Thrombophilia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2], M. Khurram Afzal, MD [3], Sogand Goudarzi, MD [4]

Thrombophilia is a complex condition which increases the risk of thrombosis or thromboembolic disease. The predisposition to clotting, or thrombotic risk, can be multi-factorial, and is due to an abnormality in coagulation described as hypercoagulability. Hypercoagulability is a component of Virchow’s Triad, which by itself or in synergy with stasis or trauma can predispose to clot formation. The thrombotic risk associated with thrombophilic states is variable and depends on the underlying coagulopathy. Thrombophilias are classified as either inherited or a primary hypercoagulable state, acquired or a secondary hypercoagulable state, or mixed/unknown. Factor V Leiden and prothrombin gene mutations are the most common forms of inherited hypercoagulable states. Patients with thrombophilia can have a family history of thrombosis, or present with frequent or unprovoked blood clots (primarily as deep vein thrombosis or pulmonary embolism), thrombosis at a young age, or blood clots in multiple or unusual sites.^[1] Thrombophilia screening is controversial, but may aid in managing the initiation and duration of anticoagulation in affected patients and primary prevention in relatives.

Rudolf Virchow described hypercoagulability in the mid 1800s, however, it was not until 1965 that the first descriptions of inherited thrombophilia were published.^[2][3][4] Later, in the 1990s, the more common mutations associated with primary hypercoagulable states were identified.^[5][6]

Thrombophilias may be classified into three groups: inherited or primary hypercoagulable states, acquired or secondary hypercoagulable states, or mixed/unknown. Certain conditions are associated with greater thrombotic risks and both venous and arterial clots.

The pathogenesis of thrombophilia is multi-factorial. It is characterized by hypercoagulability, which by itself or in synergy with endothelial injury or stasis (Virchow’s Triad) can predispose to clot formation. Multiple genetic mutations and predisposing conditions have been associated with the increased risk of thrombosis due to abnormalities in the coagulation cascade.^[7] The most common genes involved in the pathogenesis of acquired thrombophilias are Factor V Leiden and prothrombin gene mutations.

Thrombophilia may be caused by either acquired, inherited, or, more commonly, a combination of both conditions. The most frequent forms of inherited thrombophilia are Factor V Leiden (20-50% prevalence in patients with recurrent venous thrombosis) and prothrombon G20210A (5-20% prevalence in patients with recurrent venous thrombosis).^[7][8]

Thrombophilias must be differentiated from other diseases that cause the following clinical presentations: family history of thrombosis, especially at an early age (< 45 years), unprovoked thrombosis at an early age (<40-55 for venous thrombosis and <50-55 for arterial thrombosis), recurrent thrombosis including deep venous thrombosis, pulmonary embolism, or superficial venous thrombosis.

Due to the multitude and complexity of inherited thrombophilias, the true prevalence is unknown, and current data may be providing an underestimate. Comparison among different epidemiologic studies becomes difficult due to variation in study design and inclusion criteria. Prevalence of common inherited thrombophilias is variable among both healthy patients and patients with recurrent thrombosis. According to epidemiologic and modeling studies obtained from certain sources, the prevalence of inherited thrombophilias was estimated to be between 0.01-7% in caucasians.^[9][7] In certain studies, the prevalence of inherited thrombophilias, specifically, activated protein C resistance and prothrombin G20210A, rises to approximately 10-60% in patients with documented venous thrombosis compared to less than 10% among controls.^[10][11][12] The incidence of inherited thrombophilia in incident venous thrombosis is approximately 150-840 per 100,000 person years.^[8] The incidence of inherited thrombophilia in recurrent venous thrombosis is approximately 3,500-10,500 per 100,000 person-years.^[8]

Patients of all age groups may develop thrombophilias. Acquired thrombophilias are more commonly observed among elderly patients (age > 60) as age is a risk factor for thrombosis. Inherited thrombophilias can be seen among young patients aged <40-55 years old.

Epidemiologic studies have provided mixed results regarding the effect of gender on venous thrombosis. Certain groups observed increased risk of thrombosis in younger females and older males, whereas other groups found similar frequencies in both genders.^[13] A prospective follow up study performed by Christiansen et al, revealed an age corrected hazard ratio of 2.7 of recurrent thrombosis in male patients with inherited thrombophilias compared to women.^[14] In patients with inherited thrombophilias, a prospective follow up study performed by Christiansen et al revealed an age corrected hazard ratio of 2.7 for recurrent thrombosis in male patients compared to women.^[14]

The factor V leiden G1691A and prothrombin G20210A mutations are exceedingly rare in non-white populations.^[7]

The most common risk factors in the development of acquired thrombophlias are trauma, surgery, immobility, pregnancy, oral contraceptives, hormone replacement therapy, and age. Common risk factors for the development of inherited thrombophilias are a family history of thrombosis at an early age or a family history of inherited thrombophilia. Common genetic risk factors in the development of inherited thrombophilias are mutations in Factor V Leiden and prothrombin G20210A.

The annual thrombotic risks are variable and depend on the underlying thrombophilia.^[15] If left untreated, the annual incidence of incident thrombosis in asymptomatic patients with Factor V Leiden and (Prothrombin G20210A) is low (<0.06%) .^[16] The risk is approximately equivalent to treatment with oral contraceptives (OCPs). Whereas the annual incidence of significant bleeds is approximately 2-3%.^[17] Studies performed by Christiansen et al and Baglin et al revealed that inherited thrombophilia from factor V leiden and prothrombin G20210A did not predict for recurrent thrombosis.^[14][18] Christiansen et al and De Stefano et al observed a mild increased risk for recurrent thrombosis in patients with protein C, protein S, and antithrombin deficiency.^[14][19] OCPs, hormone replacement therapy, and pregnancy can significantly increase thrombotic risk in patients with thrombophilia.^[20] Certain high risk thrombophilias require indefinate anticoagulation.

