Learn About Thrombophilia

Each year, venous thombosis occurs in about 1 in 1000 people in developed countries and about many of those patients die from a pulmonary embolus, the most frequent complication of thrombosis.

The term “thrombosis” is used to designate the occlusion of a blood vessel by a blood clot which develops due to disruptions during blood clotting. Various risk factors may be responsible for these disruptions which are collectively referred to by the term “thrombophilia”.

Along with external risk factors, such as confinement to bed, genetic predispositions can also lead to an increased risk of thrombosis. In general, clotting factors are affected by these genetic changes. For example a mutation can cause inactivation of a clotting factor or cause the concentration of the clotting factor to increase. Changes in other genes can also lead to an increased risk of thrombosis.

About 60% of all venous thrombosis occurs in connection with hereditary thrombophilia. Thus, hereditary risk factors play a crucial role in the development of thrombosis. Since it is important to know all the risk-factors to assess the individual risk of thrombosis, it is essential to determine genetic risk factors.

Factor V Leiden Mutation

The Factor V Leiden mutation is the most frequent and most important change in the human genome associated with thrombophilia. The cleavage site for activated protein C is destroyed by a point mutation at position 1691 in the factor V gene. This causes the activated Factor V to be inactivated much more slowly and therefore blood clotting is stimulated over a longer period of time. The heterozygous Factor V Leiden mutation causes a five- to tenfold increased risk of thrombosis. In the homozygous disease, the risk of thrombosis is increased 100 times.

Factor II Mutation (Prothrombin Mutation)

The second most frequent mutation is the prothrombin G20210A mutation. This point mutation involves the noncoding regulatory area of the Factor II gene (prothrombin). It is assumed that the change leads to increased protein synthesis by increasing translational efficiency. In heterozygous carriers, the mutation is associated with a threefold increase in thrombosis risk.

Methylentetrahydrofolate Reductase (MTHFR)

Homocysteine affects the arterial and venous vascular system in various ways. One effect that it has is a cytotoxic effect on the cells of blood vessels. Along with an increased risk of thrombosis, particularly in connection with additional thrombosis-related mutations, this can lead to clinical pictures such as atherosclerosis, strokes or myocardial infarcts. An increase in the homocysteine level has therefore been known for a long time to be a risk factor for cerebral, cardiovascular and venous thrombosis.

Along with acquired causes, such as vitamin B12 deficiency, mutations within the methylenetetrahydrofolate reductase (MTHFR) gene lead to an increase in the homocysteine level. The best described change within the MTHFR gene is a point mutation at position 677. This change leads to the production of a thermo labile protein which is limited in its catalytic effect, giving it a loss of activity of up to 60%. An additional change at position 1298 likewise leads to a reduced enzymatic effect, which however is not as pronounced as with the previously mentioned mutation. Compound heterozygous carriers also develop reduced MTHFR activity.



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