Factor V Leiden Thrombophilia: Analysis of Underlying Mendelian Genetics

Running head: FACTOR V LEIDEN THROMBOPHILIA
Factor V Leiden Thrombophilia: Analysis of Underlying Mendelian Genetics
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FACTOR V LEIDEN THROMBOPHILIA
Introduction
Factor V Leiden thrombophilia (F-VLT) is a genetic disorder that results in the
formation of the blood clot mainly in the lower portion of the limbs (deep venous thrombosis
or DVT) or lungs (pulmonary embolism or PE). The gene mutation in the F5 gene, which
plays a significant role in the blood clotting results in the formation of the disease. However,
95% of the population living with this mutation does not develop a clot during their entire
stage of life (National Center for Advancing Translational Sciences, 2019).
The following assignment aims to analyse the underlying pathophysiology of F-VLT
followed by a detailed analysis of the Medelian genetics leading to the gene-level mutation of
F-VLT. At the end, the assignment will discuss diagnosis, ethics, treatment and prognosis of
F-VLT.
Pathophysiology of Factor V Leiden Thrombophilia (F-VLT) 300
The clotting mechanism is broken into 2 stages. First is primary hemostasis (PH) and
secondary hemostatis (SH). In PH vasoconstriction occurs due to vessel injury (damaged
endothelium) mediated by inflammatory mediators and ATP generated by von Willebrand
factor (vWF). This leads to the exposure of endothelial collagen, promoting platelet adhesion
at the site of injury. Plate adhesion occurs by platelet activation followed by platelet
aggregation. Platelet activation is mediated by thrombin. Thrombin directly activates platelets
through proteolytic cleavage. Moreover, thrombin stimulates platelet granule, which activates
platelet activating factor and ADP leading to comprehensive platelet activation. Once platelet
is activated Gp IIb/IIIa receptors adhere to vWF and fibrinogen, forming weak platelet plug.
SH involves clotting factors. Tissue factor (TF) binds to FVII, activating FVII to factor VIIa
(FVIIa), forming TF-FVIIa complex (Garmo & Burns, 2018). This complex activates factor

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FACTOR V LEIDEN THROMBOPHILIA
X (FX) (extrinsic pathway). TF-FVIIa complex can also activate factor IX (the intrinsic
pathway or alternate pathway). Once Factor X is activated, the cascade continues down the
common pathway of activation of activation of Factor Xa. Factor Xa binds with Factor Va
and calcium to form prothrombinase complex, activating prothrombin (aka Factor II) into
thrombin. Thrombin activates FXIIIa. FXIIIa crosslinks with fibrin forming stabilized clot
(Garmo & Burns, 2018).
Figure: Mechanism of blood Clot
(Source: Garmo & Burns, 2018)
F-VLT causes mutation of Factor V (F5) gene. The mutation in the F-VLT is
characterised by a guanine to adenine substitution at 1691 nucleotide at the exon 10. This
substitution mutation of a nucleotide (at codon 506) leads to a change in the amino-acid
sequence from arginine to glutamine. The mutated gene is known as FV R506 (Leiden) and
leads to resistance towards F-VLT inactivation by protein C. As a result of this, factor V

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FACTOR V LEIDEN THROMBOPHILIA
persists within the circulation leading to development of the mild hyper-coaguable state. The
Leiden mutation accounts for 90 to 95% of APA resistance. Heterozygous carriers of the
mutation have an eight to four-fold high rate of thrombosis. Homozygous individuals for the
mutation have 80 to 100 fold risk of thrombosis. Genetic counselling is recommended for the
homozygous parents (National Centre for Advancing Translational Sciences, 2019).
Genetics of Factor V Leiden Thrombophilia (F-VLT)
Inheritance pattern and pedigree
The chances abnormal blood clot depends on whether an individual has one/two
copies of the factor V Leiden mutation. People who have inherited two copies of the
mutation, one each parent, have a higher risk of developing a clot in comparison to people
who inherit one copy of the mutation (U.S National Library of Medicine, 2019). F-VLT is an
autosomal dominant disorder with but with incomplete penetrance. This signifies that the
people who have one diseased gene located in one allele, the might not have 100% of
penetrance in spite of having autosomal dominant inherence patter. The homozygous
diseased individual with diseased gene in both the alleles shows complete penetrance along
with expresitivity of the diseased trait (U.S National Library of Medicine, 2019).
Parent (RfRn) (heterozygous parent) Parent (RfRn) (heterozygous parent)
RfRf (homozygous diseased) RfRn (heterozygous diseased)
RnRf (heterozygous diseased) RnRn(homozygous normal)
Rn: Normal allele
Rf: Diseased allele
Heterozygous diseased: 50%
Homozygous diseased: 25%