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My textbook (Physiology 9th edition, People's Medical Publishing House, Beijing) tells me that coagulation factor V is produced in endothelial cells and platelets, which is different from some other books (saying in liver). So where exactly is it produced? Or is it just not quite clear?
Factor V is indeed mainly produced in liver (Wikipedia), which releases it into blood plasma.
But platelets are also an important source of factor V and "may account for "~25% of the circulating factor V" (ref 1)
Platelet factor V is synthesized in megakaryocytes (ref 1), which of course are the bone marrow cells responsible for the production of platelets.
The following reference gives a much more detailed explanation of factor V
Reference (available as free pdf)
Factor V Is Complexed with Multimerin in Resting Platelet Lysates and Colocalizes with Multimerin in Platelet α-Granules * Catherine P.M. Hayward Emilia Furmaniak-Kazmierczak Anne-Marie Cieutat Michael E. Nesheim John G. Kelton ** Graham Côté
Journal of Biological Chemistry (1995) Vol 270, pp19217-19224
The coagulation factor 5 is primarly produced in the liver, meaning that the liver isn't the only place where this factor can be produced (F5 can possibly be produced by megakaryocytes too). After it is manufactured it circulates in an inactive form and is then converted into the active form with the help of thrombin and is able to attach to platelets. However, as far as I know, factor v is not produced in endothelial cells, there are a few factors that are, like Von Willebrand factor (VWF), factor VIII, thrombomodulin, endothelin etc., but F5 is not one of them.
Platelets are key players in hemostasis, the process by which the body seals a ruptured blood vessel and prevents further loss of blood. Although rupture of larger vessels usually requires medical intervention, hemostasis is quite effective in dealing with small, simple wounds. There are three steps to the process: vascular spasm, the formation of a platelet plug, and coagulation (blood clotting). Failure of any of these steps will result in hemorrhage&mdashexcessive bleeding.
Three novel variants in the coagulation factor V gene associated with deep venous thrombosis in Chilean patients with Amerindian ethnic background
Background: The activated protein C (APC) resistance is the most common prothrombotic defect in thrombosis patients, mainly related with alterations in the F5 gene. In this work, we evaluated the presence of variants in the FV gene in Amerindian patients with deep venous thrombosis and APC resistance.
Methods: A total of 87 patients with deep venous thrombosis (DVT) confirmed by Doppler ultrasonography, and Amerindian genetic background, were included in this study. APC resistance was assayed by clotting methods and polymorphism F51691G>A was genotyped by molecular methods. In Amerindian patients with APC resistance, the promoter region, exon 7 and exon 10 of the F5 gene were screened by PCR-SSCP and DNA sequencing. The prediction of functional effect of novel mutations was analyzed using Polyphen-2 software.
Results: In DVT patients, 14.9% showed functional APC resistance in the absence of F51691G>A polymorphism. Interestingly, three novel missense mutations in exon 10 of F5 gene (M443L, E461Q and G493E) were identified. These genetic variants were absent in 100 healthy subjects. According to in silico analysis, the sequence variants G493E and E461Q are potentially deleterious.
Conclusions: Our data shows that the APC resistance phenotype is not associated with the presence of the F51691G>A variant. We described, for the first time, the presence of three novel variants in F5 gene in Chilean patients with APC resistance. Further studies are required to investigate the real contribution of these novel mutations to the APC resistance phenotype.
Keywords: Coagulation factor V Deep venous thrombosis Risk factors Thrombophilia.
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Most people have never heard of Factor V Leiden - even though it is the most common inherited risk factor for abnormal blood clotting in the United States.
- Factor V Leiden is a genetic disorder that causes you to have an increased risk of developing abnormal venous blood clots.
- It is estimated that between 3% and 8% of the Caucasian (white) U.S. and European populations carry the Factor V Leiden mutation.
- In the United States, about 5% of Caucasians of European decent and 1% to 2 % of African Americans, Hispanic Americans and Native Americans have the mutation.
Unfortunately, many people are not aware they carry the Factor V Leiden gene until they or a family member develops an abnormal venous blood clot.
Although a simple blood test can detect Factor V Leiden, very few people are ever tested for the disorder until AFTER they have a blood clot.
Being unaware that you have the disorder puts you at risk for serious or fatal outcomes.
