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Thrombophilia and Hypercoagulable States
Kirsten Vitrikas, MD
image BASICS
DESCRIPTION
  • An inherited or acquired disorder of the coagulation system predisposing an individual to thromboembolism (the formation of a venous, or less commonly, an arterial blood clot) (1)
  • Venous thrombosis typically manifests as deep venous thrombosis (DVT) of the lower extremity in the legs or pelvis and pulmonary embolism (PE) (1).
  • System(s) affected: cardiovascular, nervous, pulmonary, reproductive, hematologic
  • Synonym(s): hypercoagulation syndrome; prothrombotic state
EPIDEMIOLOGY
  • An inherited thrombophilic defect or risk can be detected in up to 50% of patients with venous thromboembolism (VTE).
  • Factor V Leiden is the most common inherited thrombophilia (1/2 of all currently characterizable inherited thrombophilia cases involve the factor V Leiden mutation), and it is present in its heterozygous form in up to ˜ 20% of patients with a first VTE.
  • Heterozygous prothrombin G20210A mutation, the second most common inherited thrombophilia, is present in up to ˜ 8% of patients with VTE.
Incidence
First-time thromboembolism
  • ˜ 100/100,000/year among the general population
  • <1/100,000/year in those age <15 years
  • ˜ 1,000/100,000/year in those age ≥85 years
Prevalence
  • 40-80% of lower extremity orthopedic procedures can result in DVT if prophylaxis is not used.
  • VTE accounts for ˜ 1.2 to 4.7 deaths per 100,000 pregnancies.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Virchow triad as a cause of VTE includes blood stasis, vascular endothelial injury, and abnormalities in circulating blood constituents (i.e., hypercoagulability).
  • An imbalance between the hemostatic and fibrinolytic pathways leads to thrombus formation.
  • VTE is considered to be the result of genetic tendencies with other acquired risks.
  • Upper extremity DVT: >60% are associated with venous catheters. Malignancy is an additional significant risk (2).
Genetics
  • The most common genetic thrombophilias (factor V Leiden, prothrombin G20210A, proteins C and S, and antithrombin III deficiency) are inherited in an autosomal dominant pattern.
  • Homozygous mutations generally have a higher risk of VTE.
  • Factor V Leiden/activated protein C (aPC) resistance is the most common inherited thrombophilia.
    • 2-5% prevalence among Caucasians; rare in African Americans or Asians
    • aPC does not cleave factor Va, so thrombin formation continues.
    • Other acquired risks are synergistic (3).
  • Prothrombin gene mutation G20210A: prevalence 6% among Caucasians. Heterozygous carriers have increased risk of thrombosis.
  • Hyperhomocysteinemia: 5-6% among the general population; increases risk of coronary artery disease/myocardial infarction, cerebrovascular accident, and DVT/PE; acquired in those with folate, vitamin B 12, and vitamin B 6 deficiencies
  • Antithrombin deficiency: <0.2% among the general population; produced in the liver; acquired deficiency in disseminated intravascular coagulation (DIC), sepsis, liver disease, nephrotic syndrome
  • Protein C and S deficiencies: 0.5% and 1% incidences, respectively, among the general population. Homozygotes and heterozygotes are hypercoagulable. Vitamin K-dependent, produced in the liver. Protein C inactivates Va and VIIIa. Protein C may become an acquired deficiency in liver disease, sepsis, DIC, acute respiratory distress syndrome, and after surgery. Protein S is a cofactor for protein C, and it may become an acquired deficiency with oral contraceptive pill (OCP) use, pregnancy, liver disease, sepsis, DIC, HIV, and nephrosis.
RISK FACTORS
  • Acquired risk factors
    • Immobilization or prolonged travel
    • Trauma
    • Surgery, especially orthopedic
    • Malignancies (especially pancreatic, ovarian, brain, and lymphoma)
    • Pregnancy
    • Acute medical illness
    • Exogenous female hormones/oral contraceptives
    • Obesity
    • Nephrotic syndrome
    • Antiphospholipid syndrome (APS) and lupus anticoagulant
    • Myeloproliferative disorders (polycythemia vera, essential thrombocythemia)
    • Hyperviscosity syndromes (sickle cell, paraproteinemias)
    • Hyperhomocysteinemia secondary to vitamin deficiencies (B6, B12, folic acid)
    • Tamoxifen, thalidomide, lenalidomide, bevacizumab, L-asparaginase, erythropoietic stimulating agents
    • Previous thromboembolism
  • Established genetic factors
    • Factor V Leiden
    • Prothrombin G20210A mutation
    • Protein C deficiency
    • Protein S deficiency
    • Antithrombin III deficiency
  • Rare genetic factors
    • Dysfibrinogenemia
    • Hyperhomocysteinemia (methylene tetrahydrofolate reductase mutation)
  • Indeterminate factors
    • Elevated factor VIII
  • Age: >60 years
  • Gender: men
  • Race: Incidence is higher among African Americans.
GENERAL PREVENTION
  • Consider prophylaxis with medications in any hospitalized patient with VTE risk factors; hospitalized patients should be encouraged to ambulate as soon as possible (4)[A].
