Maternal and neonatal bleeding complications in relation to peripartum management in hemophilia carriers: A systematic review.

Currently, there is no consensus on the optimal management to prevent postpartum hemorrhage (PPH) in hemophilia carriers. We aimed to evaluate peripartum management strategies in relation to maternal and neonatal bleeding outcomes by performing an extensive database search up to August 2020. Seventeen case-reports/series and 11 cohort studies were identified of overall 'poor' quality describing 502 deliveries. The PPH incidence in the individual patient data was 63%; 44% for those women receiving prophylaxis to correct coagulation and 77% for those without (OR 0.23, CI 0.09-0.58) and in cohort data 20.3% (26.8% (11/41) vs. 19.4% (55/284) (OR: 1.53, 95% CI: 0.72-3.24), respectively. Peripartum management strategies mostly consisted of clotting factor concentrates, rarely of desmopressin or plasma. Tranexamic acid appears promising in preventing secondary PPH, but was not used consistently. Neonatal bleeding was described in 6 affected male neonates, mostly after instrumental delivery or emergency CS, but insufficient information was provided to reliably investigate neonatal outcome in relation to management. The high PPH risk seems apparent, at most mildly attenuated by prophylactic treatment. Prospective cohort studies are needed to determine the optimal perinatal management in hemophilia.

Maternal and neonatal bleeding complications in relation to peripartum management in women with Von Willebrand disease: A systematic review.

Women with Von Willebrand disease (VWD) have an increased risk of developing postpartum hemorrhage (PPH). Our aim is to evaluate peripartum management strategies in relation to maternal and neonatal bleeding complications in VWD. Electronic databases were searched up to January 2019. Seventy-one case-reports and -series and 16 cohort studies were selected, including 811 deliveries. Cohort studies reported primary PPH in 32% and secondary PPH in 13% of the women. The overall primary PPH incidence in the individual patient data was 34%, similar between women who received prophylactic treatment to prevent PPH and those who didn't. Neonatal bleeding events were reported in 4.6% of deliveries. Overall, the available evidence on peripartum management in women with VWD was of low quality. The ongoing high risk for PPH is evident, despite prophylactic treatment, as well as the need for higher quality evidence from larger prospective cohort studies to improve management strategies.

Clinically relevant differences between assays for von Willebrand factor activity.

Essentials It is unclear whether there are differences between von Willebrand factor (VWF) activity assays. We compared the four most used VWF activity assays in 661 von Willebrand disease (VWD) patients. All assays correlated excellently, but a discrepant classification was seen in 20% of patients. Differences between VWF activity assays have a large impact on the classification of VWD. SUMMARY: Background Measuring the ability of von Willebrand factor (VWF) to bind to platelets is crucial for the diagnosis and classification of von Willebrand disease (VWD). Several assays that measure this VWF activity using different principles are available, but the clinical relevance of different assay principles is unclear. Objective To compare the four most widely used VWF activity assays in a large VWD patient population. Methods We measured VWF:RCo (ristocetin to activate VWF + whole platelets), VWF:GPIbR (ristocetin + platelet glycoprotein Ib receptor [GPIb] fragments), VWF:GPIbM (gain-of-function GPIb fragments that bind VWF spontaneously without ristocetin) and VWF:Ab (monoclonal antibody directed against the GPIb binding epitope of VWF to mimic platelets) in 661 VWD patients from the nationwide 'Willebrand in the Netherlands' (WiN) Study. Results All assays correlated excellently (Pearson r > 0.9), but discrepant results led to a different classification for up to one-fifth of VWD patients. VWF:RCo was not sensitive enough to classify 18% of patients and misclassified half of genotypic 2B VWD patients, especially those with p.Arg1306Trp. VWF:GPIbR was more sensitive, accurately classified the vast majority of patients, and was unaffected by the p.Asp1472His variant that causes artificially low VWF:RCo. VWF:GPIbM was the most precise assay but misclassified over a quarter of genotypic 2A, 2B and 3 patients. VWF:Ab, often not considered an actual VWF activity assay, performed at least equally to the other assays with regard to accurate VWD classification. Conclusion Although the different VWF activity assays are often considered similar, differences between assays have a large impact on the classification of VWD.

