How do steroids affect the clotting cascade?

Effects of Steroids on the Clotting Cascade

Steroids have complex effects on the clotting cascade, with different types of steroids (corticosteroids vs. anabolic steroids vs. sex hormones) having distinct and sometimes opposing impacts on hemostasis and thrombosis risk.

Corticosteroids

• Corticosteroids have minimal direct effects on the clotting cascade, with no significant evidence showing they increase thrombotic risk when used alone 1
• Four small randomized trials of corticosteroids for intracerebral hemorrhage showed no benefit, and one study demonstrated increased risk of infectious complications with steroid use 1
• In immune thrombocytopenia treatment guidelines, corticosteroids are noted to have side effects but these are generally less pronounced with short courses (<7 days) used to treat children 1
• When used in post-liver transplant settings, corticosteroids can contribute to metabolic syndrome components including diabetes, weight gain, and hepatic steatosis, which may indirectly increase thrombotic risk 1

Sex Hormones (Estrogen and Progesterone)

• Combined estrogen and progesterone therapy significantly increases thrombotic risk by 2-3 fold compared to non-users 2
• Meta-analyses demonstrate that hormone replacement therapy more than doubles the risk of venous thromboembolism (RR 2.14; 95% CI 1.64-2.81) 2
• The Women's Health Initiative study confirmed a two-fold increased rate of venous thromboembolic disease (RH 2.11; 95% CI 1.26-3.55) in women taking combined estrogen-progestin therapy 2
• Estrogen affects multiple hemostatic pathways in a prothrombotic direction by:
  • Increasing factor VII activity, D-dimer, and prothrombin F1.2 1, 2
  • Decreasing anti-thrombin III, tissue factor pathway inhibitor, and tissue plasminogen activator 1, 2
• The thrombogenic effect of estrogen is amplified when co-administered with other medications, including chemotherapy and steroids 1

Anabolic-Androgenic Steroids

• Anabolic steroids have complex effects on hemostasis, with some studies showing both pro-coagulant and pro-fibrinolytic effects 3, 4, 5
• The most recent evidence (2021) indicates that anabolic-androgenic steroid abuse impairs fibrin clot lysis, potentially increasing thrombotic risk 6
• Specific hemostatic changes with anabolic steroids include:
  • Increased plasma fibrinogen, plasminogen, and plasmin inhibitor 6
  • Increased coagulation factors II and V 5
  • Decreased plasminogen activator inhibitor (PAI-1) 5
• Case reports have documented pulmonary embolism and deep vein thrombosis associated with testosterone and nandrolone use 7
• The 2021 study concluded that anabolic steroid abuse may be associated with increased thrombotic disease due to depressed fibrin clot lysis 6

Steroids in Cancer Patients and Thrombotic Risk

• In cancer patients, steroids may contribute to thrombotic risk when combined with other medications 1
• The thrombogenic effect of antiangiogenic agents (bevacizumab, thalidomide, lenalidomide) is amplified by co-administration of chemotherapy and steroids 1
• For multiple myeloma patients receiving immunomodulatory drugs (lenalidomide, thalidomide, pomalidomide), guidelines note an increased risk of bleeding in patients on aspirin who are also receiving steroids 1

Genetic Factors and Steroid-Related Thrombosis

• Prothrombotic genetic variants significantly increase thrombosis risk with hormone therapy 1, 2
• Factor V Leiden carriers taking hormone therapy have significantly increased risk of venous thromboembolism compared to non-carriers taking placebo 1
• Similar increased risk is seen with the prothrombin 20210A variant in women using hormone therapy 1

Clinical Implications

• The risk-benefit profile of steroid therapy should be carefully evaluated, particularly in patients with additional thrombotic risk factors 2
• For sex hormone therapy, the U.S. Preventive Services Task Force concluded there is good evidence that hormone replacement therapy increases the risk for venous thromboembolism 2
• For anabolic steroids, the most recent evidence suggests they may increase thrombotic risk through impaired fibrinolysis, despite some earlier studies showing mixed effects 6