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Inherited Causes of Blood Clots

Inherited Causes of Blood Clots
References

Inherited Causes of Blood Clots

Inherited causes of blood clots are related to a genetic (inherited) tendency for clot formation that generally occur at a young age (for example, occurring before 40 or 45 years), with or without an apparent cause, and with a tendency to recur.

Low levels of natural anticoagulants such as antithrombin, protein C, and protein S account for less than 15% of selected cases of juvenile and/or recurrent clots, and less than 10% of unselected cases. Resistance to the anticoagulant action of activated protein C (APC) has now been shown to be the most common cause of an inherited clotting disorder , accounting for 20% to 50% of cases. Mild hyperhomocysteinemia, which is inherited, has been found in 19% of cases of venous clotting in children.

An alteration in the prothrombin gene (P20210) that results in an increased expression of prothrombin has been linked to an increased risk of clotting. 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.

Table 1 provides a list of inherited causes of blood clots. Click on the individual condition to learn more about specific causes.

Table 1. Inherited Causes of Blood Clots
Increased levels of natural procoagulants	Decreased levels of natural anticoagulants	Abnormal Fibrinolysis	Other Inherited Causes
Factor V Leiden mutation or activated protein C resistance^*	Antithrombin	Plasminogen Deficiency	Paroxysmal nocturnal hemoglobinuria
Prothrombin 20210 mutation	Protein C	Decreased Levels of Tissue Plasminogen Activator (t-PA)
Hyperhomocysteinemi	Protein S	Increased levels of plasminogen activator inhibitor (PAI-1)
FVIII, FIX, FXI, FVII, VWF	Thrombomodulin	Elevated Thrombin-Activatable Fibrinolysis Inhibitor (TAFI)
	Heparin Cofactor II
	Tissue Factor Pathway Inhibitor (TFPI)
*The Factor V Leiden mutation does not result in increased FV levels but a resistance to the anticoagulant action of activated protein C.

Increased Levels of Natural Procoagulants

Factor V Leiden (Activated Protein C Resistance)

What Is Factor V Leiden Mutation?
The factor V Leiden mutation or alteration (FVL) was identified in 1993 and has since been found to be a leading cause of blood clots among white populations. In fact, the FVL alteration is the most common genetic risk factor for blood clots. This mutation produces an altered coagulation factor V (FV) protein, commonly known as “Leiden” protein. In normal blood clotting, activated protein C, a natural anticoagulant, controls the clotting activity of FV. In people with the altered “Leiden” protein, the FV is resistant to regulation by activated protein C (APC). As a result, clotting is uncontrolled.

Population Frequency of Factor V Leiden (FVL)
The population frequency of the FVL gene alteration is high. Heterozygous FVL mutation (having two or more different versions of a gene) is found in 5% to 10% of white individuals and in up to 30% of patients with a clotting disorder. Thus FVL gene alteration is by far the most common inherited risk factor for a clotting disorder. FVL is very uncommon in African Americans, Hispanics and Asians.

Why Do Patients With Factor V Leiden Mutation Develop a Clotting Disorder?
Factor V is an important coagulation protein that is made in the liver. Normal or wild type FV has a dual role in coagulation. When it is activated, FV acts as a procoagulant (promotes clotting), whereas when it is inactivated by activated protein C (APC), it acts as an anticoagulant (prevents clotting).

As a procoagulant, activated FV (FVa) works with activated factor Xa (FXa) to generate thrombin. Thrombin generation is the key step in coagulation to form a fibrin clot, the end result of coagulation.

The anticoagulant function of FV is related to its role as a cofactor in the APC/protein S complex. This complex breaks down activated FVIII (FVIIIa), which is a coagulation protein that plays an essential role in clot formation.

Normally FV circulates in the blood in an inactive form. APC directly cuts FVa to create the anticoagulant form of FV. In patients with the FVL mutation, however, the FVa is altered and therefore cannot be cut by APC. As a result, FV cannot work as a cofactor for the APC/protein S complex in the breakdown of FVIIIa. This phenomenon is known as “APC resistance” and results in unchecked generation of FVIIIa. This, in turn, leads to uncontrolled thrombin generation and excessive clotting.

