T he role of pharmacokinetic-guided dosing of factor concentrates in hemophilia is currently a subject of debate and focuses on longterm prophylactic treatment. Few data are available on its impact in the perioperative period. In this study, a population pharmacokinetic model for currently registered factor VIII concentrates was developed for severe and moderate adult and pediatric hemophilia A patients (FVIII levels <0.05 IUmL -1 ) undergoing elective, minor or major surgery. Retrospective data were collected on FVIII treatment, including timing and dosing, time point of FVIII sampling and all FVIII plasma concentrations achieved (trough, peak and steady state), brand of concentrate, as well as patients' and surgical characteristics. Population pharmacokinetic modeling was performed using non-linear mixed-effects modeling. Population pharmacokinetic parameters were estimated in 75 adults undergoing 140 surgeries (median age: 48 years; median weight: 80 kg) and 44 children undergoing 58 surgeries (median age: 4.3 years; median weight: 18.5 kg). Pharmacokinetic profiles were best described by a two-compartment model. Typical values for clearance, inter-compartment clearance, central and peripheral volume were 0.15 L/h/68 kg, 0.16 L/h/68 kg, 2.81 L/68 kg and 1.90 L/68 kg. Interpatient variability in clearance and central volume was 37% and 27%. Clearance decreased with increasing age (P<0.01) and increased in cases with blood group O (26%; P<0.01). In addition, a minor decrease in clearance was observed when a major surgical procedure was performed (7%; P<0.01). The developed population model describes the perioperative pharmacokinetics of various FVIII concentrates, allowing individualization of perioperative FVIII therapy for severe and moderate hemophilia A patients by Bayesian adaptive dosing. ABSTRACT

A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged ≥16 years were included. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Menorrhagia, defined as occurrence of ≥2 menorrhagia symptoms, was reported by 81%. Of all VWD women, 78% received any kind of treatment for menorrhagia and 20% underwent a hysterectomy predominantly because of severe menstrual bleeding. Over half of the women reported more blood loss than can be expected with a normal delivery. In 52% of reported pregnancy losses curettage was needed because of bleeding. Mean number of live births was 1.9, which is comparable with the general Dutch population. In conclusion, women with moderate or severe VWD frequently have menorrhagia in need of treatment, and 20% of the VWD women underwent a hysterectomy. Bleeding complications occurred in over 50% of the women after childbirth or pregnancy loss. Progeny seems not to be affected in women with moderate or severe VWD.

Long-term outcome after joint bleeds in von Willebrand disease (VWD) (von Willebrand factor activity ≤ 30 IU/dL) could differ from moderate or severe haemophilia A (HA) (factor VIII [FVIII] 1–5 IU/dL or FVIII < 1 IU/dL). We performed a post hoc analysis on Haemophilia Joint Health Score (HJHS, 0–124), X-ray Pettersson scores (PS, 0–13/joint) and the Haemophilia Activities List (HAL, 0–100), using multivariable regression to adjust for age (rate ratio [RR] or odds ratio [OR] [95% confidence interval]). We included 48 VWD (median age, 47 years, type 3 VWD, n = 19), 39 moderate HA (median, 39 years) and 59 severe HA patients (median, 25 years) with documented joint bleeds. VWD patients suffered repeated bleeding (lifetime > 5/joint) less often than moderate and severe HA patients (52% vs. 77% vs. 98%). HJHS and PS in VWD were similar to moderate HA (median HJHS 5 vs. 6, RR 0.9 [0.5–1.4] and PS > 3 of ≥ 1 joint OR 0.3 [0.1–1.4]), but better than in severe HA patients (median HJHS 5 vs. 9, RR 1.8 [1.1–2.9]; PS > 3 in any joint OR 0.1 [0.0–0.3]). Self-reported limitations in activities were comparable across VWD, moderate HA (HAL score < 95: 67% vs. 49%; OR 1.4 [0.5–3.6]) and young adults with severe HA (67% vs. 48%; OR 1.7 [0.7–4.4]). Despite fewer joint bleeds, joint outcome after joint bleeds was similar in VWD and moderate HA patients. Type 3 VWD patients had worst joint outcome, comparable to younger intensively treated severe HA patients. Limitations in activities occurred as often in VWD as in both moderate and severe HA.

Background: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs).Objectives: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

We present a rare case of acquired von Willebrand syndrome (AVWS) caused by a mantle cell lymphoma. A 61-year-old male suffered from recurrent bleeding symptoms since a few months. Initially, physical examination was normal. von Willebrand factor antigen (VWF:Ag) level and factor VIII activity (FVIII:C) were low (0.31 IU/ml and 0.43 IU/ml, resp.). Ristocetin cofactor activity (VWF:RCo) was 0.09 IU/ml, and collagen binding activity (VWF:CB) was 0.10 IU/ml. VWF:RCo/VWF:Ag ratio was 0.29, and RIPA value was normal. Highest molecular weight VWF multimers were absent. A diagnosis of von Willebrand Disease (VWD) type 2A was made. However, no genetic mutation was found. No inhibitory antibodies against VWF or factor VIII were detected. A few months later, cervical, axillary, and inguinal lymphadenopathy was found on physical examination. A CT scan confirmed multiple enlarged lymph nodes, and a clonal B-cell population matching a mantle cell lymphoma was detected in the bone marrow. Chemoimmunotherapy resulted in a very good partial remission and concomitantly in a rapid decrease of bleeding problems and complete normalization of FVIII:C and VWF:Ag. The diagnosis of AVWS cannot be rejected by negative mixing studies due to difficulties in the detection of autoantibodies and because of a highly heterogeneous pathogenesis of AVWS. When the suspicion of AVWS is high, an extensive investigation should be performed to find the underlying cause.