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Hypercoagulable states

Last updated: May 28, 2021

Summary

A hypercoagulable state, i.e., thrombophilia, is characterized by an increased predisposition to form blood clots. Depending on the etiology, one or more factors from Virchow's triad (stasis, hypercoagulability, endothelial damage) may be involved. Hypercoagulability may be acquired or inherited and can affect veins and/or arteries. The most common presentation is recurrent deep venous thrombosis of the lower extremities and pulmonary embolism. Arterial involvement increases the risk of myocardial infarction, stroke, and spontaneous abortion. Evaluation for hypercoagulability includes assessment of potential risk factors (e.g., immobilization, smoking, oral contraceptive use, and malignancy) and laboratory tests to assess anomalies of the clotting cascade (e.g., factor V Leiden, antiphospholipid antibody syndrome). Treatment is based on the underlying condition and typically includes a reduction of risk factors and/or the administration of anticoagulants.

Etiology

The etiology of thrombophilia can be classified into two categories:

Hereditary
- Factor V Leiden (autosomal dominant inheritance): most common genetic cause of hypercoagulability in white populations
- Protein C deficiency
- Protein S deficiency
- Antithrombin III deficiency
  - Autosomal dominant inheritance
  - Occasionally acquired
    - Renal failure
    - Liver failure
    - Nephrotic syndrome (urinary loss of antithrombin)
- Prothrombin G20210A mutation
- Hyperhomocysteinemia
- Plasminogen deficiency
- Sickle cell anemia
- MTHFR gene mutation
Acquired
- Pregnancy
- Advanced age
- Smoking
- Obesity
- Surgery
- Immobilization
- Trauma
- Malignancy (especially adenocarcinoma)
- Antiphospholipid syndrome
- Nephrotic syndrome
- Oral contraceptive pills (OCPs)/hormone replacement therapy (HRT)
- Systemic lupus erythematosus (SLE)
- Heparin-induced thrombocytopenia

Clinical features

Thrombophilia is characterized by recurrent thromboembolism.

Venous thromboembolism (most common)
- Blood clots that form within the venous vascular system, dislodge, and travel to a distant location
- E.g., deep venous thrombosis, pulmonary embolism
Arterial thromboembolism
- Blood clots that form within the arterial vascular system, dislodge, and travel to a distant location
- Usually, an acute event that results in ischemic tissue damage (e.g., stroke, acute mesenteric ischemia, acute limb ischemia, acute coronary syndrome, pulmonary infarction)

Hereditary thrombophilia

The hereditary thrombophilias below follow an autosomal dominant inheritance pattern, with the exception of hyperhomocysteinemia.
Very rare: hereditary plasminogen deficiency, dysfibrinogenemia

Pathophysiology of hereditary thrombophilia ^[1]^[2]^[3]
Defect	Pathophysiology	Prevalence in general population
Activated protein C resistance (APC-R) Factor V Leiden	Normally, activated protein C (APC) inactivates factor V in the clotting cascade → decreases the activation of thrombin. A DNA point mutation substitutes guanine for adenine → corresponding mRNA codon forms glutamine in place of arginine on position 506 (Arg506Gln mutation) near the polypeptide cleavage site of factor V In such patients, Gln506-Va is resistant to cleavage by APC → factor V remains active → activates prothrombin → increases thrombotic events (e.g., peripheral and cerebral vein thrombosis, recurrent pregnancy loss)	Heterozygosity: ∼ 5%
Activated protein C resistance (APC-R) Factor V Leiden		Homozygosity: < 1%
Elevated factor VIII	In combination with factor IXa, factor VIIIa activates factor X → increases thrombotic events.	∼ 5%
Prothrombin mutation	Normally, prothrombin is activated to thrombin (factor II) which cleaves fibrinogen to form fibrin. Mutation (G20210A) in the noncoding three prime untranslated region (3'-UTR) of the prothrombin gene → increased expression of prothrombin → increased prothrombin serum levels → ↑ thrombotic events	∼ 3%
Protein S deficiency	Normally, endothelial cells express thrombomodulin, which binds activated thrombin → activates protein C → complexes with protein S to inhibit factor Va and factor VIIIa (both procoagulant factors in the clotting cascade). A deficiency of protein S or protein C results in overactivity of factors V and VIII (factor Va and factor VIIIa) → increases thrombotic events.	∼ 1%
Protein C deficiency		< 1%
Antithrombin III deficiency	Normally, antithrombin III binds to and inactivates thrombin and factor X → inhibits coagulation. Deficiency leads to decreased inhibition and elevated thrombin and factor X. Heparin normally increases PTT; however, in patients with antithrombin III deficiency, this increase is diminished. No other direct effects on PT, PTT, or thrombin time	∼ 0.1%
Hyperhomocysteinemia	Changes in thrombomodulin function are due to increased activation of factor VIIa and V, inhibition of protein C, increased blood viscosity, and decreased endothelial antithrombotic activity. Homocysteine levels are elevated in patients with vitamin B6 deficiency and mutations in enzymes that metabolize homocysteine (autosomal recessive).	∼ 5–7%

