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	Methodology	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	706994
Factor V Leiden mutation	Screen: Activated protein C resistance	117762
	Confirmation: Genetic testing	511154
Prothrombin 20210	Genetic testing only	511162
Increased factor VIII5	Factor VIII activity	086264
Protein S deficiency	Protein S (activity, total/free antigen profile)	117754
Protein C deficiency	Protein C (activity and antigen profile)	080465
Antithrombin deficiency	Antithrombin (activity and antigen profile)	015594
Dysfibrinogenemia	Fibrinogen activity	001610
	Fibrinogen antigen	117052

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	Effect
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

References

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.