Activated protein C resistance (APCR) is a

hypercoagulability Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who ...

(an increased tendency of the blood to clot) characterized by a lack of a response to activated

protein C Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaini ...

(APC), which normally helps prevent blood from clotting excessively. This results in an increased risk of

venous thrombosis Venous thrombosis is the blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lu ...

(blood clots in veins), which resulting in medical conditions such as

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...

(usually in the leg) and

pulmonary embolism Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain ...

(in the lung, which can cause death). The most common cause of hereditary APC resistance is

factor V Leiden Factor V Leiden (rs6025 or ''F5'' p.R506Q) is a variant (mutated form) of human factor V (one of several substances that helps blood clot), which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoa ...

mutation.

Presentation

Associated conditions

An estimated 64 percent of patients with

venous thromboembolism Venous thrombosis is the blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off ( embolizes) and flows to the lun ...

may have APC resistance.

Genetics

The disorder can be acquired or inherited, the hereditary form having an

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...

dominant inheritance pattern.

Pathophysiology

APC (with protein S as a cofactor) degrades

Factor V Coagulation factor V (Factor V), also less commonly known as proaccelerin or labile factor, is a protein involved in coagulation, encoded, in humans, by ''F5'' gene. In contrast to most other coagulation factors, it is not enzymatically active b ...

a and

Factor VIII Coagulation factor VIII (Factor VIII, FVIII, also known as anti-hemophilic factor (AHF)) is an essential blood clotting protein. In humans, it is encoded by ''F8'' gene. Defects in this gene result in hemophilia A, an X-linked bleeding disorder ...

a. APC resistance is the inability of protein C to cleave

a and/or

a, which allows for longer duration of thrombin generation and may lead to a hypercoagulable state. This may be hereditary or acquired. The best known and most common hereditary form is

Factor V Leiden Factor V Leiden (rs6025 or ''F5'' p.R506Q) is a variant (mutated form) of human factor V (one of several substances that helps blood clot), which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoa ...

, which is responsible for more than 95% of cases. Other genetic causes include Factor V Cambridge (VThr306) and the factor V HR2 haplotype (A4070G mutation). Acquired forms of APC resistance occur in the presence of elevated Factor VIII concentrations.

Antiphospholipid antibodies Antiphospholipid syndrome, or antiphospholipid antibody syndrome (APS or APLS), is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-relate ...

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

, and certain forms of

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

therapy, such as

ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. Ethinylestradiol was widely used for various indications such as the treatment of menopausal symptoms, gynecological ...

-containing

birth control pill The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. It is the oral form of combined hormonal contra ...

s, have been found to produce acquired APC resistance.

Diagnosis

APC resistance can be evaluated using an APC resistance test. There are two types of APC resistance tests with different properties: the activated partial thromboplastin (aPTT)-based test and the endogenous thrombin potential (ETP)-based test.

Treatment

Asymptomatic individuals with APC resistance (e.g.,

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

) are not normally treated unless additional

risk factor In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...

s for

thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...

are also present. An example is

surgery Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery s ...

, in which perioperative short-term

anticoagulation An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which h ...

may be used. However, people with

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

factor V Leiden, and people with heterozygous factor V Leiden who have an additional thrombophilic condition (e.g.,

antithrombin deficiency Antithrombin III deficiency (abbreviated ATIII deficiency) is a deficiency of antithrombin III. This deficiency may be inherited or acquired. It is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venou ...

, protein C deficiency, or

protein S deficiency Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activate protein C in the degradation of factor Va and factor V ...

), should be considered for lifelong

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

anticoagulation therapy. People with APC resistance and initial DVT are treated with a standard anticoagulant regimen, for instance

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

heparin Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Heparin is a blood anticoagulant that increases the activity of antithrombin. It is used in the treatment of myocardial infarction, ...

therapy followed by oral anticoagulation.

References

External links

{{Diseases of megakaryocytes, us=y Coagulopathies Defects of enzyme cofactors