Activated Protein C Resistance

The Factor V Leiden (FVL) mutation was first identified in 1993. It has since been found to be a leading cause of blood clots among white populations. In fact, the Factor V Leiden alteration is the most common genetic risk factor for blood clots.

There are a large number of people with Factor V Leiden. Heterozygous Factor V Leiden mutation (where one of two Factor V Leiden genes are altered) is found in 5–10% of white individuals and in up to 30% of patients with a blood clot. Factor V Leiden gene alteration is by far the most common inherited risk factor for a clotting disorder. Factor V Leiden is very uncommon in African Americans, Hispanics, and Asians.


People with Factor V Leiden make an altered Factor V (FV) protein. In the normal blood clotting process, activated protein C (APC), turns off the clotting activity of Factor V when it is no longer required. In people with Factor V Leiden, activated protein C cannot successfully turn off Factor V once it is no longer required. As a result, clotting continues for an excessive period leading to an enlarged blood clot.

Risk of a Clotting Disorder in People with Two Abnormal Factor V Genes

People with two abnormal Factor V genes are known as Factor V Leiden homozygotes. These people have only the Leiden protein. Factor V Leiden homozygotes have an 80-fold increased risk of developing a blood clot compared to the unaffected population.

Risk of a Clotting Disorder in People with One Abnormal Factor V Gene

People with one abnormal Factor V gene are known as Factor V Leiden heterozygotes. These people are believed to produce about 50% of the Leiden protein. There is a five- to seven-fold increased risk of a clotting disorder compared to the general population. In heterozygous patients, the clot is usually related to a trigger event, such as pregnancy, injury, or surgery.


The most common triggering events with Factor V Leiden are:

  • Pregnancy

  • Birth control pills

  • Hormone replacement therapy after menopause

These events cause the natural hemostatic balance to be tilted towards excessive clotting. Pregnancy causes an increase in the proteins that assist with blood clotting; hormonal replacement therapy and birth control pills mimic this change in the body.

In one study in Europe, 60% of women who experienced clots during pregnancy were found to have the Factor V Leiden mutation, with the risk of blood clots being at its greatest 6 to 8 weeks after the birth of a child.

In heterozygous men with Factor V Leiden, blood clots may occur after surgery or injury; particularly with injuries to the leg.

Not everyone who has a heterozygous Factor V Leiden condition develops a blood clot. For some people with heterozygous Factor V Leiden, neither they or their parents have a history of abnormal blood clotting.


Besides the Factor V Leiden mutation, several other changes can occur in the Factor V gene which may also contribute to activated protein C resistance. People with the Factor V Cambridge mutation and the Factor V Hong Kong mutation have mild activated protein C resistance. A complex set of closely linked genetic markers of the Factor V gene (FV HR2) have been found to contribute to activated protein C resistance, although to a lesser degree than Factor V Leiden.