Hypercoagulable states

A hypercoagulable state, i.e., thrombophilia, is a predisposition to forming blood clots. Depending on the etiology, one or more factors of the Virchow triad (stasis, hypercoagulability, 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 deep venous thrombosis of the lower extremities or 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.

• 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 traditional risk factors for thromboembolic disease, e.g., ≥ 1 strong trigger OR multiple weak triggers ^[1][2][3]
    • Unprovoked VTE: VTE occurring in the absence of identifiable triggers. ^[4][5]
  • Arterial thromboembolism
    • 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)

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. ^[6]

Traditional risk factors for thromboembolic disease ^[1][2][3]

• Venous thrombosis: See also “Risk factors for VTE.” ^[7]
  • 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 “Atherosclerotic risk factors.”
  • Smoking
  • Obesity
  • Hyperlipidemia
  • Diabetes mellitus
  • Hypertension

Hereditary causes of hypercoagulability ^[6][8]

• Predisposing to venous thrombosis ^[9]
  • Factor V Leiden (autosomal dominant inheritance): most common genetic cause of hypercoagulability in white populations
  • Protein C deficiency
  • Antithrombin III deficiency
    • Autosomal dominant inheritance
    • Occasionally acquired
      • Renal failure
      • Liver failure
      • Nephrotic syndrome (urinary loss of antithrombin)
  • Prothrombin G20210A mutation
  • Hyperhomocysteinemia and MTHFR gene mutation ^[6]
  • Sickle cell anemia ^[10][11]
• Predisposing to both venous and arterial thrombosis
  • Protein S deficiency ^[6]
  • Hyperhomocysteinemia ^[6]
  • Lipoprotein(a) ^[6]

Acquired causes of hypercoagulability ^{[6][12][13][14]}

• Predisposing to venous thrombosis
  • HIV ^[12]
  • Malignancy ^[12]
  • Nephrotic syndrome
  • Inflammatory bowel disease
  • Cirrhosis ^[13]
  • Paroxysmal nocturnal hemoglobinuria (PNH) ^[6]
• Predisposing to both venous and arterial thrombosis
  • Antiphospholipid syndrome (APLAS) ^[6]
  • Heparin-induced thrombocytopenia ^[8]
  • Myeloproliferative disorders ^[8]
  • Systemic lupus erythematosus (SLE) ^[14]

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 DVT”, “Clinical features of PE”, “Clinical features of cerebral venous thrombosis”, and “Portal vein thrombosis.”
• Arterial thromboembolism
  • Ischemic stroke: See “Stroke symptoms by affected vessel” and “Stroke symptoms by affected region.”
  • Acute coronary syndrome: See “Clinical features of ACS.”
  • Others: e.g., the 6 P's of acute limb ischemia, clinical features of intestinal ischemia, splenic infarction

Clinical features suggestive of underlying thrombophilia ^[1][6]

• VTE characteristics
  • Onset at age < 50 years of either of the following:
    • Unprovoked VTE
    • VTE associated with only weak risk factors (See “Traditional risk factors for thromboembolism.”)
  • Unusual thrombus localization: e.g., portal vein thrombosis, mesenteric vein thrombosis, cerebral venous thrombosis, central retinal vein occlusion.
  • Strong family history of VTE
  • Recurrent VTE or multiple VTE
  • History of warfarin-induced skin necrosis ^[15]
• Frequent obstetrical complications: e.g., recurrent pregnancy loss, IUFD, IUGR, preeclampsia ^[16]
• Arterial thromboembolism (e.g., stroke) in a young patient with no cardiovascular risk factors

Consider antiphospholipid syndrome in young patients with stroke with no cardiovascular risk factors.

Underlying mechanisms vary depending on whether thrombophilia is hereditary or acquired.

• Hereditary thrombophilias: typically caused by mutations of proteins and enzymes involved in the coagulation cascade
• Acquired thrombophilias: varying underlying mechanisms that include stasis, endothelial injury, changes in elements of the coagulation cascade, as well as the formation, release, or exposure to additional procoagulant substances.

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

General principles

• Most thrombophilias are identified following a thromboembolic event, the majority of which are multifactorial, involving a combination of transient and chronic risk factors.
• Thrombophilia testing 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.