Plasma levels of plasminogen activator inhibitor-1 and bleeding phenotype in patients with von Willebrand disease.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. In VWD patients, large variations in bleeding tendency are observed, which cannot be completely explained by the variation in von Willebrand factor levels or activities. Thus, there must be additional factors, for instance, changes in fibrinolysis that have an effect on the variation in bleeding tendency in VWD patients. AIM: To investigate whether plasminogen activator inhibitor-1 (PAI-1) level influences the variation in bleeding tendency in VWD patients. METHODS: PAI-1 antigen levels were measured in the plasma of 633 patients with moderate or severe VWD who participated in the 'Willebrand in the Netherlands' (WiN) study, a nationwide multicentre cross-sectional study. Bleeding severity was assessed using the Tosetto bleeding score. RESULTS: PAI-1 levels increased with age (Spearman's rho: 0.225, P < 0.001) and were higher in men (23 [IQR 12-60] vs. 20 [IQR 10-44] ng mL-1 in women, P = 0.039), whereas the bleeding score was higher in women (11 [IQR 7-17] vs. 9 [IQR 5-14] ng mL-1 in men, P = 0.002). After adjustment for age and sex by stratification, PAI-1 level and bleeding score were negatively correlated (Spearman's rho: -0.170, P = 0.017) in the group of 196 young (age ≤ 45 year) female VWD patients, accounting for 31% of our study population. CONCLUSION: In young female VWD patients, we observed that low PAI-1 levels were associated with a higher bleeding score, which may partly explain the observed variability in bleeding phenotype in VWD patients.

The association of haemophilic arthropathy with Health-Related Quality of Life: a post hoc analysis.

BACKGROUND: The aim of replacement therapy in haemophilia is to improve Health-Related Quality of Life (HRQoL) by preventing bleeding and arthropathy. However, the association of arthropathy with HRQoL is unknown. AIM: To explore the association of haemophilic arthropathy with HRQoL. METHODS: A post hoc analysis on patients with severe/moderate haemophilia with SF36 questionnaire (SF36) and X-rays of ankles, knees and elbows made within 2.5-years. The SF36 scores of 'physical functioning' (SF36-PF, range 0-100, optimum 100) and Utility (SF6D-Utility, range 0-1, optimum 1) and radiological Pettersson scores (PS, range 0-78, optimum 0) were calculated. The association of PS with reduced SF6D-Utility and SF36-PF ( 21 points, the risk of reduced SF6D-Utility was stable (OR 4.16; 95% CI: 2.03-8.51) but SF36-PF continued to decrease: compared to lowest PS, OR for reduced SF36-PF was 5.69 (95% CI: 1.62-20.06) for PS 22-39 and 25.15 (95% CI: 6.53-96.81) for PS 40-78. CONCLUSION: Health-Related Quality of Life only showed a significant deterioration in patients with a Pettersson score of >21 points. This suggests that HRQoL is relatively insensitive to early joint changes.

Evidence for and cost-effectiveness of physiotherapy in haemophilia: a Dutch perspective.

INTRODUCTION: Musculoskeletal impact of haemophilia justifies physiotherapy throughout life. Recently the Dutch Health Care Institute constrained their 'list of chronic conditions', and withdrew financial coverage of physiotherapy for elderly persons with haemophilia (PWH). This decision was based on lack of scientific evidence and not being in accordance with 'state of science and practice'. METHODS: In general, evidence regarding physiotherapy is limited, and especially in rare diseases like haemophilia. 'Evidence based medicine' classifies and recommends evidence based on meta-analyses, systematic reviews and randomized controlled trials, but also means integrating evidence with individual clinical expertise. For the evaluation of physiotherapy - usually individualized treatment - case studies, observational studies and Case Based Reasoning may be more beneficial. RESULTS: Overall annual treatment costs for haemophilia care in the Netherlands are estimated over 100 million Euros, of which 95% is covered by clotting factor concentrates. The cost for physiotherapy assessments in all seven Dutch HTCs (seven centres for adult PWH and seven centres for children) is limited at approximately 500 000 Euros annually. Costs of the actual physiotherapy sessions, carried out in our Dutch first-line care system, will also not exceed 500 000 Euros. Thus, implementation of physiotherapy in haemophilia care the Netherlands in a most optimal way would cost less than 1% of the total budget. AIM: The present paper describes the role of physiotherapy in haemophilia care including available evidence and providing suggestions regarding generation of evidence. Establishing the effectiveness and cost-effectiveness of physiotherapy in haemophilia care is a major topic for the next decennium.

