BIOLOGY 2F03 Lecture Notes - Lecture 8: Factor V Leiden, Myeloproliferative Neoplasm, Warfarin
19 May 2018
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INTRODUCTION TO THROMBOPHILIA
1. Venous thromboembolism is a disorder predisposed to by a number of genetic and environmental
factors
The key notion is that most people with recurrent VTE disease have a transient risk factor which pushes
them over their thrombotic threshold in the context or pre-existing genetic and/or environmental
predispositions to clot.
Genetic
Environmental
Mixed
Transient
AT deficiency
Antiphopholipid syndrome
Hyperhomocysteinaemia
Surgery
Protein C def
Myeloproliferative disease
High F7/9/ fibrinogen
Long distance travel
Protein S def
Increasing Age
OCP
F5 leiden
Previous Thrombosis
HRT
PT G20210A
Cancer
pregnancy
2. An important polymorphism is Factor V leiden confers resistance to activated protein C
Normal physiology
• APC cleaves the 5a heavy chain in two places on phospholipid membranes of platelets and
endothelial cells to inactivate it - the two places where APC splices are Arg 506 & Arg 306
• Arg 506 is rapidly cleaved and cleavage makes 5a moderately less active
• Arg 306 is slowly cleaved and cleavage makes 5a completely inactive
F5 leiden
• A common single polymorphism occurs at 506 Arg → Gln
• this polyorphis is likely to hae ee a fouder polyorphis that has sie spread
amongst Europeans in particular
• this stops rapid cleavage of 5a and confers resistance to activated protein C
• slow cleavage at Arg306 still occurs
F5 leiden polymorphism interacts with other genetic/environmental pro-thrombotic predispositions
• Genetic – F5 leiden (homozygosity), Protein C/S def, AT def, PT G20210A
• Environmental – OCP
3. An important polymorphism in prothrombin confers increased thrombotic potential
The G20210A polymorphism increases prothrombin production, which subsequently increases thrombin
production = thrombosis.
4. Polymorphisms are more common and have less thrombotic potential than single gene mutations
Single gene mutations are implicated in AT def, Protein C def and Protein S def
Homozygotes for single gene mutations tend to be severely disabled or die in utero. Heterozygotes do
not have increased mortality but may experience the following symptoms due to increased risk of
thrombosis:
• Common – DVT/PE/ pregnancy associated thromboembolism
• Rare – warfarin induced skin necrosis, clotting in other veins (i.e not legs) and arteries
o warfarin inhibits protein C/S so if the person is already deficient then the drug makes
the problem worse
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Venous thromboembolism is a disorder predisposed to by a number of genetic and environmental. The key notion is that most people with recurrent vte disease have a transient risk factor which pushes them over their thrombotic threshold in the context or pre-existing genetic and/or environmental predispositions to clot. Hrt pregnancy: an important polymorphism is factor v leiden confers resistance to activated protein c. F5 leiden polymorphism interacts with other genetic/environmental pro-thrombotic predispositions: genetic f5 leiden (homozygosity), protein c/s def, at def, pt g20210a, environmental ocp, an important polymorphism in prothrombin confers increased thrombotic potential. The g20210a polymorphism increases prothrombin production, which subsequently increases thrombin production = thrombosis: polymorphisms are more common and have less thrombotic potential than single gene mutations. Single gene mutations are implicated in at def, protein c def and protein s def. Homozygotes for single gene mutations tend to be severely disabled or die in utero.
