Hypercoagulable States

Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. There are both inherited and acquired causes, with factor V Leiden being the most common inherited cause. Clinically, hypercoagulable states present with thrombotic events, which cause vessel occlusion and can lead to organ damage. Thrombotic disorders can be fatal if not treated, and management usually involves anticoagulants.

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Overview

Definition

Hypercoagulability, also referred to as a thrombophilia, refers to the increased tendency for blood to form clots, known as thrombi. Hypercoagulable states can be inherited or acquired.

Epidemiology

Prevalence of inherited thrombophilias:

Table: Prevalence and risk of venous thromboemolism (VTE) in inherited thrombophilias
ConditionPrevalenceRisk of VTE
Factor V Leiden3%–7%4.3%
Prothrombin G20210A mutation1%–3%1.9%
Protein C deficiency (heterozygous)0.02%–0.05%11.3%
Protein S deficiency (heterozygous)0.01%32.4%
Antithrombin deficiency0.02%–0.04%17.5%

Most common acquired hypercoagulable states:

  • Antiphospholipid syndrome: most common
  • Malignancy: 2nd most common

Clinical impact:

  • VTE is 2nd only to MI as the most common cardiovascular disorder.
  • Up to 4% of strokes are attributable to hypercoagulability disorders.
  • Thrombosis risk factors are identified in over 80% of patients with thrombotic events.

Virchow’s triad

Thrombotic events occur under 3 primary conditions, which make up Virchow’s triad. These 3 conditions are:

  1. Endothelial injury/subendothelial exposure:
    • Initiates formation of the platelet plug and the coagulation cascade
    • Factors involved in initiating thrombosis: 
      • Tissue factor
      • von Willebrand factor
      • Collagen 
  2. Stasis of blood flow:
    • Allows more time for platelet aggregation and clot formation
    • Slows the removal of coagulation factors
  3. Hypercoagulable states (alteration in blood constituents): 
    • May result from:
      • An increase in procoagulants
      • A decrease in anticoagulants
      • A decrease in fibrinolysis 
    • Balance is tipped to favor thrombosis.
Vichows triad

Virchow’s triad

Image by Lecturio.

Etiology and Pathophysiology

Hypercoagulable states may be primary (inherited) or secondary (acquired).

Primary (inherited) causes of hypercoagulable states

Table: Etiology and pathophysiology of primary (inherited) hypercoagulable states
ConditionInheritance patternPathophysiology
Factor V LeidenAutosomal dominant with incomplete penetrance
  • Point mutation substitutes glutamine for arginine at position 506 in the F5 gene, which codes for factor V.
  • Results in resistance to factor Va degradation by protein C
  • ↑ Factor Va available → enhanced thrombin formation
Prothrombin G20210A (also known as factor II mutation)Autosomal recessive
  • Transposition at the promoter region of the prothrombin gene
  • Results in overtranslation of prothrombin
  • ↑ Thrombin precursor → enhanced thrombin formation
Antithrombin deficiencyAutosomal dominant
  • Antithrombin inactivates thrombin (and is augmented by heparin)
  • Deficiency of antithrombin leads to:
    • ↑ Levels of thrombin and factor Xa
    • Resistance to heparins
  • Can also be acquired through antithrombin protein loss (nephrotic syndrome) or decreased antithrombin production (liver disease)
Protein C or S deficiencyAutosomal dominant (rare; can be recessive)
  • Protein C inactivates factors Va and VIIIa using protein S as a cofactor.
  • Deficiencies of either result in overactivity of factors Va and VIIIa.
  • ↑ Activity of Va and VIIIa → enhances thrombin formation
  • Can also be acquired in nephrotic syndrome and liver disease
Sticky platelet syndromeAutosomal dominant
  • Platelets are hyperaggregable.
  • When platelets are activated, they induce a hypercoagulable state.
Overview of the physiologic thrombolytic pathway

Overview of the physiologic thrombolytic pathway:
Several hypercoagulable disorders occur because of abnormalities at the following locations.
Mutations at 1: Factor V Leiden makes factor Va resistant to degradation by activated protein C.
Mutations at 2: Prothrombin mutation produces an increased amount of prothrombin, leading to excess thrombin formation.
Mutations at 3: Antithrombin deficiency leads to reduced inactivation of thrombin and factors Xa and IXa.
Mutations at 4: Protein C or S deficiency leads to reduced inactivation of factors Va and VIIIa.

