Alex Alikiotis
Activated protein C resistance (APCR) is a hypercoagulability that results in an increased risk of venous thrombosis. The most common cause of APC resistance is the factor V Leiden mutation, which is found in about 5% of the population. This mutation impairs the degradation of FVIIIa and FVa, yielding a hypercoagulable state. APC resistance can be hereditary, with an autosomal dominant inheritance pattern, or acquired. The condition was first discovered by Dahlback in 1993 and has since revolutionized our understanding and management of thrombotic problems.
What You'll Learn
Factor V Leiden mutation
Activated protein C resistance (APCR) is a hypercoagulability characterised by a lack of response to activated protein C (APC). APC is a natural anticoagulant that prevents blood from clotting excessively. APCR results in an increased risk of venous thrombosis, which can lead to medical conditions such as deep vein thrombosis and pulmonary embolism.
The most common cause of hereditary APCR is the Factor V Leiden mutation, which is a single point mutation in the factor V gene. This mutation affects the function of the protein C system. APC inhibits coagulation by cleaving a limited number of peptide bonds in both intact and activated forms of factor V and factor VIII. However, the Factor V Leiden mutation results in the elimination of the cleavage site in factor V and factor Va. This means that APC cannot bind and inactivate factor V, leading to an increased risk of thrombosis.
Factor V Leiden thrombophilia is an inherited disorder of blood clotting. People with this condition have a higher-than-average risk of developing deep venous thrombosis (DVT), which can occur in the legs or other parts of the body, including the brain, eyes, liver, and kidneys. The chance of developing an abnormal blood clot depends on whether a person has one or two copies of the mutation. Those with two copies have a higher risk. It is estimated that only about 10% of individuals with the Factor V Leiden mutation will develop abnormal clots.
The Factor V Leiden mutation is also associated with a slightly increased risk of pregnancy loss (miscarriage). Women with this mutation are two to three times more likely to have multiple miscarriages or a pregnancy loss during the second or third trimester. However, most women with Factor V Leiden thrombophilia have normal pregnancies. The mutation is found in about 3 to 8% of people with European ancestry, and about 1 in 5,000 people have two copies of the mutation.
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Hypercoagulability
Activated protein C (APC) is a natural anticoagulant that inhibits blood clotting by inactivating active factor V and factor VIII. APC resistance is characterised by a lack of response to APC, resulting in an increased tendency of the blood to clot or hypercoagulability. This condition is associated with an increased risk of venous thrombosis, which can lead to serious medical conditions such as deep vein thrombosis and pulmonary embolism.
The most common cause of APC resistance is the factor V Leiden mutation, a single point mutation in the factor V gene. This mutation prevents protein C from inactivating active factor V, leading to a hypercoagulable state. The disorder can be acquired or inherited, with the hereditary form following an autosomal dominant inheritance pattern.
In heterozygous adult carriers of the factor V Leiden mutation, the relative risk for thromboembolism (TE) is increased sevenfold. This risk increases to 80-fold in homozygous individuals. Additionally, the usual decrease in Protein S levels observed during normal pregnancies can further enhance the prothrombotic effects of the mutation in heterozygous women, increasing their risk of VTE up to 50-fold.
The risk of developing APC resistance is also influenced by other factors such as oral contraceptive use and underlying medical conditions. For example, individuals with severe thrombophilia and inherited defects in proteins S, C, or antithrombin often exhibit APC resistance as a contributing genetic risk factor.
Diagnosis of APC resistance can be performed using APC resistance tests, including the activated partial thromboplastin (aPTT)-based test and the endogenous thrombin potential (ETP)-based test. These tests help evaluate the presence of APC resistance and guide treatment decisions.
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Thrombin generation
Thrombin is a coagulation factor that plays a key role in the process of blood clotting. Normally, activated protein C (APC) helps prevent blood from clotting excessively by inhibiting the conversion of prothrombin to thrombin. However, in individuals with APC resistance, the body's ability to regulate thrombin generation is impaired, leading to an increased risk of blood clots.
APC resistance is characterized by a lack of response to APC, which can be caused by mutations in the factor V gene, specifically the factor V Leiden mutation. This mutation affects the function of the protein C system, a natural anticoagulant pathway. As a result, thrombin generation is no longer adequately inhibited, leading to a hypercoagulable state.
In individuals with APC resistance, the endogenous thrombin potential is higher in the presence of APC compared to normal controls. This indicates an increased ability to generate thrombin, which contributes to the formation of blood clots. The thrombin generation assay is a useful tool for evaluating the hypercoagulable state and the occurrence of APC resistance.
Several factors can influence thrombin generation in individuals with APC resistance. For example, in patients with essential thrombocythemia and polycythemia vera, the JAK2V617F mutation is associated with an increased thrombotic risk and can lead to a more pronounced APC-resistant phenotype. Additionally, protein S levels can modulate the APC resistance phenotype induced by elevated prothrombin levels, further impacting thrombin generation.