Risk of Clotting Disorder Associated With FVL Mutation

Risk of a Clotting Disorder in FVL homozygotes: FVL homozygotes (people with two identical genes at the same position on two chromosomes) have only the Leiden protein and an 80-fold increased risk of a clotting disorder compared to the general unaffected population.
Risk of a Clotting Disorder in FVL heterozygotes: FVL heterozygotes (people with two dissimilar gene forms) are believed to produce about 50% of Leiden protein and have a 5- to 7-fold increased risk of a clotting disorder compared to the general population. Remember that Factor V Leiden by itself does not cause blood clotting in individuals who are FVL heterozygotes; usually a triggering event is required.

Most blood clots in a heterozygous individual occur in association with another cause or “trigger.” In heterozygous women, the most common triggers are pregnancy, the use of birth control pills, and hormone replacement therapy after menopause. This is because the balance of coagulation is tipped towards clotting during pregnancy. Hormonal replacement and birth control pills mimic this condition. In one study from Europe, 60% of women who experienced clots during pregnancy were found to have the FVL mutation. The risk of blood clots is actually highest 6 to 8 weeks after the birth of a baby. In heterozygous men with FVL, blood clots may occur after surgery or an injury, especially injuries to the leg. Not everyone with heterozygous FVL develops a blood clot. For some people with heterozygous FVL, there is no history of abnormal blood clotting in their parents, even if one of their parents has this gene.

Other Mutations within Factor V gene
Besides the FVL mutation, several other alterations in the FV gene also contribute to APC resistance. People with the Factor V Cambridge mutation¹ and the Factor V Hong Kong mutation² have mild APC resistance. Recently a complex set of closely linked genetic markers of the FV gene (FV HR2) have been found to contribute to APC resistance, although to a lesser degree than FVL³.

Acquired causes of APC resistance
Acquired causes of APC resistance include states associated with increased clotting, such as pregnancy, use of estrogen therapy, antiphospholipid antibody syndrome, and conditions with inflammation, such as sepsis syndrome or disseminated intravascular coagulation (DIC).

Prothrombin 20210 Mutation

A specific alteration of the prothrombin gene, which has been found to be present in 18% of people with a clotting disorder, increases the risk of blood clots almost threefold. This gene alteration or mutation, called the prothrombin 20210 mutation, is associated with higher levels of prothrombin and therefore increases an individual’s risk for blood clots. This mutation is also linked to other clotting events such as coronary artery disease (especially 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

Hyperhomocysteinemia, or increased levels of the amino acid homocysteine, is estimated to affect 5% of the general population. Among persons with symptoms of coronary artery disease, the prevalence of hyperhomocysteinemia is estimated to be 13% to 47%.⁴ Mild to moderate hyperhomocysteinemia is an independent risk factor for stroke, heart attack, peripheral arterial disease, and narrowing of the extracranial carotid artery. High levels of homocysteine are associated with enzyme defects or shortages 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 venous clots. The condition also has been shown to have a high frequency (10%) in patients with first episodes of venous blood clots. Several inherited or acquired conditions may lead to an increase in homocysteine levels.

Inherited causes of hyperhomocysteinemia include low levels of an enzyme necessary for the conversion of homocysteine to cysteine, which increase the risk of a clotting event.⁵ Studies in families with low levels of the enzyme suggest that this disorder may be inherited.

Acquired causes of hyperhomocysteinemia include advanced age, tobacco use, coffee intake, low levels of folate in the diet, and low intake of vitamin B. Higher homocysteine levels are also associated with diabetes mellitus, cancers, low level of thyroid function, lupus, inflammatory bowel disease, and certain medications such as cholesterol-lowering agents, metformin, methotrexate, anticonvulsants, theophylline, and levodopa.⁵

Elevated Levels of Clotting Factors

High levels of other procoagulants such as factors VIII, IX, XI, VII, fibrinogen, and Von Willebrand factor (VWF) are associated with an increased risk of clotting. Specifically, persistently high levels of FVIII have been shown to be associated with recurrence of a clotting disorder.⁶ Currently there are no specific recommendations to include analysis of these clotting factor levels in an evaluation for a clotting disorder.