Image by Lecturio.

Secondary (acquired) causes of hypercoagulable states

  • Antiphospholipid syndrome: 
    • Antibodies form against phospholipid-binding proteins.
    • Antibodies result in:
      • Activation of inflammatory cells, endothelial cells, and platelets, promoting thrombosis
      • Inactivation of anticoagulant factors (proteins C and S)
    • Antibodies may form spontaneously due to genetic predispositions or in association with other disorders, such as:
      • Systemic lupus erythematosus (SLE; most common, 35%)
      • Rheumatoid arthritis
      • Sjögren syndrome
      • Immune thrombocytopenic purpura (ITP)
      • HIV
  • Antithrombin deficiency
  • Protein C or S deficiencies
  • Malignancy:
    • Tumor cells can release procoagulants: tissue factor and cancer procoagulant
    • Tumors may also cause vessel compression → stasis
    • Most common with adenocarcinomas (especially lung, pancreatic, and colorectal)
  • Increased estrogen exposure:
    • Estrogens cause a hypercoagulable state by: 
      • ↑ Concentration of procoagulants: prothrombin, fibrinogen, factor VII, and factor X
      • ↓ Antithrombin levels
    • States associated with ↑ estrogen:
      • Pregnancy
      • Use of estrogen-containing contraceptives
      • Hormone replacement therapy

Other conditions that increase thrombotic risk

Many other conditions and states increase thrombotic risk by affecting components of Virchow’s triad (typically, stasis, endothelial injury, or both) in ways that promote thrombosis. These conditions include:

  • General risk factors (many are cardiovascular risk factors):
    • Prior history of a VTE
    • Older age (≥ 65 years)
    • Obesity
    • Diabetes mellitus
    • Immobilization (e.g., cast, stroke patient, post–knee surgery, long flight)
    • Current/recent hospitalization
    • Family history
    • Smoking
  • Related to surgery or procedures:
    • Surgery, especially orthopedic, vascular, neurologic, and cancer surgeries
    • Recent trauma
    • Presence of a vascular prosthesis (e.g., central venous catheter)
  • Cardiovascular conditions:
    • Heart failure
    • Chronic venous insufficiency
    • Congenital heart disease
    • Vasculitis
    • Atherosclerosis
  • Renal conditions:
    • Chronic renal disease, especially end-stage renal disease
    • Nephrotic syndrome
    • Renal transplantation
  • Hematologic/oncologic conditions:
    • Myeloproliferative neoplasms:
      • Essential thrombocythemia
      • Polycythemia vera
    • Paroxysmal nocturnal hemoglobinuria (PNH)
    • Hypogammaglobulinemias associated with hyperviscosity:
      • Waldenström’s macroglobulinemia
      • Multiple myeloma
  • Autoimmune and inflammatory conditions:
    • SLE
    • Rheumatoid arthritis
    • Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)
    • Infection/sepsis
  • Medications:
    • Estrogen- and testosterone-containing drugs
    • Tamoxifen
    • Bevacizumab
    • Glucocorticoids
    • Antidepressants
    • Drugs known to induce antiphospholipid antibodies (e.g., hydralazine, procainamide, phenothiazines)

Clinical Presentation

The primary clinical presentation of a hypercoagulable state will be a thrombotic event or an asymptomatic family member of a patient with a known primary hypercoagulable condition presenting for evaluation.

Thromboembolic presentations

  • Superficial vein thrombosis (rarely severe)
  • Deep venous thrombosis (DVT):
    • DVTs of the lower extremities (most common DVTs):
      • Unilateral swelling, redness, and/or pain in the extremity
      • Pain with dorsiflexion of the foot distal to a DVT
    • DVTs of the upper extremities
    • Cerebral sinus thrombosis
    • Hepatic and portal vein thrombosis (Budd-Chiari syndrome)
    • Renal vein thrombosis
    • Adrenal vein thrombosis
  • Pulmonary embolism (PE)
    • Dyspnea
    • Chest pain
    • Acute respiratory distress
    • Pulmonary hypertension
  • Arterial thrombosis:
    • Stroke (most common arterial thrombosis) and transient ischemic attacks (TIAs):
      • Focal neurologic findings
      • Cognitive deficits
    • MI:
      • Chest pain
      • Dyspnea on exertion
    • Retinal thrombosis
    • Nephropathy due to vaso-occlusion in the small renal vessels
  • Recurrent thromboembolic events
Pitting oedema of right leg