  • Consider mechanical prophylaxis in patients at increased risk for VTE in whom anticoagulation may be contraindicated (4)[A].
  • Consider prophylaxis with low-molecular-weight heparin (LMWH) plus aspirin in pregnant patients with APS or other thrombophilia.
  • Consider prophylaxis using LMWH in patients with solid tumors who have additional risk factors for VTE.
  • Prophylaxis with unfractionated heparin (UFH) or LMWH should be considered in patients with genetic or acquired risks of thrombosis and an anticipated additional risk, such as the immobilization associated with surgery.
  • Use caution with procoagulant medicines (e.g., OCPs) in asymptomatic individuals who have a known hereditary predisposition.
COMMONLY ASSOCIATED CONDITIONS
Advanced age, cancer, pregnancy, obesity, prior history of thrombosis, surgery, immobilization
image DIAGNOSIS
PHYSICAL EXAM
  • DVT: swelling, pain, warmth, and redness, usually of one extremity
  • PE: dyspnea, pleurisy, hemoptysis, hypoxia, tachycardia
  • Superficial phlebitis: red, painful cord palpable along the path of thrombosed vein
  • Postthrombotic syndrome: pain, swelling, pigmentation, and/or ulceration
DIAGNOSTIC TESTS & INTERPRETATION
Testing for heritable thrombophilia in all patients with a first episode of VTE is not required (2,5)[B].
Initial Tests (lab, imaging)
  • CBC
  • aPC profile: ≤2.0 implies factor V Leiden mutation; 95-100% are factor V Leiden-positive; false-positive finding in pregnancy or with use of OCPs, confirm with factor V Leiden mutation testing or consider Factor V Leiden mutation testing up front.
    • aPC resistance may be unreliable while taking LMWH or UFH.
  • Prothrombin G20210A genetic assay
  • ATIII functional assay
    • Will be low with acute thrombosis and on heparin therapy
  • Protein C functional assay
    • May be low with acute thrombosis; will be lower on warfarin
  • Protein S antigen and functional assay and free S
    • May be low with acute thrombosis; will be lower on warfarin
  • Antiphospholipid antibodies: phospholipid-dependent tests and anticardiolipin antibodies, lupus anticoagulant
    • May be unreliable on heparin
  • Consider evaluation for subclinical malignancy in an unprovoked thrombosis in those >40 years of age or at greater risk.
  • Consider homocysteine level, although treatment of hyperhomocysteinemia (vitamins B12 and B6, folate) does not alter the thrombophilic risk.
P.1031

Follow-Up Tests & Special Considerations
Dysfibrinogenemia and plasminogen deficiency are very rare causes of thrombophilia.
image TREATMENT
MEDICATION
First Line
  • Parenteral anticoagulation: LMWH has largely replaced UFH as first-line therapy for VTE.
    • Enoxaparin (Lovenox): 1 mg/kg SC BID for at least 5 days (with concomitant warfarin) until international normalized ratio (INR) has reached 2 for at least 24 hours; adjust dose for renal disease.
      • Enoxaparin is preferred in patients with active cancer for a minimum of 6 months (can dose at 1.5 mg/kg SC daily), after which time the patient can be reevaluated to continue enoxaparin or transition to warfarin (4).
      • Adverse reactions: bleeding, heparin-induced thrombocytopenia (HIT) <0.5% incidence, bone loss (uncommon)
      • Reversal: Stop LMWH.
    • UFH: 80 U/kg or 5,000 U IV bolus, then 18 U/kg/hr or 1,000 U/hr to target the activated partial thromboplastin time (aPTT) to a corresponding anti-Xa level of 0.3 to 0.7 U/mL. The first aPTT should be checked 6 hours after initial therapy and adjusted per standard heparin nomograms, aiming for an adequate level within 24 hours. Transition to warfarin is similar to the recommendations for enoxaparin.
      • SC UFH is an alternative and can be given as 5,000 U IV (once) followed by 250 U/kg SC BID, or 250 U/kg bolus followed by 250 U/kg BID (monitored as for IV UFH), or 333 U/kg once followed by 250 U/kg SC BID (unmonitored).
      • Adverse reactions: bleeding, HIT 3% incidence, bone loss (long-term use)
      • Reversal: Stop heparin, protamine.
  • Oral anticoagulation
    • Warfarin (Coumadin): 10 mg/day initially and adjust to INR 2 to 3 for at least 3 months, potentially indefinitely in those with high risk of recurrence, recurrent or unprovoked VTE
      • Warfarin requires careful and frequent monitoring because of many drug-drug and drug-diet (e.g., vitamin K) interactions.
      • Adverse reactions: bleeding, skin necrosis (rare and early in course)
      • Reversal: four-factor prothrombin complex concentrate (PCC); fresh frozen plasma and/or vitamin K
  • Pregnancy (controversial): Low-dose aspirin and/or LMWH or UFH; warfarin is contraindicated.
  • Several other newly approved anticoagulant medications are indicated for acute management. Their main benefit is the decreased need for frequent testing. However, most of the new medications do not have a reversal agent.