Long-term effects of joint bleeding before starting prophylaxis in severe haemophilia.

INTRODUCTION: Early initiation of prophylaxis in severe haemophilia is critical for effective prevention of arthropathy. However, the optimum time for starting prophylaxis has not been established yet. AIM: This study assessed long-term effects of age at starting prophylaxis and joint bleeding before prophylaxis on haemophilic arthropathy. METHODS: In patients with severe haemophilia (FVIII/IX <0.01 IU mL-1 ), born between 1965 and 2000, haemophilic arthropathy was evaluated on X-rays. Patient groups were compared by multivariable regression analysis, adjusted for bleeding phenotype and lifetime intensity of prophylaxis. RESULTS: One hundred and twenty-four patients were evaluated at a median age of 22 years. When comparing patients according to age at starting prophylaxis, starting before age 6 years was significantly better than starting later (P < 0.01), but no additional benefit of starting before age 3 years was demonstrated. The number of joint bleeds before prophylaxis had a stronger association with arthropathy than age at starting prophylaxis. Starting prophylaxis before the onset of joint bleeding resulted in the best long-term outcome (P ≤ 0.02); starting after one joint bleed appeared to have acceptable long-term outcome. The difference between starting after 0-1 and 2-5 joint bleeds was notable, but statistical significance was not reached (P = 0.15). CONCLUSION: Future research with more patients on early prophylaxis will have to clarify whether starting prophylaxis before joint bleeding is superior.

Joint surgery in von Willebrand disease: a multicentre cross-sectional study.

BACKGROUND: Joint bleeds are reported by 23% of von Willebrand disease (VWD) patients and associated with orthopaedic surgery. Limited data are available on joint surgery in VWD. AIM: To assess the prevalence, indications, management and complications of joint surgery in VWD patients. METHODS: 804 VWD patients with historically lowest von Willebrand factor (VWF) activity ≤30 U dL-1 completed a questionnaire on joint bleeds, joint damage and orthopaedic surgery. We retrieved additional medical file data of patients who underwent surgery on large joints (shoulder, elbow, hip, knee or ankle). RESULTS: 116 out of 804 patients (14%) reported large joint surgery. Compared to VWD patients without previous orthopaedic surgery, these 116 patients reported more frequently a history of joint bleeds and joint damage (41% vs. 20%, P < 0.001 and 61% vs. 20%, P < 0.001). Medical file data on 126 large joint surgeries in 79 VWD patients revealed that this surgery was associated with joint damage due to prior joint bleeds in 24% of the procedures. Preoperative clotting factor correction (CFC) to prevent bleeding was administered in most cases (81%). Documentation on postoperative bleeding was found in 23 surgeries (18%). CONCLUSIONS: Large joint surgery is reported by 14% of VWD patients, related to joint bleeds in 24% and seems associated with bleeding complications frequently despite perioperative CFC.

Inhibitor development and mortality in non-severe hemophilia A.

BACKGROUND: The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. OBJECTIVES: We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. METHODS: In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. RESULTS: During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). CONCLUSION: Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients.

CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease.

