THROMBOPHILIA Mail Email this article
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Thrombophilia, or hypercoagulability, means an increased risk for thrombosis. Thrombophilia may be congenital or acquired. Thrombosis may be cardiovascular, including angina, myocardial infarction (MI), and peripheral vascular disease (PVD); cerebrovascular, including transient ischemic attack (TIA) and stroke, or venous thromboembolic disease, including deep venous thrombosis (DVT) or pulmonary embolism (PE). Cardiovascular and cerebrovascular diseases are highly dependent on platelet aggregation while venous thromboembolic diseases may be related to coagulation system abnormalities and are the focus of the following discussion:

Why Perform Thrombophilia Testing?
Circumstantial Thrombophilia Risk Factors
Disease-Related Thrombophilia Risk Factors
Circumstances that Require a Workup for Thrombophilia
Primary Thrombophilia Laboratory Test Profile
Acute Thrombophilia Test Profile
Lupus Anticoagulant Testing Algorithm
Lupus Anticoagulant Testing
Anti-cardiolipin Antibodies Testing
Antiphospholipid Syndrome (APS)
Relative Risk of Initial DVT or PE for Acquired Thrombophilia Factors
Prevalence of Congenital Thrombophilia
Relative Risk of First DVT or PE in Congenital Thrombophilia


Why Perform Thrombophilia Testing?

  • To establish the pathologic basis of the thrombotic event and provide the opportunity to communicate etiologic factors to patients
  • To influence duration of therapy during a thrombotic episode
  • To offer prophylaxis for high risk patients during periods of potentially in-creased stimulus (see "Circumstantial Thrombophilic Risk Factors" below)
  • To alert the patient's kindred to the presence of inherited risk factors
  • To determine the need for alternative laboratory testing when condition affects primary testing mode such as heparin monitoring in patients with a pro-longed PTT due to LA

Refer to the acute thrombophilia test profile for UAB assays to order during thrombotic episodes.


Circumstantial Thrombophilic Risk Factors

  • Age, previous thrombosis, smoking

  • Pregnancy, contraceptive therapy, hormone replacement therapy (HRT)

  • Immobilization: travel, bedfast, wheelchair, sedentary lifestyle

  • Diet, obesity = lipids and immobilization

  • Orthopedic surgery, neurosurgery, trauma, fractures

  • Blood group non-O with increased VWF and VIII


Disease-Related Thrombophilic Risk Factors

  • Autoimmune disorders: systemic lupus erythematosus; antiphospholipid syndrome

  • Malignancies: Adenocarcinoma; myeloproliferative diseases such as CML or PV; acute myeloid leukemia, especially M3, M5

  • Paroxysmal nocturnal hemoglobinuria (PNH)

  • Chronic inflammatory diseases: chronically elevated factor VIII and fibrinogen

  • Congestive heart failure


Circumstances That Require a Laboratory Workup For Thrombophilia

  • Venous thrombosis before 40-50 years of age

  • Unprovoked thrombosis at any age

  • Recurrent thromboses at any age

  • Unusual sites such as cerebral, mesenteric, portal, or hepatic veins

  • Positive family history for thrombosis

  • Thrombosis during pregnancy, oral contraceptives, or hormone replacement therapy (HRT)

  • Unexplained abnormal laboratory test such as prolonged PTT


Primary Thrombophilia Laboratory Test Profile

Order the following series of assays when the patient is not taking an anticoagulant such as Coumadin® (warfarin) or heparin and has taken no anticoagulant or has not had a thrombotic event for at least ten days:


  • Activated protein C resistance (APCR)

    • Perform factor V Leiden mutation assay when the APCR ratio is below the cutoff, indicating resistance

  • Lupus anticoagulant testing

  • Anticardiolipin antibodies IgG and IgM

  • Antithrombin activity

    • Perform antithrombin antigen assay when activity is consistently low

  • Fasting homocysteine

  • Factor VIII activity

  • Protein C activity

    • Perform protein C antigen assay when activity is consistently low

  • Protein S activity

    • Perform free and total protein S antigen when activity is low

  • Prothrombin 20210 mutation assay


Acute Thrombophilia Test Profile

Order the following assays when the patient is currently taking an anticoagulant such as Coumadin® (warfarin) or heparin, has had a thrombotic event, or has taken an anticoagulant within the last ten days:

