Hypercoagulable states

Last updated: May 2, 2022

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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.

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]

Hereditary causes of hypercoagulability [6][8]

Acquired causes of hypercoagulability [6][12][13][14]

Clinical features of thromboembolism

These typically depend on the location of thromboembolism, the vasculature involved, and the underlying condition.

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

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

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

Pathophysiology of hereditary thrombophilia [17][18][19]
Defect Pathophysiology Prevalence in general population

Activated protein C resistance (APC-R)

Factor V Leiden [20]

  • Heterozygosity: ∼ 5%
  • Homozygosity: < 1%
Elevated factor VIII
  • ∼ 5%
Prothrombin mutation
  • ∼ 3%

Protein S deficiency

  • ∼ 1%
Protein C deficiency
  • < 1%
Antithrombin III deficiency
  • ∼ 0.1%

Hyperhomocysteinemia

∼ 5–7%

Pathophysiology of acquired thrombophilia [21][22][23]
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

Immobilization

  • Prolonged immobilization (e.g., extended travel, hospitalization, bed rest) → increased venous stasis
Smoking
Obesity

Antiphospholipid syndrome

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)

Heparin-induced thrombophilia
Pregnancy
Advanced age [22]
  • 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

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.

Thrombophilia testing [1]

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][24]

Patient selection

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][25]

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

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]

Screening for occult malignancy [15][26][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

Venous thromboembolism

Acute management of specific thrombophilias

Consult a hematologist to tailor treatment according to individual patient risks.

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][25][32]

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:

There is no clear guidance for thrombophilia screening and VTE prophylaxis for asymptomatic patients; decisions should be guided by a specialist. [32]

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][25][32]

Primary prophylactic measures are also recommended in the absence of laboratory findings of thrombophilia if patients have a strong family history of thrombophilia. [25]

Avoid OCPs in patients who are carriers of Factor V Leiden. [33]

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