BACKGROUND: von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown. OBJECTIVES: To investigate the association between single-nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype. PATIENTS/METHODS: In 364 type 1 VWD and 240 type 2 VWD patients from the nationwide cross-sectional 'Willebrand in The Netherlands' (WiN) study, we studied the association between eight SNPs in STXBP5, SCARA5, ABO, VWF, STAB2, STX2, TC2N, and CLEC4M, and VWF antigen (VWF:Ag), VWF activity (VWF:Act), and bleeding phenotype as assessed with the Tosetto bleeding score. RESULTS: In type 1 patients, STXBP5 was associated with a lower VWF:Ag level (adjusted difference of -3.0 IU dL(-1) per allele; 95% confidence interval [CI] -6.0 to 0.1) and CLEC4M with both a lower VWF:Ag level (-4.3 IU dL(-1) per allele; 95% CI -7.9 to -0.6) and lower VWF:Act (-5.7 IU dL(-1) per allele; 95% CI -10.9 to -0.5). In type 2 patients, none of the SNPs was associated with VWF levels. None of the genetic variants was associated with bleeding score. CONCLUSIONS: Genetic variations in STXBP5 and CLEC4M are associated with VWF level variation in type 1 VWD, but not in type 2 VWD. This study increases our understanding of the pathophysiology of VWD, and provides a further indication of the involvement of STXBP5 and CLEC4M in determining VWF levels in VWD.

Joint bleeds in von Willebrand disease patients have significant impact on quality of life and joint integrity: a cross-sectional study.

BACKGROUND: Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown. OBJECTIVES: The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD. METHODS: In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity ≤30U dL(-1)] completed a questionnaire on occurrence, sites and consequences of JB. To analyse JB number, onset, treatment and impact on joint integrity we additionally performed a patient-control study on medical file data comparing patients with JB to age, gender, factor VIII (FVIII)- and VWF activity matched VWD patients without JB. RESULTS: Of all VWD patients 23% (184/804) self-reported JB. These 184 patients reported joint damage more often (54% vs. 18%, P < 0.001) and had lower HR-QoL (SF36, P < 0.05) compared to VWD patients not reporting JB. Of 55 patients with available JB data, 65% had the first JB before age 16. These 55 patients used more clotting factor concentrate (CFC; median dose 43 vs. 0 IE FVIII kg(-1) year(-1) , P < 0.001), more often had X-ray joint damage (44% vs. 11%, P = 0.001] and chronic joint pain (44% vs. 18%, P = 0.008) compared to 55 control VWD patients without JB. CONCLUSION: In conclusion, joint bleeds are reported by 23% of moderate and severe VWD patients, mostly start in childhood, are associated with more CFC use, joint pain, lower HR-QoL and significantly more radiological and self-reported joint damage.

Medical co-morbidities and practice.

All-oral treatments of hepatitis C (HCV) have been trialled in patients with hereditary bleeding disorders and found to be effective. Further refinements of dosing and duration are being established. Importantly for patient acceptability these regimens are interferon-free. Cohort studies in older patients with haemophilia direct the need for attention to weight control, exercice, assessment of cardiovascular risk, especially hypertension and detection of osteoporosis. Where patients live a long way from a comprehensive care centre, telemedicine connections can engage centre experts with the patient and his/her local practitioners in devising and monitoring care plans.

von Willebrand disease and aging: an evolving phenotype.

BACKGROUND: Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. OBJECTIVES: To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related differences in bleeding phenotype between elderly VWD patients and those < 65 years. We also studied co-morbidity in elderly patients. PATIENTS/METHODS: We included VWD patients with VWF levels ≤ 30 U dL(-1) in the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN-) study. Patients reported bleeding episodes and treatment of VWD in the year preceding inclusion and during life. This was compared between VWD patients older (n = 71) and younger (16-64 years, n = 593) than 65 years. In elderly patients, age-related changes in VWF and FVIII levels were studied longitudinally by including all historically measured levels. All medical records were examined for co-morbidity. RESULTS: In elderly type 1 patients, a decade age increase was associated with a 3.5 U dL(-1) (95% CI, -0.6 to 7.6) VWF:Ag increase and 7.1 U dL(-1) (95% CI, 0.7 to 13.4) FVIII:C increase. This increase was not observed in elderly type 2 patients. Elderly type 2 patients reported significantly more bleeding symptoms in the year preceding inclusion than younger patients (16/27, 59% vs. 87/221, 39%; P = 0.048), which was not observed in type 1 VWD. CONCLUSIONS: von Willebrand factor parameters and bleeding phenotype evolve with increasing age in VWD. VWF and FVIII levels increase with age in type 1 patients with no mitigation in bleeding phenotype. In type 2 patients VWF parameters do not increase with age and in these patients aging is accompanied by increased bleeding.