The diagnosis of an inherited thrombophilia is made with specific laboratory tests for each inherited condition.

Common symptoms of thrombophilias may include symptoms of Deep venous thrombosis, Pulmonary embolus, and superficial venous thrombosis.

Physical examination of patients with thrombophilia is usually remarkable for signs of deep venous thrombosis, pulmonary thrombosis, renal vein thrombosis, cerebral vein thrombosis, superficial vein thrombosis, arterial thrombosis, portal hypertension which can be sign of portal vein thrombosis, warfarin skin necrosis, or livedo reticularis.^[1][8][7]

According to the American Society of Hematology, screening for inherited thrombophilias in adult patients with venous thrombosis in the setting of major transient risk factors which include surgery, trauma, or prolonged immobility is not recommended.^[21] However, given the associated risks for recurrent thrombosis, patients who have significant risk factors including a positive family history or concurrent treatment with hormonal therapies should seek expert consultation.

Laboratory findings consistent with the diagnosis of inherited thrombophilias include specific laboratory findings associated with each inherited thrombophilia.^[7]

Ultrasongraphy, computed tomography angiography (CTA or CT Angiography), magnetic resonance angiography (MRA or MR Angiography) and projectional angiography may be diagnostic of acute thrombosis, which is associated with the diagnosis of thrombophilia.

The treatment for thrombophilia depends on the underlying hypercoagulable state and the clinical presentation.^[1][8][7] The mainstay of therapy for thrombophilia is anticoagulation with either warfarin, low molecular weight heparin, direct Xa inhibitors, or direct thrombin inhibitors.^[22][23][24] Treatment should be tailored to the individual patient. The risks and benefits, required monitoring, and costs associated with each form of anticoagulation should be discussed with the patient prior to initiation of therapy. All patients on anticoagulation should be monitored for bleeding.

Surgery is not required for treatment for thrombophilia. IVC filter placement may be indicated if the patient has contraindications to or complications from anticoagulation, recurrent thrombosis on anticoagulation, or failure to acheive therapeutic anticoagulation levels.^[25]

Prophylaxis with anticoagulation may be recommended for primary prevention of acute thrombosis in certain scenarios. Once diagnosed and successfully treated, patients with thrombophilia are followed-up routinely to monitor anticoagulation and clinically if thrombosis recurrs

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

Hypercoagulability was first discovered by Dr. Rudolf Virchow, a German physician, in the mid-1800s. In 1965, the first descriptions of inherited thrombophilia were published by Dr. Roger O. Egeberg, an American physician.^[1][2][3] Later, in the 1990s, the more common mutations associated with primary hypercoagulable states were identified.^[4][5]

• 1821-1902: A German physician, Rudolf Virchow, began describing the pathophysiology of hemostasis at age 24.^[1]
• 1856: Rudolf Virchow proposed a hypothesis to explain the etiology of pulmonary emboli, which lead to the understanding of the three primary causes of venous and arterial thrombosis: stasis, injury to the vessel wall and abnormalities in the circulating blood. ^[6]
• 1906: Wasserman et al. described the antiphospholipid syndrome. ^[7]
• 1965: The first descriptions of inherited thrombophilias were Antithrombin deficiency by Egeberg et al. and dysfibrinogenemia by Beck et al.^[2][3]
• 1981-1984: Dr. John Griffin and Dr. Philip Comp described protein C deficiency and protein S deficiency respectively as a primary hypercoagulable state.^[8][9]
• 1993-1994: Dr. Rogier Bertina and his colleagues identified that activated protein C (APC) resistance was primarily due to a mutation in the factor V gene (guanine to adenine substitution at nucleotide 1691, G1691A) resulting in the Factor V Leiden molecule.^[4]
• 1996: Swibertus R Poort described a prothrombin gene mutation, specificaly the substitution of adenine to guanine at nucleotide 20210 (Prothrombin G20210A), and its association with inherited thrombophilia.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

Thrombophilia may be classified into three subtypes: inherited or primary hypercoagulable states, acquired or secondary hypercoagulable states, and mixed/unknown.^[1][2]

• Prothrombotic states which can be origin from venous or both venous and arterial clots might be classified into heritable, acquired or mixed resulting from the interactions between the environment (e.g. oestrogen use, obesity or other lifestyle factors) and genetic factors as elaborated in the following Table 1.^[1][2]

Table 1: Classification of thrombophilias

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

The pathogenesis of thrombophilia is multi-factorial. It is characterized by hypercoagulability, which by itself or in synergy with endothelial injury or stasis (Virchow’s Triad) can predispose to clot formation. Multiple genetic mutations and predisposing conditions have been associated with the increased risk of thrombosis due to abnormalities in the coagulation cascade.^[1] The most common genes involved in the pathogenesis of acquired thrombophilias are Factor V Leiden and prothrombin gene mutations.