Elevated Factor VIII
Coagulation factor VIII (FVIII) activity levels may vary widely due to various reasons, such as pregnancy, use of hormonal therapy, stress, exercise, or presence of an inflammatory state. It is often difficult to know whether a high FVIII level is caused by an acute event or leads to it. A high level of FVIII is a known independent risk factor for blood clotting.^6-8 High levels of FVIII are an even stronger risk factor for recurrent blood clots. The likelihood of recurrence of a clotting event at 2 years was found to be 37% in people with a high FVIII level versus 5% among persons with a lower FVIII level.⁹

Elevated Factor IX Levels
High levels of coagulation factor IX (FIX) may play a role in clotting disorders. The Leiden Thrombophilia Study found that levels of FIX in the 90^th percentile and higher increased the risk of blood clots by 2- to 3-fold.¹⁰

Elevated Factor XI Levels
Coagulation factor XI (FXI) has procoagulant and antifibrinolytic roles in blood clotting. FXI contributes to the formation of fibrin. It also protects the fibrin that has formed from being broken down. People with high FXI levels have an age- and sex-adjusted increased risk of a blood clot in a deep vein, such as a vein in the leg. This type of blood clot is called a deep vein thrombosis (DVT). The higher the FXI level, the greater the risk of a blood clot.¹¹ Increased levels of FXI also have been associated with an increased risk of heart disease in women.¹²

Elevated Factor VII Levels
Some studies have shown an increased risk of heart disease with high levels of coagulation factor VII (FVII). FVII levels, however, are not an independent risk factor after controlling for cholesterol, LDL-cholesterol, and triglycerides.¹³ Elevated FVIIa levels have been reported in people with blockage of a retinal vein.¹⁴

Elevated Von Willebrand Factor Levels
Von Willebrand factor (VWF) is produced in cells that line the blood vessels (the endothelium). Damage to or swelling of the endothelial lining lead to increased VWF levels. FVIII circulates with VWF 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 VWF would also be associated with and contribute to an increased risk of clots. Additionally, VWF plays an important role in platelet adhesion to areas of damaged endothelium. Elevated VWF levels may have more than one mechanism through which they contribute to clots.

Decreased Levels of Natural Anticoagulants

Antithrombin(AT)

Antithrombin is a naturally occurring anticoagulant that inactivates thrombin and clotting factors IXa, Xa, XIa, and XIIa. Heparin increases this inactivating effect of antithrombin. Changes in the antithrombin gene may cause deficiencies or abnormal activity of antithrombin. Antithrombin deficiency is an inherited condition.

Patients with a deficiency of AT are at risk for clotting in both arteries (arterial) and veins (venous). The frequency of people with symptoms of AT deficiency is estimated to be 1 in 2,000 to 1 in 5,000 people. AT deficiency without symptoms may occur as frequently as 1 in 600 people. In patients with a history of a clotting disorder, the incidence of AT deficiency ranges from 0.5% to 4.9%. People with AT deficiency who have defects in the heparin-binding site have a severe clotting tendency that presents early in life and often involves a clotting disorder in the arteries.

Types of AT deficiency

There are two types of AT deficiency: Type I and II. In people with Type I AT deficiency, a genetic alteration leads to low levels of the AT protein. People with Type II AT deficiency have an abnormally functioning protein because of a genetic alteration in the gene that codes for AT. The genetic alteration can affect how AT binds to heparin or how AT neutralizes the effect of thrombin in the absence of heparin.

