AssessmentsFactor V Leiden
Factor V Leiden
USMLE® Step 1 style questions USMLE
A 52-year-old woman, para 4 gravida 2 aborta 2, comes to the clinic for a follow-up appointment after a hospitalization. Two weeks ago, she had an incident of acute, severe abdominal pain and bloody stools. She was diagnosed with portal vein thrombosis. She denies similar episodes in the past. Medical history is notable for Legg-Calvé-Perthes disease as a child. She does not smoke, drink excessive alcohol, or use illicit drugs. She had 2 spontaneous abortions in the first trimester, following 2 successful pregnancies. Family history is remarkable for DVT in her maternal uncle and colon cancer in her father. The physician suspects an inherited condition. Which of the following will prompt further evaluation in this patient?
Factor V Leiden is a disorder where blood clots form more easily due to a mutation in a clotting protein called factor V. Factor V Leiden is the most common hypercoagulable disorder in people of caucasian descent, and was named after the town Leiden in Holland, where the disease was first described.
Primary hemostasis involves the formation of a platelet plug at the site of injury, and secondary hemostasis involves the coagulation cascade, where several clotting factors come into play to form a fibrin mesh over the platelet plug to reinforce it - forming a blood clot.
Hemostasis can be both stimulated, and inhibited by several factors.
So one way to inhibit hemostasis is actually to inhibit thrombin.
This happens with the help of anticoagulant proteins like protein C. Protein C is a vitamin K dependent circulating plasma protein produced in the liver along with a cofactor called protein S.
Both protein C and S interact with a protein called thrombomodulin, which is on the surface of intact endothelial cells that line our blood vessels.
So, let’s say you cut your finger and now a blood clot has formed.
When there’s a lot of thrombin around a damaged blood vessel, excess thrombin binds to thrombomodulin and it can no longer participate in the coagulation cascade.
So in a sense, the undamaged cells help ensure that the coagulation process is limited to the injury site.
Furthermore, the thrombin-thrombomodulin complex binds to protein C. Protein S then joins the party, forming a complex that includes protein C, protein S, and thrombin-thrombomodulin. Protein S binding to this complex activates the proteolytic site of protein C which then cleaves and inactivates active factor V, which is a cofactor for factor X in the common pathway of the coagulation cascade, as well as factor VIII, which is a cofactor for factor IX in the intrinsic pathway of the coagulation cascade.
This slows down coagulation. What is more, the factor V degradation product also binds to this complex and further enhances its ability to cleave more active factor V and active factor VIII, further limiting coagulation.
So anticoagulation prevents clots from growing too large and blocking blood flow to tissues supplied by the vessel.
It also prevents clots from getting so big that small parts of the growing clot break off in the form of emboli.
So with Factor V Leiden, both active factor V, termed Va and inactivated factor V become resistant to cleavage by activated protein C because of a mutation that results in a misshapen cleavage site.
So when activated protein C, protein S, and the thrombin-thrombomodulin complex binds and tries to cleave factor Va or inactivate factor V, it can't because the normal cleavage site isn’t there!
Usually, these clots develop in the deep veins of the lower limbs, like the popliteal and femoral veins, causing a venous thromboembolism, where small parts of the clot can break off and travel to other organs, like the lungs, the brain or the liver, cutting off blood flow to those organs.
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