Routine investigations

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
• Coagulation studies: e.g., ↑ aPTT in antiphospholipid antibody syndrome
• ESR: e.g., can be elevated in malignancy or SLE
• β-hCG: sensitive and specific for undiagnosed pregnancy

Thrombophilia testing ^[1][24]

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 ^[1][25]

Patient selection

• Evaluate the presence, type, extent, and underlying triggers of thromboembolic events.
• Further testing is typically unnecessary for patients with:
  • Clear and strong traditional risk factors for thromboembolic disease
  • Previously diagnosed acquired causes of thrombophilia
• Consider referral to a specialist for further testing in patients with clinical features suggestive of underlying thrombophilia, 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, recurrent pregnancy loss
  • 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)

Thrombophilia workup can safely be deferred in most patients with a provoked VTE, e.g., due to a strong trigger. ^[1]

Laboratory studies ^{[6][8][16][26]}

Consider the following based on clinical suspicion as guided by a specialist:

• Hereditary thrombophilias ^[16]
  • Activated protein C resistance assay; followed by genetic testing for Factor V Leiden if positive
  • Prothrombin G20210A mutation testing
  • Activity assays for protein C, protein S, antithrombin
• Acquired thrombophilias
  • APLAS: antiphospholipid antibody panel (lupus anticoagulants, anticardiolipin antibodies, and anti-β2-glycoprotein antibodies)
  • MPNs: peripheral blood smear and bone marrow biopsy
  • PNH: flow cytometry
  • HIT (with intermediate or high 4T score): HIT-specific diagnostic tests, e.g., PF4 heparin immunoassay, serotonin release assay
  • ASCVD: lipoprotein(a) levels

Timing of investigations

• Not indicated during an acute event ^[1]
• Only conduct once initial anticoagulation therapy has been completed.
• Ensure there has been a sufficient duration since the completion of therapy. ^[1]
  • Vitamin K antagonists: ≥ 2 weeks
  • Direct oral anticoagulants: usually 2–3 days

Screening for occult malignancy ^[15][27][28]

• Indications: : unprovoked VTE (especially in patients aged > 50 years), recurrent VTE, unusual thrombus location
• Investigations
  • Routine age-appropriate cancer screening is recommended and may include: routine laboratory studies, urinalysis, FOBT, serum calcium levels.
  • Consider CXR, colonoscopy, mammogram, digital rectal examination, Pap smear. ^[27]

General principles

• A diagnosis of thrombophilia seldom alters the management of acute thromboembolic events, except in select cases (see “Acute management of specific thrombophilias”). ^[1]
• Most patients are diagnosed following a thromboembolic event and long-term management consists mostly of secondary prevention.
  • Options include anticoagulation and reduction of modifiable risk factors.
  • Recommendations vary depending on the type and extent of thromboembolism and patient characteristics (see conditions in “Standard management of thromboembolic disease”).
• 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

Arterial thromboembolism

• 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 “Secondary prevention strategies for ASCVD.”
• See also “Treatment” in “Acute limb ischemia”, “Intestinal ischemia”, and “Splenic infarct.”

Venous thromboembolism

• Acute management typically involves anticoagulant administration.
  • Therapeutic approach to DVT varies for provoked DVT and unprovoked DVT and depends on location and risk of recurrence.
  • Most patients with PE require anticoagulation; in some causes empiric anticoagulation for PE or thrombolysis for PE 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. ^[29]
  • High-risk conditions include:
    • Mechanical mitral valve
    • Stroke or TIA in the last three months
    • A-fib with CHADS2 score ≥ 5
  • High-risk thrombophilias include:
    • Antithrombin, Protein C, or protein S deficiency
    • Antiphospholipid syndrome
    • Homozygous factor V Leiden mutation
• Consider an inferior vena cava filter if anticoagulant therapy is contraindicated.
• See also “Treatment of DVT”, “Treatment of PE”, and “Treatment” in “Portal vein thrombosis”, and “Cerebral venous thrombosis.” ^[1]

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 ^[30]
• Protein C deficiency and protein S deficiency: To avoid warfarin-induced skin necrosis, bridge oral anticoagulation with heparin. ^[30]
• Antiphospholipid syndrome ^[31][32]
  • Anticoagulation regimens: lifelong anticoagulation usually required
    • VTE: VKAs (e.g., warfarin) with heparin bridging
    • Arterial thromboembolism: High-dose VKA OR standard-dose VKA combined with ASA
  • Consider adjunctive therapy for recurrent or very severe disease.

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 VTE prophylaxis is indicated in select circumstances regardless of thrombophilia status (e.g., postoperative status, prolonged immobilization or hospitalization, active malignancy).

Indications for thrombophilia screening ^[6][26][33]

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

There is no clear guidance for thrombophilia screening and VTE prophylaxis for asymptomatic patients; decisions should be guided by a specialist. ^[33]

Management of asymptomatic thrombophilia

Primary prevention is generally not recommended. However, some high-risk patients may benefit from managing modifiable risk factors and primary prophylaxis measures. ^[8][26][33]

• 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.
  • Immobilization and travel lasting > 4 hours
  • Cancer
  • Pregnancy: Consider prophylaxis with LMWH plus ASA for patients with APLAS who desire children. ^[31][32]
  • Surgery: Consider pneumatic stockings, early physiotherapy, and hydration in addition to the above measures.
• 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. ^[26]

Avoid OCPs in patients who are carriers of Factor V Leiden. ^[34]