AT Levels
The levels of AT reach normal adult range by around age 6 months and depend on the patient’s age and other associated conditions. Several conditions can reduce AT levels. These conditions include liver abnormalities, consumptive coagulopathy, complications during pregnancy or labor and delivery, kidney disease, cancer, malnutrition, gastrointestinal abnormalities, use of oral contraceptives, and other medications. Use of medicines like Coumadin® may lead to increases in AT levels. In some people with an altered AT gene, the levels of AT range between 40% and 70% of normal.

Protein C

Protein C, a vitamin K dependent protein, is made in the liver and contributes to the inactivation of FVIII. Protein C deficiency is an inherited condition. Protein C is slowly activated by thrombin to activated protein C (APC). The activation is increased 20,000 fold when protein C forms a complex with thrombin that is bound to a receptor in the blood vessel lining. This receptor is called thrombomodulin. APC helps regulate the coagulation pathway by inactivating FVa and FVIIIa that are bound to membranes. Aside from its role in coagulation, APC also has anti-inflammatory and cell-protective functions.

The frequency of protein C deficiency ranges from 1.4% to 8.6%. In a study of healthy subjects, 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.

Types of Protein C deficiency

Protein C deficiency is divided into Type I or Type II deficiency. People with Type I deficiency have low levels of protein C and proportionally low levels of protein C activity. In people with Type II deficiency, the activity of protein C is low because the genetic alteration produces an abnormally functioning protein.

Homozygous protein C deficiency usually appears in newborn infants as a rare and potentially catastrophic skin condition called purpura fulminans. Patients with purpura fulminans have sudden massive areas of bleeding in the skin that can become severely infected. Purpura fulminans is associated with severe illness if not death unless promptly identified and treated. The symptoms are caused by the formation of blood clots in capillaries and small blood vessels, which lead to tissue death as a result of lack of blood flow in the affected skin. 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 severe tendency to clot at an early age. These patients need lifelong anticoagulation to prevent recurrent blood clots.

Warfarin-Induced Skin Necrosis (WISN)
People with protein C deficiency can experience a potentially catastrophic complication of warfarin therapy, commonly known as warfarin induced skin necrosis (WISN). When warfarin therapy is started, it can lead to a rapid drop in levels of protein C and coagulation factor FVII. The levels of other clotting factors remain relatively high. This upsets the normal balance between bleeding and clotting states, resulting in a temporary super-clotting state, particularly in the small blood vessels of the extremities. This imbalance between procoagulants (promote clotting) and anticoagulants (prevent clotting) is further exaggerated in protein C deficiency. This effect may be more pronounced when large loading doses of warfarin are used. WISN typically occurs during the first few days of warfarin therapy. The skin damage of WISN is distributed on the extremities, torso, breasts, and penis. The symptoms begin as redness of the skin. If appropriate therapy is not started promptly the redness progresses to become purplish blotches on the skin (purpura). The skin tissue can eventually die as a result of blood clots that interrupt the blood flow in skin tissue. To avoid this catastrophic complication, people with protein C deficiency are treated simultaneously with other blood thinners such as heparins until the appropriate level of blood thinning is achieved through warfarin. Infusion of protein C concentrate or fresh frozen plasma may be used to increase protein C levels.

Protein C Levels
Protein C levels depend on the patient’s age and other conditions, with adult levels being reached at late adolescence. Many medical conditions may reduce protein C levels. These conditions include liver disease, disseminated intravascular coagulation (DIC), clotting disorders, respiratory distress syndrome (RDS) in newborns, preeclampsia, acquired purpura fulminans, systemic lupus erythematosus, ulcerative colitis, oral contraceptives, and oral blood thinners.

Protein S

Protein S, a vitamin K-dependent protein, is made by the liver and acts as the principal cofactor to protein C. Protein S exists as two forms in the blood circulation: a free form and a bound form. Approximately 60% to 65% of total protein S in the circulation exists in the bound form and ˜35% to 40% in the free form. Free protein S is the form involved in the activated protein C (APC) blood thinning activity.

There are no data on the frequency of protein S deficiency in the general population, but the frequency is believed to be roughly the same as for protein C deficiency (1.4% to 7.5%).

Types of Protein S deficiency

There are three subtypes of protein S deficiency.