Pitting edema with swelling of the right leg due to a deep venous thrombosis

Image: “Pitting oedema of right leg” by Department of medicine (ward 45), the National hospital of Sri Lanka, (Regent Street), Colombo, (00800), Sri Lanka. License: CC BY 2.0

Additional specific findings associated with hypercoagulable states

Factor V Leiden and prothrombin G20210A mutations do not have any unique presentations beyond recurrent thrombotic events. Several specific findings may be noted in:

  • Protein C or S deficiency:
    • Neonatal purpura fulminans:
      • Purpuric lesions developing at many different sites during the 1st 72 hours of life
      • Lesions enlarge and produce hemorrhagic bullae with subsequent necrosis and black eschar formation.
    • Warfarin-induced skin necrosis:
      • Diffuse necrosis of the skin and/or subcutaneous tissue due to thrombosis
      • Occurs during the 1st few days of warfarin administration
  • Antithrombin deficiency:
    • Heparin resistance: There is no ↑ in the aPTT with heparin administration.
  • Antiphospholipid syndrome may present with obstetric complications, including:
    • Recurrent pregnancy loss (i.e., miscarriage)
    • Premature birth
    • Placental insufficiency
  • Other medical conditions: 
    • Many additional clinical findings related to an underlying condition associated with hypercoagulability may be present.
    • For example:
      • Weight loss and loss of appetite → can be seen in malignancy
      • Rash, joint pain, and fatigue → SLE
      • Characteristic skin changes associated with chronic venous insufficiency
      • Splenomegaly → myeloproliferative disorders

Diagnosis

Basic evaluation

These studies should be performed in most patients with suspected thrombotic events.

  • CBC and peripheral blood smear may reveal clues to the underlying etiology, for example:
    • ↑ Hematocrit → polycythemia
    • ↓ Hematocrit → PNH
    • ↑ Platelets → thrombocytosis/thrombocythemia
    • Abnormal lymphocytes on smear → bone marrow malignancy
  • D-dimer: 
    • A fibrin-degradation product that will be ↑ in the presence of a DVT
    • Multiple conditions can ↑ the D-dimer level, but a DVT is highly unlikely if the D-dimer level is normal.
  • Coagulation studies:
    • ↑ PT/INR may suggest underlying liver disease
    • ↑ aPTT in antiphospholipid syndrome (1 of the antibodies, lupus anticoagulant, acts as an anticoagulant in vitro, but it promotes thrombosis in vivo)
  • Chemistries: to evaluate liver and kidney function
  • Age-appropriate screening for malignancy: 
    • Pap smear test
    • Mammography
    • Prostate specific antigen (PSA) test
    • Stool Hemoccult and/or colonoscopy
  • Imaging:
    • CT pulmonary angiography and/or V/Q for suspected PE
    • Duplex ultrasonography of the limbs for suspected DVT; findings of DVT include:
      • Noncompressible lumen
      • Hyperechoic mass
      • Decreased/absent flow
    • Other imaging may be indicated based on clinical presentation (e.g., chest X-ray for suspected malignancy).
CT of saddle pulmonary embolism

CT angiogram of the chest showing a saddle pulmonary embolus

Image: “Large saddle pulmonary embolism” by Rhode Island Hospital, Brown University School of Medicine, 2 Dudley Street, Providence, RI, USA. License: CC BY 2.0

Indications for a thrombophilia workup

Consider ordering additional specific tests to screen for an inherited thrombophilia if patients meet any of the following criteria:

  • Recurrent thrombosis
  • Thrombosis in patients < 40 years old
  • Idiopathic venous thrombosis: thrombosis without any obvious risk factors 
  • Family history of a thrombophilia
  • Thrombosis at unusual sites
  • Arterial thrombosis
  • Recurrent pregnancy loss
  • History of warfarin-induced skin necrosis