Acquired thrombophilia

Pathophysiology of acquired thrombophilia ^[4]^[5]^[6]
Etiology	Pathophysiology
Surgery	Extended immobilization during procedure → blood stasis Vessel instrumentation → endothelial damage
Trauma	Results in decreased venous blood flow, immobilization (blood stasis), and release of tissue factor (hypercoagulability) → increased clotting
Malignancy	Cancers excrete procoagulant factors (e.g., tissue factor and cancer procoagulant). The risk of thromboembolism is highest during first hospitalization and initiation of chemotherapy.
Immobilization	Prolonged immobilization (e.g., extended travel, hospitalization, bed rest) → increased venous stasis
Smoking	Causes endothelial damage The risk is significantly higher in women who also use oral contraceptives.
Obesity	Leads to chronic systemic inflammation and impaired fibrinolysis The risk of thromboembolism increases with increasing BMI.
Antiphospholipid syndrome	Acquired antibodies directed against plasma proteins bound to phospholipids (e.g., lupus anticoagulant, anti-cardiolipin, beta2-glycoprotein I antibodies) → aggregation of plasma proteins (e.g., clotting factors) → induces venous and arterial clotting → miscarriages, DVTs, portal vein thrombosis, and strokes Associated with SLE and rheumatoid arthritis
Nephrotic syndrome	Loss of plasma antithrombin in urine and an increase in blood viscosity due to extravasation of fluid from albumin loss in urine
Oral contraceptive pills (OCPs) or hormone replacement therapy (HRT)	Increased estrogen and progestin → increase in prothrombin and fibrinogen and a decrease in protein S
Heparin-induced thrombophilia	Antibodies against platelet factor 4 (PF-4) → increased activation of platelets (hypercoagulability) and a depletion of platelets
Pregnancy	Clotting factors increase (hypercoagulability) Protein C and protein S decrease Venous stasis as the uterus enlarges
Advanced age ^[5]	Progressive endothelial damage Increase in pro-clotting factors without a concomitant increase in protein C Increase in other pro-clotting comorbidities (e.g., malignancy) Decreased physical activity

Diagnostics

History
- A family history of thromboembolism should raise suspicion of a hereditary etiology.
- Inquire about acquired causes and risk factors (e.g., medications, obstetric history, trauma).
Laboratory tests
- Coagulation studies: active partial thromboplastin time (prolonged in antiphospholipid antibody syndrome)
- ESR: elevated in malignancy or lupus
- Antiphospholipid antibody panel (lupus anticoagulant, anticardiolipin, beta2-glycoprotein I antibody)
- Heparin-induced thrombocytopenia tests: complete blood count (thrombocytopenia with heparin use), serotonin release assay (positive), antiplatelet factor 4 antibody (positive)
- Hypercoagulability panel: APC resistance/factor V Leiden assay, prothrombin gene molecular analysis, protein C and S levels, antithrombin-heparin cofactor assay
Imaging: consider CT scan if a malignancy is suspected

Treatment

Approach

Anticoagulant administration (therapeutic heparin bridged to warfarin): for pulmonary embolism or deep vein thrombosis
- 1^st episode: 3 months
- 2^nd episode: minimum of 6 months
- > 3 events: lifetime anticoagulation
Consider an inferior vena cava filter if anticoagulant therapy is contraindicated.
Reduce risk factors
- Avoid oral contraceptive pills
  - Patients with factor V Leiden
  - Women > 35 years old who smoke
- Smoking cessation
- Weight loss

Special considerations

Avoid anticoagulation in trauma, hemorrhage, and severe hypertension.
Heparin is contraindicated in patients with heparin-induced thrombocytopenia type II. Argatroban or lepirudin should be prescribed instead.
Heparin is less effective in antithrombin III deficiency and may require also antithrombin concentrate to be effective
Administering warfarin to a person with protein C and S deficiencies can precipitate warfarin-induced skin necrosis.

The risk of venous thromboembolism is reduced with administration of an anticoagulant (e.g., heparin) following surgery!

References:^[7]

Prevention

Consider prophylaxis in the following high-risk groups:

Postoperative patients
Prolonged immobilization or hospitalization
Malignancy
Orthopedic conditions

References

Colman RW. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. Lippincott Williams & Wilkins ; 2006
Den Boer NC, Van der Heiden C, Leijnse B, Souverijn JHM. Clinical chemistry: an overview . Plenum Press ; 1989
Kumar A, Afreen S, Mohd Yusuf, Gupta A. Mechanism and pathophysiology of activated protein C-related factor V leiden in venous thrombosis. Asian Journal of Transfusion Science. 2012; 6 (1): p.47. doi: 10.4103/0973-6247.95053 . | Open in Read by QxMD
Kim JY, Khavanin N, Rambachan A, et al. Surgical duration and risk of venous thromboembolism. JAMA Surg. 2015; 150 (2): p.110-117. doi: 10.1001/jamasurg.2014.1841 . | Open in Read by QxMD
Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol. 2015; 20 (5): p.437-444. doi: 10.1097/MOH.0b013e3283634443 . | Open in Read by QxMD
Esmon CT. Basic Mechanisms and Pathogenesis of Venous Thrombosis. Blood Rev. 2009; 23 (5): p.225–229. doi: 10.1016/j.blre.2009.07.002 . | Open in Read by QxMD
Tchaikovski SN, Rosing J. Mechanisms of estrogen-induced venous thromboembolism. Thromb Res. 2010; 126 (1): p.5-11. doi: 10.1016/j.thromres.2010.01.045 . | Open in Read by QxMD