  • Activated protein C resistance (APCR)

    • Perform factor V Leiden mutation assay when the APCR ratio is below the lower limit of the reference interval, indicating resistance

  • Fasting homocysteine

  • Anticardiolipin antibodies IgG and IgM

  • Prothrombin G20210A mutation assay


Lupus Anticoagulant Testing Algorithm

Click to enlarge

Click to enlarge





Lupus Anticoagulant Testing

LA testing requires two clot-based assays . Laboratories may choose to perform a low phospholipid PTT reagent designed to detect LA (PTT-LA) and the dilute Russell viper venom time (DRVVT) test (see figures above and table below). Warfarin prolongs the DRVVT and heparin affects the PTT-LA.

When the PTT-LA is prolonged, perform a thrombin time to detect heparin. If present, treat specimen with Hepzyme® before further testing.

  • When heparin is ruled out, the next step is to check for the presence of an inhibitor by a mixing study, which should fail to correct.
  • LA is confirmed by correction of the prolonged PTT-LA and/or DRVVT with a high phospholipid reagent. If LA only affects PTT-LA, rule out factor VIII inhibitor by checking a factor VIII level.

Click to enlarge



Anti-cardiolipin Antibodies Testing

Anti-cardiolipin antibodies of IgG or IgM isotype are measured in immunologic assays (ELISA) and do not prolong clot-based tests. Results of medium or high titer on two or more consecutive occasions at least 12 weeks apart are evidence for chronicity and possible APS.



Antiphospholipid Syndrome (APS)

APS is the most common acquired thrombotic disease. Anti-phospholipid antibodies (APLs) in the form of lupus anticoagulant, anti-cardiolipin antibody, or anti-beta 2 glycoprotein 1 are found in 5% of unselected individuals, and 2% remain on repeat testing . They are in 10 to 50% of people with autoimmune disorders. The relative risk of thrombosis for people with primary APLs is 1.6 to 3.2.

APS is diagnosed when a patient has a history of thrombosis or pregnancy complications AND a positive LA or anticardiolipin antibody which persist for 12 weeks.

Vascular thrombosis

  • One or more clinical episodes of arterial or venous thrombosis in any tissue con-firmed by imaging, Doppler, or histopathology without evidence of vessel wall in-flammation is evidence for APS.

Obstetric morbidity

  • APS is suspected if a patient has a history of one or more unexplained documented fetal deaths beyond ten weeks of gestation, one or more premature births of normal neonates at or before 34 weeks dues to eclampsia or placental insufficiency, or three or more unexplained consecutive spontaneous abortions before 10 weeks.

Relative Risk of Initial DVT or PE for Acquired Thrombophilia

·        Femoral and tibial fractures


·        Hip, knee, GYN, prostate surgery


·        Adenocarcinoma


·        Chronically elevated factor VIII


·        Oral contraceptives (30 mg)


·        Pregnancy


·        Hormone replacement (5 mg)


·        Homocysteinemia due to vitamin deficiency


·        Chronic APL without a known autoimmune disorder





Prevalence of Congenital Thrombophilia



People With

·        APCR: factor V Leiden mutation

3-8% of Caucasians


·        Prothrombin G20210A

2-3% of Caucasians


·        Antithrombin deficiency

1 in 2-5000


·        Protein C deficiency

1 in 300


·        Protein S deficiency



·        Hyperhomocysteinemia





Relative Risk of First DVT or PE in Congenital Thrombophilia


Odds of Thrombosis

·        APCR: heterozygous factor V Leiden mutation


·        APCR: homozygous factor V Leiden mutation


·        Prothrombin G20210A heterozygotes


·        Antithrombin deficiency heterozygotes


·        Protein C deficiency heterozygotes


·        Protein S deficiency heterozygotes

1.6 to 11.5x



Test Interpetation & Therapy Menu:

Reference Intervals for Premature Infants | Reference Intervals for Full-term Infants | Reference Intervals for Children | UAB Reference Intervals For Adults | Biochemical Properties of the Coagulation Proteins | The Coagulation Cascade Mechanism | Dos and Don'ts in Coagulation Testing | Blood Specimen Management | UAB Hemostasis and Coagulation Test Menu | Thrombophilia |Anticoagulant Therapy Monitoring | Management of Bleeding | Management of Platelet Disorders | Glossary of Hemostasis Terms with Abbreviations

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