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Diseases / Disorders Related to Factor V Leiden

Mutations Within the Factor V Gene

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.

Inherited Causes of Thrombosis

Factor V Leiden

The Factor V Leiden mutation is 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. The Factor V Leiden mutation is a leading cause of blood clots among white populations.

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.


Why Factor V Leiden Leads to Blood Clots

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.

Prothrombin 20210 Mutation

The prothrombin 20210 mutation is a specific alteration of the prothrombin gene, which has been found to be present in 18% of people with a blood clot. It is associated with higher levels of prothrombin (which is a clotting protein) and increases the risk of a blood clot three-fold. Age-related increases in coagulation proteins, specifically increased levels of factors VIII, IX and XI, have also been linked to an increased risk of clotting. This mutation is also linked to other clotting events such as coronary artery disease (particularly in young women and people with stroke), venous blood clots, clots in the mesenteric vein, and clots in the central retinal artery or portal vein.


Hyperhomocysteinemia, or increased levels of the amino acid, homocysteine, affects about 5% of the general population. Approximately 13-47% of people with symptoms of heart disease have this condition. Mild to moderately high levels of homocysteine is a single risk factor for stroke, heart attack, peripheral arterial disease, and narrowing of the extracranial carotid artery.


High levels of homocysteine are also associated with enzyme defects or decreased amounts of folate or vitamin B6, particularly in the elderly. Mild or moderate hyperhomocysteinemia has been associated with venous blood clots in the young and recurrent blood clots. The condition also has been found in approximately 10% of patients who experience their first episode of a venous blood clot.


Several inherited or acquired conditions may lead to an increase in homocysteine levels.


Inherited causes of hyperhomocysteinemia include low levels of an enzyme needed to change homocysteine into cysteine. In turn, this increases the risk of a clotting event. Mild inherited hyperhomocysteinemia has been found in 19% of cases of venous clotting in children.


Acquired causes of hyperhomocysteinemia include:

  • Advanced age
  • Tobacco use
  • Coffee intake
  • Low levels of folate in the diet
  • Low intake of vitamin B

Increased homocysteine levels are also associated with diabetes mellitus, cancers, low level of thyroid function, lupus, and inflammatory bowel disease; and are a side-effect of certain medications such as cholesterol-lowering agents, metformin, methotrexate, anticonvulsants, theophylline, and levodopa.

Elevated Clotting Factor Levels

High levels of other procoagulants such as factors VII, VIII, IX, XI, VII, fibrinogen, and von Willebrand factor are associated with an increased risk of clotting. Specifically, high levels of FVIII over time have been shown to be associated with repeat blood clots.



Some studies have shown an increased risk of heart disease with high levels of coagulation factor VII. FVII levels, however, are not a single risk factor after controlling for cholesterol, LDL-cholesterol, and triglycerides. Elevated FVII levels have been reported in people with blockage of a retinal (eye) vein.



Coagulation factor VIII activity levels may vary widely due to various reasons, such as:

  • Pregnancy
  • Use of hormonal therapy
  • Stress
  • Exercise
  • Presence of an inflammatory state

A high level of FVIII is a known independent risk factor for blood clotting. High levels of FVIII are an even stronger risk factor for repeatblood clots. The likelihood of a second clotting event within two years of the first clot was found to be 37% in people with a high FVIII level versus 5% among persons with a lower FVIII level.



High levels of coagulation factor IX may play a role in the risk of developing a blood clot. The Leiden Thrombophilia Study found that levels of FIX in the 90th percentile and higher increased the risk of blood clots by two- to three-fold.



Coagulation factor XI plays two roles in blood clotting. FXI contributes to the formation of fibrin (which is one of the main components of a clot). It also protects the fibrin that has formed from being broken down.

People with high FXI levels have an increased risk of a blood clot in a deep vein, such as a vein in the leg. The higher the FXI level, the greater the risk of a blood clot. Increased levels of FXI also have been associated with an increased risk of heart disease in women.



Von Willebrand factor (VWF) is produced in cells that line the blood vessels (the endothelium). Damage to or swelling of this blood vessel lining leads to increased Von Willebrand factor levels. FVIII circulates with Von Willebrand factor, and often the levels of these two clotting factors are similarly affected by stress, inflammatory states, or endothelial injury.


Continuously high levels of FVIII lead to an increased risk of blood clots; therefore it might be reasonable to assume that elevated levels of Von Willebrand factor would also be associated with and contribute to an increased risk of clots. Additionally, Von Willebrand factor plays an important role in platelet adhesion (platelet stickiness) to the damaged blood vessel lining.

Antithrombin (AT)

Antithrombin (AT) is a naturally occurring anticoagulant that stops the action of thrombin and other clotting factors when clot formation is no longer necessary. Heparin also increases the effect of antithrombin. Changes in the antithrombin gene may cause low levels of antithrombin or abnormal antithrombin protein activity.


It should be recognized that antithrombin levels are usually lower at birth and typically don’t reach ‘normal’ levels until approximately six months of age.