Testing for specific conditions

If patients meet any of the above criteria for a thrombophilia workup, the following tests can be ordered to screen for specific inherited thrombophilias:

  • Factor V Leiden: activated protein C resistance assay
  • Prothrombin gene mutation: molecular analysis of the prothrombin gene
  • Antithrombin: antithrombin–heparin cofactor assay 
  • Proteins C: functional assay to detect quantitative and qualitative defects
  • Protein S: 
    • Free protein S antigen assay
    • Protein S functional assay
  • Antiphospholipid syndrome: serologies to detect the presence of antibodies
    • Anticardiolipin antibodies
    • β2-glycoprotein antibodies
    • Lupus anticoagulant

Note: Acute thrombosis and/or anticoagulants may reduce plasma concentrations of antithrombin, protein C, and protein S.

Management

Management prior to a 1st thrombotic event

In patients with known inherited thrombophilias or who have risk factors for thrombosis:

  • Encourage smoking cessation.
  • Avoid estrogen-containing contraceptives.
  • Early mobilization after surgery
  • Manage underlying medical conditions (e.g., hyperlipidemia, hypertension, nephrotic syndrome).
  • Consider low-dose aspirin (evidence is limited; consider entire clinical picture).
  • For patients with deficiencies of anticoagulants (antithrombin or protein C or S): Replace missing factors.
  • For patients with a temporary ↑ risk of thrombosis (e.g., postsurgery, pregnancy): anticoagulation for 3–6 months or until the risk factor is no longer present

Management for acute thrombotic events

Anticoagulation is the mainstay of therapy for thrombotic events. Options for initial anticoagulation include:

  • Unfractionated heparin (UFH)
  • Subcutaneous low-molecular-weight heparin (LMWH)
  • Subcutaneous fondaparinux (indirect factor Xa inhibitor)
  • Oral rivaroxaban or apixaban (direct factor Xa inhibitors)
  • Note: Warfarin (vitamin K antagonist) should not be used as monotherapy for initial treatment:
    • The half-lives of the vitamin K–dependent anticoagulants are much shorter than those of the vitamin K–dependent procoagulants → warfarin causes an initial period of hypercoagulability
    • Warfarin may be started in combination with other agents (e.g., LMWH).
    • Useful for maintenance therapy

Duration of therapy:

  • Should be started immediately on diagnosis
  • Typically continue for 3–6 months, sometimes longer.

Prophylaxis after a thrombotic event

  • Patients who typically require ongoing prophylactic anticoagulation:
    • Inherited thrombophilia and history of a thrombotic event 
    • Nonmodifiable causes of hypercoagulability (e.g., malignancy)
  • For patients who do not desire pregnancy, options include: 
    • Warfarin therapy (goal INR, 2–3)
    • Rivaroxaban or apixaban
  • For patients who do desire pregnancy: 
    • LMWH and aspirin (warfarin is teratogenic)
  • For patients with contraindications to anticoagulation (e.g., severe bleeding diathesis, planned surgeries with high bleeding risk): Place an inferior vena cava (IVC) filter.

References

  1. Bauer, K. (2020). Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors. Retrieved May 1, 2021, from https://www.uptodate.com/contents/evaluating-adult-patients-with-established-venous-thromboembolism-for-acquired-and-inherited-risk-factors
  2. Bauer, K. (2021). Overview of the causes of venous thrombosis. Retrieved May 1, 2021, from  https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis
  3. Lip, G. (2020). Overview of the treatment of lower extremity deep vein thrombosis (DVT). Retrieved May 1, 2021, from  https://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt
  4. Lip, G. (2021). Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation. Retrieved May 1, 2021, from https://www.uptodate.com/contents/selecting-adult-patients-with-lower-extremity-deep-venous-thrombosis-and-pulmonary-embolism-for-indefinite-anticoagulation
  5. Thomas, R.H. (2001). Hypercoagulability syndromes. Arch Intern Med 161:2433–2439.
  6. Schick, P. (2020). Hereditary and acquired hypercoagulability. Medscape. Retrieved May 4, 2021, from https://emedicine.medscape.com/article/211039-overview

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