Second Line
Usually indicated when contraindication to heparin or LMWH, such as heparin-associated thrombosis and thrombocytopenia, if there is an inability to use IV drugs, or renal failure. Direct oral anticoagulants may become first line as more clinical experience is developed.
  • Factor Xa inhibitors
    • Fondaparinux: acute VTE/PE. Weight <50 kg: 5 mg/day SC; weight 50 to 100 kg: 7.5 mg/day SC; weight > 100 kg: 10 mg/day SC; use for 5 to 9 days until oral anticoagulation is therapeutic.
      • Prophylaxis: 2.5 mg/day SC
      • Dose adjustments: needed for renal insufficiency; if creatinine clearance is <30 mL/min, use is contraindicated.
  • Oral factor Xa inhibitors
    • Rivaroxaban: FDA-approved for postoperative thromboprophylaxis after hip/knee replacement, treatment of DVT/PE, and for thromboembolic prophylaxis in patients with nonvalvular atrial fibrillation (6)[C]
    • Apixaban: can be used without need for preceding heparin therapy, less renal clearance than other oral anticoagulants
    • Edoxaban: requires treatment with heparin prior to initiation, needs adjustment for renal impairment
  • Direct thrombin inhibitors: most commonly used for anticoagulation in HIT. Representative drugs include the following:
    • Lepirudin: excreted by kidneys, crosses the placenta; dosing based on creatinine clearance; therapeutic dose based on aPTT
    • Argatroban: liver metabolized; may be doseadjusted in liver dysfunction; therapeutic dose based on aPTT
    • Dabigatran: oral direct thrombin inhibitor, FDA-approved for treatment of DVT/PE after parenteral anticoagulant and for thromboembolic prophylaxis in patients with nonvalvular atrial fibrillation (noninferior to warfarin). Reversal agent newly available. May be dialyzable (6)[C]
SURGERY/OTHER PROCEDURES
  • Catheter extraction/thrombectomy or thrombolysis for unstable cases (e.g., massive PE with hypotension)
  • Inferior vena cava filter
    • Reduces short-term risk of PE in those with contraindications to anticoagulation (e.g., GI bleeding, cerebral hemorrhage)
    • May increase long-term risk of recurrent DVT
    • Used for patients with multiple episodes of recurrent thromboembolism despite therapeutic anticoagulation and contraindication to anticoagulation
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Avoid significant risk for trauma (e.g., contact sports, climbing a ladder).
Patient Monitoring
Monitor warfarin as frequently as needed to maintain an INR goal of 2 to 3.
DIET
Vitamin K-stable diet if patient is taking warfarin
PATIENT EDUCATION
  • Assume that any drug may enhance or attenuate the warfarin effect.
  • Increase the frequency of monitoring following any medication change to ensure therapeutic anticoagulation and to avoid overanticoagulation, especially with antibiotics.
  • Many drugs may modulate warfarin effect: alcohol, antibiotics, aspirin, NSAIDs, acetaminophen.
PROGNOSIS
  • Anticoagulation should be continued for 3 months and consideration of longer in those with unprovoked VTE.
  • Patients with a provoked VTE (i.e., surgery, hospitalization) not receiving chronic anticoagulation have a risks of recurrence of 7% (year 1), 16% (year 5), and 23% (year 10).
  • Patients with an unprovoked VTE not receiving chronic anticoagulation have risks of recurrence of 15% (year 1), 41% (year 5), and 53% (year 10).
  • Currently, there are no data from randomized controlled trials or controlled clinical trials about the benefits of thrombophilia testing to decrease the risk of recurrent VTE (1).
REFERENCES
1. Cohn DM, Vansenne F, de Borgie CA, et al. Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane Database Syst Rev. 2012;(12):CD007069.
2. Baglin T, Gray E, Greaves M, et al. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209-220.
3. Anderson JA, Weitz JI. Hypercoagulable states. Clin Chest Med. 2010;31(4):659-673.
4. Hill J, Treasure T. Reducing the risk of venous thromboembolism in patients admitted to hospital: summary of NICE guidance. BMJ. 2010;340:c95.
5. National Institute for Health and Care Excellence. Venous Thromboembolic Diseases: Diagnosis, Management and Thrombophilia Testing (NICE Clinical Guidelines No. 144). London, United Kingdom: National Institute for Health and Care Excellence; 2012.
6. Bacchus F, Schulman S. Clinical experience with the new oral anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol. 2015;35(3):513-519.
Additional Reading
&NA;
Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2)(Suppl): 7S-47S.
Codes
&NA;
ICD10
  • D68.59 Other primary thrombophilia
  • D68.51 Activated protein C resistance
  • D68.2 hereditary deficiency of other clotting factors
Clinical Pearls
&NA;
  • Factor V Leiden (resistance to aPC) is the most common inherited thrombophilia, with a prevalence of 2-7% in the U.S. Caucasian population.
  • Test patients <50 years of age with a history of venous thrombosis, and consider testing first-degree relatives.
  • Rule out malignancy, especially in those >50 years of age.