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Prothrombotic States and Vascular Thromboses
Procoagulant states may be divided into acquired and genetic causes. Acquired factors include advanced age, obesity, malignancy, surgery, prolonged immobilization, use of estrogens, antiphospholipid syndrome (APS), heparin-induced thrombocytopenia and thrombosis (HITT), and pregnancy. Genetic conditions include male gender, antithrombin III (ATIII) deficiency, protein C and S deficiencies, factor V Leiden, prothrombin G20210A, hyperhomocysteinemia, and non-O blood group. Tests exist for the most common hypercoagulable states.
Some conditions, such as HITT, hyperhomocysteinemia, and APS, predispose patients to developing arterial as well as venous thrombosis. In contrast, ATIII deficiency, protein C and S deficiency, and factor V Leiden and prothrombin 20210 mutation are almost exclusively seen in patients with venous thrombosis ( Table 1 ).
TABLE 1
Hypercoagulable States
| Condition | Incidence (%) | Site of Thrombosis |
|---|---|---|
| ATIII deficiency | 1–2 | Venous > arterial |
| Protein C deficiency | 3–5 | Venous > arterial |
| Protein S deficiency | 2–3 | Venous > arterial |
| HITT | 0.2–2.6 | Venous and arterial |
| Antiphospholipid syndrome | 8–12 | Venous and arterial |
| Factor V Leiden | 20–60 | Venous > arterial |
| Prothrombin G20210A | 4–5 | Venous |
| Hyperhomocysteinemia | 10 | Venous and arterial |
ATIII , Antithrombin III; HITT , heparin-induced thrombocytopenia and thrombosis.
Antithrombin III Deficiency
ATIII is synthesized in the liver and binds to serine proteases such as factors IXa, Xa, XIa, and XIIa, inhibiting thrombin formation. The anticoagulant effect of heparin occurs by potentiating the effects of ATIII. ATIII deficiency is diagnosed with levels less than 70% of normal while off anticoagulation. The heterozygous form of ATIII deficiency has a prevalence of 1/1200 to 1/1500 people, whereas the homozygous form is generally believed to be incompatible with life.
ATIII deficiency may be suspected when thrombosis occurs while the patient is on heparin or there is an inability to achieve a therapeutic activated partial thromboplastin time (aPTT). Patients with ATIII deficiency have a high rate of recurrent thrombosis, approaching 60%, which is generally accepted as an indication for lifelong anticoagulation. ATIII levels are decreased by acute thrombosis, heparin therapy, liver disease, nephrotic syndrome, oral contraceptive pills (OCPs), and pregnancy.
Treatment of ATIII deficiency involves administering fresh frozen plasma, 2 units every 8 hours, followed by a decreasing dose along with heparin or low-molecular-weight heparin.
Protein C and S Deficiency
Protein C and S are vitamin K–dependent glycoproteins that inactivate factors Va and VIIIa. Protein C has a plasma concentration of 3 to 5 mg/L and a relatively short half life of 8 hours. Protein S has a plasma concentration of 20 to 25 mg/L and a half life of 42 hours. The depletion of protein C and protein S can contribute to the development of skin necrosis when initiating warfarin therapy. Protein S has some independent anticoagulant effects, but it is best known for its role as a cofactor for protein C, which is activated by thrombin in the presence of thrombomodulin.
Protein C deficiency is relatively common, with a prevalence of 1/200 to 1/500, and protein S deficiency is closer to 1/1000. Protein C and protein S are decreased in acute thrombosis and liver disease and in patients on OCPs or vitamin K antagonists. Patients with protein C and protein S deficiency and venous thrombosis are at elevated risk for recurrent thrombosis similar to ATIII deficiency and are treated with lifelong anticoagulation.
Protein C deficiency may be classified as type 1, or quantitative , which has decreased activity caused by decreased protein C levels; type 2 is considered a qualitative defect, with normal levels of protein C but decreased activity. Therefore, laboratory confirmation of protein C deficiency includes functional tests, usually used for screening, and antigen assays, used for differentiating type 1 from type 2. Patients with heterozygous protein C deficiency generally have protein C activity levels between 30% and 65% of normal.
Protein S deficiency is more complicated, and classification depends on total and free levels as well as activity. Type 1 patients demonstrate decreased activity corresponding to decreased total and free levels of protein S. Type 2 patients have decreased protein S activity with normal antigen levels. Type 3 patients have low protein S activity associated with decreased free levels, but they have normal total levels. Patients with protein S deficiency generally have activity levels less than 60% of normal; there is significant variation in protein S levels depending on the type of test used as well as patient characteristics including age, gender, and coexisting medical conditions. For example, protein S levels decrease significantly during pregnancy.
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