What are the causes of deep vein thrombosis (DVT)?

Causes of Deep Vein Thrombosis

Deep vein thrombosis results from the interaction of three fundamental mechanisms—venous stasis, endothelial injury, and hypercoagulability (Virchow's triad)—which are triggered by specific patient-related, disease-related, and treatment-related risk factors. 1

Pathophysiologic Mechanisms

The formation of venous thrombi requires disruption of normal hemostatic balance through three core pathways 2, 3:

• Venous stasis causes endothelial activation and promotes platelet and leukocyte adhesion, particularly in valve pockets where blood flow naturally slows 3
• Endothelial injury triggers tissue factor expression and initiates the coagulation cascade 3
• Hypercoagulability from inherited or acquired thrombophilias shifts the balance toward clot formation 2

These mechanisms work synergistically: altered venous flow activates endothelium, which recruits platelets and leukocytes that express tissue factor and form neutrophil extracellular traps, ultimately trapping red blood cells and propagating the thrombus 3.

Patient-Related Risk Factors

Inherited Thrombophilias

• Prior DVT is the single strongest predictor (OR 6.08), accounting for 22.7% of total risk 1
• Inherited thrombophilia (protein C, protein S, or antithrombin deficiency) increases risk nearly 6-fold (OR 5.88) and represents 22.2% of overall risk 1
• Factor V Leiden is present in 15-20% of DVT patients; heterozygotes have ~10% lifetime risk, homozygotes >80% 4
• Prothrombin G20210A mutation occurs in ~6% of DVT patients and confers 2- to 4-fold increased risk 4
• Protein C deficiency carries an odds ratio of 11.1 for DVT 5
• Antiphospholipid antibodies are detected in 22.6% of cerebral venous thrombosis cases versus 3.2% of controls 4

Demographic and Constitutional Factors

• Advanced age (>60 years) modestly raises risk (OR 1.34) and accounts for 3.6% of overall risk burden 1
• Obesity (BMI >30 kg/m²) is an established independent risk factor 1

Disease-Related Risk Factors

Malignancy

• Active cancer increases DVT risk 4- to 7-fold (OR 2.65), responsible for 12.3% of total risk and ~20% of community VTE cases 1, 4
• Highest-risk cancers include pancreatic, brain, lung, ovarian, renal, gastric, bladder, and testicular tumors 4
• Hematologic malignancies (lymphoma, acute leukemia, multiple myeloma) carry particularly high risk 4
• Metastatic disease amplifies risk ~20-fold compared to localized cancer 4
• First three months after cancer diagnosis represent the period of maximal thrombotic risk 1

Acute Medical Conditions

• Acute infections increase DVT odds by 1.48-fold, contributing 4.9% of overall risk 1
• Critical illness requiring ICU care raises risk 1.65- to 2.10-fold (6.3-13.7% of total risk) 1
• Renal insufficiency is an established independent risk factor 1
• Heart failure and acute myocardial infarction or ischemic stroke each independently increase risk 4

Treatment-Related Risk Factors

Immobility and Hospitalization

• Prolonged immobility markedly raises risk (OR 3.17), accounting for 14.4% of total risk 1
• Hospital admission alone increases annual incidence to 239 per 100,000 hospitalized patients, generating >547,000 DVT events annually in the United States 1, 4
• Acute paralysis (e.g., spinal cord injury) elevates odds 2.97-fold (13.6% of total risk) 1

Surgical and Traumatic Injury

• Recent major surgery in cancer patients roughly doubles postoperative DVT risk and triples fatal PE risk 1
• Traumatic injury, especially in individuals >60 years, is a major predictor 1
• Lower-extremity fractures significantly increase thrombotic risk 1

Cancer Therapies

• Active chemotherapy raises DVT odds ~6.5-fold 1, 4
• Anti-angiogenic agents (thalidomide, lenalidomide, bevacizumab) substantially increase risk 1, 4
• Hormonal therapies (tamoxifen, oral contraceptives) are associated with higher incidence 1, 4
• Erythropoiesis-stimulating agents have been linked to elevated VTE risk 1, 4

Intravascular Devices

• Central venous catheters cause 50-80% of pediatric DVT 4
• Indwelling devices (catheters, pacemakers, defibrillators) confer the greatest risk for upper-extremity DVT 4, 6
• Left-sided CVC insertion significantly increases thrombotic complications versus right-sided placement 6
• Catheter tip position above the SVC-right atrium junction increases thrombosis rates 6

Pregnancy and Hormonal Factors

• Pregnancy and puerperium elevate VTE risk, with most pregnancy-related cerebral venous thrombosis occurring in third trimester or postpartum 4
• Combined oral contraceptives increase VTE risk ~4-fold alone and ~30-fold when combined with Factor V Leiden 4

Laboratory and Clinical Markers

• Thrombocytosis (pre-chemotherapy platelet count ≥350×10⁹/L) predicts increased risk 1
• Leukocytosis is an established laboratory risk factor 1
• Elevated D-dimer and fibrinogen serve as biomarkers indicating heightened risk 1
• Elevated C-reactive protein is probably associated with DVT (moderate certainty evidence) 1
• Clinical signs including tachycardia, fever, and peripheral leg edema correlate with higher risk 1

Critical Clinical Considerations

Most patients have multiple risk factors from different categories operating simultaneously 1, 4. The NCCN guidelines emphasize that DVT arises when slow venous flow, vessel injury, and hypercoagulable state coexist, and patients rarely present with a single isolated risk factor 4. In cancer patients, the combination of hospitalization and active malignancy creates particularly high thrombotic risk 4. Each additional risk factor compounds overall thrombotic risk, emphasizing the need for comprehensive assessment rather than focusing on individual causes 4.