Reduced prevalence of arterial thrombosis in von Willebrand disease.

BACKGROUND: High von Willebrand factor (VWF) levels are an established risk factor for arterial thrombosis, including coronary heart disease and ischemic stroke. It has been hypothesized that von Willebrand disease (VWD) patients are protected against arterial thrombosis; however, this has never been confirmed in clinical studies. OBJECTIVES: To investigate the prevalence of arterial thrombosis in VWD patients relative to the general population. PATIENTS/METHODS: We included 635 adult patients with VWF levels ≤ 30 U dL(-1) , aged 16-85 years, from the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN) study and compared the prevalence of arterial thrombosis with two reference populations from the general Dutch population adjusted for age and sex as standardized morbidity ratios (SMRs). RESULTS: Twenty-nine arterial thrombotic events occurred in 21 patients (3.3%). Five patients suffered an acute myocardial infarction and three an ischemic stroke. Unstable angina pectoris was recorded 12 times, transient ischemic attack nine. The prevalence of all arterial thrombotic events combined (acute myocardial infarction, ischemic stroke and coronary heart disease) was 39% and 63% lower than in the two reference populations. The prevalence of cardiovascular disease in VWD was lower than in the general population, SMR 0.60 (95% CI, 0.32-0.98) for coronary heart disease and SMR 0.40 (95% CI, 0.13-0.83) for acute myocardial infarction. For ischemic stroke the prevalence was 35-67% lower compared with two reference populations, SMR 0.65 (95% CI, 0.12-1.59) and 0.33 (95% CI, 0.06-0.80), respectively. CONCLUSIONS: This is the first study showing that VWD patients have a reduced prevalence of arterial thrombosis and provides important insights into the role of VWF in the pathogenesis of arterial thrombosis.

Cardiac catheterization and intervention in haemophilia patients: prospective evaluation of the 2009 institutional guideline.

Ageing haemophilia patients are increasingly confronted with ischaemic heart disease (IHD). Treatment is complex because of the delicate equilibrium between bleeding and thrombosis. In 2009, we developed an institutional guideline on how to treat IHD in this patient population. The aim of this study was to evaluate feasibility and safety of this guideline. Haemophilia patients who underwent coronary angiography or percutaneous coronary intervention between January 2009 and June 2012 were included in the current case series. Nine diagnostic or therapeutic cardiac catheterizations were performed in six haemophilia patients. One patient with moderate haemophilia B was included, whereas the other patients had mild haemophilia A. In six of nine procedures, access to the circulation was gained via the radial artery. Only bare-metal stents were implanted, after which dual antiplatelet treatment was given for at least 4 weeks. During cardiac catheterization/intervention and dual antiplatelet treatment, clotting factor levels were corrected. No thrombotic or clinically relevant bleeding complications occurred. In one patient, a low-titre inhibitor recurred 10 months after catheterization. In-stent restenosis was diagnosed in one patient. This case series indicates that treatment according to the guideline is feasible and safe. Furthermore, based on the case series and developments in new guidelines for non-haemophilic patients with IHD, some adjustments on the 2009 guideline are proposed.

Anticoagulation therapy in haemophilia. Managing the unknown.

Patients with haemophilia (PWH) are relatively protected from cardiovascular death. Recent insights have shown that this is not due to less formation of atherosclerosis than in non-haemophilic men, therefore protection from the final occlusive thrombus will be the major determinant. Prevalence and incidence rates of cardiovascular disease (especially non-fatal events) are scarce, although ongoing studies are addressing this issue. Meanwhile, because the haemophilia population is aging, we are increasingly confronted with cardiovascular events. The main cardiovascular risk factors that should be part of regular screening programs are hypertension, overweight, lipometabolic disorders and smoking. Anticoagulation therapy in haemophilia is feasible, provided that individual tailored coagulation therapy and close monitoring is provided. Here, we present our view on anticoagulation management in PWH. There is an absolute need for risk assessment tools and prospective validation of suggested anticoagulation management strategies in PWH. Until then, we are managing the unknown.