Conservation of the X-Linkage Group in Toto by All Eutherian Mammals
III Of Glucose-6-Phosphate Dehydrogenases and Mules, Hinnies, and Hares
In 1964, it was already known that the human X-linked traits, hemophilia A and B, caused by deficiency of coagulation factors VIII and IX, are also X-linked in the dog ( Hutt, 1953 ). Hemophilia A has been identified in the Aberdeen terrier and the greyhound, whereas hemophilia B was found among the Cairn terrier. Hutt was apparently intrigued by these and other indications of homologous X-linked traits in divergent mammals, to the extent that his 1953 article was entitled “Homologous X-Linked Mutations in Man and Other Mammals.” For example, the human X-linked trait known as “anhydrotic ectodermal dysplasia” is characterized by developmental absence of sweat glands, as the name implies. A similar trait, apparently X-linked, had already been described in cattle by French authors. Hutt, however, interpreted such homology as an indication that X-linkage confers selective advantage to certain individual genes. In the 1950s, the Darwinian notion of natural selection reigned supreme, for it was yet to be tempered by the realization that protein amino acid sequences change very little with time, and that the maintenance of the status quo is an all consuming concern of every multicellular organism.
At any rate, we decided to see whether X-linkage could be established in mammalian species other than the human for glucose-6-phosphase dehydrogenase (G6PD), the first enzyme of the pentose phosphate shunt. This decision was influenced in no small part by the presence at our institution of Ernest Beutler, who had just demonstrated the cohabitation of two populations of erythrocytes in women heterozygous for G6PD deficiency. Our attempts to detect electrophoretic variants of G6PD, analogous to A+ and B+ of man, in rats, mice, and other common laboratory animals, totally failed. Since it appeared that this enzyme is monomorphic in most mammalian species, we decided to utilize interspecific hybrids for this purpose.
When a jackass is crossed with a mare, a mule results. The reciprocal cross (stallion with jenny) results in a hinny. Since we already knew that G6PD of the horse could be distinguished from that of the donkey by electrophoresis, the proposition was a simple one: If G6PD were X-linked in both parental species, male mules should inherit only the horse-type G6PD from their mothers, whereas we should see only the donkey-type G6PD in male hinnies. The problem was that whereas mules were still bred in California in reasonable abundance, hinnies, which seem to combine the worst characteristics of their parental species, were not. Accordingly, we briefly engaged ourselves in purchasing and breeding of these hybrids. The net result was that the gene encoding G6PD was found to reside indeed on the equine X chromosome ( Trujillo et al., 1965 ). While the above project was being held in abeyance for the want of hinnies, we were informed by Ingmar Gustavsson that the Royal Veterinary College of Sweden, then in Stockholm, had successfully produced reciprocal hybrids between the common European hare (Lepus europaeus) and the northern variegating hare (Lepus timidus). Through use of these reciprocal hybrids, we quickly established the X-linkage of G6PD in the order Lagomorpha as well ( Ohno et al, 1965 ).
The results of our work fill existing gaps in our molecular understanding of fV and fVa. Especially important is the new information on the A2 domain and the spatial organization of the epitopes of binding of fXa, APC, and prothrombin. In addition, the sites of thrombin activation at R709 and R1545 and the sites of APC cleavage at R306 and R506 are fully resolved. Residue R506 associated with fV Leiden15,16,19,21,22,60 is exposed to solvent for proteolytic attack by APC in fVa but not in fV and sits atop the A2 domain (Figure 2C,F), in close proximity to the epitope that recognizes APC. Hence, proteolytic attack at R506 by APC, leading to fVa inactivation, most likely takes place as a rapid “rigid-body” association limited only by diffusion 61 and at a rate significantly faster than in fV, in agreement with biochemical data. 49 The isosteric R506Q substitution does not affect exposure of the side chain but strongly reduces electrostatic coupling with the primary specificity pocket of APC, thereby compromising the kcat/Km for inactivation of fVa. Cleavage at R306 is also required for fVa inactivation by APC. 6,7 This residue is exposed to solvent in fVa, as well, but not in fV, suggesting that activation of fV produces conformational changes that prime R306 and R506 for proteolysis. The structure of fVa suggests independent cleavage at the 2 separate sites, rather than an ordered sequence of cleavage at R506 first, followed by R306, as suggested by recent molecular modeling 29 and mutagenesis studies. 49 The site of thrombin activation at R1545 is visible in the short fragment that connects the highly dynamic B domain to the A3 domain and is exposed to solvent. About 67 Å away from it, residue R709 in the A2 domain is fully exposed to solvent and is positioned in close proximity to the site of APC cleavage at R306. Thrombin attack at these sites is not sterically impeded and should be limited only by diffusion.
