Factor V Leiden

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Introduction0:00–0:53

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.
Now, Factor V Leiden is a hemostasis disorder. Hemostasis is the process where blood flow is stopped after there’s damage to a blood vessel, and it has two steps.
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.

Physiology0:53–3:14

Hemostasis can be both stimulated, and inhibited by several factors. One way to stimulate hemostasis is with thrombin, or factor II, which increases platelet activation, and cleaves several factors involved in secondary hemostasis to their active form.
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.

Pathology3:14–4:16

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!
And when factor V can’t be inactivated, you guessed it - coagulation doesn’t slow down, so there’s increased blood clot formation.
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.

Causes4:16–5:04

Factor V Leiden is caused by a single point mutation in the factor V gene. This is where a single nucleotide in the factor V gene sequence is replaced by another.
This leads to the change in a single protein building block called an amino acid, so the resulting factor V protein has a cleavage site that contains glutamine where it should have been arginine.
This mutation is an autosomal dominant condition, so a single abnormal copy of the gene, which can be inherited from either parent, is needed to get the disease.
If someone has two copies of the factor V Leiden gene, these people are homozygotes, and they have a higher risk of developing a venous thromboembolism, which is the most common clinical presentation for Factor V Leiden.

Symptoms5:04–5:46

Symptoms of a venous thromboembolism occur in the affected leg and include pain and swelling. If parts of the clot break off and travel to the lungs, there can be signs of respiratory distress like pain with inhalation, fast heart rate, and a fast respiratory rate.
If clots get lodged in the cerebral vessels, there may be signs of a stroke, like numbness or weakness in the face, arm or leg, confusion, or slurred speech.
If a clot blocks the hepatic or portal vessels, there may be signs of liver failure, like right upper quadrant pain and jaundice, which is a yellowish pigmentation of the skin and eyes.

Diagnosis5:46–6:48

When considering a diagnosis, Factor V Leiden should be suspected in a person who presents with venous thromboembolisms that are recurrent, has a strong family history of venous thromboembolism, or suffers a venous thromboembolism at a young age.
Coagulation studies can show a Partial Thromboplastin Time or PTT that is shortened or normal. PTT is a lab value that shows how long it takes for clots to form via the intrinsic and common pathway.
Functional assays can also be done. That’s when purified protein C gets mixed with the person's plasma and PTT is measured before and after.
In individuals without factor V Leiden, the PTT is usually prolonged. In individuals with Factor V Leiden, PTT stays the same.
Finally, DNA testing is the gold standard. That’s when the person’s DNA is sequenced to look for the factor V Leiden mutation.

Treatment6:48–7:13

Treatment with anticoagulant medication like heparin is required when the person develops a venous thromboembolism. Interestingly, studies have demonstrated there’s no role for venous thromboembolism prophylaxis in people with Factor V Leiden, except those at high risk during surgery, pregnancy, or the presence of additional thrombophilic mutations.
All right, as a quick recap, Factor V Leiden is an inherited disorder of hemostasis where factor V cannot be cleaved by activated protein C.

Review7:13–7:41

This results in increased clot formation, most frequently in the deep veins of the leg. Treatment with heparin is done when a venous thromboembolism develops, and studies have shown no role for prophylaxis in Factor V Leiden.