Understanding the mechanisms underlying thrombin generation in APC resistance is crucial for developing effective treatments and preventing thrombotic events in affected individuals. While some individuals with asymptomatic APC resistance may not require treatment, those with additional risk factors or homozygous factor V Leiden may need lifelong oral anticoagulation therapy to manage their increased risk of thrombosis.
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APC-resistance test
Activated protein C (APC) resistance is a hypercoagulability that can result in an increased risk of venous thrombosis. APC resistance can be evaluated using an APC-resistance test.
Types of APC-Resistance Tests
There are two types of APC-resistance tests: the activated partial thromboplastin (aPTT)-based test and the endogenous thrombin potential (ETP)-based test.
Who Should be Considered for APC-Resistance Testing?
Asymptomatic individuals with APC resistance are generally not treated unless additional risk factors for thrombosis are also present. However, people with homozygous factor V Leiden and people with heterozygous factor V Leiden who have an additional thrombophilic condition should be considered for lifelong oral anticoagulation therapy.
APC, in a complex with protein S, inactivates procoagulant factors Va and VIIIa by proteolytic cleavage at specific arginine residues. This serves to control coagulation and limit the extent of thrombus formation.
The functionality of the APC inhibitory system in a given individual can be assessed through an in vitro clotting assay. APC is added to a patient's plasma, which extends the aPTT for individuals who are sensitive to APC. Individuals are considered APC resistant when the addition of APC fails to extend the time to clot formation in this assay. Ratios less than 2.00 suggest APC resistance.
In 95% of cases, APC resistance is caused by a mutation in the FV gene, the FV Leiden mutation. This mutation affects the function of the protein C system, a natural anticoagulant pathway. The FV mutation is common in Caucasians, with 3-7% of persons of Northern European descent presenting as heterozygous for this mutation. Other, rarer polymorphisms can also cause APC resistance.
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Hereditary APC resistance
Activated protein C resistance (APCR) is a hypercoagulability characterised by a lack of response to activated protein C (APC). This results in an increased risk of venous thrombosis, which can lead to medical conditions such as deep vein thrombosis and pulmonary embolism. APC resistance is caused by mutations in the factor V gene, namely the factor V Leiden mutation, which is the most common hereditary form of APC resistance.
The factor V Leiden mutation is a single point mutation in the factor V gene that predicts the replacement of Arg506 with a Gln (FVR506Q, FV: Q506 or FV Leiden). This mutation affects the function of the protein C system, a physiologically important natural anticoagulant pathway. APC inhibits coagulation by cleaving a limited number of peptide bonds in both intact and activated forms of factor V (FV/FVa) and factor VIII (FVIII/FVIIIa). The FVR506Q mutation not only confers partial resistance of FVa to APC but also impairs the degradation of FVIIIa because APC-mediated cleavage of FV at Arg506 is required for the expression of the anticoagulant activity of FV.
The impaired degradation of both FVIIIa and FVa yields a hypercoagulable state, conferring a lifelong increased risk of thrombosis. The FV mutation is common in Caucasians, found in about 5% of the population, and is rarely found among other groups worldwide. The carrier frequency for the factor V Leiden mutation varies depending on the population. Approximately 5% of asymptomatic white Americans of non-Hispanic ancestry are heterozygous carriers, while the carrier frequency among African Americans, Asian Americans, and Native Americans is less than 1%. The hereditary form of APC resistance has an autosomal dominant inheritance pattern.
People with homozygous factor V Leiden and people with heterozygous factor V Leiden who have an additional thrombophilic condition should be considered for lifelong oral anticoagulation therapy. APC resistance can be evaluated using an APC resistance test, which includes the activated partial thromboplastin (aPTT)-based test and the endogenous thrombin potential (ETP)-based test.
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Frequently asked questions
Activated protein C resistance (APCR) is a hemostatic disorder characterised by a poor anticoagulant response to activated protein C (APC). This results in an increased risk of venous thrombosis, including deep vein thrombosis and pulmonary embolism.
In most cases, activated protein C resistance is caused by a mutation in the factor V gene, known as the factor V Leiden mutation. This mutation affects the function of the protein C system, a natural anticoagulant pathway.
APC resistance is a hereditary condition with an autosomal dominant inheritance pattern. The carrier frequency is highest among whites of Northern European or Scandinavian ancestry, at up to 14%.
APC resistance can be evaluated using an APC resistance test. There are two types: the activated partial thromboplastin (aPTT)-based test and the endogenous thrombin potential (ETP)-based test. If the APC resistance test is abnormal, DNA-based testing for the factor V Leiden mutation can be performed to confirm or exclude hereditary APC resistance.
