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Department of Pathology
Two Patients with a History of Thromobosis Tiffany Harper MD; Patricia Canfield MD Discusssion Inherited thrombophilias increase a patient’s likelihood of thrombosis, and when mixed with other acquired risk factors such as pregnancy, oral contraceptive therapy, hormone replacement therapy, and autoimmune diseases, can significantly increase a patient’s risk . The most common manifestation is venous thrombosis with arterial thrombosis occurring less frequently 1 . The following inherited conditions can cause a hypercoagulable state: activated protein C resistance, prothrombin mutation, hyerhomocysteinemia, protein C deficiency, protein S deficiency, elevated Factor VIII, and antithrombin deficiency. Factor V Leiden is the most common congenital prothrombotic disorder in Caucasians, and occurs in 5 to 7% of this population. It also accounts for greater than 90% of activated protein C resistance cases 2 . Factor V is an inactive cofactor circulating in plasma. It is activated by thrombin to form factor Va, which is a cofactor in the conversion of prothrombin to thrombin. Factor Va is inactivated when activated protein C (APC) proteolyses factor Va at Arg506 then at Arg306 and Arg679 on the heavy chain 3 . When a single point mutation takes place in the Factor V gene, inherited as an autosomal dominant trait, this leads to activated protein C resistance 3 . In Factor V Leiden, adenine replaces guanine at nucleotide 1691 in exon 10, thus replacing arginine with glutamine at position 506. Other mutations that can occur include: threonine replacing arginine at position 306 (Factor V Cambridge) or glycine replacing arginine (Factor V Hong Kong Chinese) 5 . Although Factor V Leiden is common in the Caucasian population, the mutation is rare in African American, Chinese, and Japanese populations. Factor V Leiden can result in a seven-fold relative risk for idiopathic venous thromboembolism in heterozygous states and an 80-fold increase in homozygous states 2 . The Factor V Leiden mutation is inactivated 10 times more slowly than normal Factor Va 1 . Inactivation of Factor V Leiden occurs more slowly at position 306 1 . Since there is still an inactivation pathway for Factor V Leiden, as well as other in vivo proteases, the lifetime risk for thrombosis is less for heterozygous patients than other less common inherited thrombophilias. Furthermore, Factor V Leiden has a lower risk of pulmonary embolism than other thrombophilic states 8 . Thromboembolic events such as deep vein thrombosis and superficial thrombophlebitis usually occur after puberty in both homozygous and heterozygous states. This also carries an increased risk for cerebral vein thrombosis. In homozygous or heterozygous children under the age of one year, thrombotic events may occur if other concurrent risk factors exist 4 . The mutation can cause inadequate placental perfusion resulting in unexplained recurrent pregnancy losses, severe preeclampsia, abruptio placentae, and fetal growth restriction due to intervillous or spiral artery thrombosis 1 . The risk of venous thromboembolism markedly increases in women on oral contraceptives (OR 15.62) or hormone replacement therapy (OR 13.16) 6 . Unlike prothrombin mutation, there is no definite risk for increased arteriosclerotic heart disease 1 . There are two functional assays to test for activated protein C resistance (Factor V Leiden). These assays are used as a preliminary screen before molecular testing is performed. The original assay uses patient plasma with the addition of a standard amount of APC to measure the prolongation of the aPTT (4,7) . This assay depends on the patient’s plasma concentrations of Factor V and Factor VIII. Results of this assay can be erroneously influenced by oral anticoagulation or antiphospholipid antibodies (lupus anticoagulant). The second assay created is performed by diluting the patient’s plasma with Factor V deficient plasma and adding APC then measuring aPTT ratio. This assay is highly specific for Factor V Leiden deficiency. Molecular testing by polymerase chain reaction (PCR) is available in most reference laboratories and can be used to determine the difference between a homozygous and heterozygous patient. As shown in the Factor V Leiden graph, melting curves can be used to analyze the three genotypes of the Factor V Leiden sequence. The normal genotype has one peak at a melting temperature of 65 °C ( green line) while the mutant genotype shows a peak at a melting temperature of 57 ° C (blue line). Patients heterozygous for Factor V Leiden mutation show a peak at both temperatures (black line). Both the patients in this case were homozygous for Factor V Leiden which accounts for less than 1% of all Factor V Leiden mutations. However, given the increased risk for thrombotic disease, a higher percentage of cases coming to clinical attention are homozygous. Because thrombophilic defects are common in the general population, multiple defects are often observed in patients presenting with a thrombosis 8 . Factor V Leiden can occur with any of the following singly or in combination: protein C deficiency, protein S deficiency, prothrombin gene mutation, and elevated levels of factor VIII. Multiple defects can increase the risk of a venous thromboembolism three-fold above the risk of a single defect 9 . Pseudohomozygous patients have both a factor V Leiden mutation and a deficiency in factor V creating an APC resistance similar to a homozygous patient 5 . Patients with a factor V Leiden deficiency are often treated with heparin or LMW heparin followed by anticoagulants (INR 2-3). If a provoking factor is discovered (injury, oral contraceptives, etc.), only six months of treatment is required. Long-term treatment may be needed for patients with multiple thrombotic episodes 8 .
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