Aetiology
Hypercoagulable state can be inherited or acquired, but in some cases the underlying cause cannot be identified. Patients may have multiple co-existing heritable and acquired risk factors; it is the complex interplay between these factors that determines the overall risk of venous thromboembolism (VTE).
The inherited causes include the thrombophilias associated with reduced levels of inhibitors of the coagulation cascade (group 1) and thrombophilias associated with increased levels or function of the coagulation factors (group 2).[3] Group 3 thrombophilias consist of those with mixed or unknown aetiology.
Group 1 inherited thrombophilias include antithrombin (AT) deficiency, protein C deficiency, protein S deficiency, plasminogen deficiency, and dysfibrinolysis. Many patients with these disorders will have had venous thrombosis by the age of 60 years.[3]
Group 2 inherited thrombophilias include gene mutations in coagulation factor V (factor V Leiden), prothrombin (factor II), and sickle cell disease. These disorders are associated with a lower risk for thrombosis than the group 1 disorders, and most affected people will not have had thrombosis by the age of 60 years. In patients with suspected thrombophilia, group 2 disorders are found at least 5 times more frequently than group 1 disorders.[3]
Group 1 inherited causes of thrombophilia
AT deficiency: AT is a major inhibitor of blood coagulation and is essential for effective heparin therapy. AT inhibits the coagulation proteases, including IIa, Xa, IXa, and XIa. AT deficiency is associated with a high risk of thrombotic disorders. Its prevalence is 1 in 5000 in white people.[15] Genetic mutations cause either a quantitative deficiency or qualitative defect in AT. Reported in up to 3% of white people and 6% of Southeast Asian people with VTE.[10][11][16] Severe AT deficiency may increase the risk of VTE up to 50-fold.[17] Homozygosity for an AT defect results in death in utero.
Protein C deficiency: protein C is part of the anticoagulant regulatory mechanism. It is converted to activated protein C (APC) by thrombin in the presence of thrombomodulin. APC inactivates activated coagulation factors V and VIII, a reaction that requires its co-factor, protein S.[3] The condition in which a patient's plasma does not produce the appropriate anticoagulant response to APC is termed APC resistance. This can be caused by the R506Q gene mutation of coagulation factor V (termed factor V Leiden), which is resistant to cleavage by APC. Acquired APC resistance can be seen in pregnancy, use of oral contraception, hormone replacement therapy, and elevated factor VIII. Protein C deficiency has a prevalence of 1 in 500 in white people and a higher prevalence in Southeast Asian people.[11][18] It is present in up to 5% of white people with VTE and up to 8% of Southeast Asian people with VTE.[10][16][19] Homozygous deficiency can result in a severe phenotype with neonatal purpura fulminans.[20]
Protein S deficiency: prevalence of 1 in 1000 in white people; higher prevalence in Southeast Asian people.[10][12][19] Protein S is a vitamin K-dependent co-factor for the anticoagulant activity of APC. It has two forms: free protein S (40%) and protein S linked to the C4b binding protein (60%). Only the free form has co-factor activity. Protein S deficiency has been associated with a high risk of developing VTE, particularly in young people.
Plasminogen deficiency: may be a quantitative deficiency (hypoplasminogenaemia) or a qualitative deficiency (dysplasminogenaemia); studies suggest that the frequency of plasminogen deficiency is higher than expected in patients with venous thrombosis.[3]
Dysfibrinogenaemia: a rare inherited disorder associated with bleeding but complicated by thrombosis in 21% of patients.[21]
Group 2 inherited causes of thrombophilia
Factor V Leiden: genetic mutation of coagulation factor V that confers hypercoagulability. Prevalence of up to 6% in white people, but rare in other ethnic groups.[5][7] Found in up to 20% of white people with VTE.[22][23] Approximately 90% of patients with APC resistance have factor V Leiden.[3] Risk of VTE is increased up to sevenfold in heterozygotes and 80-fold in homozygotes.[7] More than 75% of carriers will never develop VTE.[24] However, among carriers with a family history of VTE, approximately 50% will develop VTE before the age of 65 years.[24]
Prothrombin (factor II) gene mutation (G-20210-A; also referred to as F2 c.*97G>A variant): people carrying the mutation have higher levels of prothrombin than normal, and the increased risk of thrombosis is thought to be a function of this. It has a prevalence of up to 2% in white people but is rare in other ethnic groups.[6][25] It is present in up to 6% of those presenting with VTE, and in 18% of those with a positive family history of VTE.[6] Risk of VTE is increased two- to threefold in heterozygotes. Compound heterozygosity with factor V Leiden increases risk of VTE 20-fold.[26]
Sickle cell disease: role in producing a hypercoagulable state is controversial. The disease leads to increased levels of markers of thrombin generation, abnormal activation of the fibrinolytic system, increased tissue factor expression, and platelet activation.[27] It has been suggested that sickle cell disease is associated with increased rates of pulmonary embolism, but deep venous thrombosis (DVT) rates are equivalent to age-matched controls.[28]
Group 3 mixed or unknown aetiology
Elevated fibrinogen levels: associated with a twofold increase in the risk of VTE.[29] Homozygosity of the fibrinogen gene FGG-H2 is associated with a weak genetic predisposition to VTE.[30]
Elevated levels of coagulation factor VIII: levels >150 U/litre increase the risk of VTE up to fivefold, but risk is more than 10-fold in black people.[14][31] Pathogenesis is unclear but may have a genetic component.[3] Found in approximately 25% of patients with VTE.[32] Risk of VTE increases by 10% for every 10 U/litre increment in factor VIII level.[31][32][33] Associated with increased risk of recurrent VTE.[33]
Elevated levels of coagulation factor IX or XI: associated with a two- to threefold increase in risk of VTE.[34][35] Underlying cause is not known. However, factor IX increases with age and use of combined oral contraceptive pills.