The cryo-EM structures also provide context for the functional consequences of posttranslational modifications and mutations in the C1 and C2 domains that reduce binding of fV to phospholipid membranes and perturb its cofactor activity. Perturbation of the spikes is likely the molecular origin of the effects. Residue N2181 is close to W2063 and W2064 and is exposed to solvent (Figure 2A,D). Glycosylation of this residue in the fV1 isoform, accounting for 33% of the circulating fV, 62 may easily cause steric hindrance for binding to phospholipid membranes. Local electrostatic repulsion and reduced binding to phospholipid membranes may explain the functional defect reported recently for fV Besançon (A2086D) 63 affecting the nearby, solvent-exposed A2086 (Figure 2A,D). On the other hand, the mutation W1920R in fV Nara64 affects a residue completely buried under Y1903 and W1904 in the C1 domain (Figure 2A,D) in a hydrophobic cage lined by L1901, P1933, I1935, P2017, and L2026. Introduction of Arg in this hydrophobic cage most likely disrupts the orientation of the spikes above it.
The B domain of fV is surprisingly dynamic, but it provides the connectivity necessary to order the A1-A2-A3-C1-C2 assembly and to reveal its entire architecture for the first time. Removal of the B domain during transition to fVa increases disorder of the A1-A2-A3-C1-C2 assembly, which likely influences the conformation of prothrombinase. This effect makes a cryo-EM structure of the prothrombin-prothrombinase complex of paramount importance in establishing the conformational plasticity of its components and in conclusively assigning the epitopes of interaction between fVa, prothrombin, and fXa. The structures reported herein will facilitate the task.
Structures have been deposited in the Protein Data Bank (accession codes 7KVE for fV 7KXY for fVa). Protein structures have been released to the public, and are also available by e-mail request to the corresponding author ([email protected]).
The online version of this article contains a data supplement.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Coagulation and Blood Consistency
Blood is a fluid that delivers necessary nutrients and oxygen to the body’s cells and from which retains metabolic waste products that are supposed to be eliminated by the specific organs and body’s systems.
It is composed of blood cells suspended in blood plasma which represents the 55% of blood fluids and is mainly constitute by water, in addition to proteins, glucose, minerals ions and carbon monoxide, result product of the respiration during which oxygen reacts with organic compounds to release water and CO2. The blood cells are mainly red blood cells, or RBCs, or erythrocytes, white cells, or WBCs, or leucocytes, and platelets, or thrombocytes.
The erythrocytes contain hemoglobin the iron-binding protein responsible of the transport of oxygen to the cells in all Vertebrates, carbon monoxide is transported instead outside the cells as bicarbonate ion through the plasma.
Coagulation and Hemostasis
The coagulation is the response to a broken blood vessel and the conversion of blood from a liquid form to a semisolid gel to try to stop the bleeding process. The cells responsible for this process are the platelets and other components like the clot factors or coagulation factors.
Blood is a fluid, but its consistency can vary to an almost solid status of a gel. It can be also defined as a suspension of cells inside a liquid that delivers oxygen and vital nutrients to the cells through the circulatory system.
Coagulation is a cascade of events that leads to hemostasis there are two different pathways, intrinsic and extrinsic which originate separate but then converge at specific point leading to fibrin activation. The extrinsic pathway is activated by external trauma that causes blood to escape from the vascular system, this pathway involves Factor VII. The intrinsic pathway is activated instead for internal trauma by platelets, it involves Factors VIII, IX, XI, XII, common pathways include Factors I, II, V, X.
Coagulation factors are essential to normal blood clotting, their absence, or decrease can lead to bleeding disorders while the increasing in number to abnormal clots. The body produce a blood clot to stop the bleeding, after the bleeding stops the body breaks down and removes clots.
The coagulation factors are twelve and are indicated with Romans numbers, they function in a cascade series of events which involves other molecules and cofactors.
The Coagulation Factors
Factor I, or Fibrinogen, common coagulation blood marker, is converted into Fibrin through the action of Thrombin, deficiency of this factor causes Afibrinogenemia and Hypofibrinogenemia which manifest, of course with bleeding problems. Factor II, or Prothrombin, is converted in Thrombin in the common coagulation pathway. Factor III, or Thromboplastin, other typical coagulation factor activates factor X. Factor IV represents Calcium which is required in many stages of coagulation. Factor V is in plasma but not in serum, is involved in both intrinsic and extrinsic pathways of coagulation and causes the cleavage of Prothrombin in the active Thrombin, its deficiency is cause of Parahemophilia. Factor VI is not more included in this cascade of factors.
