A hypercoagulable state, i.e., thrombophilia, is a predisposition to forming blood clots. Depending on the etiology, one or more factors of the endothelial damage) may be involved. Hypercoagulability may be acquired or inherited and can affect veins and/or arteries. It leads to an increased risk of developing venous thromboembolism (VTE), which most commonly manifests as of the lower extremities or . Arterial involvement increases the risk of , , and spontaneous . 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., , ). Treatment is based on the underlying condition and typically includes a reduction of risk factors and/or the administration of anticoagulants.(stasis, hypercoagulability,
- Thrombophilia: A predisposition to increased coagulation that typically manifests as recurrent thromboembolism.
Thromboembolism: The formation and/or migration of blood clots in different locations of the venous or arterial vasculature that can occlude or impair the pulmonary or systemic circulation.
Venous thromboembolism (VTE)
- Blood clots that form within the venous vascular system, dislodge, and travel to a distant location, e.g., the pulmonary arteries via the right heart
- Examples include deep venous thrombosis, pulmonary embolism, portal vein thrombosis, cerebral venous thrombosis
- Provoked VTE: VTE occurring in the presence of , e.g., ≥ 1 strong trigger OR multiple weak triggers 
- Unprovoked VTE: VTE occurring in the absence of identifiable triggers. 
- Blood clots that form within the arterial vascular system, dislodge, and travel to a distant location, e.g., distal systemic arteries and arterioles
- Usually, an acute event that results in ischemic tissue damage (e.g., stroke, acute mesenteric ischemia, acute limb ischemia, acute coronary syndrome, pulmonary infarction)
- Venous thromboembolism (VTE)
The development of thromboembolic disease is multifactorial and more commonly triggered by traditional risk factors than by inherited or acquired thrombophilia. A single patient may have multiple underlying conditions or risk factors (both hereditary and acquired) which can lead to a higher cumulative risk of thromboembolism. 
Traditional risk factors for thromboembolic disease 
Venous thrombosis: See also “ .” 
- Strong: trauma, fractures, major orthopedic surgery, oncological surgery, immobilization combined with other risk factors
- Moderate: nononcological surgery, exogenous estrogen (e.g., OCPs, HRT); , pregnancy and puerperium, previous VTE
- Weak: advanced age, prolonged travel, bed rest (e.g., > 3 days) as a sole risk factor, metabolic syndrome
- Arterial thrombosis: See also “ .”
Hereditary causes of hypercoagulability 
- Predisposing to venous thrombosis 
- Predisposing to both venous and arterial thrombosis
Acquired causes of hypercoagulability 
- Predisposing to venous thrombosis
- Predisposing to both venous and arterial thrombosis
Clinical features of thromboembolism
These typically depend on the location of thromboembolism, the vasculature involved, and the underlying condition.
- VTE (most common): See “ ”, “ ”, “Clinical features of cerebral venous thrombosis”, and “Portal vein thrombosis.”
- : See “ ” and “ .”
- : See “ .”
- Others: e.g., the of , clinical features of ,
Clinical features suggestive of underlying thrombophilia 
- VTE characteristics
- Frequent obstetrical complications: e.g., IUFD, IUGR, preeclampsia  ,
- Arterial thromboembolism (e.g., stroke) in a young patient with no cardiovascular risk factors
Underlying mechanisms vary depending on whether thrombophilia is hereditary or acquired.
- 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 |
|Defect||Pathophysiology||Prevalence in general population|
Activated protein C resistance (APC-R)
Factor V Leiden 
| || |
|Elevated factor VIII|| |
|Prothrombin mutation|| |
Protein S deficiency
| || |
|Protein C deficiency|| |
|Antithrombin III deficiency|| || |
| || |
|Pathophysiology of acquired thrombophilia |
( or (
|Advanced age |
- Most thrombophilias are identified following a thromboembolic event, the majority of which are multifactorial, involving a combination of transient and chronic risk factors.
- is unnecessary in most cases.
- Perform a detailed clinical evaluation to identify patients who may benefit from additional testing.
- See “Prevention” for screening recommendations in asymptomatic patients.
Often performed as part of the initial workup of a thromboembolic event and can help identify some predisposing conditions.
- CBC: E.g., cell counts may be abnormal in MPNs.
- BMP: e.g., can suggest nephrotic syndrome
- LFTs: abnormalities can suggest liver disease, e.g, cirrhosis
- ↑ aPTT in antiphospholipid antibody syndrome: e.g.,
- ESR: e.g., can be elevated in malignancy or SLE
- β-hCG: sensitive and specific for undiagnosed pregnancy
Thrombophilia testing 
Thrombophilia testing is only warranted in select cases, however, there are no universally agreed-upon indications. The final decision on specific investigations is usually done by a specialist based on a detailed individual assessment, clinical judgment, and whether results will alter management 
- Evaluate the presence, type, extent, and underlying triggers of .