• Coagulation is an inherent property of the hematologic system and normal blood flow is maintained by the balance between the pro-coagulant and anti-thrombotic factors under healthy conditions. A hypercoagulable state and subsequent thromboembolism is a result of overactivity of pro-coagulant factors or a deficiency in anti-coagulants. Anticoagulants that regulate thrombin include antithrombin, protein C, and protein S. The primary mechanism for thrombus formation in common inherited thrombophilic states involves thrombin dysregulation. However, the interplay of these factors is complicated process consisting of coagulation activators and inhibitors and their production and degradation (quantitative) and functional properties (qualitative) influencing the thrombosis process.

Figure 1: Thrombus formation in inherited thrombophilias. Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31.^[1]

• Antithrombin (previously called antithrombin III) is synthesized by the liver but is not vitamin K-dependent. Its inhibitory effect is not confined to thrombin. It also inhibits the activated clotting factors IXa, Xa, XIa, XIIa and tissue factor-bound factor VIIa. Antithrombin III binds to heparin on endothelial cells and forms a complex between antithrombin and the serine proteases and thus, inhibiting coagulation. Mutations in antithrombin can lead to increased thrombus formation. ^{[2] [3]}
• The prevalence may be 1 in 500 in the general population. Affected patients have antithrombin levels 40–60% of normal, and 70% of those affected experience thrombo-embolic events before the age of 50. Thrombotic episodes are rare before puberty in AT-deficient individuals. They start to occur with some frequency after puberty, with the risk increasing substantially with advancing age. ^{[4] [5]}
• Type of inheritance: Antithrombin (AT) deficiency is a heterogeneous disorder. It is usually inherited in an autosomal dominant fashion, thereby affecting both sexes equally. Homozygous ATIII deficiency is incompatible with life unless affecting the heparin-binding site. ^[6]
• Causes: ATIII deficiency can occur as a consequence of reduced synthesis (liver damage) or increased loss (nephrotic syndrome, enteropathy, DIC, sepsis, burn, trauma, microangiopathy, and cardiopulmonary bypass surgery). Usually these patients present with venous thrombosis and less likely with arterial thrombosis. ^[7]
• Classification: Three major types of heritable AT deficiency are recognized as follows: ^[3]
  • Type I: It is characterized by a quantitative reduction of qualitatively (functionally) normal antithrombin protein and thereby reducing both the antigenic and functional activity of AT in the blood. The values are reduced by approximately 50 percent in the heterozygote. The 1997 antithrombin mutation database included 80 distinct mutations in patients with type I deficiency. The database shows that the molecular basis for this disorder is usually a small deletion or insertion (less than 22 base pairs) or a deletion of a major segment of the AT gene. ^{[8] [9]}
  • Type II: It is produced by a discrete molecular qualitative mutational defect within the protein which either affect the heparin-binding site (HBS), the reactive site (RS) or result in pleiotropic effects (PE). While the AT immunologic activity is normal in this deficiency, plasma AT functional activity is markedly reduced leading to risk of thrombosis. It is subclassified according to the site of the molecular defect: ^{[6] [10]}
    • Reactive site (RS) and abnormalities residing in the reactive (thrombin binding) site.
    • Heparin binding site (HBS) and abnormalities residing in the heparin binding site.
    • Pleiotropic effect (PE) and abnormalities residing in both reactive and heparin binding sites.
  • Type III: This type is characterized by normal functional and antigenic antithrombin levels but impaired interaction between AT and heparin. ^[11]

• Protein C is a vitamin K-dependent protease synthesized in the liver and circulates in plasma at low concentrations which serves a critical role in the regulation of thrombin. Protein C becomes activated to form activated protein C (APC) via interactions with thrombin. APC acts as one of the major inhibitors of the coagulation system by cleaving and inactivating clotting factors V and VIII which are necessary for efficient thrombin generation, and thereby exerting potent anticoagulant activity. Moreover, APC also reduces platelet prothrombinase activity by degrading platelet bound factor Va at the receptor for factor Xa. Additionally, the inhibitory effects of APC are facilitated through the cofactor activity of protein S, another vitamin K-dependent protein. ^[3][12]
• Protein C deficiency is a rare acquired or congenital disorder characterized by a reduction in the activity of protein C, a plasma serine protease involved in the regulation of blood coagulation which results in the excessive formation of blood clots (thrombophilia).
• Congenital protein C deficiency results from mutations in the PROC gene and inherited in an autosomal dominant manner. The gene for protein C is located on chromosome 2 (2q13–14) and appears to be closely related to the gene for factor IX. ^[13]
• Mode of inheritance: ^[14]
  • Heterozygous: Mutations in a single copy in heterozygous individuals cause mild protein C deficiency.
  • Homozygous: Individuals with homozygous mutations present with severe protein C deficiency and thrombotic tendency in infancy characterized as purpura fulminans. ^[15]
• Inherited: Two major subtypes of heterozygous protein C deficiency have been delineated using immunologic and functional assays. Over 160 different gene abnormalities have been associated with the two subtypes.^{[14] [16]}
  • Type I: This state is more common with a reduced plasma protein C concentration at approximately 50% of normal in both immunologic and functional assays. Most affected patients are heterozygous and carries an increased risk of developing warfarin-induced skin necrosis. More than half of the mutations are missense and nonsense mutations and other includes promoter mutations, splice site mutations, in-frame deletions, frameshift deletions, in-frame insertions, and frameshift insertions. Moreover, there is marked phenotypic variability among patients with heterozygous type I protein C deficiency. Similar mutations have been found among symptomatic and asymptomatic individuals which suggests that the nature of the protein C gene defect alone does not explain the phenotypic variability. ^{[16] [17]}
  • Type II: It has normal plasma protein C antigen levels with decreased functional activity; and a variety of different point mutations affecting protein function have been identified in this disorder. ^[16]
• Acquired: Protein C is known to have a role in the regulation of inflammation and sepsis which demonstrates its cytoprotective functions. Reduced protein C activity is observed in DIC, liver disease, coumarins use, and adverse pregnancy outcomes such as DVT, preeclampsia, intrauterine growth restriction and recurrent pregnancy loss. ^{[12] [18]}
• Additionally, the half-life of protein C is shorter than the half-life of other vitamin K-dependent coagulation factors; hence, the risk of increased coagulation with the initiation of vitamin K antagonists can be seen; and thereby need the bridging with parenteral heparin to avoid warfarin-induced skin necrosis.