Several conditions can reduce antithrombin levels, including:

  • Liver and kidney disease
  • Complications during pregnancy or labor and delivery
  • Cancer
  • Malnutrition
  • Gastrointestinal problems
  • Oral contraceptives or other medications

There are two types of antithrombin deficiency:

  • Type I: caused by low levels of the normal antithrombin protein
  • Type 2: caused by an abnormally functioning antithrombin protein

Antithrombin deficiency is an inherited condition.Patients with both types of antithrombin deficiency are at risk of clotting in both arteries and veins. The number of people presenting with symptoms related to antithrombin deficiency is estimated to be one in 2,000-5,000 people. Antithrombin deficiency in people who don’t display symptoms may occur as frequently as one in 600 people.


In patients with a history of a blood clot, the incidence of antithrombin deficiency ranges from 0.5% to 4.9%. People with antithrombin deficiency who also have defects in the heparin-binding site have a severe clotting phenotype that occurs early in life and often involves blood clots forming in the arteries. An abnormally-functioning antithrombin protein can affect how antithrombin binds to heparin or neutralizes the effect of thrombin in the absence of heparin.


Protein C Deficiency

Protein C (PC) is a vitamin K-dependent protein. It is produced in the liver and through its activated form helps to stop the clotting activity of FVII. Thrombin activates protein C. The resulting activated protein C(APC) then works to shut down the clotting ability of activated FV and FVIII. In addition to its role in blood clotting, activated protein C is also involved in controlling inflammation and cell protection.

Protein C levels are dependent on the patient’s age and other medical conditions, with adult levels being reached at late adolescence. Several conditions can reduce protein C levels, including:

  • Liver disease
  • Complications during pregnancy or labor and delivery
  • Respiratory problems in the newborn
  • Blood clots
  • Gastrointestinal problems
  • Disseminated intravascular coagulation
  • Oral contraceptives or other medications

Protein C deficiency is an inherited condition and occurs in 1.4% to 8.6% of the population. In a study of healthy people, the frequency of the deficiency was found to be 1 in 200 to 1 in 300, while a study of almost 10,000 blood donors found a frequency of 1 in 500 to 1 in 700.

Protein C deficiency is divided into Type I or Type II deficiency.

  • Type 1: caused by low levels of normal protein C
  • Type 2: caused by an abnormally functioning protein

Homozygous protein C deficiency (where a person has two abnormal protein C genes, one from each parent) is usually evident in newborn infants. The first sign is often a rare and potentially catastrophic skin condition called purpura fulminans. Laboratory testing of babies with this condition reveals a severe deficiency (protein C levels of <1% of normal).

Some infants who do not have neonatal purpura fulminans but still have low levels of protein C (5% to 20%) often have a tendency to clot excessively at an early age. These patients require lifelong treatment with a blood-thinning medication to prevent recurrent blood clots.

Protein S Deficiency

 Protein S (PS), a vitamin K-dependent protein which is made by the liver and acts as the principal cofactor to protein C. Protein S exists as two forms in the blood: a free form and a bound form. Approximately 35% to 40% of total protein S exists as the free form, which is the form that acts with activated protein C (APC) to promote blood thinning.


Adult levels of protein S levels are reached when a child is approximately six months to one-year-old. Compared to men, women tend to have on average a lower level of free protein S, particularly when pregnant or using oral contraceptives. Newborn infants also have lower free and total protein S levels. Levels in heterozygotes (patients with only one abnormal protein S gene) are approximately 40-70% of the normal level.


Many medical conditions may be associated with abnormal protein S levels, including:

  • Liver disease
  • Disseminated intravascular coagulation
  • Herpes infections
  • Systemic lupus erythematosus
  • Ulcerative colitis

Protein S deficiency is rare in the healthy population, with an estimated frequency of approximately one in 700. When considering a selected group of patients with recurrent blood clots or a family history of clotting, the frequency of protein S deficiency ranges from 3% to 6%. The frequency of homozygous deficiency has been estimated to be one in 160,000 to one in 360,000. Infants and babies within the first year of life who have homozygous protein S deficiency characteristically have purpura fulminans.


There are three subtypes of protein S deficiency:

  • Type I: the decrease in the activity of protein S is proportional to the decrease in the level of protein S
  • Type II: the levels of the free and bound forms of the protein are normal, but they do not function properly because of a gene alteration
  • Type III: there is a normal level of total protein S, but the level of free protein S is abnormally low


Thrombomodulin is a protein found on the surface of cells lining the blood vessels. It acts as an attachment point for thrombin and plays an important role in blood clotting and clot breakdown. Thrombomodulin-bound thrombin initiates the protein C anticoagulant pathway by activating protein C.


Defects in thrombomodulin result in increased clotting. Thrombomodulin also activates the thrombin-activated fibrinolysis inhibitor, which affects clot breakdown. Small thrombomodulin pieces circulate in the plasma of healthy individuals. These pieces retain their activity and can be measured in plasma using a laboratory test.


Increased levels are seen in patients with venous and arterial clotting conditions, including clots in the brain and eyes, and DIC. The impact of thrombomodulin levels in treating clotting disorders is not fully known.

