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Confirmation and characterization of protein C deficiency.
Individuals with heterozygous PC deficiency may have low normal PC levels.7 Treatment with warfarin decreases the levels of vitamin K-dependent factors including PC. PC levels start to drop after six hours of warfarin treatment and do not regain pretreatment levels until generally two weeks after cessation of therapy. Elevated factor VIII levels, as can be seen in acute phase reaction, can normalize the aPTT and effectively reduce PC levels.6 PC levels can be falsely low in patients with the factor VLeiden mutation. PC levels can become depleted as the result of activation of coagulation limiting the utility of testing for congenital PC deficiency during the immediate convalescent period after a thrombotic event.7 Heparin therapy up to 1 unit/mL does not affect PC levels.7 This test should not be used for patients receiving thrombin inhibitors such as hirudin and argatroban.6
Protein C (PC) is a vitamin K-dependent plasma protein that is synthesized by the liver as an inactive precursor.7-9 This protein is then further transformed into activated PC by a complex of thrombin and the endothelial factor, thrombomodulin, that is bound to phospholipid membrane in a calcium-dependent manner. aPC regulates the coagulation process by inactivating factors Va and VIIIa. Protein S, another vitamin K-dependent protein, serves as an essential cofactor of aPC for the inactivation of factors Va and VIIIa. In inhibiting these factors, PC serves to limit thrombus extension, and thus acts as a major regulator of the coagulation process.
Congenital protein C deficiency: Congenital PC deficiency has been estimated to occur in approximately 3 out of 1000 individuals.7,8 Between 2% and 5% of cases of recurrent venous thrombosis are related to congenital PC deficiency.7 Nearly 50% of individuals with heterozygous PC deficiency and 10% of their relatives experience thrombotic episodes by age 45. Initial thrombotic events frequently occur between 20 and 30 years of age. The probabilities of thrombosis or pulmonary emboli increase dramatically when PC activity levels fall to <50%.7 Thrombosis can sometime occur at unusual sites, including mesenteric and axillary veins. Recurrent thrombotic events are common.7 In the majority of cases, thrombosis can be linked to trauma, surgery, pregnancy oral contraceptive usage, or other risk factors. However, thrombosis can occur spontaneously with no precipitating events or other known risk factors in about 33% of cases.7
Congenital PC deficiency can be classified as either type I or type II.9 Type I deficiency results from a quantitative reduction in PC production, resulting in a simultaneous decrease of both the functional and antigenic levels of PC. In type II deficiency, PC antigen concentration is normal but its activity is diminished because the PC is dysfunctional due to genetic defect. This is reflected by a diminished PC activity in the context of normal PC antigen levels. Neonates born with homozygous or doubly heterozygous PC deficiency suffer from DIC or purpura fulminans of the newborn, devastating conditions requiring immediate treatment.8
Acquired protein C deficiency: Acquired PC deficiency occurs more frequently than congenital deficiency.7 PC levels can be transiently diminished after a thrombotic event or surgery. Oral anticoagulant therapy with warfarin will lower PC levels. Vitamin K deficiency, due to dietary insufficiency or malabsorption, will also lead to reduced PC levels. Acquired deficiency can be found in individuals with disseminated intravascular coagulation (DIC) and sepsis. Severe hepatic disorders (hepatitis, cirrhosis, etc), renal failure, malignancy, and inflammatory bowel disease can lead to diminished PC levels.7 Drug therapy with L-asparaginase or fluorouracil can also reduce PC levels.
In some cases, warfarin anticoagulation of thrombotic patients with heterozygous PC deficiency will induce skin necrosis due to the rapid drop in already low PC activity.7,9
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2. Reneke J, Etzell J, Leslie S, NG VL, Gottfried EL. Prolonged prothrombin time and activated partial thromboplastin time due to underfilled specimen tubes with 109 mmol/L (3.2%) citrate anticoagulant. Am J Clin Pathol. 1998 Jun; 109(6):754-757. PubMed 9620035
3. National Committee for Clinical Laboratory Standardization. Collection, Transport, and Processing of Blood Specimens for Coagulation Testing and General Performance of Coagulation Assays; Approved Guideline. 5th ed. Villanova, Pa: NCCLS; 2008. Document H21-A5:28(5).
4. Gottfried EL, Adachi MM. Prothrombin time and activated partial thromboplastin time can be performed on the first tube. Am J Clin Pathol. 1997 Jun; 107(6):681-683. PubMed 9169665
5. McGlasson DL, More L, Best HA, Norris WL, Doe RH, Ray H. Drawing specimens for coagulation testing: Is a second tube necessary? Clin Lab Sci. 1999 May-Jun; 12(3):137-139. PubMed 10539100
6. Van Cott EM, Laposata M. Coagulation. In: Jacobs DS, DeMott WR, and Oxley DK eds. Laboratory Test Handbook With Key Word Index. Hudson, Ohio: Lexi-Comp; 2001: 327-358.
7. Adcock DM, Bethel MA, Macy PA. Coagulation Handbook.
Aurora, Colo: Esoterix−Colorado Coagulation; 2006.
8. Zwicker J, Bauer KA. Thrombophilia. In: Kitchens CS, Alving BM, Kessler CM, eds.Consultative Hemostasis and Thrombosis. Philadelphia, Pa: WB Saunders Co; 2002:181-196.
9. Triplett DA. Thrombophilia. In: McClatchey KD, ed. Clinical Laboratory Medicine. 2nd ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2002:1050-1056.
