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Thrombophilia Panel

• Introduction
• Indication for Testing
• Detection method
• Interpretation of results
• Specimen Collection and Shipping Requirements
• Turn Around Time
• Cost
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Intoduction
Thrombophilia is defined as a predisposition for thrombosis.  Increased thrombosis can result from defects in coagulation, fibrinolysis, platelet aggregation and endothelial damage.  About 40% of patients with thrombosis are inherited.   Inherited thrombophilias have been associated with early and late recurrent pregnancy loss as a result of uteroplacental microvascular thrombosis and hypoperfusion.    Obstetrical complications such as intrauterine growth retardation, placental abruption as well as preeclampsia have also been related to abnormal placental vasculature.  Genetic thrombophilia are suspected to account for about 30% of these obstetrical complications.   Poor pregnancy outcomes are associated with maternal thrombophilia but may also be associated with fetal thrombophilia by inheritance of maternal and paternal thrombophilic genes.

Successful pregnancy requires fibrin polymerization to stabilize the placental basal plate as well as to prevent excess fibrin deposition in placental vessels and intravillous spaces.  Thus, a balance between coagulation and fibrinolysis is mandatory to ensure successful pregnancy outcome as early as implantation.  Coagulation factors linked to reproductive disorders include mutations of Factor V, Factor II and Factor XIII.  Factor V mutations associated with reproductive problems have included G1691A (von Leiden), H1299R (R2) and Y1702C.  Factor V von Leiden and Factor II prothrombin mutation G20210A are twice as common among women experiencing recurrent first trimester pregnancy loss and are suspected of tripling the risk of late fetal loss.  The mechanism of loss is through generation of thrombin.  Thrombin converts fibrinogen to fibrin.  Fibrinogen is a protein with 3 polypeptide chains.  A mutation in the b chain   (-455G1A) has been associated with thrombosis.  Fibrin is stabilized by cross-linking polymers under the influence of Factor XIII.  One of the variations in the Factor XIII A gene, the Val34Leu polymorphism, has been correlated with thrombosis.  Women who are homozygous for Factor XIII mutations also have a high risk for recurrent spontaneous abortion.

Increased thrombosis can result from a defect in fibrinolysis as well as coagulation.  The main cause of defective fibrinolysis is an increase in plasmin activator inhibitor (PAI 1) concentrations.   PAI 1 is induced by insulin and is increased in patients with polycystic ovary syndrome (PCOS) associated with insulin resistance.  Clotting problems associated with increased PAI 1 may cause abnormal uterine artery blood flow, thus contributing to miscarriage associated with PCOS.

Thrombosis can also result from increased platelet aggregation and endothelial cell damage.  Human platelet activator 1 (HPA-1) is part of the thrombosis system involved in platelet aggregation.  It is a member of the integrin family.  The integrin b3 gene encodes glycoprotein IIIa (GP IIIa) which is part of GP IIb/IIIa complex when activated interacts with fibrinogen to cross-link platelets to one another and causes platelet aggregation.  Two allelic forms of GPIIIa have been identified (PLA1 and PLA2).  The A2 form has been associated with increased thrombosis.  Endothelial damage leading to thrombosis can be caused by hyperhomocysteinemia or antiphospholipid antibodies.  Methylenetetrahydrofolate reductase (MTHFR) catalyzes remethylation of homocysteine to methionine.  Several mutations in the MTHFR gene, C677T and A1298C, leads to hyperhomocysteinemia via decreased enzyme activity.  Hyperhomocysteinemia is a major risk factor for both arterial and venous thrombolic disease.  Individuals homozygous for the MTHFR gene are at increased risk for thrombosis and pregnancy related disorders.  The risk of embryonic and fetal loss is increased if the MTHFR gene mutation is combined with additional thrombophilic factors.  Disturbance of maternal and fetal homocysteine metabolism has also been implicated in a decrease in incidence of dizygotic twinning and an increase in fetal neural tube defects.

Indication for Testing
All individuals with a history of thrombosis and all women experiencing recurrent embryonic loss, fetal loss, severe pre-eclampsia, placenta abruptio, or intrauterine growth retardation should be tested for thrombophilic risk factors.

Detection Method
The Thrombophilia Panel includes testing for the following mutations:

• Factor VY 1702
• Factor V G1691A (Leiden)
• Factor V H1299R (R2)
• Factor II Prothrombin G20210A
• B-Fibrinogen-455 G>A
• Factor XIII V34L
• PAI I 4G/5G
• HPAI a/bHuman Platelet Glycoprotein (PLAI/PLA2)
• MTHFR C677T
• MTHFR A1298C

Gene mutations are detected by DNA probes and gel electrophoreses.

Interpretation of results
Results are reported as normal, heterozygous or homozygous.

Specimen Collection, Handling and Shipping Requirements

• Collect a sample DNA with a buccal swab.
• Ship at room temperature in prepaid FedEx mailer overnight, next day delivery.

Turn Around Time
Processing of specimens begins immediately upon receipt at our facilities. Results are routinely available within 10 to 14 days and are initially faxed, then mailed to the requesting physician.

Cost
Included in our test are specimen collection and shipping materials, shipping charges, telephone and written reports as well as consultations with the referring physicians. Please call (312) 274-1928 for pricing information.

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