Heparin Cofactor II

Heparin cofactor II is found in plasma and rapidly blocks thrombin in the presence of heparin.


Heparin cofactor II deficiency is classified into two ways:

  • Type I (quantitative): a decrease in both cofactor level and its functioning
  • Type II (qualitative): a decrease in the functional activity of the protein with normal cofactor levels

Only a few cases of heparin cofactor II deficiency have been described. Further research is needed to understand the clinical importance of heparin cofactor II deficiency.

Tissue Factor Pathway Inhibitor (TFPI)

Tissue factor pathway inhibitor (TFPI) inhibits a complex that starts the process of clotting. 60-80% of TPFI is bound to the lining of the blood vessels, with only 20% free to circulate in the blood.


Recent evidence suggests that low levels of tissue factor pathway inhibitor are a risk factor for a blood clot. Interestingly, different forms of the tissue factor pathway inhibitor gene have been found that result in higher levels of tissue factor pathway inhibitor in the circulation.

Tissue Plasminogen Activator (tPA)

Tissue plasminogen activator (tPA) is synthesized by cells that line blood vessels. When tissue-plasminogen activator is released, it helps change plasminogen to plasmin.


Theoretically, decreased release of tissue-plasminogen activator could lead to a super-clotting state (or hypercoagulable state) due to decreased clot breakdown fibrinolysis.

Plasminogen Activator Inhibitor 1 (PAI-1)

Plasminogen activator inhibitor 1 (PAI-1) functions as the primary blocker of plasminogen activator in plasma. Increased levels of plasminogen activator inhibitor 1 could lead to excessive blocking of tissue-plasminogen activator, leading to decreased clot breakdown and eventually an unwanted blood clot. Increased plasminogen activator inhibitor 1 levels have been shown in some cases to be an inheritable trait.

Thrombin-activatable Fibrinolysis Inhibitor

Increased levels of thrombin are needed for clot formation and to prevent clot breakdown. If thrombin levels are too high, they activate thrombin-activatable fibrinolysis inhibitor (TAFI).

Thrombin-activatable fibrinolysis inhibitor helps to stop clot breakdown by preventing plasminogen from binding to the fibrin clot.

Increased levels of thrombin-activatable fibrinolysis inhibitor may prevent the start of normal clot breakdown and therefore could theoretically increase the tendency for a super-clotting state. The Leiden Thrombophilia Study suggests that high levels of thrombin-activatable fibrinolysis inhibitor may be a mild risk factor for a super-clotting state. However, these results require confirmation.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder of stem cells and is caused by a gene alteration on the X chromosome. Paroxysmal nocturnal hemoglobinuria is known to be associated with an increased risk of clotting.


Paroxysmal nocturnal hemoglobinuria results in the breakdown of red blood cells, which causes the release of hemoglobin into the blood. Ultimately, the hemoglobin is released into the urine. This release produces dark-colored urine most often in the morning. It is called “nocturnal” because it was believed that the breakdown of red blood cells occurred during sleep, but this belief was later disproved. Hemolysis has been shown to occur throughout the day, but the quantity of urine that occurs during sleep results in the dramatic color change.


Paroxysmal nocturnal hemoglobinuria is an inherited condition related to a genetic change in stem cells. In people with paroxysmal nocturnal hemoglobinuria, surface proteins are missing in the membrane of all blood cells (including platelets as well as red and white blood cells).

This disorder usually presents in adulthood and is less common in childhood. In adults, paroxysmal nocturnal hemoglobinuria is most commonly seen as hemolytic anemia with nighttime episodes, while in children, paroxysmal nocturnal hemoglobinuria is most commonly associated with bone marrow failure.


Blood clots may occur in 39% of adults and 31% of children with paroxysmal nocturnal hemoglobinuria. The clots usually occur in the veins, particularly in the veins of the liver (Budd-Chiari syndrome); however, the portal veins, central nervous system, and peripheral venous system may also be involved. Increased circulating activated platelets have been implicated in clotting events due to paroxysmal nocturnal hemoglobinuria, but no consistent abnormality with clotting has been reported.

Diseases/Disorders Thought to be Associated With Factor V Leiden

  • Thrombophilia due to activated protein c resistance        
  • Factor v deficiency                       
  • Thrombophilia  
  • Thrombophilia due to thrombin defect   
  • Osteonecrosis   
  • Pulmonary embolism                  
  • Placental abruption                     
  • Gastroesophageal reflux              
  • Legg-calve-perthes disease                       
  • Buerger disease
  • Chronic ulcer of skin      
  • Paroxysmal nocturnal hemoglobinuria                
  • Pre-eclampsia  
  • Pneumothorax               
  • Pericarditis                     
  • Antiphospholipid Syndrome                     
  • Hemoglobinuria
  • Vasculitis                         
  • Prothrombin-related thrombophilia       
  • Kienbock’s disease         
  • Osteonecrosis of the jaw                           
  • Thrombosis       
  • Hemiplegia                      
  • Papilledema    

Please reference the Factor V Leiden Research and Resource Library for more information on each of these topics.

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