Factor VII, or Proconvertin is a stable factor in serum and plasma which participates in the extrinsic pathway with the activation of Factor X in cooperation with Factor III, its deficiency is involved with vitamin K deficiency and so with hemorrhagic tendency. Factor VIII, or Antihemophilic Factor is a labile factor involved in the intrinsic pathway which behaves as cofactor in the activation of Factor X, its deficiency is associate to an X-linked recessive trait that results in Hemophilia A, the classic Hemophilia. Factor IX, or Plasma Thromboplastin Component, or Antihemophilic B is a stable factor involved with intrinsic coagulation pathway, activates Factor X, its deficiency is involved with Hemophilia B, or Christmas Disease and is treated with purified preparations of the factor from human plasma ore recombinant, or Factor IX Complex.
Factor X, or Stuart-Prower Factor is a labile factor involved in both pathways, activated combines with calcium and phospholipid to activate Factor V to form Prothrombinase which cleaves and activates Prothrombin to Thrombin. Factor XI, or Plasma Thromboplastin Antecedent (PTA), or Antihemophilic Factor C, is stable and involved in the intrinsic pathway to activate Factor IX, its deficiency results in Hemophilia C. Factor XII, or Hageman Factor, is stable and activated by contact with foreign agents, is involved in the intrinsic pathway to activate Factor XI. Factor XIII, or Fibrin-stabilizing Factor, is a factor that polymerizes Fibrin monomers enabling fibrin to form blood clots, deficiency causes Clinical Hemorrhagic Diathesis.
Causes, Complications and Disease Associated with Abnormal Clotting
Some people get too many clots or their blood clots abnormally. Reasons for blood clotting abnormally, or hypercoagulability are different, like genetic disorders, cancer, atherosclerosis, diabetes, atrial fibrillation, overweight, obesity, dehydration, metabolic syndrome, stroke, some medicines as birth controls pills, or any other type of steroid’s medications, sitting in one position for long time as when driving for long distance or travelling in plane.
Two type of cancers are associate with hypercoagulability, Polycythemia Vera, which is a blood cancer that originate in the bone marrow and that cause the production of too many blood cells, all types, causing blood clotting, and Multiple Myeloma which cause increasing number of white blood cells.
Blood clots can form everywhere in the body, a clot in deep veins is called Deep Vein Thrombosis, or DVTs, symptoms associate are swelling, redness and warmth of the area, leg cramps in calves, if a clot travels through the bloodstream to the lungs it causes Pulmonary Embolism, other complications include, strokes, heart attack and kidney problems, peripheral artery diseases, or PAD, anti-phospholipids syndrome.
Blood clots are also a critical complication of Covid-19, cause of strokes and all other type of consequences that we all know very well now, it looks like based on reports that the most severely ill patients present hypercoagulability and Disseminated Intravascular Coagulation, or (DIC), which is a massive intravascular clot production. Therefore, coagulation tests may be useful to discriminate severe cases of Covid, same as for some of the vaccine’s risks and side effects.
The mechanism of the coagulopathy in regard of the infection from the Coronavirus are not still clear, it is speculated that the dysregulated immune response triggered by the inflammatory cytokines, lymphocytes cells death, hypoxia and endothelial damage are involved.
Factor V Leiden is one of the factors involved in coagulation process, it is a result of a mutation which increases a person risk of blood clots, especially in deep veins, the additional risk is due to its resistance of being deactivated by the protein C that keeps normal Factor V activity under control. Protein C and S deficiency are hereditary deficiency, people with these are at risk of blood clotting.
Prothrombin gene 20210A mutation is another genetic disorder associate, people with this have too much of blood clotting Factor II, or Prothrombin, one of the factors that allows blood to clot properly, with too much of this high risk of blood clots.
Symptoms, Therapies and Natural Remedies
Usually there are not symptoms with blood clots, but occasionally people may experience, blurred vision, headaches, easy bruising, high blood pressure, lack of energy, shortness of brief, menstrual bleeding with clots. Recurrent pregnancy loss are also reasons to be concerned about thick blood.
Therapies for blood clots includes blood thinner, as warfarin or coumadin, or anticoagulants like aspirin, or any other natural remedies with blood thinning properties like fish oil, garlic, ginger, turmeric or curcumin, bromelain and so on, B-vitamins and methylated folates and B-12 vitamins are also useful to lower homocysteine, other cardiovascular associate marker, another supplement suggested is nattokinase, a Japanese product, lemon, pineapple, cinnamon also are elements that support fluidification of blood, and water, of course.
