand's disease type 3. Prophylactic treatment for delivery and early postpartum period is recommended. Vaginal delivery is considered safe. However, experience is based on rare case reports. We report the management of two pregnancies and successful deliveries in a woman with von Willebrand's disease type 3.     

On laboratory problems in diagnosing mild von Willebrand's disease.

By providing some examples of variations in the levels of von Willebrand factor antigen (vWF:Ag), ristocetin cofactor, and Factor VIII during one month, the authors wish to emphasize the difficulty of diagnosing mild forms of von Willebrand's disease (vWD), especially type I. In three of 15 normal female volunteers the vWF:Ag levels, on some sampling occasions, were so low (0.25-0.30 IU/mL, normal greater than 0.50 IU/mL) that the diagnosis of vWD type I might be made while on other occasions normal levels were obtained. The coefficients of variation (CV) for vWF:Ag in these three women were 12%, 25%, and 43%. However, CVs of similar magnitude were also observed for "non-diseased" males and females. The ratio F VIII/vWF:Ag also varied greatly. In the three women with suspected vWD it was 36%, 15%, and 34%. A representative level for the entire cycle of vWF:Ag and ristocetin cofactor seems to have been obtained in the follicular phase and therefore it is suggested that in order to make the diagnosis of vWD type I, at least in females, blood samples should be taken in this phase.     

Response of patients with mild and moderate hemophilia A and von Willebrand's disease to treatment with desmopressin

Desmopressin was administered intravenously to 68 patients with hemophilia and von Willebrand's disease of mild or moderate severity to assess the safety, reproducibility, and range of response to this new therapeutic alternative. A rise in factor VIII-von Willebrand factor levels was seen in 64 patients, and the magnitude was sufficient to provide normal hemostasis in 55 to 68 spontaneous or traumatic bleeding episodes, dental procedures, or operations. Thus, our experience shows that most patients with mild or moderate hemophilia and von Willebrand's disease can be treated effectively without plasma derivatives. Patients who had two or more infusions of desmopressin at different times had similar responses each time, and members of the same family also had similar responses after desmopressin infusions. Because this drug can be administered without significant side effects, it should have an important role in the management of patients with mild or moderate hemophilia and von Willebrand's disease.     

Current understanding of von Willebrand's disease in women – some answers, more questions

Summary.  Considerable progress has been made in the past decade in describing the obstetrical and gynaecological aspects of von Willebrand's disease (VWD). In addition, epidemiological studies have established an approximately 11–16% prevalence of the laboratory diagnosis of VWD in women presenting with menorrhagia. However, it is not established presently whether an upfront VWD screening should be a part of the standard evaluation of menorrhagia. This is because it is presently not known whether therapy in the VWD patient tailored specifically for VWD will appreciably alter the natural history of menorrhagia compared with the non-VWD menorrhagia patient. There are also subtleties involved in securing the diagnosis of VWD in women presenting with menorrhagia in terms of fluctuation of von Willebrand factor (VWF) levels vis-à-vis the menstrual cycle and the potential impact of oral contraceptive on VWF levels. Regarding management of VWD-related menorrhagia, pending ongoing comparative trials of intranasal desmopressin (DDAVP), tranexamic acid, oral contraceptive and the levonorgestrel intrauterine device, specific recommendations cannot be made presently regarding the superiority of one intervention compared with the other. The management of VWD-related postpartum haemorrhage is also an area of active debate in terms of 'best practice' in type 1 (? prophylactic DDAVP), type 2 [? expectant management if factor VIII:C (FVIII:C) level normalizes] and type 3 patients (? intensity and duration of infusional therapy with a VWF-containing plasma-derived FVIII concentrate). This review summarizes the present state of knowledge and highlights numerous questions for future study based on our present understanding of VWD in women.