Gynaecological management of women with inherited bleeding disorders. A UK Haemophilia Centres Doctors' Organisation Guideline.

Women with inherited bleeding disorders (IBDs) may present to healthcare professionals in a variety of ways and commonly will be encountered by either haematology or gynaecology services. Heavy menstrual bleeding is very often the first manifestation of an IBD. There is a wide variation in severity of bleeding for women with IBD and diagnosis and subsequent management of their condition requires multidisciplinary specialised care which is tailored to the individual and includes excellent cross-specialty communication between gynaecology and haematology teams. This guideline is intended for both haematologists and gynaecologists who are involved in the diagnosis and management of women with bleeding disorders. It sets out recommendations about how to investigate heavy menstrual bleeding (HMB), the commonest presentation for women with IBD to hospital services, to guide physicians about how to diagnose an IBD and covers the management of women with known IBD and HMB. The second section sets out recommendations for patients known to have IBD and covers management of patients with IBD in the setting of gynaecological surgery and management for all other non-surgical gynaecological situations.

Postpartum bleeding in women with inherited bleeding disorders: a matched cohort study.

: Women with inherited bleeding disorders (IBDs) are reported to have higher rates of primary and secondary postpartum haemorrhage (PPH), even with optimal haemostatic management. We evaluated whether women with IBD have higher odds of PPH compared with those without, when controlled for mode of delivery with a control group of women without IBDs. The obstetric experiences and outcomes of all women with IBD delivering at a tertiary centre between 2008 and 2017, were compared with matched controls (1 : 1). Obstetric care was provided according to national guidelines to both women with IBD and controls. Primary PPH was defined as estimated blood loss at least 500 ml. There were 46 completed pregnancies in women with IBD: 16 haemophilia A carriers, eight haemophilia B carriers, eight factor XI deficiency patients and 14 von Willebrand disease patients (type 1 = 6; type 2 = 8). No peripartum haemostatic treatment was received by carriers of haemophilia A or B. There were 74 control pregnancies. Women with IBD had higher odds of primary PPH, in a model controlling for mode of anaesthesia (adjusted odds ratio 5.30, 95% confidence interval 1.02-27.59, P = 0.048). Carriers of haemophilia A had a higher, statistically nonsignificant, odds for primary PPH than controls (adjusted odds ratio 6.85, confidence interval 0.77-60.73, P = 0.084). An increase in primary PPH was observed in women with IBD, particularly in haemophilia A, despite management according to guidelines. These results warrant further investigation and consideration should be given as to which factor levels to target.

Multiple myeloma and acquired von Willebrand disease: a combined cause of preanalytical interference causing gel formation?

We report a patient with acquired von Willebrand disease, associated with multiple myeloma. At one stage in his illness, we were unable to analyse a sample sent in a serum separator tube, due to the presence of a gel within the separated serum layer. We suggest this was due to anomalous position of the gel because of the density of the sample caused by its high total protein concentration, exacerbated by fibrin strand formation because of inhibition of appropriate fibrin clot formation secondary to clotting disorder.

Diagnostic accuracy study of a factor VIII ELISA for detection of factor VIII antibodies in congenital and acquired haemophilia A.

Antibody formation to factor VIII (FVIII) remains the greatest clinical and diagnostic challenge to the haemophilia-treating physician. Current guidance for testing for inhibitory FVIII antibodies (inhibitors) recommends the functional Nijmegen-Bethesda assay (NBA). A FVIII ELISA offers a complementary, immunological approach for FVIII antibody testing. It was the aim of this study to retrospectively evaluate the performance of a FVIII ELISA (index) for detection of FVIII antibodies, compared with the NBA (reference). All samples sent for routine FVIII antibody testing at two haemophilia Comprehensive Care Centres, were tested in parallel using the NBA and a solid-phase, indirect FVIII ELISA kit (Immucor). A total of 497 samples from 239 patients (severe haemophilia A=140, non-severe haemophilia A=85, acquired haemophilia A=14) were available for analysis. Sixty-three samples tested positive by the NBA (prevalence 12.7%, 95% confidence interval [CI], 9.9-15.9 %), with a median inhibitor titre of 1.2 BU/ml (range 0.7-978.0). The FVIII ELISA demonstrated a specificity of 94.0% (95%CI, 91.3-96.0), sensitivity of 77.8% (95%CI, 65.5-87.3), negative predictive value of 96.7% (95%CI, 94.5-98.2), positive predictive value 65.3% (95%CI, 53.5-76.0), negative likelihood ratio 0.2 (95%CI, 0.1-0.4), positive likelihood ratio 13.0 (95%CI, 8.7-19.3) and a diagnostic odds ratio of 54.9 (95%CI, 27.0-112.0). Strong positive correlation (r=0.77, p<0.001) was seen between the results of the NBA (log adjusted) and FVIII ELISA optical density. In conclusion, FVIII ELISA offers a simple, specific, surveillance method enabling batch testing of non-urgent samples for the presence of FVIII antibodies.

Associations of haemostatic variables with body mass index: a community-based study.

Obesity is a risk factor for venous and arterial thrombosis. We examined relationships between body mass index (BMI) and a number of haemostatic and inflammatory variables in a community-based study of 150 adults (73 male, 77 female; age range, 23-80 years). Associations with BMI were sought after adjustment for age, smoking and diurnal variation. There were significant interactions of gender on the associations of BMI with fibrinogen (P = 0.002) and C-reactive protein (P = 0.02). In women, there were strong positive associations of BMI with fibrinogen (r = 0.57, P < 0.0001) and C-reactive protein (r = 0.40, P = 0.001). In men, these associations were non-significantly inverse. For all other variables there were no sex differences, so results for men and women were combined. Significant positive associations with BMI were seen for factor VIIc, activated factor XII, antithrombin activity, protein C activity and plasminogen activator inhibitor-1 activity. Inverse associations with BMI were seen for tissue plasminogen activator activity and activated protein C ratio. Increasing BMI is associated with elevation of certain coagulation factors, inhibitors of fibrinolysis, and inhibitors of coagulation, the latter potentially reflecting a compensatory response. Gender influences the association of certain inflammatory variables with BMI so the sexes should be considered separately in studies of inflammation and obesity.

Inherited thrombophilias and anticoagulation in pregnancy.

Thromboprophylaxis, primary or secondary, should be considered in selected pregnant women with inherited thrombophilias; such women may be divided into high-, medium- and low-risk categories on the basis of the specific thrombophilic defect and any personal or family history of venous thromboembolism (VTE). Women at high risk of VTE should receive treatment doses of low-molecular-weight heparin (LMWH) throughout pregnancy and should remain on anticoagulation for 6 weeks postpartum, or, where appropriate, long-term. Women at moderate risk should be treated with prophylactic fixed-dose LMWH throughout pregnancy and for 6 weeks postpartum. Women at low risk should receive prophylactic fixed-dose LMWH for 6 weeks postpartum, and low-dose aspirin LDA should be considered during pregnancy. LWMH offers important advantages over unfractionated heparin (UFH); heparin-induced thrombocytopaenia (HIT) and osteopaenia are rarely seen. For treatment doses of LMWH, dosage adjustment based on anti-Xa levels is usually required as pregnancy progresses. Warfarin should be avoided throughout pregnancy. LMWH, UFH and warfarin are safe for breast-feeding mothers.