Medications are prescribed only with increased risks, many people with thick blood never experience blood clots and this is the reason why doctors usually only recommend lifestyle changes like, quitting smoke, losing weight, exercise, and avoiding long time in same position.
Blood Consistency or Viscosity
Blood consistency should be not too thin to cause bleeding, but also not too thick to cause clots, this property is defined as viscosity, and represent a measure of a fluid’s resistance to flow it is important to know the type of blood consistency or viscosity to prevent consequences, to address therapies, lifestyle, and supplementation.
Thick blood is caused by heavy proteins load or by too much blood in circulation, too many red and white blood cells, and many platelets or thrombocytosis, and from imbalance of the blood clotting system made of clotting factors and other components.
For heart and circulatory system thinner and more watery blood might be better than a thicker or more viscous blood that can cause more risks for heart attack and stroke.
There are more agreements in regard of the fact that watering down our blood can prevent heart disease, a quote from the Harvard Education School states that, “The more viscous the blood is, the harder the heart must work to move it around the body, and it is more likely to clot inside arterial and veins”.
Viscosity is also associate with high cholesterol and blood pressure, and can be controlled by drinking enough water, more statements in regard of something that looks so obvious and so simple, and the reason why naturopaths keep reminding of drinking enough water, not simply to hydrate but for its multiple function.
How much blood is thin or thick it depends on many factors. The red blood cells have the major influence since they account for half of the volume of total blood. The hematocrit is a measure of the number and size of RBCs, its number in % account for percentage of blood volume occupied by red cells.
Blood fats such as LDL affect viscosity, the more LDL the thicker the blood is, same thing with fibrinogen, soluble protein, coagulation marker that can be transformed into insoluble fibrin, the basis for blood clots. Chronic inflammation also increases the viscosity of blood, so as smoking, high levels of homocysteine, high level of platelets and clotting factors, diabetes, and genetic disorders.
Laboratory’ s studies generally link blood viscosity with cardiovascular markers, and more studies have shown that people with highest viscosity are more prone to develop heart disease and that statins therapy decrease viscosity with long term use, but not all studies convene on this last connection, as we all know there are multiple alternatives today for reducing blood viscosity and the risks related.
To mention an example from conventional medicine point of view a book titled “The blood Thinner Cure” written by a cardiologist, Kenneth R. Kensey talks about “The Sludge Factor” and enlists several steps to thin blood like quitting smoking, eating healthy diet to lower LDL cholesterol, reducing stress, taking low dose aspirin, donating blood, or drawing blood for blood tests, or phlebotomy therapy, drinking 10-12 glasses of water per day.
Thin blood or thrombocytopenia, due to decreased number of platelets is less common than thick blood. Chronic bleeding and excessive bruising may be caused by overly thin blood.
Hemophilia and Von Willebrand’s disease are two medical conditions due to the missing of clotting factors in the first case, and because blood platelets lack a sticky coating, women with Von Willebrand’s disease may have heavy periods. People with thin blood are given blood thickeners before of a surgery to prevent bleeding complications.
Reasons for decreased platelets production are viral infections, bone marrow disorders, leukemia or lymphoma, disorders of spleen, some autoimmune diseases like RA or SLE, chronic liver disorders, or physiologic factors like aging and pregnancy.
Signs are bleeding gums, nose bleeding, blood in stool, heavy menstrual periods with clots, bruising, causes are those mentioned above, or overuse of aspirin and pain killers.
Therapies for bleeding disorders vary based on site of bleeding and are different and specific for each casualty, for bleeding nose for example there are different remedies and the most are of local application and of pressure and tamponing of nostrils, for other type of bleeding steroids as estrogens and progesterone are suggested, or natural remedies like sugars or salts or herbal elements. Medications for bleeding are not easily prescribed for the risks associated, and side effects.
The Genetics of Thrombophilia
Thrombophilia is a medical term used to describe the condition where the blood has an increased tendency to clot. There are many reasons why the blood can have this increased tendency.
Thrombophilia is usually categorized into two types–acquired and inherited. In acquired thrombophilia the abnormal clotting is usually related to a specific cause, such as prolonged periods of bed rest after surgery, trauma to the leg, or having cancer. People with inherited thrombophilia tend to form clots due to a genetic predisposition inherited from their parents. People with inherited thrombophilia may have a family history of relatives with abnormal or excessive blood clotting. This brochure will explain how genes play a role in blood clotting and are related to inherited thrombophilia.
