What is the relationship between Hormone Replacement Therapy (HRT) and venous sinus thrombosis?

From the Guidelines

Hormone replacement therapy (HRT) is associated with an increased risk of venous thromboembolism, including venous sinus thrombosis, and should be used with caution in women with a history of such conditions. The risk of venous thromboembolism is highest within the first year of HRT use, with a relative risk of 3.49 (95% CI, 2.33 to 5.59) 1.

Key Considerations

• The increased risk of venous thromboembolism with HRT is due to the effect of estrogen on clotting factors and natural anticoagulants, creating a prothrombotic state.
• Transdermal estrogen preparations (patches, gels) are preferred over oral formulations as they have less impact on clotting factors due to bypassing first-pass liver metabolism.
• The lowest effective dose of HRT should be used for the shortest duration possible.
• Before initiating any form of HRT in women with a history of venous sinus thrombosis, anticoagulation therapy should be established and maintained, typically with direct oral anticoagulants (DOACs) like apixaban (5mg twice daily) or rivaroxaban (20mg daily with food), or warfarin (dose adjusted to maintain INR 2-3) 1.
• Close monitoring with regular follow-up appointments every 3-6 months is essential to assess for any signs of recurrent thrombosis.
• Non-hormonal alternatives for managing menopausal symptoms should be considered first, including selective serotonin reuptake inhibitors (SSRIs) like paroxetine (7.5mg daily) for hot flashes, or gabapentin (300mg at bedtime) for sleep disturbances and vasomotor symptoms.

Risk Factors

• Major trauma, surgery, lower-limb fractures and joint replacements, and spinal cord injury are strong provoking factors for VTE 1.
• Cancer is a well-recognized predisposing factor for VTE, with the risk varying with different types of cancer 1.
• Oestrogen-containing oral contraceptive agents are associated with an elevated VTE risk, and contraceptive use is the most frequent VTE risk factor in women of reproductive age 1.

From the Research

Relationship Between Hormone Replacement Therapy (HRT) and Venous Sinus Thrombosis

• The relationship between HRT and venous sinus thrombosis has been studied extensively, with evidence suggesting that HRT is associated with an increased risk of venous thromboembolism 2, 3, 4, 5, 6.
• The absolute risk of venous thromboembolism remains small, but the relative risk is significantly higher, particularly during the first year of HRT use 2.
• The mechanism of this association is poorly understood, but potential mechanisms include unmasking of an underlying thrombophilia or combination with other recognized risk factors for venous thromboembolism 2.
• Epidemiological studies have shown that the risk of venous thromboembolism differs according to the type of HRT used, with estrogen-only HRT appearing to have a lower risk than estrogen-progestin HRT 5.
• The presence of thrombophilia, such as the factor V Leiden mutation, further increases the risk of venous thromboembolism in HRT users 5.
• Patients with a personal or family history of venous thromboembolism should be screened for underlying thrombophilia, and HRT should be used with caution in these patients 2, 4.
• The risk of venous thromboembolism with HRT use should be weighed against the established benefits of HRT, including relief of menopausal symptoms, prevention of osteoporosis, and arterial-vascular disease 2.

Risk Factors and Management

• Patient-specific factors, such as hormone type, dose, route, personal and family history of thrombosis, and other prothrombotic risk factors, should be considered when making decisions about HRT use 3.
• Anticoagulation is protective against future thrombosis in patients who develop thrombosis on HRT, and the duration of anticoagulation depends on ongoing and future hormone therapy choice 3.
• The optimal management of HRT for individuals diagnosed with prothrombotic illnesses, such as COVID-19, remains unclear 3.

Clinical Implications

• Clinicians should consider the risk of venous thromboembolism when prescribing HRT, particularly in patients with a history of thrombosis or thrombophilia 2, 4, 5.
• Patients without risk factors should be advised of the small increase in risk of venous thrombosis, which is greatest during the first year of HRT use 2.
• The beneficial effects of HRT in patients at risk of arterial disease may outweigh the small risk of thrombosis, and the situation should be assessed on an individual basis for each patient 2.