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Haematology

Haematology

Factor V Leiden

The Factor V Leiden mutation is present in 45% of familial thrombophilia and is the most common genetic risk factor identified in patients with thrombosis. Heterozygous individuals have an approximate 8-fold increase risk for venous thrombosis. The relative increase in risk for homozygous individuals is approximately 80-fold. When the mutation is found, family studies are recommended. Also, full thrombophilic screens are suggested, if not previously performed

Prothrombin 20,210

The Prothrombin 20,210 gene mutation is the second most common cause of inherited thrombophilia. Carriers have a predisposition to elevated prothrombin concentrations. Heterozygotes for the mutation constitute approximately 2 % of the normal population and up to 20% of those with recurrent or familial thrombotic events. Heterozygotes carry an estimated 2-5 fold increased risk of venous thrombosis. Thrombosis risk increases synergistically in the presence of the Factor V Leiden mutation. When the mutation is found, family studies are recommended. Also, full thrombophilic screens are suggested, if not previously performed.

MTHFR

High blood levels of an amino acid called homocysteine, is recognized as a risk factor for coronary artery disease, venous thrombosis and stroke. High blood levels have also been associated with neural tube defects, stillbirths and recurrent pregnancy loss. The major cause of high homocysteine levels (or hyperhomocysteinemia) is folate deficiency. Other factors include insufficient vitamin B12 and genetic mutations in the MTHFR gene.  Methylenetetrahydrofolate Reductase (MTHFR) is a key enzyme required to metabolise homocysteine. The most common mutation in MTHFR is called C677T. People with two copies of this mutation are called homozygotes, and are found in 5-10% of the population. These individuals are predisposed to developing high blood levels of homocysteine, particularly when their diets are low in folate. A second mutation in the MTHFR gene called A1298C has also been implicated with high levels of homocysteine, when found together with the C677T mutation. MTHFR gene mutations found in individuals with other inherited clotting genes (eg Factor V Leiden) have a dramatically increased risk of venous thrombosis.

Warfarin Dose Predict

Warfarin is one of the most widely prescribed anti-coagulants today. It’s use is indicated in the prevention of thromboembolism, as well as the management of thrombotic disease (or blood clots).The selection of the correct initial warfarin dose has until recently, been determined empirically using both clinical and biochemical indicators, such as patients age, other medications and liver function. Despite this traditional approach to warfarin dosing considerable patient to patient variation is frequently seen, as assessed by the INR, and clinically, by the complication of bleeding when the initial dose is set too high. Therefore, predicting a patients standard warfarin dose remains sub-optimal resulting in the potential for over anti-coagulation and hemorrhage.Recently, two liver enzymes were identified as key components of warfarin breakdown and activity. Genetic variants of these enzymes called CYP2C9 and VKOCR1have been found to be responsible for up to 50% of patient to patient variation in the response to standard warfarin doses.Indentifying these genetic variants in patients prior to warfarin dosing should lead to more accurate personalized doses and reduce the risk of serious hemorrhage.

BCR-ABL1

The BCR-ABL1 gene fusion is acquired when pieces of chromosome 9 and chromosome 22 break off and switch places. The resulting chromosome 22 that has the BCR-ABL1 gene sequence is known as the Philadelphia chromosome. The BCR-ABL1 gene encodes an abnormal protein that is responsible for the development of CML and a type of ALL. This abnormal protein drives uncontrolled growth of leukemic cells. At diagnosis, 90-95% of cases of CML show the characteristic t(9;22) BCR-ABL1reciprocal chromosomal translocation.

JAK2

The JAK2 V617F mutation is present in approximately 90% of polycythemia vera cases and approximately 40% of primary myelofibrosis or essential thrombocythemia. Mutation analysis helps differentiate reactive conditions from myeloproliferative neoplasms