• Protein S is a vitamin K-dependent protease that circulates in plasma at low concentrations and serves a crucial role in the regulation of coagulation.
• In circulation, approximately 40% of protein S is free, remains uncomplexed and is the active moiety; while about 60% is in a high-affinity complex with the complement regulatory factor C4b-binding protein (C4BP) and has no cofactor activity. The bioavailability of protein S is closely linked to the concentration of C4bBP, which acts as an important regulatory protein in the activated protein C:protein S inhibitory pathway. ^[20]
• The anticoagulant activity of protein S is two-fold as follows: ^[21]
  • Protein S operates as a cofactor for activated protein C (APC) and inactivates coagulation Factor Va and Factor VIIIa;
  • Protein S is also a cofactor for the tissue factor pathway inhibitor (TFPI) protein resulting in the inactivation of Factor Xa and tissue factor (TF)/Factor VIIa.
• Protein S deficiency is usually congenital caused by mutations in the PROS1 gene and mainly an autosomal dominant pathology. ^[20]
• Mode of inheritance:
  • Heterozygous: Mutations in a single copy in heterozygous individuals cause mild protein S deficiency
  • Homozygous: Individuals with homozygous mutations present with severe protein S deficiency
• Inherited: More than 200 PROS mutations have been described and may result in three different forms of protein S deficiency: ^[20]
  • Type I: It is a quantitative defect presenting with low levels of total protein S (TPS) and free protein S (FPS) with reduced levels of functional protein S activity. ^[22]
  • Type II (or Type IIb): This type of protein S deficiency is characterized by decreased functional protein S activity with normal levels of TPS and FPS antigens. Interestingly, all five mutations originally described were missense mutations located in the N-terminal end of the protein S molecule consisting of the domains that interact with activated protein C. ^[23]
  • Type III (or Type IIa): It consists of a quantitative defect presenting with normal levels of TPS, but selectively reduced levels of FPS and functional protein S activity to less than approximately 40 percent of normal. ^[24]
• Acquired: Causes of temporary acquired fluctuations in protein S levels may include vitamin K-antagonist therapy (coumarins), antiphospholipid antibodies, chronic infections, severe hepatic disease, nephritic syndrome, and DIC. ^[25]
• Gender predilection: Protein S levels are slightly higher in men than in women. Contrarily, protein S levels fall progressively during pregnancy and are reduced to a lesser extent in women using oestrogen containing oral contraceptives or hormone replacement therapy. Moreover, the risk of VTE is also increased in patients using oral contraceptives and pregnancy. ^{[1] [26]}

• The most common inherited thrombophilia is Factor V Leiden which is a polymorphism of Factor V that is resistant to APC inactivation. Other FV mutations include factor V Cambridge and factor V Hong Kong. ^{[1] [10] [27]}
• Activated protein C (APC): Protein C interacts with thrombomodulin to become APC which has anticoagulant, anti-inflammatory, and cytoprotective properties. The signal cascade leading to APC can become distorted through many acquired or inherited mechanisms leading to APC resistance. Hence, APC resistance occurs when APC fails to inactivate downstream coagulation factors, specifically Factor V and Factor VIII. ^[7]
• The factor V Leiden mutation further increases arterial thrombosis risk by enhancing thrombin production. Protein C and S are natural anticoagulants which inhibit thrombin formation. Dysregulation in APC can occur as either defects in the protein C or S molecule (Protein C and S deficiency) or as resistance to APC activity.^{[1] [6] [28]}

• Prothrombin (factor II) is the precursor to thrombin, the end-product of the coagulation cascade. Prothrombin has procoagulant, anticoagulant and antifibrinolytic activities and thus a disorder involving prothrombin results in multiple hemostasis imbalances.
• It is the second most common inherited thrombophilia which involves a gain of function mutation of the prothrombin gene (Prothrombin G20210A) resulting in increased protein activity and thrombus formation. ^{[10] [27] [29]}
• It is due to a single point mutation which involves the G to A transition at nucleotide 20210 in the 30-untranslated region of the prothrombin gene and thereby associated with elevated plasma prothrombin levels and demonstrating a higher risk for arterial and venous thrombotic events. ^[29]

• Homocystinuria and hyperhomocysteinemia are rare metabolism disorder associated with the marked elevations of plasma and urine homocysteine concentrations resulting from an impaired intracellular metabolism of homocysteine which can be due to both genetic and acquired abnormality.
• Homocysteine is an amino acid derived from methionine which is metabolized by the body in two possible following pathways: ^[30]
  • Transsulfuration of homocysteine produces cysteine, and this reaction is catalyzed by cystathionine-β-synthase which requires pyridoxal phosphate (Vitamin B) as a cofactor.
  • Remethylation of homocysteine produces methionine which is catalyzed either by methionine synthase or by betaine homocysteine methyltransferase. Vitamin B12 (cobalamin) is the precursor of methylcobalamin, which is the cofactor for methionine synthase.
• Nutritional deficiencies in vitamin cofactors such as vitamin B6, B12, and folate or genetic defects of enzymes such as cystathionine beta-synthase (CBS) or methylenetetrahydrofolate reductase (MTHFR) decrease the efficiency of homocysteine metabolism. Furthermore, chronic medical conditions such as renal failure, hypothyroidism, and drugs such as methotrexate, phenytoin, and carbamazepine increase homocysteine levels. ^{[6] [10] [27]}
• Hence, premature atherosclerosis and arterial thrombosis is associated with severe hyperhomocysteinemia.

