Activated protein C resistance

A 30-year-old man with recurrent thrombosis is referred to you for diagnosis. The PT and APTT results determined on his freshly drawn plasma sample are 10.1 s (normal 10-12 s) and 18 s (normal 20-32 s). Which components of the hemostatic system would you initially suspect as being 

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Protein C, protein S, antithrombin III, activated protein C resistance, lipoprotein(a) anticardiolipin antibodies, lupus anticoagulant, prothrombin gene mutation 20210a... 

Hypercoagulable states include malignancy activated protein C resistance deficiency of protein C, protein S, or antithrombin factor VIII or XI excess antiphospholipid antibodies and other situations. Estrogens and selective estrogen receptor modulators have been linked to venous thrombosis, perhaps due in part to increased serum clotting factor concentrations. Although a thrombus can form in any part of the venous circulation, the majority of thrombi begin in the lower extremities. Once formed, a venous... 

As low levels of protein C activation peptide are found in healthy individuals, it is suggested that protein C is constantly activated to a small degree (124). Protein C administration has been shown to inhibit both arterial and venous thrombosis in animal models (125). Heterozygous protein C deficiency or activated protein C resistance due to factor V mutation is thought to explain 60% to 70% of the cases of familial thrombophilia (I 16). 

The inherited (primary) hypercoagulable states include activated protein C resistance due to the factor V Leiden mutation, prothrombin gene mutation, antithrombin deficiency, protein C or protein S deficiency, and dysfibrino-genemia. The most important cause of activated Protein C resistance is the defect in factor V involving the mutation of Arg506 to Gln506 (191). 

Epidemiological studies indicate that elevated plasma tHcy increases the risk of venous thromboembolism (43,44), In homocystinuria, the presence of the factor V Leiden mutation further increases the risk of thromboembolism (45). It has been proposed that hyperhomocysteinemia might interfere with the inhibition of activated factor V by activated protein C, possibly via similar effects as those caused by the factor V Leiden mutation (46,47), However, one in vitro study (48) and one large clinical study failed to demonstrate an association between hyperhomocysteinemia and activated protein C resistance (49). 

Zarychanski R, Houston DS. Plasma homocysteine concentration is not associated with activated protein C resistance in patients investigated for hypercoagulability. Thromb Haemost 2004 91 (6) I I 15-1 122. 

Ekberg H, Swensson PJ, Simanaitis M, et al, Factor V R506Q mutation (activated protein C resistance) is additional risk factor for early renal graft loss associated with acute vascular rejection, Transplantation 2000 69(8) I 577-1 581. 

Thrombophilias and other causes of hypercoagulability are rare causes of stroke (Matijevic and Wu 2006). Antithrombin III deficiency, protein C deficiency, activated protein C resistance owing to factor V Leiden mutation, protein S deficiency and plasminogen abnormality or deficiency can all cause peripheral and intracranial venous thrombosis. Thrombosis is usually recurrent and there is often a family history. Thrombophilia may cause arterial thrombosis, although the alternative diagnosis of paradoxical embolism should always be considered in patients with these disorders. It should be noted that deficiencies in any one of the factors associated with thrombophilia may be an incidental finding and cannot necessarily be assumed to be the cause of stroke. 

Heeb MJ, Kojima Y, Greengard JS, Griffin JH. Activated protein C resistance molecular mechanisms based on studies using purified Gln506 — Factor V. Blood 1995 85 3405-ll. 

Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995 85 1504-8. 

Mutations that result in amino acid substitution at the cleavage site in a protein substrate cause two changes in the proteolytic process. First, the rate of cleavage of the peptide bond is reduced because of the altered orientation of the substrate within the active site. Second, the altered substrate is very likely to be a competitive inhibitor of the proteinase responsible for the cleavage. Both of these effects are evident in the phenomenon called activated protein C resistance. 

A 30-year-old man with chronic hepatitis C infection developed activated protein C resistance, increased factor VIII activity, a raised fibrinogen concentration, and hyper-homocysteinemia after taking peginterferon alfa-I-ribavirin for 6 months, when he had a pulmonary embolism The hemato-... 

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