Type I deficiency: The decrease in the activity of protein S is proportional to the decrease in the level of protein S.
Type II deficiency: 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 deficiency: There is a normal level of total protein S, but the level of free protein S is abnormally low.

Protein S deficiency is rare in the healthy population, with an estimated frequency of approximately 1 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 1 in 160,000 to 1 in 360,000. Infants and babies within the first year of life who have homozygous protein S deficiency characteristically have purpura fulminans.

Protein S Levels
Adult levels of protein S levels are reached when a child is approximately 6 months to 1 year old. Compared to men, women tend to have on average a lower level of free protein S, especially when pregnant or taking oral contraceptives. Newborn infants also have lower free and total protein S levels. Many medical conditions may be associated with abnormal protein S levels including liver disease, DIC, a clotting disorder, herpes infections, systemic lupus erythematosus, ulcerative colitis, and use of oral contraceptives and oral blood thinners. Levels in heterozygotes are approximately 40% to70% of the normal level.

Thrombomodulin

Thrombomodulin is a transmembrane protein found on the surface of cells lining the blood vessels (endothelium). It acts as a receptor for thrombin and plays an important role in coagulation and clot breakdown (fibrinolysis). Thrombomodulin-bound thrombin starts the protein C anticoagulant pathway by activating protein C. Defects in thrombomodulin result in increased coagulation. Thrombomodulin also activates thrombin-activated fibrinolysis inhibitor (TAFI), which affects clot breakdown. Small thrombomodulin fragments circulate in soluble form in plasma of healthy individuals. These soluble fragments retain their functional activity and can be measured in plasma. Increased levels are seen in patients with venous and arterial clotting conditions, including clots in the brain and eyes, and DIC. The clinical relevance of soluble thrombomodulin levels in treating clotting disorders is not fully known.

Heparin Cofactor II

Heparin cofactor II is found in plasma and rapidly inhibits thrombin in the presence of dermatan sulfate or heparin.

Heparin cofactor II deficiency is classified into:

Type I (quantitative): There is a decrease in both cofactor level and its functioning
Type II (qualitative): There is 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 find out 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. Most of TFPI (60% – 80%) is bound to the lining of the blood vessels (endothelium), with only 20% free in the blood. Recent evidence suggests that low levels of TFPI are a risk factor for clotting disorders.¹⁵ Interestingly, different forms of the TFPI gene have been found that result in higher levels of TFPI in the circulation. One report suggested that these higher levels “correct the balance” in patients with Factor V Leiden, and normalize their risk for a clotting event.¹⁶

Abnormalities of Fibrinolysis

Plasminogen Deficiency

Plasminogen is synthesized in the liver and is present in most tissues. Plasminogen is converted to the enzyme plasmin by plasminogen activators such as tissue-plasminogen activator (tPA) and urokinase-plasminogen activator(uPA). The main action of plasmin is to break down fibrin. Defective clot breakdown (fibrinolysis) has been associated with clotting diseases.

Types of Plasminogen Deficiency

There are two types of plasminogen deficiency. In people with Type I deficiency, there is a proportionate decrease in both the level of plasminogen and its activity. In Type II deficiency (also called dysplasminogenemia), there is a decrease in the functional activity of the protein, although the plasminogen levels are normal.

Plasminogen levels do not reach the healthy adult range until late adolescence. Higher levels of plasminogen are found in women in the last trimester of pregnancy; newborns have levels approximately one-half of levels in healthy adults.

The most common clinical symptom of plasminogen deficiency is ligneous (‘wood-like’) conjunctivitis (inflammation of conjunctiva in the eye). The conjunctiva becomes irritated because of a build-up of white, yellow-white, or red thick masses with a wood-like consistency that may replace normal tissue. The build-up (also called lesions) occurs mostly on the eyelids and may be triggered by injury or infection. The build-up often recurs after it has been removed. The wood-like lesions have been reported to occur in other mucous membranes, such as the mouth, nasopharynx, windpipe, and female genital tract. Some affected children may experience congenital occlusive hydrocephalus (increased fluid around the brain). Removal of the lesions does not cure the condition and may promote recurrence. The lesions are responsive to systemic plasminogen replacement or to local therapy in the eyes. The incidence of plasminogen deficiency is not well known and may be underestimated because ophthalmologists, dentists, obstetricians, gynecologists, and ENT physicians may see these patients and not refer them or not recognize the symptoms to be related to plasminogen deficiency.