• Higher levels: African-Americans appear to have its higher levels. It further increases the risk of thrombosis, and found to be correlated with acute phase reactions, estrogen usage, pregnancy, and aerobic exercise.
• Lower levels: Individuals with blood group “O” tend to have lower levels of FVIII and correlated with bleeding in hemophilia A patients.

• Plasminogen deficiency, dysfibrinogenemia, tissue plasminogen activator (tPA) deficiency, plasminogen activator inhibitor (PAI) increase, and factor XII deficiency impairs plasmin generation. ^[4]
• Dysfibrinogenemia: The patients with structural or functional changes to fibrinogen result in dysfibrinogenemia through an abnormal thrombin-mediated conversion to fibrin and thereby, developing the risk for thrombosis or bleeding. Most patients are clinically asymptomatic inspite of having predisposition for bleeding, thrombosis or both.^[31]

• It is the most common acquired thrombophilia in which antibodies are directed against natural constituents of cell membranes, the phospholipids.
• These antiphospholipid antibodies (APLA) consisting of lupus anticoagulant, anticardiolipin, and anti-beta-2-glycoprotein occur in 3 to 5% of the population and may cause arterial or venous thrombosis and fetal loss.
• APLA may occur secondary to other diseases such as collagen vascular disease or infections or drugs like phenytoin.
• Hence, any patient presenting with stroke, deep vein thrombosis, and rheumatological disorder should be screened for underlying antiphospholipid antibody syndrome.

• It is the second most common acquired hypercoagulability which leads to a prothrombotic state through the production of procoagulant factors (tissue factor and cancer procoagulant) and the interaction of tumor cells with blood and vascular endothelium further associated with vascular stasis from tumor compression, paraproteinemia, and cytokine release.
• In 85% cases, cancer procoagulant (CP) is elevated which activates factor X, and thus causing hypercoagulability in cancer patients. ^[33]
• Migratory thrombophlebitis known as Trousseau syndrome and Polycythemia vera poses a thrombotic risk in addition to hyperviscosity. ^[10]
• The interaction of malignancy and coagulation not only favors thrombosis but also the hemostatic system which influences angiogenesis and support tumor growth and spread. Hence, targeting the hemostatic system might offer treatment options for anticancer therapy. ^{[34] [35] [36]}

• Smoking tobacco contains various toxins such as nicotine which results in endothelial cell damage.
• The release of tissue plasminogen activator (tPA) and tissue factor pathway inhibitor (TFPI) get reduced.
• Carbon monoxide increases the permeability of endothelium to lipids thus leading to atheroma formation. ^[10]
• Hence, arterial bypass grafts fail prematurely in smokers.

• Exercise influences coagulation, fibrinolysis, and platelet aggregation which is usually kept in balance; however, in some cases the immediate postexercise period is characterized by a hypercoagulable state with an increase of factor eight (intrinsic pathway activation) and platelet activation. ^{[37] [38] [39]}
• Although exercise improves the cardiovascular risk profile; but older individuals carry more cardiovascular risk factors and are less well trained. Thus, they are prone to suffer adverse effects from the temporary hypercoagulable state following exercise. ^[40]

• The physiological changes that occur during pregnancy presents a time of hypercoagulability extending from 2 months of gestation into the postpartum period through the increase of procoagulants (diverse coagulation factors and the number of platelets) and the decrease of anticoagulants (PAI) in addition to stasis caused by compression of the gravid uterus.
• Hematological changes: A number of clotting factors including factor VII, factor VIII, Factor X, von Willebrand factor, and fibrinogen are elevated as a result of hormonal changes. At the same time, resistance to activated protein C increases in the second and third trimesters and the activity of protein S is decreased due to changes in the total protein S antigen level. There is also an increase in a number of inhibitors of the fibrinolytic pathway such as activatable fibrinolytic inhibitor (TAFI) and plasminogen activator inhibitor 1 and 2 (PAI-1 and PAI-2). ^{[41] [42] [43]}
• Physical changes: An increased pressure on the pelvic veins from the gravid uterus and decreased flow in the lower extremities result in increased stasis and thrombotic state. Relative compression of the left iliac vein by the right iliac artery as it courses across the vessel leads to an increase of clots in the left iliac vein. Although stasis increases throughout the course of pregnancy and leg pain and swelling are more frequent during the third trimester, incidence of DVT is distributed relatively equally across trimesters. ^{[44] [45] [46]}
• Concomitant diseases such as systemic lupus erythematous or sickle cell disease along other risk factors including obesity, decreased mobility, increased age, and smoking further elevates the thrombosis risk.
• Predisposing factors: It has been observed that the pregnant women over 35yrs of age have a 1.38 fold increased risk of having a clotting event during the peripartum period. Additionally, women who have had spontaneous clotting events in the past have an increased risk of developing a second event with an estimated rate of recurrence of 10.9% during pregnancy. ^{[47] [48]}
• Overall, both the physiologic and anatomic changes of pregnancy take several weeks to resolve after delivery, and the risk of thrombosis remains elevated compared to pregnancy until approximately 6 weeks postpartum. ^[49]

• Heparin is a commonly used anticoagulant and under certain circumstances, arterial and venous thrombosis concomitantly with thrombocytopenia paradoxically results from its prolonged administration which is called heparin-induced thrombocytopenia (HIT). The conformational change of heparin following heparin binding to platelet factor 4 triggers antibody production to heparin. Subsequently, monocytes become activated and attack the vascular endothelium leading to thrombotic events. ^[10]
• Type-I HIT: Platelets show a weak reduction and have little clinical consequences.
• Type-II HIT: It characterizes the strong reduction of thrombocytes and serious clinical sequelae.

