Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network.

BACKGROUND: Treatment of mucosal bleeding (epistaxis, gastrointestinal bleeding, and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may require von Willebrand factor (VWF) replacement therapy. There are little data on the use of prophylaxis in VWD, and none have been applied in a prospective, treatment escalation design. OBJECTIVE: Evaluate the effect of escalating dose prophylaxis in severe VWD. METHODS: Patients eligible for enrollment in this prospective study included those with type 1 VWD with VW factor activity-ristocetin cofactor ratio ≤ 20% and unresponsive to desmopressin, patients with type 2 VWD not responsive to desmopressin and all subjects with type 2B and type 3 VWD. Entry criteria were strictly defined, as were therapy escalation parameters and clinical data collection. RESULTS: Eleven subjects completed the study. Six had type 2A, and five had type 3 VWD. Six patients presented with epistaxis, three with GI bleeding, and two with joint bleeding. Seven had dose escalation above the first level. Among the 10 subjects with evaluable bleeding log data, use of prophylaxis decreased the median annualized bleeding rate from 25 to 6.1 (95% confidence interval of the rate difference: -51.6 to -1.7), and the median annualized bleeding rate was even lower (4.0; 95% confidence interval: -57.5 to -5.3) when the subjects reached their final dosing level. CONCLUSION: This is the first prospective study to demonstrate that prophylaxis with VW factor concentrates is highly effective in reducing mucosal and joint bleeding rates in clinically severe VWD.

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

The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed-rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥ 18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious.

Factor VIII inhibitors: von Willebrand factor makes a difference in vitro and in vivo.

BACKGROUND: The important association between von Willebrand factor (VWF) and factor VIII (FVIII) has been investigated for decades, but the effect of VWF on the reactivity of FVIII inhibitory antibodies, referred to as inhibitors, is still controversial. OBJECTIVE: To investigate the interaction among VWF, FVIII and FVIII inhibitory antibodies. METHODS: Three sources of inhibitors were used for in vitro studies, including the plasma from immunized VWF(null) FVIII(null) mice, purified plasma IgG from human inhibitor patients, or human monoclonal antibody from inhibitor patients' B-cell clones. Inhibitors were incubated with recombinant human FVIII (rhFVIII) either with or without VWF. The remaining FVIII activity was determined by chromogenic assay and inhibitor titers were determined. For in vivo studies, inhibitors and rhFVIII were infused into FVIII(null) or VWF(null) FVIII(null) mice followed by a tail clip survival test. RESULTS: VWF has a dose-dependent protective effect on FVIII, limiting inhibitor inactivation of FVIII in both mouse and human samples. A preformed complex of VWF with FVIII provides more effective protection from inhibitors than competitive binding of antibodies and VWF to FVIII. The protective effect of VWF against FVIII inactivation by inhibitors was further confirmed in vivo by infusing inhibitors and FVIII into FVIII(null) or VWF(null) FVIII(null) mice followed by a tail clip survival test. CONCLUSION: Our results demonstrate that VWF exerts a protective effect, reducing inhibitor inactivation of FVIII, both in vitro and in vivo.

Adenotonsillectomy in patients with desmopressin responsive mild bleeding disorders: a review of the literature.

SUMMARY: Many patients with mild inherited bleeding disorders such as von Willebrand disease (VWD), mild haemophilia A (HA) and platelet function defects (PFD) undergo adenoidectomy and/or tonsillectomy (AT) procedures each year. Management of bleeding in these patients can be challenging, as little published data exist to guide haemostatic management during these relatively common procedures. Therefore, the literature was reviewed to identify AT procedures in patients with 1-deamino-8-D-argine vasopressin responsive mild bleeding disorders. The review revealed no randomized prospective trials of haemostatic management in this patient population. Case reports and small case series identified 144 patients who had AT procedures. Frequency of desmopressin and antifibrinolytic dosing varied widely. Fifteen percentage of patients experienced postoperative bleeding with nearly half being early (<24 h) bleeding and half being late (>24 h) bleeding. Hyponatraemia complicated the procedures in 47% of cases and six hyponatremic seizures were reported. Issues identified by this review that need to be addressed in future clinical trials include type and amount of fluid restriction when utilizing desmopressin, duration of antifibrinolytic therapy and duration and frequency of desmopressin dosing.

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.

Type 2M von Willebrand disease: F606I and I662F mutations in the glycoprotein Ib binding domain selectively impair ristocetin- but not botrocetin-mediated binding of von Willebrand factor to platelets.

von Willebrand disease (vWD) is a common, autosomally inherited, bleeding disorder caused by quantitative and/or qualitative deficiency of von Willebrand factor (vWF). We describe two families with a variant form of vWD where affected members of both families have borderline or low vWF antigen levels, normal vWF multimer patterns, disproportionately low ristocetin cofactor activity, and significant bleeding symptoms. Whereas ristocetin-induced binding of plasma vWF from affected members of both families to fixed platelets was reduced, botrocetin-induced platelet binding was normal. The sequencing of genomic DNA identified unique missense mutations in each family in the vWF exon 28. In Family A, a missense mutation at nucleotide 4105T --> A resulted in a Phe606Ile amino acid substitution (F606I) and in Family B, a missense mutation at nucleotide 4273A --> T resulted in an Ile662Phe amino acid substitution (I662F). Both mutations are within the large disulfide loop between Cys509 and Cys695 in the A1 domain that mediates vWF interaction with platelet glycoprotein Ib. Expression of recombinant vWF containing either F606I or I662F mutations resulted in mutant recombinant vWF with decreased ristocetin-induced platelet binding, but normal multimer structure, botrocetin-induced platelet binding, collagen binding, and binding to the conformation-sensitive monoclonal antibody, AvW-3. Both mutations are phenotypically distinct from the previously reported variant type 2MMilwaukee-1 because of the presence of normal botrocetin-induced platelet binding, collagen binding, and AvW-3 binding, as well as the greater frequency and intensity of clinical bleeding. When the reported type 2M mutations are mapped on the predicted three-dimensional structure of the A1 loop of vWF, the mutations cluster in one region that is distinct from the region in which the type 2B mutations cluster.

Nonsurgical therapy of splenic rupture in a hemophiliac.

A boy with known hemophilia A sustained severe blunt abdominal trauma that caused major splenic rupture and hypovolemia. The administration of blood and aggressive clotting factor replacement therapy stabilized his course and he was successfully managed without resorting to operation.