Blood clotting (coagulation)
Blood clotting is the body’s natural defense against bleeding. A clot, or “thrombus”, develops whenever there is damage to a blood vessel (arteries and veins). Clots are formed through a series of chemical reactions between special blood cells (platelets) and proteins in the blood (clotting factors). The platelets and factors work together to regulate the clotting process in other words, they start and stop clotting as the body needs it. If the process does not work correctly, a clot can form in the blood vessels, blocking blood flow to the surrounding tissues. When this happens the clot is called a thrombosis.
Thrombophilia and the clotting process
In order for the clotting process to work, clotting factor proteins need to be present in the right amounts and work correctly. People who have inherited thrombophilia may not make the right amount of a specific clotting factor, or the factor may be abnormal in some way. These people tend to develop a thrombosis more easily or frequently than people who do not have inherited thrombophilia.
Proteins and blood clotting
Proteins are large molecules that give the body structure, help it to function, and regulate the way it works. There are many proteins in the body and each protein has a unique function. The process of blood clotting is an example of proteins working together. Blood cells, platelets and clotting factors are all made up of proteins. If there is a problem with these proteins, this can lead to problems with blood clotting.
Genetics, proteins, and blood clotting
To understand how genetics influences blood clotting, it is important to understand how proteins are made:
Blood clotting proteins, like all proteins, are made by linking together a chain of chemicals called amino acids. The order of the amino acids in the chain make up a specific protein this order is determined by our genes, which are inherited by us from our parents. Genes consist of DNA, which contains our genetic code.
DNA is a molecule shaped like a twisted ladder, and is made up of trillions of chemical bases. These chemical bases are organized in sets of three and “read” by the body much like a sentence. A, T, G, and C are the “letters” of the DNA “alphabet”, or code they stand for the chemicals adenine, thymine, guanine, and cytosine, respectively, that make up the chemical bases of DNA. Each three-letter code represents a specific amino acid. Just as your brain is able to assign meaning to words, your body is able to assign specific amino acids to each three-letter DNA code.
A segment of DNA code looks like this:
The body reads it as:
Based on this, the amino acids are assigned creating a chain of amino acids that makes a protein. Problems arise if there is a spelling error (mutation) in the DNA code. Mutations in the DNA code may result in an incorrect amino acid being assigned.
DNA with a mutation causes a change in the amino acid assigned at a certain position:
If this occurs, the protein that is being made is altered. This alteration could cause the protein to be a different shape or could cause the body to make too much protein, thus the function of the protein will be different.
- Inherited thrombophilia occurs when an inherited DNA mutation results in the body producing
- too much or too little of a blood clotting protein
- a blood clotting protein that does not function correctly
While there are a number of mutations that can cause inherited thrombophilia, the most common DNA mutations are named factor V Leiden and prothrombin G20210A. Understanding how these two mutations occur can be applied to the other mutations that result in inherited thrombophilia.
Factor V (five) Leiden
All individuals make a protein called factor V that helps blood clot. However, there are certain individuals who have a DNA mutation in the gene used to make the factor V protein. These individuals are said to have the “factor V Leiden” mutation. The mutation was named after a city called Leiden, where research on the first family found to have the mutation was performed. Individuals with the factor V Leiden mutation have inherited thrombophilia.
Factor V Leiden and the tendency to develop blood clots
Normally the factor V protein is produced to help the blood clot, and is produced in greater amounts after a blood vessel is damaged.
The amount of factor V protein produced is controlled by other proteins, including protein C and protein S. Protein C and protein S combine to help break up factor V, thus preventing it from being reused and clotting the blood.
When a person has factor V Leiden, the mutation causes the protein to be abnormally shaped. This abnormal shape prevents it from being broken down properly by proteins C and S. Since the factor V protein is not broken down, it is left in the blood for a longer period of time and increases the tendency for clotting.
Testing for factor V Leiden
- Factor V Leiden testing is done by taking a blood sample, and there are two types of tests that can be done to determine whether a person has factor V Leiden.
- In some cases, a sample may be tested to see if the blood is resistant to activated protein C (one of the proteins that helps control factor V).
- If the blood is resistant to activated protein C, there is a 90-95% likelihood that the person has a mutation in the factor V gene.
- A genetic test is usually done to confirm the activated protein C blood test. Sometimes, the genetic test is ordered first, without ever doing the activate protein C testing. In this case, the DNA is isolated from blood cells and the factor V gene is examined to see if there is a mutation in the DNA code. If a mutation is found, then the person has factor V Leiden.