• Trauma causes the procoagulant disbalance which is more pronounced during the first 24 hours following injury and in women.
• The onset of respiratory distress syndrome and multiorgan failure following trauma has been correlated with elevated tissue factor. ^[50]

• There is an interplay between inflammation and the coagulation system as inflammation triggers a hypercoagulable state which can be observed clinically in patients with purpura, vasculitis, and septic thromboembolism. ^[51]
• Endotoxin activates the complement system leading to thrombocytopenia and hypercoagulability. Moreover, coagulation helps to limit the expansion of infection and some bacteria use fibrinolytic properties to oppose this response. The cytomegaly virus (CMV) has correlations to atherogenesis through a change of the cellular lipid metabolism and leukocyte adherence. ^{[52] [53]}
• Autoimmune diseases like systemic lupus erythematosus, immune thrombocytopenic purpura, polyarteritis nodosa, polymyositis, dermatomyositis, inflammatory bowel disease, and Behcet’s syndrome increase the risk of thrombotic events. Other conditions associated with a hypercoagulable state include myeloproliferative disorders, multiple myeloma, paroxysmal nocturnal hemoglobinuria, heart failure. ^{[54][55] [56] [57] [58]}
• Cardiac events: The endothelium of the left atrial appendage (LAA) showed higher expression of tissue factor and plasminogen activator inhibitor compared to the right atrial appendage. This inherent prothrombotic property of the LAA in addition to flow disturbances of atrial fibrillation leads to thromboembolic events.^[59]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

Thrombophilia may be caused by either acquired, inherited, or, more commonly, a combination of both conditions.

• Virchow’s triad: The cause of thrombosis is multifactorial which causes an imbalance in endogenous anticoagulation and hemostasis through a complex pathophysiologic mechanism. Rudolf Virchow proposed Virchow’s triad in 1856 and described the three common factors which predisposes to thrombosis as follows: ^[1]
  • Damage to the endothelial lining of the vessel wall: It leads to the production of pro-inflammatory and prothrombotic cytokines, an increase in available tissue factor, the proliferation of adhesion molecules, and enhanced platelet activation. Cytokines initiate inflammation-promoting interaction between leukocytes and endothelial cells. Inflammation is a normal body reaction to unwanted stimuli such as foreign pathogens or infection and endothelial damage, whether acute (e.g., catheter placement, trauma or surgery) or chronic (underlying inflammatory disorders or peripheral vascular disease). ^[2]
  • Hypercoagulable state: It is due to a variety of alterations in the coagulation and hemostatic system, which can result from inflammatory factors, variations in the viscosity of blood and blood components, increased cytokines, and prothrombotic proteins in circulation, or deficiencies of natural or endogenous anticoagulant factors. ^[3]
  • Arterial or venous blood stasis: This third aspect could be due to immobility, pregnancy, or impaired blood flow resulting from previous thrombosis such as residual blood clot, remodeling or fibrosis of blood vessels, or atherosclerosis. Long trips with limited mobility in cases where concurrent additional risk factors are present can be considered as a relative risk factor for thrombosis. ^[4]

• Hypercoagulable states: Hypercoagulability disorders are either acquired or inherited. However, actual thrombosis occurs due to the interplay of both genetic and environmental factors and follows the multiple hit hypothesis, thereby explaining the inter-individual differences observed in patients with inherited mutations. ^{[3] [5] [6] [7]}
  • Inherited forms can be identified in up to 30% of patients with venous thromboembolism and are mainly attributable to factor V Leiden and prothrombin G2021A mutation. These two thrombophilias implicate a weak thrombotic risk. However, other inherited thrombophilias are rare such as antithrombin III, protein C and protein S deficiency (around 1% in the general population) but pose a higher risk for thrombosis. Mutations influencing coagulation factors can present in heterozygous or homozygous genotype. ^[3]
  • Acquired factors are far more common and influence the coagulation cascade by multitude of factors including medications (e.g., oral contraceptives, estrogen or other hormonal replacement), recent inflammatory conditions such as pregnancy, surgery, trauma, or infection, and chronic inflammatory conditions (e.g., morbid obesity, rheumatologic disease, ulcerative colitis, heavy smoking). ^{[7] [8]}
  • Malignancy (occult or diagnosed) can predispose to hypercoagulability as tumor cells can express a variety of procoagulant proteins including increased expression tissue factor. Some solid tumors such as pancreatic cancer are known to significantly increase the risk of thrombosis. ^[9]
  • Typically, venous thrombosis is initiated by endothelial damage, while arterial thrombosis starts with atherosclerosis, and acquired hypercoagulable states leading to both venous and arterial thrombus include acquired antiphospholipid syndrome (APS) and heparin-induced thrombocytopenia & thrombosis (HITT). ^[3]

