Which medications are known to increase the risk of venous thromboembolism (VTE)?

Medications That Increase Risk of Blood Clots

Multiple medication classes significantly increase venous thromboembolism (VTE) risk, with cancer chemotherapy agents, hormonal therapies, immunomodulators, and certain antipsychotics posing the highest risk.

Cancer Treatment Agents

Chemotherapy

• Cytotoxic chemotherapy increases VTE risk 4-6.5 fold compared to patients without cancer or those not receiving chemotherapy 1, 2
• The mechanism involves acute vascular damage, endothelial injury, depletion of natural anticoagulants (proteins C and S, antithrombin III), and platelet activation 2
• Cisplatin-based regimens carry particularly high risk (12.9-16.7% incidence of thromboembolic events), causing direct vascular injury and platelet activation 3

Antiangiogenic Agents

• Bevacizumab increases VTE risk by 33% relative to chemotherapy alone, with overall VTE incidence of 11.9% (any grade) and 6.3% (high-grade) 2
• Thalidomide and lenalidomide carry VTE risk of 1-58% and 3-75% respectively when combined with glucocorticoids and/or chemotherapy 3
• The highest risk occurs with thalidomide plus doxorubicin-containing chemotherapy (up to 34% VTE rate) 2
• Lenalidomide combined with high-dose dexamethasone (480 mg per 28-day cycle) produces 11-26% VTE incidence 1
• These agents cause endothelial cell and platelet activation, with thalidomide specifically elevating factor VIII and von Willebrand factor while reducing soluble thrombomodulin 3

Other Cancer Agents

• Vorinostat (histone deacetylase inhibitor) causes PE in 5% and DVT in 8% of patients 3
• Vascular signaling pathway (VSP) inhibitors (sorafenib, sunitinib) increase arterial thrombotic events (RR 3.03-3.54) but have unclear effects on venous thromboembolism 3

Hormonal Therapies

Estrogen-Containing Compounds

• Selective estrogen receptor modulators (tamoxifen, raloxifene) significantly increase VTE risk 1
• Combined oral contraceptives increase VTE risk, with variation depending on progestogen type 1
• Hormone replacement therapy is associated with increased VTE risk 1
• Adjuvant hormonal therapy in breast cancer increases VTE risk 1.5-7 fold 4

Supportive Care Medications

Erythropoiesis-Stimulating Agents (ESAs)

• ESAs increase VTE risk, particularly when combined with other thrombogenic therapies like lenalidomide 1, 2
• ESA use is included in the Khorana VTE risk assessment model as a risk factor 2

JAK Inhibitors

Dose-Dependent VTE Risk

• JAK inhibitors carry dose-dependent VTE risk, particularly pulmonary embolism, especially in patients with existing VTE risk factors 5
• Tofacitinib 10 mg twice daily shows higher cumulative probability of VTE and PE compared to TNF inhibitors 6
• Risk factors across treatments include prior VTE, BMI ≥35 kg/m², older age, and chronic lung disease 6

Psychotropic Medications

Antipsychotics

• Atypical antipsychotics significantly increase VTE risk: risperidone (adjusted HR 1.98), olanzapine (adjusted HR 1.87), and clozapine/quetiapine (adjusted HR 2.68) 7
• Conventional antipsychotics (phenothiazines) do not show increased VTE risk 7
• Antipsychotics are associated with increased VTE risk in surgical patients requiring enhanced monitoring 8

Antidepressants

• Tricyclic antidepressants and low-potency serotonin reuptake inhibitors increase VTE risk 3, 8

Other High-Risk Medications

Corticosteroids

• Corticosteroids have the strongest association with VTE among non-cancer medications (aOR exceeding 1.5) 9
• High-dose dexamethasone (≥480 mg per month) combined with immunomodulators dramatically increases VTE risk 1, 3, 1

Additional Medications

• Gabapentinoids and pramipexole show strong VTE associations (aOR exceeding 1.5) 9
• Risedronic acid is associated with increased VTE risk 9
• Diclofenac, ibuprofen, and rofecoxib increase VTE risk among NSAIDs, while naproxen does not 8
• Diuretics may increase VTE risk, particularly through hyponatremia 8

Risk Assessment and Prevention

Khorana VTE Risk Model

The validated risk assessment model for ambulatory cancer patients receiving chemotherapy assigns points for 2:

• Very high-risk cancers (stomach, pancreas): 2 points
• High-risk cancers (lung, lymphoma, gynecological, bladder, testicular): 1 point
• Platelet count ≥350,000/µL: 1 point
• Hemoglobin <10 g/dL or ESA use: 1 point
• Leukocyte count >11,000/µL: 1 point
• BMI ≥35 kg/m²: 1 point

Scores ≥3 confer 7-41% VTE risk and warrant prophylaxis consideration 3

Prophylaxis Recommendations

For multiple myeloma patients on thalidomide/lenalidomide with high-dose dexamethasone or doxorubicin: Use aspirin (for low-risk patients with ≤1 risk factor), or LMWH (enoxaparin 40 mg daily) or warfarin (INR 2-3) for high-risk patients with ≥2 risk factors 1, 3, 1

For hospitalized medical patients: LMWH or unfractionated heparin is recommended for all acutely ill patients at increased thrombosis risk 10

For surgical cancer patients: Extended prophylaxis up to 4 weeks post-surgery, particularly for abdominal/pelvic procedures, reduces VTE by >50% 1

Common Pitfalls

• Underestimating cumulative risk: Multiple medications with modest individual VTE risk can compound significantly when used together 1, 2
• Ignoring cancer-specific factors: The combination of cancer type, stage, and treatment creates multiplicative rather than additive risk 2
• Overlooking patient-specific factors: Age >60 years, obesity (BMI ≥35), prior VTE, immobilization, and central venous catheters substantially amplify medication-related VTE risk 3, 1, 3
• Failing to reassess risk: VTE risk changes with disease progression, treatment modifications, and development of new comorbidities requiring ongoing evaluation 2, 11