Genetic Thrombophilia

Specific genetic defects should be suspected when a thrombotic event has any of the following characteristics:1-3

  • Spontaneous with no predisposing condition, such as prolonged immobilization or surgery
  • Patient suffers from more than one thrombotic event
  • Patient has a positive family history of thrombosis
  • Patient is <50 years old
  • Thrombosis occurs at an unusual site (eg, mesenteric or cerebral brain)

Three general categories of test methodology are useful in the assessment of congenital thrombotic conditions:

  1. Genetic tests for specific mutations
  2. Clotting-based measurements for specific factor activity levels
  3. Immunoassays to measure the concentration of specific antigens

Genetic conditions associated with thrombophilia are listed below in order of their relative frequency of occurrence.1,2,4

Table 1. Genetic Conditions Associated With Thrombosis

Genetic Condition


Test Number

5While factor VIII elevation is associated with a number of acquired conditions, some individuals appear to have congenitally elevated factor VIII levels that are associated with increased risk of thrombosis.1

Methylenetetrahydrofolate reductase (MTHFR) gene mutation

Screen: Homocysteine level


Factor V Leiden mutation

Screen: Activated protein C resistance


Confirmation: Genetic testing


Prothrombin 20210

Genetic testing only


Increased factor VIII5

Factor VIII activity


Protein S deficiency

Protein S (activity, total/free antigen profile)


Protein C deficiency

Protein C (activity and antigen profile)


Antithrombin deficiency

Antithrombin (activity and antigen profile)



Fibrinogen activity


Fibrinogen antigen


Genetic testing is useful for the diagnosis or confirmation of MTHFR, factor V Leiden, and the prothrombin 20210 mutations. Regardless of clinical status, genetic testing can be definitive because the patient's DNA remains constant. Antigen and activity levels must be measured to diagnose the other congenital thrombotic conditions. It is important to understand, however, that the results of activity and antigen level tests can be affected by the clinical state of the patient. In many clinical circumstances, such as those listed below, tests for activity or antigen levels may produce misleading results.2,4

Table 2. Clinical Conditions That Affect Tests for Congenital Thrombotic Risk

Clinical Condition


Heparin therapy or contamination

Decreases antithrombin

Warfarin therapy/vitamin K deficiency

Decreases protein C and protein S

Recent thrombosis or surgery

Decreases antithrombin, protein C, protein S; Increases homocysteine

DIC, liver disease, sepsis, L-asparaginase therapy

Decreases antithrombin, protein C, protein S

Kidney disease/nephrotic syndrome

Decreases antithrombin and protein S

Acute phase reaction, inflammation, infection

Decreases protein S; Increases factor VIII

Pregnancy or postpartum period

Decreases protein S and APCR; Increases homocysteine

Oral contraceptives or estrogen replacement

Decreases antithrombin and protein S

Lupus anticoagulants (LA)

Decreases APCR, protein S, and factor VIII

Vitamin B12, folate, or B6 deficiency

Treatment with methotrexate, phenytoin, or theophylline; Hypothyroidism, malignancy, menopause

Increases homocysteine


1. Adcock DM. Laboratory evaluation of venous thrombosis risk. Clin Hemost Rev.2003; 17(12):1,2,5,6,8.

2. Marques MB. Testing for genetic predisposition to venous thrombosis. MLO Med Lab Obs. 2002; 34(1):8-13. PubMed 11828956

3. Marlar RA, Adcock DM. The multifactorial threshold model of thrombotic risk. Clin Hemost Rev. 2003; 17(6):1,2,4-6.

4. Triplett DA. Thrombophilia. In McClatchey KD, ed. Clinical Laboratory Medicine.2nd ed. Baltimore, Md: Lippincott Williams and Wilkins; 2002:1033-1049.

5. Brandt JT. Overview of hemostasis. In McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed. Baltimore, Md: Lippincott Williams and Wilkins; 2002:987-1009.


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