• Venous thromboembolism (VTE): Stasis behind venous valves contributes to venous thrombosis and red thrombus formation. An anatomy of the deep veins of the extremities and the pulmonary system should be considered such as the deep veins of the lower extremity include the femoral, iliac, and popliteal veins; and the upper extremity veins include the subclavian, axillary, brachial veins. Other thrombosis sites include superior vena cava thrombosis, jugular vein thrombosis, cerebral venous sinus thrombosis, cavernous sinus thrombosis, and retinal vein occlusion. Thrombosis of superficial veins is possible with provoking factors such as intravenous catheterization or localized cellulitis; however, the treatment of superficial vein thrombosis does not typically require any anticoagulation. ^{[10] [11]}

• Arterial thrombosis: ^[12]
  • Arterial thrombosis results from atherosclerotic plaque rupture around which a platelet-rich white thrombus forms. Arterial thrombosis and microthrombi formation typically initiates by the accumulation of lipid plaques in the arterial wall provoking chronic inflammatory cells and platelet activation.
  • Atherosclerosis: The initial lipid plaques evolve into fibrous plaques. Fibrous plaques could rupture, and the erosion of the surfaces of these plaques could lead to the release of additional pro-coagulating factors. This process is called atherosclerosis which further allows the activation of platelets, causing adhesion and aggregation, and the clot formation predisposing to the ischemic heart disease and myocardial infarction.
  • In the heart, microthrombi can develop as a result of blood stasis in the ventricles or atria due to underlying valvular heart disease, cardiomyopathies, or arrhythmias such as atrial fibrillation predisposing to ischemic emboli and CVA. Hence, an increased incidence of obesity, hypertension, diabetes, and hypercholesterolemia all can contribute to the risk of an arterial thrombosis. Other risk factors include underlying connective tissue or rheumatologic conditions such as SLE, vasculitis; HITT, antiphospholipid syndrome, myeloproliferative disorders, and PNH.
  • Thereby, it can present as an acute stroke, myocardial infarction, or acute on the chronic peripheral arterial disease. Other less common sites can include renal arteries, mesenteric arteries, and retinal arteries.
  • Antiplatelet agents: Platelets play a significant role in the development of arterial thrombosis compared to venous thrombosis; and hence, explains why antiplatelet agents form a cornerstone of the prevention and treatment of arterial thrombosis. ^[4]

Table 1: System wise causative factors of thrombophilia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2], Sogand Goudarzi, MD [3], Asiri Ediriwickrema, M.D., M.H.S. [4], Jaspinder Kaur, MBBS[5]

Thrombophilias must be differentiated from other diseases that cause the following clinical presentations: family history of thrombosis, especially at an early age (< 45 years), unprovoked thrombosis at an early age (<40-55 for venous thrombosis and <50-55 for arterial thrombosis), recurrent thrombosis including deep venous thrombosis, pulmonary embolism, or superficial venous thrombosis.

Thrombophilias must be differentiated from other diseases that cause the following clinical presentations:^[1][2]

• Family history of thrombosis, especially at an early age (< 45 years)
• Unprovoked thrombosis at an early age (<40-55 for venous thrombosis and <50-55 for arterial thrombosis)
• Recurrent thrombosis including deep venous thrombosis, pulmonary embolism, or superficial venous thrombosis
• Thrombosis at multiple sites, or unusual locations including in cerebral, hepatic, portal, mesenteric, and renal veins
• Thrombosis in arteries with the abscence of arterial disease
• History of fetal loss
• History of warfarin skin necrosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

Due to the multitude and complexity of inherited thrombophilias, the true prevalence is unknown; current data may be providing an underestimate. The prevalence of thrombophilia in Caucasians is approximately 10-7,000 per 100,000 individuals worldwide.^[1][2] The prevalence of inherited thrombophilias, specifically, activated protein C resistance and prothrombin G20210A , rises to approximately 10-60% in patients with documented venous thrombosis compared to less than 10% among patients without documented venous thrombosis.^[3][4][5] The incidence of inherited thrombophilia in incident venous thrombosis is approximately 150-840 per 100,000 person years.^[6] The incidence of inherited thrombophilia in recurrent venous thrombosis is approximately 3,500-10,500 per 100,000 person-years.^[6]

• The epidemiology of thrombosis varies depending upon the following factors:
  • Venous vs Arterial
  • Provoked vs Unprovoked
  • First episode vs Subsequent episode
• Inherited thrombophilia: The incidence of incident and recurrent venous thrombosis in inherited disorders is approximately 150-840 and 3,500-10,500 per 100,000 individuals respectively. ^[6]
• Venous thromboembolism: It is the second most common cardiovascular disorder following myocardial infarction and more frequent than stroke with the incidence range of 1-5 in 1000 per year in the general population. Its annual incidence is age dependent which follow as:
  • Children: 1 per 100000 per year
  • Adults: 1 per 1000 per year
  • Elderly: 1 per 100 per year ^[7]
• Frequency of thrombophilias:
  • APS, APC resistance, elevated factor VIII: 25 to 28% ^[8]
  • Protein C deficiency, Protein S deficiency, Hyperhomocysteinemia and Prothrombin mutation: 5 to 10% ^[8]
  • Pulmonary embolism: 29 to 48 per 100000 person-years
  • Deep vein thrombosis: 45 to 117 per 100000 person-years ^[9]

The prevalence of thrombophilia in Caucasian populations is:^{[2][6][10][11][12]}

• Thrombophilias may develop in patients irrespective of their age groups.
• Acquired thrombophilias: They are more commonly observed among elderly patients who are more than 60 years old.
• Inherited thrombophilias: Young patients between 40-55 years old more likely carries the risk of inherited thrombophilias.

