Platelets compensate for poor thrombin generation in type 3 von Willebrand disease.

In type 3 von Willebrand disease (VWD3), the most severe form with absent von Willebrand factor (VWF), the bleeding phenotype is variable. Platelet contribution to the hemostatic defect in VWD3 calls upon further studies. We investigated the contribution of platelets to in vitro thrombin generation (TG) and platelet procoagulant activity in VWD3. TG was assessed by calibrated automated thrombogram (CAT) in platelet-poor (PPP) and -rich plasma (PRP) from 9 patients before and in 6 patients also 30 min after receiving their regular VWF therapy. Responsiveness of PPP to FVIII and protein S was also investigated. TG data were compared with routine laboratory variables, rotational thromboelastometry (ROTEM) and platelet expression of P-selectin and phosphatidylserine in flow cytometry. Compared with healthy controls, TG was markedly decreased in VWD3 PPP (peak thrombin was 16% of normal median), but not in PRP (77% of normal median) (p = 0.002). Six out of nine patients (67%) were high responders in their platelet P-selectin, and 5/9 (56%) in phosphatidylserine expression. Replacement therapy improved TG in PPP, while in PRP TG only modestly increased or was unaffected. In PPP, FVIII levels associated with TG and in vitro FVIII-supplemented TG inclined up to threefold. Conversely, a FVIII inhibitory antibody reduced plasma TG in all, but especially in patients with remnant FVIII levels. Inhibition of protein S improved plasma TG, particularly at low FVIII levels. ROTEM failed to detect VWD3.In VWD3, TG is reduced in PPP and regulated by FVIII and protein S, but TG is close to normal in PRP. VWD3 platelets seem to compensate for the FVIII-associated reduction in TG by their exposure of P-selectin and phosphatidylserine.

Higher rates of bleeding and use of treatment products among young boys compared to girls with von Willebrand disease.

There are limited observational studies among children diagnosed with von Willebrand Disease (VWD). We analyzed differences in bleeding characteristics by sex and type of VWD using the largest reported surveillance database of children with VWD (n = 2712), ages 2 to 12 years old. We found that the mean ages of first bleed and diagnosis were lowest among children with type 3 VWD. It was even lower among boys than girls among all VWD types, with statistically significant difference among children with type 1 or type 3 VWD. Children with type 3 VWD also reported higher proportions of ever having a bleed compared to other VWD types, with statistically higher proportions of boys compared to girls reporting ever having a bleed with type 1 and type 2 VWD. A similar pattern was observed with the use of treatment product, showing higher usage among type 3 VWD, and among boys than girls with type 1 and type 2 VWD. While there were no differences in life quality or in well-being status by sex, children with type 3 VWD showed a greater need for mobility assistance compared to children with type 1 and type 2 VWD. In an adjusted analysis among children with type 1 VWD, boys showed a significant association of ever bleeding [hazard ratio 1.4; P-value <.001)] compared to girls. Understanding phenotypic bleeding characteristics, well-being status, treatment, and higher risk groups for bleeding among pre-adolescent children with VWD will aid physicians in efforts to educate families about bleeding symptoms.

Gastrointestinal angiodysplasia in two patients with type 3 von Willebrand disease.

: Angiodysplastic (AD) lesion is the most common cause of recurrent gastrointestinal (GI) bleeding in inherited Von Willebrand disease (VWD) patients lacking high-molecular-weight multimers. Defect or dysfunction of von Willebrand factor (VWF) may lead to enhanced endothelial cell proliferation followed by the development of neoangiogenesis and vascular malformation, which result in severe bleeding. Recurrent bleeding causing by GI AD is a challenging complication of VWD. The management of VWD could be difficult due to frequent recurrence and severity of bleeding episodes. The primary aim of management is not only to stop but also to prevent bleeding. We present two patients of type 3 VWD associated with AD and severe GI bleeding, which were successfully treated by endoscopic coagulation and prophylactic therapy with different regimens of plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrate to maintain a trough level in the patient unresponsive to standard treatment.

Recurrent hemorrhage caused by type 3 von Willebrand disease in a domestic long-haired cat.

OBJECTIVE: To describe a case of spontaneous epistaxis in a cat with type 3 von Willebrand disease (VWD) and detail the successful management of hemorrhagic episodes on 2 occasions. CASE SUMMARY: A 3.6 kg, 1-year-old, female mixed-breed domestic long-haired cat presented for spontaneous epistaxis. Hemostasis testing at presentation revealed normal prothrombin and activated partial thromboplastin times, a slightly decreased platelet count of 168 × 10(9) /L [168 × 10(3) /µL] (reference interval 200-500 × 10(9) /L [200-500 × 10(3) /µL]) and prolonged buccal mucosal bleeding time of 168 seconds (reference interval <150 s). Specific activities of coagulation factors VIII, IX, XI, and XII were all within reference intervals. Plasma von Willebrand factor concentration, however, was markedly reduced at <0.1% of normal. These findings are compatible with a diagnosis of severe type 3 VWD. The initial occurrence of epistaxis resolved spontaneously soon after admission; however, the cat required a packed RBC transfusion for blood loss anemia. Desmopressin acetate was administered, but failed to arrest hemorrhage during a second episode of epistaxis 12 months later. The second episode was successfully controlled by transfusion of 6.7 mL/kg feline fresh frozen plasma. NEW AND UNIQUE INFORMATION: This is the first description of severe type 3 VWD in a domestic cat and only the second report of VWD in this species. Unlike human beings and primates with type 3 VWD, the affected cat did not have a concomitant deficiency of coagulation factor VIII or consistent prolongation of activated partial thromboplastin time. Clinicians should therefore include VWD in the list of differentials for cats with signs of abnormal hemorrhage and confirm the diagnosis with specific measurement of plasma von Willebrand factor concentration.