Prevalence of factor V Leiden
It is estimated that about 5% (1 out of 20) of Caucasians (white people) have factor V Leiden, and it is more common in individuals of European ancestry. In the United States, approximately 1-2% (1 in 100 to 1 in 50) of African Americans, Hispanic Americans and Native Americans also have the mutation. Factor V Leiden is rare in Asians.
Prothrombin G20210A mutation
All individuals make the prothrombin (also called factor two) protein that helps blood clot. However, there are certain individuals who have a DNA mutation in the gene used to make prothrombin (also called prothrombin G20210A or the factor II (two) mutation). They are said to have an inherited thrombophilia called prothrombin G20210A. When this occurs, they make too much of the prothrombin protein.
Prothrombin G20210A and the tendency to develop blood clots
- Normally, the prothrombin protein is produced to help the blood clot, and is produced in greater amounts after a blood vessel is damaged.
- People who have a mutation in the prothrombin gene produce more prothrombin protein than is normal. Since there is more of the prothrombin protein in the blood, this increases the tendency for clotting.
Testing for prothrombin G20210A
Prothrombin testing is done by taking a blood sample, and using a genetic test to look at the prothrombin gene.
- The DNA is isolated from blood cells and the prothrombin gene is examined to see if there is a mutation in the DNA code. If a gene change is found (the 20210st letter is changed from a G to an A), then the person has a prothrombin (or factor II) mutation.
Prevalence of prothrombin G20210A
A change in the prothrombin gene is present in 2-4% (or 1 in 50 to 1 in 25) of Caucasians, and is more common in individuals of European ancestry. In the United States, approximately 0.4% (about 1 in 250) of African Americans also have the mutation. Prothrombin G20210A mutation is rare in other groups.
Inheritance of factor V Leiden and prothrombin G20210A
Genetic mutations are passed from generation to generation, because we receive our DNA from our parents. Our genetic information is inherited in pairs. Every gene has two copies one comes from our mother and one from our father. Different conditions can be inherited in different ways thrombophilia is considered a dominant trait. That means a person with inherited thrombophilia only has to have a mutation in one of his/her two gene copies to have the condition. This is also called dominant inheritance.
If a person inherits only one copy of the gene mutation, they are said to be heterozygous (“hetero” means different, “zygous” means bodies). If both copies of a person’s gene have a mutation, they are said to be homozygous (“homo” means same, “zygous” means bodies).
If a person is homozygous (that is, he or she inherits a mutation in both copies of their gene, one from each parent) they are at a greater risk to develop a blood clot than an individual who is heterozygous.
An individual can also have a greater risk to develop a blood clot if they inherit a mutation in more than one of the genes that lead to thrombophilia. For example, a person has a greater risk to develop a blood clot if they have both factor V Leiden and prothrombin G20210A.
Chance to inherit thrombophilia
Every individual inherits two copies of each gene. One copy is inherited from their mother, the other copy from their father. To predict the risk to a child, a few factors must be considered.
The first is whether or not you are heterozygous (only one of your two gene copies contains a mutation) or homozygous (both copies of your two genes contain a mutation). A genetic test can tell you whether you are heterozygous or homozygous.
The first is whether or not you are heterozygous for the gene mutation, there is a 50:50 (or one half) chance that your child will inherit the gene mutation, because there is an equal chance of passing on the gene copy with the mutation OR the gene copy without the mutation. The gene copy your child inherits is due to chance, and there is nothing an individual can do to alter this chance. (See diagram below.)
If you are homozygous for the gene mutation, your child will inherit the mutation. Since you do not have a copy of the gene without a mutation, it is impossible to pass on a gene without a mutation to your child.
Another consideration is whether the child’s other parent carries a gene mutation that leads to thrombophilia. This would also influence your child’s chances of inheriting thrombophilia.
Genetic counselors are medical professionals who can help interpret genetic concepts. If you are interested in learning more about genetic risks, you can consult with a genetic counselor, or a healthcare professional who has specialized training in genetics. To locate a genetic counselor in your area, you may contact the National Society of Genetic Counselors at http://www.nsgc.org.
Genetic testing of family members
There are many issues surrounding the decision to pursue genetic testing. It is important to consider how genetic information will be used in medical management before having any testing done. It is recommended that these issues be discussed with a knowledgeable healthcare provider. You may also wish to see the NBCA brochure entitled “Family Testing for Blood Clotting Disorders” for more information.
The National Blood Clot Alliance (NBCA) and its Medical and Scientific Advisory Board (MASAB) do not endorse or recommend any commercial products, processes, or services. The views and opinions of authors expressed on the NBCA or MASAB websites or in NBCA or MASAB written materials do not necessarily state or reflect those of NBCA or MASAB, and they may not be used for advertising or product endorsement purposes.
