Bleeding management in type 3 von Willebrand disease with anti-von Willebrand factor inhibitor: A literature review and case report.

Treatment of type 3 von Willebrand disease by infusion of von Willebrand factor (VWF) and factor VIII (FVIII) concentrates may lead to the development of anti-VWF antibodies, challenging haemostasis management. The systematic review of the literature presented here retrieved 15 such cases (surgery n = 11, bleeding n = 4). The heterogeneous patient management mostly involved continuous infusion of FVIII, or recombinant FVIIa together with various other strategies. Off-label infusion of the bispecific monoclonal antibody emicizumab was prescribed in three cases and in a complex local case, ultimately well-controlled with emicizumab. This illustrates the fact that emicizumab appears as a therapeutic option in this context of allo-immunisation.

Efficacy and safety of a recombinant von Willebrand factor treatment in acquired von Willebrand syndrome in case of bleeding and surgical procedures.

INTRODUCTION: Acquired von Willebrand syndrome (AVWS) is a rare haemorrhagic disorder. The prophylaxis and treatment of bleeding before surgery are complex. Since 2018, a new recombinant VWF (rVWF) concentrate that contains no factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France. AIM: To describe the real-world experience of using rVWF in non-surgical bleeding and surgical procedures in patients with AVWS. METHODS: Fifteen bleeding episodes in seven patients and 16 surgeries in 10 patients were retrospectively analysed in t French haemostasis centres. RESULTS: During bleeding, the median number of infusions was only 1 (range 1-27) with a median loading dose of 58 IU/kg (range 17-116) rVWF and a total median dose of 65 IU/kg (range 35-1488) rVWF. Bleeding control was rated markedly effective in 73% (11/15) of the cases and ineffective in 27% (4/15). During surgeries, the median number of infusions was 3 (range 1-8) with a preoperative loading dose of 60 IU/kg (range 23-118) rVWF and a total median dose of 123 IU/kg (range 31-542). The overall clinical efficacy was qualified as excellent, good and poor (ISTH criteria) in respectively 7 (43%), 6 (38%) and 3 (19%) procedures. There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events nor adverse events were reported. CONCLUSION: This French 'real-world' experience shows that rVWF could be of interest in the treatment and prophylaxis of bleeding in patients with AVWS, with no clinically significant safety concern.

Efficacy and safety of turoctocog alfa in patients with hemophilia A requiring surgical procedures: A multicentre retrospective study.

BACKGROUND: Turoctocog alfa is a recombinant Factor VIII used in patients with hemophilia A. The aim is to assess the real-life evidence of turoctocog alfa in surgery. STUDY DESIGN AND METHODS: Data were extracted from a national database. RESULTS: Turoctocog alfa was used for 86 surgeries (49 major and 37 minor) in 56 patients. The results are expressed as medians (interquartile range). Six (10.7%) patients had severe hemophilia A, four (7.1%) moderate, and 46 (82.2%) mild. For patients who underwent major surgeries, basal plasma FVIII coagulant activity (FVIII:C) levels were 15 IU.dL-1 (8-22). Eight (5-14) infusions were given, at a preoperative loading dose of 40.0 (35.0-45.5) IU.kg-1 and a total dose of 253.3 (125.0-507.0) IU.kg-1 . In patients who underwent minor surgeries, basal FVIII:C levels were 18 IU.dL-1 (9-31). Two (1-3) infusions were required, at a preoperative loading dose of 34.0 (28.8-38.5) IU.kg-1 and a total dose of 73.7 (37.6-122.1) IU.kg-1 . The overall clinical efficacy was judged excellent/good in 77 procedures (89.5%) and fair/poor in nine (10.5%). The fair/poor efficacy concerned seven patients (six mild hemophilia and one severe), for four urological surgeries, two dermatological procedures, one heart surgery, one ear-nose-throat procedure, and one dental avulsion in the patient with severe hemophilia. Three out of those seven patients received antiplatelet therapy. No thromboembolic events, anti-FVIII antibodies, or adverse events were reported. DISCUSSION: The efficacy and safety of turoctocog alfa were confirmed for the management of surgery in patients with hemophilia A. No adverse events were observed and overall efficacy was good.

Prostate interventions in patients with mild haemophilia: Safe and feasible.

INTRODUCTION: To date, there is no specific recommendation or evaluation of the morbidity of prostate surgery in patients with haemophilia (PWH) although this surgery is common and at high risk of bleeding. AIM: To assess the post-operative morbidity of benign prostate hyperplasia (BPH) surgeries and of oncological prostate interventions in patients with mild haemophilia A or B. METHODS: We performed a monocentre, epidemiological, in real life study. Data were collected between 1 January, 1997 and 1 September, 2020 and focused on prostate biopsy, radical prostatectomy, prostate radiotherapy, simple prostatectomy, transurethral resection of prostate (TURP) and laser-vaporisation in patients with mild haemophilia A or B. RESULTS: Between 1 January, 1997 and 1 September, 2020, 51 interventions were performed on 30 patients with mild haemophilia. Haemophilia A represented 93.33% of the population and haemophilia B 6.67%. For prostate biopsies (n = 24), median length of hospitalisation was 4 days and only one patient needed a blood transfusion. No patient needed re-admission. For prostatectomy (n = 10), one patient presented with intra-operative and post-operative bleeding. Two patients required re-admission. The other patients did not present any significant haemorrhagic symptoms. For radiotherapy (n = 4), two patients presented a grade II complication (radiocystitis and radiorectitis). For BPH surgeries, during hospitalisation, laser-vaporisation (n = 5) was less haemorrhagic than TURP (n = 5) but after hospital discharge, 60% of patients presented a haemorrhagic complication with two readmissions and one surgical re-explorations. CONCLUSION: Performed in a specialised centre, prostate surgeries and interventions in patients with mild haemophilia is feasible with acceptable morbidity.