Plasminogen deficiency that runs in families appears to be an uncommon but recognized cause of an inherited clotting disease. The clotting complications of this deficiency predominantly involve the veins and include thrombophlebitis, PE, and stroke. It is interesting to note that in affected individuals, there have not been reports of clotting disease in association with pregnancy or oral contraceptive use, and even more intriguing is the report that plasminogen levels become normal in a deficient patient during pregnancy or with use of oral hormonal therapy. This finding indicates that in heterozygotes, the normal gene form may be able to increase plasminogen synthesis. Because homozygous patients infrequently develop clots, especially spontaneous events, the possibility of heterozygous plasminogen deficiency as a cause for a clotting event may be dismissed or overlooked.

Decreased Levels of Tissue Plasminogen Activator (tPA)

Tissue plasminogen activator (tPA) is synthesized by endothelial cells. When tPA is released, it converts plasminogen to plasmin. Theoretically, decreased release of tPA could lead to a super-clotting state (also called hypercoagulable) due to decreased clot breakdown (fibrinolysis).

Increased Levels of Plasminogen activator inhibitor 1 (PAI-1)

Plasminogen activator inhibitor 1 (PAI-1) functions as the primary inhibitor of plasminogen activator in plasma. Increased levels of PAI-1 could lead to excessive inhibition of tPA, leading to decreased activation of fibrinolysis and a clotting tendency. Increased PAI-1 levels have been shown in some cases to be an inheritable trait.

Elevated levels of thrombin-activatable fibrinolysis inhibitor (TAFI)

Increased levels of thrombin are needed for clot formation and to prevent clot breakdown. If the thrombin levels are too high, they activate thrombin-activatable fibrinolysis inhibitor (TAFI). TAFI helps to stop (inhibit) clot breakdown by preventing plasminogen from binding to the fibrin clot. Increased levels of TAFI may prevent the start of normal clot breakdown and therefore could theoretically increase the tendency for a clotting state. The Leiden Thrombophilia Study suggests that high levels of TAFI may be a mild risk factor for a super-clotting state.¹⁷ However, these results require confirmation.

Other Inherited Causes Associated with Increased Risk of Blood Clots

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder of stem cells and is caused by a gene alteration on the X chromosome. PNH is known to be associated with an increased risk of clotting. PNH results in the breakdown of red blood cells (hemolysis), which causes the release of hemoglobin into the blood. Ultimately the hemoglobin is released in the urine. This release produces dark-colored urine most often in the morning (also called hemoglobinuria). This type of hemoglobinuria was called “nocturnal” because it was believed that the breakdown of red blood cells occurred during sleep. This observation was later disproved. Hemolysis has been shown to occur throughout the day, but the concentration of urine that occurs through sleep results in the dramatic color change.

Once considered to be an acquired hemolytic anemia, PNH has been reclassified as an inherited condition related to a genetic alteration in stem cells In people with PNH, surface proteins are missing not only in the membrane of red blood cells but also in all blood cells, including platelets and white cells.¹⁸

This disorder usually presents in adulthood and is less common in childhood. In adults PNH is most commonly seen as hemolytic anemia with nighttime episodes while in children PNH is most commonly associated with bone marrow failure. Blood clots may occur in 39% of adults and 31% of children with PNH. The clots usually occur in the veins, particularly in the veins of the liver (Budd-Chiari syndrome), but the portal veins, central nervous system, and peripheral venous system also may be involved. Increased circulating activated platelets have been implicated in clotting events due to PNH, but no consistent fibrinolytic or coagulation abnormality has been documented.

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