Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs (September 2023)

This was a nationwide (Denmark) cohort study, following 2,029,065 women of reproductive age (15 to 49 years) from 1996 to 2017. The aim of the research was to look at the influence of simultaneous use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism (VTE).

Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of VTE of:

• 4.5 in users of low/no risk hormonal contraception,
• 7.2 in women not using hormonal contraception,
• 7.9 in those using medium risk hormonal contraception, and
• 11.0 in women using high risk hormonal contraception.

Compared with non-use of NSAIDS, the number of additional VTE events per 100 000 women over the first week of NSAID treatment was:

• 3 in users of low/no risk hormonal contraception.
• 4 in women not using hormonal contraception,
• 11 in those using medium risk hormonal contraception, and
• 23 in women using high risk hormonal contraception,

These results show that NSAIDs are positively linked with the occurrence of VTE, with the extent of the increased risk being dependent on the usage of hormonal contraception. However, further research is required to determine whether these findings represent an actual drug interaction.

The effects of coagulation factors on the risk of endometriosis: a Mendelian randomization study (May 2023)

The aetiology and pathogenesis of endometriosis remains unclear however, it is largely known that endometriosis is a chronic inflammatory disease and that patients with the disorder appear to be in a hypercoagulable state. Therefore, the aim of this study was to use publicly available Genome-wide association study (GWAS) summary statistics to investigate the causal relationship between coagulation factors and the risk of endometriosis.

The cohort comprised of 4354 cases and 217,500 controls. Analysis was carried out to estimate the causal effects of 11 coagulation factors – platelet adhesion (vWF and ADAMTS13), intrinsic pathway (aPTT, FVIII and FXI), extrinsic pathway (FVII), common pathways (FX and ETP), and fibrin clot dissociation (PAI-1, protein C, and plasmin). Results found:

• ADAMTS13 levels were inversely associated.
• vWF levels showed a positive causal association.
• Heterogeneity – vWF, aPTT and FVIII.
• FXI - mild negative causal relationship.

Therefore, the main results were that ADAMTS13 levels are causally associated with a decreased risk of endometriosis, vWF was positively associated with endometriosis, and is potentially a causal factor.

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Von willebrand disease, hemophilia, and other inherited bleeding disorders in pregnancy (March 2023)

Von Willebrand Disease (VWD) is the most common diagnosed bleeding disorder among women. Haemophilia is less common, however carriers are unique, as they are at an increased risk of giving birth to severely affected male neonate. This review focuses on these two blood disorders with the objective of providing doctors a practical clinical approach to their management during pregnancy and the postpartum period.

Maternal supervision of VWD includes assessment of von Willebrand factor (VWF) activity in the third trimester (approx. 36 weeks), VWF concentrates (plasma derived or recombinant), and antifibrinolytics. Research has shown that VWD is not an indication for caesarean delivery, as the risk to foetal intracranial haemorrhage is extremely low. 

For haemophilia carriers, management of delivery requires attention to both maternal and foetal bleeding. Factor IX levels do not increase during pregnancy, and despite an increase in factor VIII levels, it is not to the same extent as in women who are not haemophilia A carriers.

It is a general consensus and definite guidance that women with factor VIII or IX levels lower than 50% should receive treatment with factor concentrate at the time of delivery. The World Federation of Haemophilia also recommend this treatment for women with VWD – virally inactivated plasma-derived or recombinant concentrates over cryoprecipitate or fresh-frozen plasma.

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The diagnosis, natural history, and management of von Willebrand disease in women in the age of guidelines (January 2023)

This review highlights the 2021 ASH/ISTH/NHF/WFH guidelines on von Willebrand disease (VWD), latest recommendations on diagnosis and management. The article also focuses on the burden of bleeding complications in women with VWD, heavy menstrual bleeding among adolescents, and post-partum management with antifibrinolytics.

Adolescents with low VWF are particularly vulnerable, as the diagnosis is often delayed due to the potential presence of other diseases or medical conditions such as iron deficiency anaemia and associated symptoms. Research found that up to 42% of adolescents with low VWF experience nosebleeds, 45% have bleeding under the skin from burst bleed vessels, 35% bleed from minor wounds, and 32% suffer from oral cavity bleeding. Anaemia was found in 21% of the patients, with 60% having iron deficiency.

The bleeding phenotype (or observable characteristics or traits) in adolescents results in a significant decline in quality of life due to iron deficiency anaemia causing fatigue. Iron deficiency also is associated with reduced cognition in adolescents and girls. A retrospective study found that adolescents presenting with heavy menstrual bleeding (HMB), 50.9% noted to have depression, compared to 24.2% of patients without HMB.

A multidisciplinary approach is recommended for women, especially adolescents with HMB. The treatment team should comprise of a paediatric/adult haematologist, adolescent medicine specialist, gynaecologist, coagulationist, nutritionist, and nurse professional.

The federally funded haemophilia treatment centres primarily include males, however over the last decade, it has rapidly extended to comprise female patients with bleeding disorders. Yet, screening for inherited bleeding disorders is done in less than 25% of the women with HMB. Consequently, this review recommends a multifaceted team of health professionals for the appropriate management of women and adolescents with VWD and heavy bleeding issues.

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Challenges in the management of women with type 2B von Willebrand disease during pregnancy and the postpartum period: evidence from literature and data from an international registry and physicians’ survey-communication from the Scientific and Standardization Committees of the ISTH (January 2023)

This study investigated the current diagnostic and management approaches, and outcomes in women with von Willebrand disease (VWD) during pregnancy. Type 2B VWD represents approximately 5% of all VWD cases and results from dysfunctional von Willebrand factor and from gain-of-function mutations that cause spontaneous platelet-VWF binding and mild-moderate thrombocytopenia.

The study analysed data on clinical and laboratory features, management and bleeding complications and pregnancy outcomes of a total of 55 pregnancies from 49 women, and data reported by 112 physicians. The key issues highlighted were:

• Bleeding complications remain a concern,
• The target safe VWF level and the ideal monitoring approach are unknown,
• There is a wide range of haemostatic management practices in the type and timing of treatment, and
• Physicians have diverse views on the mode of delivery and use of neuraxial anaesthesia.

Brief summary of results:

• Pregnancy-induced alterations in plasma VWF, FVIII and platelet levels – the mean platelet counts dropped from baseline to the third trimester. 
• Pregnancy outcomes – 3 patients reported a comorbidity; 2 patients reported SLE with nephritis; 1 reported elevated liver enzymes/low platelet syndrome. Of the 32 patients reporting, 12 reported placenta-mediated complications. From 55 pregnancies, 50 resulted in a live birth.
• Bleeding complications and disease management – a total of 19 of 36 pregnancies reported clinically significant bleeding.

This review emphasises the difficulties in recognising and assessing bleeding disorders in with type 2B VWD, as it showed that despite the significant bleeding phenotype, delayed diagnosis of 2B VWD were frequently observed. An interesting observation was that 21% of women received a diagnosis during pregnancy which was prompted because of progressive thrombocytopenia VWD testing with a progressive fall in platelet count was recommended. Therefore, this study demonstrates the complex, challenging and multifactorial the management of pregnant women with Type 2B VWD is. A proposal has been submitted to the ISTH guidelines committee regarding the diversity and uncertainty of the evidence presented in this study, which calls for international consensus and guidance to improve patient care and clinical outcomes.