Comparative Analysis of a French Prospective Series of 144 Patients with Heparin-Induced Thrombocytopenia (FRIGTIH) and the Literature.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature. METHODS: The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis. RESULTS: Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries, p = 0.042) with a shorter recovery time (median = 3 vs. 5 days, p < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis, p = 0.03). CONCLUSION: This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.

A novel ELISA-based diagnosis of acquired von Willebrand disease with increased VWF proteolysis.

Von Willebrand disease-type 2A (VWD-2A) and acquired von Willebrand syndrome (AVWS) due to aortic stenosis (AS) or left ventricular assist device (LVAD) are associated with an increased proteolysis of von Willebrand factor (VWF). Analysis of VWF multimeric profile is the most sensitive way to assess such increased VWF-proteolysis. However, several technical aspects hamper a large diffusion among routine diagnosis laboratories. This makes early diagnosis and early appropriate care of increased proteolysis challenging. In this context of unmet medical need, we developed a new ELISA aiming a quick, easy and reliable assessment of VWF-proteolysis. This ELISA was assessed successively in a LVAD-model, healthy subjects (n=39), acquired TTP-patients (n=4), VWD-patients (including VWD-2A(IIA), n=22; VWD-2B, n=26; VWD-2A(IIE), n=21; and VWD-1C, n=8) and in AVWS-patients (AS, n=9; LVAD, n=9; and MGUS, n=8). A standard of VWF-proteolysis was specifically developed. Extent of VWF-proteolysis was expressed as relative percentage and as VWF proteolysis/VWF:Ag ratio. A speed-dependent increase in VWF-proteolysis was assessed in the LVAD model whereas no proteolysis was observed in TTP-patients. In VWD-patients, VWF-proteolysis was significantly increased in VWD-2A(IIA) and VWD-2B and significantly decreased in VWD-2A(IIE) versus controls (p< 0.0001). In AVWS-patients, VWF-proteolysis was significantly increased in AS- and LVAD-patients compared to controls (p< 0.0001) and not detectable in MGUS-patients. A significant increase in VWF-proteolysis was detected as soon as three hours after LVAD implantation (p< 0.01). In conclusion, we describe a new ELISA allowing a rapid and accurate diagnosis of VWF-proteolysis validated in three different clinical situations. This assay represents a helpful alternative to electrophoresis-based assay in the diagnosis and management of AVWS with increased VWF-proteolysis.

Monitoring treatments with unfractionated heparin: CTAD must be used instead of citrate as the anticoagulant solution when using partial-draw collection tubes. Results of a multicenter evaluation.

BACKGROUND: Sampling small volumes of blood may be necessary, particularly in pediatric patients, or in case of difficult or recurrent venipunctures. METHODS: Routine hemostasis test results evaluated in partial- and full-draw evacuated polymer tubes obtained in 4 centers were compared. RESULTS: No relevant discrepancy (Bland-Altman) was found between test results measured in partial- and full-draw tubes obtained from untreated patients and from patients on vitamin K-antagonist or low molecular weight heparin. In patients on unfractionated heparin (UFH), significantly lower anti-FXa activity [median=0.29IU/mL (range:0.04-1.15) vs. 0.39 (0.05-1.25), n=89, p<0.0001] and shorter aPTT were measured in partial-draw tubes. This discrepancy was likely to be related to the release of higher amounts of PF4 after increased platelet activation in partial-draw tubes. As CTAD is known to counteract platelet activation, we then collected blood into partial-draw CTAD tube and full-draw citrate tube. Both in patients on UFH and in untreated patients, no relevant difference could be demonstrated for all studied parameters (Bland-Altman), including aPTT and anti-FXa activity, even if analytical comparison showed significantly higher anti-FXa activity in partial-draw CTAD than in full-draw citrated tubes with a mean bias of 0.02 IU/mL, identical throughout the measuring range. CONCLUSIONS: These results suggest that samples collected into partial-draw citrate tubes allow accurate routine coagulation testingin all patients but those requiring UFH assessment,in which their use led to a significant underestimation ofanticoagulation. In such cases, partial-draw tubes containing CTAD could be validly used to monitor heparin therapy as well as to perform routine coagulation testing.

High-dose intravenous immunoglobulin treatment in two patients with acquired factor V inhibitors.

We report two patients who developed acquired factor V (FV) inhibitors not related to exposure to bovine thrombin. Associated conditions were found in one patient (surgery, antibiotic administration) but none in the other one. Bleeding complications occurred only in the patient with idiopathic FV inhibitor, leading to packed red cell infusion. Laboratory findings showed the presence of specific FV inhibitors with titers of 5.5 and 5 Bethesda units, respectively. These two patients received high-dose intravenous immunoglobulin and FV levels normalized within a few days with a concomitant disappearance of FV inhibitors.