It is not the intention of NBCA or MASAB to provide specific medical advice, but rather to provide users with information to better understand their health and their diagnosed disorders. Specific medical advice will not be provided and both NBCA and MASAB urge you to consult with a qualified physician for diagnosis and for answers to your personal questions.
<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More. </a></p> Family & Domains i
Domains and Repeats
|Feature key||Position(s)||Description Actions||Graphical view||Length|
|<p>This subsection of the <a href="http://www.uniprot.org/help/family%5Fand%5Fdomains%5Fsection">Family and Domains</a> section describes the position and type of a domain, which is defined as a specific combination of secondary structures organized into a characteristic three-dimensional structure or fold.<p><a href='/help/domain' target='_top'>More. </a></p> Domain i||30 – 327||F5/8 type A 1 Add BLAST||298|
|Domain i||30 – 193||Plastocyanin-like 1 Add BLAST||164|
|Domain i||203 – 327||Plastocyanin-like 2 Add BLAST||125|
|Domain i||348 – 686||F5/8 type A 2 Add BLAST||339|
|Domain i||348 – 525||Plastocyanin-like 3 Add BLAST||178|
|Domain i||535 – 686||Plastocyanin-like 4 Add BLAST||152|
|<p>This subsection of the 'Family and Domains' section indicates the positions and types of repeated sequence motifs or repeated domains within the protein.<p><a href='/help/repeat' target='_top'>More. </a></p> Repeat i||1124 – 1137||1-1 Add BLAST||14|
|Repeat i||1138 – 1151||1-2 Add BLAST||14|
|Repeat i||1188 – 1196||2-1||9|
|Repeat i||1197 – 1205||2-2||9|
|Repeat i||1206 – 1214||2-3||9|
|Repeat i||1215 – 1223||2-4||9|
|Repeat i||1224 – 1232||2-5||9|
|Repeat i||1233 – 1241||2-6||9|
|Repeat i||1242 – 1250||2-7||9|
|Repeat i||1251 – 1259||2-8||9|
|Repeat i||1260 – 1268||2-9||9|
|Repeat i||1269 – 1277||2-10||9|
|Repeat i||1278 – 1286||2-11||9|
|Repeat i||1287 – 1295||2-12||9|
|Repeat i||1296 – 1304||2-13||9|
|Repeat i||1305 – 1313||2-14||9|
|Repeat i||1314 – 1322||2-15||9|
|Repeat i||1323 – 1331||2-16||9|
|Repeat i||1332 – 1340||2-17||9|
|Repeat i||1341 – 1349||2-18||9|
|Repeat i||1350 – 1358||2-19||9|
|Repeat i||1359 – 1367||2-20||9|
|Repeat i||1368 – 1376||2-21||9|
|Repeat i||1377 – 1385||2-22||9|
|Repeat i||1386 – 1394||2-23||9|
|Repeat i||1395 – 1403||2-24||9|
|Repeat i||1404 – 1412||2-25||9|
|Repeat i||1413 – 1421||2-26||9|
|Repeat i||1422 – 1430||2-27||9|
|Repeat i||1431 – 1439||2-28||9|
|Repeat i||1440 – 1444||2-29 truncated||5|
|Repeat i||1445 – 1453||2-30||9|
|Domain i||1569 – 1890||F5/8 type A 3 Add BLAST||322|
|Domain i||1569 – 1738||Plastocyanin-like 5 Add BLAST||170|
|Domain i||1748 – 1890||Plastocyanin-like 6 Add BLAST||143|
|Domain i||1894 – 2048||F5/8 type C 1 PROSITE-ProRule annotation|
<p>Manual validated information which has been generated by the UniProtKB automatic annotation system.</p> <p><a href="/manual/evidences#ECO:0000255">More. </a></p> Manual assertion according to rules i
Manual assertion according to rules i
|Feature key||Position(s)||Description Actions||Graphical view||Length|
|<p>This subsection of the 'Family and Domains' section describes a region of interest that cannot be described in other subsections.<p><a href='/help/region' target='_top'>More. </a></p> Region i||696 – 1564||B Add BLAST||869|
|Region i||814 – 844||Disordered Sequence analysis|
<p>Information which has been generated by the UniProtKB automatic annotation system, without manual validation.</p> <p><a href="/manual/evidences#ECO:0000256">More. </a></p> Automatic assertion according to sequence analysis i