Leiden Mutation

leiden mutation

  • Blood clot in scanning electron microscopyLeiden mutation was described by professor Dahlback et al in 1993. The so-called Resistance to activated protein C (APC-R), the cause is usually a point mutation in factor V.
  • In 1995, a group headed by Professor Bertin made a major discovery of point mutation in the gene for coagulation factor V. This thrombophilia mutation was detected in more than 90% of individuals with laboratory manifestations of resistance to activated protein C. The place of discovery was the city of Leiden and the mutant protein was named FV Leiden.
Leiden mutation
The process of blood coagulation – cascade containing coagulation factors

How Leiden mutation affects blood clotting?

Leiden mutation in Factor V is the most common thrombophilia and genetic predisposition to thrombosis. This is a point mutation in the form of nucleotide substitution G (guanine) to A (adenine) at the point 1691 in the DNA molecule of this gene (FV G1691A), see picture. Consequence of, the nucleotide substitution is the substitution of the amino acid arginine (Arg = R), glutamine (Gln = Q) in the peptide chain in place 506 (FV R506Q). This causes resistance to Factor V anticoagulant activity of APC (Activated Protein C), i.e. APC resistance. More about genes, DNA and causes of mutations HERE.

Protein C is a natural inhibitor of the coagulation cascade, acting as an anticoagulant in the blood coagulation cascade. In the plasma protein C occurs as an inactive precursor. On the surface of the vascular endothelium causing thrombin, which is bound to thrombomodulin, change of Protein C into its activated state (APC). The APC is then able, together with protein S, to inactivate coagulation factor V and VIII. This mechanism hinders the excessive production of thrombin. This way is inhibited the whole coagulation cascade.

Natural inhibitor of activated Factor V is activated protein C. Thus, when due to mutation  the factor V resistant to APC, then there  occurs an imbalance in the coagulation cascade. The vast majority of cases of resistance to APC (up to 95%) is subject to point mutation in the factor V G1691A.

Leiden mutation and risk of thrombosis

Resistance to APC is an important risk factor, since it greatly increases the risk of thrombotic complications in comparison with the norm. Other factors boosting the risk of thrombophilia include hormonal contraceptives, hormone replacement therapy, higher age, being overweight, lack of physical activity, smoking and family history. The risk can be up to 100 times higher when the Leiden mutation is combined with other mutations (FII, MTHFR).

Leiden mutation or a mutation in factor V increases the risk of thromboembolic complications 5-10 times in heterozygotes and 50-100 times in homozygotes. It , also increases the risk of re-thrombosis. Leiden mutation is found in 20-60% of persons suffering from thrombophilia. This mutation is present in approximately 20% of all cases of venous thrombosis, about 50% of deep vein thrombosis with a family history, and about 60% thrombosis associated with pregnancy. The risk of venous thrombosis for homozygous individuals is approximately 10 times higher than in heterozygotes and about 90x higher than for individuals without the mutation. Higher incidence of thrombosis in homozygotes for the Leiden mutation than in heterozygotes shows codominant mode of inheritance.

Leiden mutation is not considered a risk factor for idiopathic pulmonary embolism or for arterial thrombosis. In the literature associated with this,  there are reports of an association the mutation with higher incidence of the transient cerebral ischemia and cerebral venous thrombosis. Only in smokers with Leiden mutation was also described a higher incidence of heart attack.

Diagnosis of Leiden mutation

Factor V Leiden mutation is inherited thrombophilia and can be diagnosed only by molecular genetic testing for Factor V (PCR testing). Determining APC-R is not specific, because there is also acquired form of APC-R e.g. in pregnancy, usage of oral contraceptives etc. APC resistance may be triggered simply by reducing the levels of factor V. If one person meets the reduced levels of factor V while being a heterozygote for FV Leiden, this state is referred to as, pseudo homozygous APC resistance ‘.

Incidence of Leiden mutation

Heterozygous Leiden mutation accounts for about 5% among white population, homozygotes F V Leiden occurs 1 in 5,000 people.

Leiden mutation has an interesting dependence on race and geographic factors. Most frequently it has been demonstrated in the Caucasian population of northern countries, especially in Scandinavia and in some northern areas of Germany this mutation was

detected in 20% of the general population. The highest incidence of FV Leiden mutation in Sweden and gradually southwards prevalence rate decreasing, the lowest rate is in Italy and Spain. The incidence of this dominantly inherited mutation in factor V in Europe and North America in whites is   about , 3-15% of the healthy population and in other parts of the world it occurs rather rarely. ence Among  f Europeans and North Americans it is   5%.

Leiden mutation shows a clear ,,founder effect ‘, which was found in population genetic research. This mutation was  formed about 30 to 40 thousand years ago, at a certain ,, founder’’ of white Caucasian origin. Scientists suspect that this thrombophilia brought some genetic advantage to its bearers. For example, serious bleeding injuries that resulted in Nordic conditions quickly into a hemorrhagic shock, in carriers of this mutation caused less bleeding or the loss of blood mutation carriers during childbirth were more moderate. Mutations F V Leiden in the Asian and black population is virtually absent.

Heredity of Factor V Leiden

Leiden mutation is an autosomal intermediate disease. It means that the symptoms occur in homozygotes and heterozygotes. However, at homozygotes are expressed more intensely.

  • Homozygote Leiden mutation – has both alleles mutated and therefore always transmit one mutated allele on offspring, which means that his children are at least heterozygous for this mutation.
  • Heterozygote Leiden mutation – has one healthy and one mutated allele. That means that the mutated allele can be imparted to children but does not have to. This mutation at heterozygous carriers does not have to be passed on to the offspring. When meet the couple of heterozygous for this mutation, their baby may be completely healthy, may be heterozygous or homozygous for this mutation.
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