- Further testing is typically unnecessary for patients with:
- Clear and strong
- Previously diagnosed
Consider referral to a specialist for further testing in patients with , for example:
- Hereditary thrombophilias: unprovoked VTE, recurrent VTE, young patients with provoked VTE and only weak risk factors, or VTE occurring at an unusual location
- Antiphospholipid syndrome: patients with arterial thrombosis in the absence of traditional cardiovascular risk factors ., or patients with extensive DVT or PE
- Myeloproliferative neoplasms and PNH: VTE involving the splanchnic veins (e.g., portal vein thrombosis, mesenteric vein thrombosis)
can safely be deferred in most patients with a , e.g., due to a strong trigger. 
Laboratory studies 
Consider the following based on clinical suspicion as guided by a specialist:
Timing of investigations
- Not indicated during an acute event 
- Only conduct once initial anticoagulation therapy has been completed.
- Ensure there has been a sufficient duration since the completion of therapy. 
Screening for occult malignancy 
- Indications: : unprovoked VTE (especially in patients aged > 50 years), recurrent VTE, unusual thrombus location
- A diagnosis of thrombophilia seldom alters the management of acute thromboembolic events, except in select cases (see “Acute management of specific thrombophilias”). 
- Most patients are diagnosed following a secondary prevention. and long-term management consists mostly of
- Management of asymptomatic patients consists primarily of nonpharmacologic prophylaxis against thromboembolic events; see “Prevention” for details.
Weigh risks and benefits of anticoagulation individually for patients with increased bleeding risk, e.g., risk of falls, severe hypertension.
Standard management of thromboembolic diseases
- Acute management can include revascularization, fibrinolytics, and anticoagulation depending on the location and extent of thromboembolism and patient factors.
- See “Management of STEMI”, “Management of NSTEMI/UA”, “Management of ischemic stroke”, and “ .”
- See also “Treatment” in “Acute limb ischemia”, “Intestinal ischemia”, and “Splenic infarct.”
Acute management typically involves anticoagulant administration.
- varies for and and depends on location and risk of recurrence.
- Most patients with PE require anticoagulation; in some causes or may be necessary.
- For high-risk patients (based on individual risk assessment), consider bridging anticoagulation: i.e., parallel administration of warfarin and heparin until target INR is reached, typically for 4–6 days. 
- Consider an if anticoagulant therapy is contraindicated.
- See also “Treatment of DVT”, “Treatment of PE”, and “Treatment” in “Portal vein thrombosis”, and “Cerebral venous thrombosis.” 
Acute management of specific thrombophilias
Consult a hematologist to tailor treatment according to individual patient risks.
- Heparin-induced thrombocytopenia type II: Heparin is contraindicated and argatroban or lepirudin should be prescribed instead; see “Empirical management of HIT” and “Nonheparin anticoagulation.”
- Antithrombin III deficiency: can lead to heparin resistance and may require antithrombin concentrate in addition to heparin in order to be effective 
- Protein C deficiency and protein S deficiency: To avoid warfarin-induced skin necrosis, bridge oral anticoagulation with heparin. 
- Antiphospholipid syndrome 
This section describes screening for asymptomatic patients at risk of thrombophilia and primary prevention measures for thromboembolism in patients with positive screening or risk factors (see “Treatment” for secondary prevention measures). Standard is indicated in select circumstances regardless of thrombophilia status (e.g., postoperative status, prolonged immobilization or hospitalization, active malignancy).
Indications for thrombophilia screening 
Screening for thrombophilia in asymptomatic patients may be indicated in patients at high risk and, depending on the results, a specialist may choose to start prophylaxis. Possible indications for screening include:
- Patients with a personal history of a thromboembolic event who wish to conceive or start contraception
- Selection of contraception in patients with a strong family history
- High-risk patients who are pregnant or having fertility counseling
Management of asymptomatic thrombophilia
- Obesity: Recommend weight loss.
- Tobacco use: Encourage smoking cessation.
- Medications: Avoid estrogens (e.g., OCPs), erythropoietin, and testosterone.
- Extended varicosis: Consider compression stockings, an LMWH, and referral for surgical repair.
- Myeloproliferative neoplasms: Start treatment in consultation with a specialist (e.g., anticoagulation, immunotherapy, or allogeneic stem cell transplant).
- High-risk situations: Primary prophylaxis (compression stockings, chemical prophylaxis with an LMWH or direct oral anticoagulant) may be appropriate.
- See also “Approach to VTE prophylaxis” and “ASCVD prevention.”
Primary prophylactic measures are also recommended in the absence of laboratory findings of thrombophilia if patients have a strong family history of thrombophilia.