• Several epidemiologic studies have reported mixed results regarding the effect of gender on venous thrombosis.
• Certain groups observed an increased risk of thrombosis in younger females and older males, while others found similar frequencies in both the genders.^[13]
• Christiansen et al conducted a prospective follow up study in patients with inherited thrombophilias, and revealed an age corrected hazard ratio of 2.7 for recurrent thrombosis in male patients compared to women. ^[14]

• The Factor V Leiden G1691A and prothrombin G20210A mutations usually affects individuals of the Caucasian race in comparison to non-white individuals. ^[2]

• The most frequent form of inherited thrombophilia is Factor V Leiden with 20-50% prevalence in patients with recurrent venous thrombosis.
• The prevalence of Factor V Leiden thrombophilia in African and Asian populations is approximately 500 per 100,000 individuals worldwide.^[2][6]

• The second most frequent form of inherited thrombophilia is prothrombin G20210A.
• Its prevalence in African and Asian populations is approximately 600 per 100,000 individuals worldwide.^[2][6]

• Mild protein C deficiency: 1 in 200 to 1 in 500 individuals. ^[15]
• Clinically significant protein C deficiency: 1 in 20000 people.
• Severe protein C deficiency: Rarely found among 1 in 4 million infants which may be attributable to underdiagnosis or under-reporting. ^[16]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

Common risk factors in the development of acquired thrombophlias are trauma, surgery, immobility, pregnancy, oral contraceptives, hormone replacement therapy, and age. Common risk factors for the development of inherited thrombophilias are a family history of thrombosis at an early age or a family history of inherited thrombophilia. Common genetic risk factors in the development of inherited thrombophilias are mutations in factor V leiden and prothrombin G20210A.

• Risk factors for inherited thrombophilias are as follows:^[1][2][3]
  • Family history of thrombosis at an early age
  • Family history of inherited thrombophilia

• Risk factors in the development of acquired thrombophlias are enlisted in the following Table 1: ^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

In general, screening for inherited thrombophilias is controversial and should be performed in the appropriate clinical context.^[1]According to the American Society of Hematology, screening for inherited thrombophilias is not recommended in adult patients with venous thrombosis in the setting of major transient risk factors which include surgery, trauma, or prolonged immobility.^[2] However, patients who have significant risk factors, including a positive family history or concurrent treatment with hormonal therapies, should seek expert consultation.

• The American Society of Hematology, British Committee for Standards in Hematology, and the British Society for Hematology have proposed the following recommendations for the screening of inherited thrombophilias as follows in Table 1:^{[1] [2] [3]}

• Steps to be taken before pursuing the screening tests are as follows:
  • Family members and patients should receive genetic counseling before genetic testing; and informed consent must be obtained before conducting such testing procedures.
  • Counseling should include the following: ^[5]
    • Reasons for testing: Higher potential for avoiding the clinical thrombosis by risk factor modification or prophylactic measures for both the family member their children,
    • Reasons for not testing: Stigmatization and mental anguish, the potential effect on obtaining personal health insurance or employment, and the possibility of nonpaternity.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2] Jaspinder Kaur, MBBS[3]

The annual thrombotic risks are variable and depend on the underlying thrombophilia.^[1]

• Factor V Leiden and Prothrombin G20210A: If left untreated, the annual incidence of incident thrombosis in asymptomatic patients is low (<0.06%). However, the occurrence of recurrent thrombosis can not be predicted in such inherited thrombophilias. ^[2][3][4]
• Protein C, Protein S, and Antithrombin deficiencies: These conditions carries an increased risk for recurrent thrombosis in untreated patients. ^[3][5]
• Oral contraceptives, hormone replacement therapy, and pregnancy can significantly increase thrombotic risk in patients with underlying thrombophilia.^[6]
• Certain high risk thrombophilias require indefinite anticoagulation. However, such patients on preventive oral anticoagulant therapy for venous thromboembolism still carries the annual incidence of significant bleeds of ~2-3%.^[7]

• The primary complication of thrombophilia is the development of blood clots, also known as thrombus formation.
• The most common complications of thrombophilia are as follows: ^[1][2][6]
  • Deep vein thrombosis
  • Pulmonary embolism
  • Postthrombotic syndrome (PTS) with chronic venous ulceration (CVU) ^[8]

Table 1: The risk of future thrombosis in patients with thrombophilia:

Table 2: The effect of concurrent hormone exposure on incident thrombosis and thrombotic risk in patients with underlying thrombophilia:

• The prognosis depends on the underlying thrombophilia as each disorder has a different associated thrombotic risk (Table 1 and 2).
• Thrombophilias associated with the development of multiple or atypical clots, arterial thrombosis, or life-threatening thrombosis carries worse prognosis which are as follows:
  • Antiphospholipid Syndrome
  • Paroxysmal nocturnal hemoglobinuria
  • Antithrombin III deficiency
  • Factor V Leiden homozygosity
• High risk thrombophilic conditions require consideration for lifelong anticoagulation under the supervision of an expert consultant.
  • Antiphospholipid Syndrome
  • Paroxysmal nocturnal hemoglobinuria
  • Recurrent thrombosis regardless of underlying thrombophilia
  • History of life-threatening thrombosis or atypical locations
  • Malignancy with history of thrombosis

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