Elevated levels of thrombin-activatable fibrinolysis inhibitor (TAFI): associated with a twofold increase in risk for both first and recurrent VTE.[36]
Hyperhomocysteinaemia: can be congenital or acquired. Acquired forms found in patients with dietary deficiencies of folate, or vitamins B6 or B12. Congenital form is due to mutation, which results in impaired folate binding and reduced methylenetetrahydrafolate reductase (MTHFR) activity. The mechanism by which hyperhomocysteinaemia predisposes to thrombosis is unclear; potential mechanisms include endothelial activation, proliferation of smooth muscle cells, changes in endothelial nitric oxide production, and changes in endothelial sterol metabolism.[3] Its role in hypercoagulability is controversial; may not predispose to VTE.[37][38]
Acquired causes
Ageing: risk of VTE increases with age, from 1 in 100,000 children, to 1 in 1000 adults over the age of 40 years, to 1 in 100 in those aged >80 years.[39][40][41] Ageing is associated with increased levels of activated factors VII, IX, and X and increased levels of factor VIII, fibrinogen, and D-dimer (marker of fibrinolysis), which are associated with increased risk of thrombosis.[42] The increased prevalence of comorbidities associated with increasing age can further elevate coagulation factor levels.
Pregnancy/postpartum: increases the risk of VTE fourfold compared with non-pregnant females.[43][44][45] Pregnancy results in a physiological fall in protein S, and increases in fibrinogen, factor VIII, and von Willebrand factor. This results in APC resistance. All changes persist for at least 2 months postpartum.[46] VTE is a leading cause of maternal mortality.[47][48]
Malignancy: the predisposing risk factor in 16% to 18% of patients with thrombophilia.[49][50] Prothrombotic state results from activation of the coagulation system due to tissue factor expression, fibrinolytic activity, and cytokine release by malignant cells and their interaction with endothelial cells and platelets.[51][52] Prevalence of occult malignancy at diagnosis of unprovoked (idiopathic) VTE is 6.1%, and is 10% at 12 months post VTE diagnosis.[53] Occult malignancy is less frequent in cases of provoked VTE (1.6% and 2.4% at diagnosis, and 12 months post VTE diagnosis, respectively).[53] The subsequent diagnosis of cancer is usually advanced metastatic disease.[54] Occult malignancy and VTE are associated with a high incidence of early recurrence, bleeding, and death.[50]
Acute inflammatory state: risk of VTE is increased in hospitalised patients with acute infection, arthritis, connective tissue disease, or inflammatory bowel disease.[44][55][56] The rates are approximately 9% to 40% of those admitted with acute medical illness. Patients in the community with infectious disease have up to a twofold increased risk of VTE.[57] Inflammatory bowel disease increases risk of VTE threefold.[58] The underlying mechanism has not been elucidated.
Antiphospholipid antibodies (aPLs): associated with autoimmune disease (e.g., systemic lupus erythematosus) or malignancy (e.g., lymphoma).[59] Most patients with aPLs who develop VTE have additional risk factors for thrombosis.[59] Up to 20% of patients presenting with VTE have been found to have high levels of anticardiolipin antibodies before the event.[60] Antiphospholipid syndrome is characterised by persistent aPLs (lupus anticoagulant, anticardiolipin antibodies, anti‐beta-2 glycoprotein 1 antibodies tested at least twice, 12 weeks apart), and either an objectively confirmed thrombotic event or pregnancy-related morbidity.[61][62][63] Confirmed antiphospholipid syndrome is associated with high risk of recurrent VTE following withdrawal of anticoagulation.
Myeloproliferative disorders: these include polycythaemia vera, essential thrombocythaemia, primary or idiopathic myelofibrosis, and chronic myelogenous leukemia. Between 12% and 39% of cases present with thrombosis.[64] High rates of abdominal vein thrombosis are observed.[65] JAK2 V617F gene mutation is found in >95% of patients with polycythaemia vera and up to 50% of patients with essential thrombocythaemia and myelofibrosis.[66] The JAK2 V617F mutation may be responsible for the prothrombotic phenotype.[65]
Nephrotic syndrome: high incidence of hypercoagulable state in the first 6 months post diagnosis.[67] High prevalence of renal vein thrombosis.[68] Pathogenesis is unclear but probably due to combination of altered levels of coagulation and fibrinolytic proteins, platelet activation, hyperviscosity, hyperlipidaemia, low serum albumin, and therapy with corticosteroids or diuretics.[68]
Behcet's disease: a rare multisystem disorder characterised by recurrent oral and genital ulceration with ocular involvement. VTE is a common complication, affecting 6% to 39% of patients.[69][70] The pathogenesis is poorly understood. Increased markers of thrombin generation and fibrinolysis have been found in all patients.[70]
Disseminated intravascular coagulation: complication of an underlying condition such as sepsis, malignancy, trauma, or liver disease. Complex pathogenesis that results in increased thrombin generation due to increased tissue factor expression, impaired functioning of natural anticoagulants, and accelerated fibrinolysis.[71] It can be complicated by bleeding or thrombosis.
Paroxysmal nocturnal haemoglobinuria: hypercoagulable state occurs in 50% of patients with severe disease, and leads to death in one third.[72] Pathogenesis is not well understood but is thought to relate to haemolysis and possibly direct complement activation of platelets.[73]
Heparin-induced thrombocytopenia: caused by formation of antibodies to the complex formed between heparin and platelet factor 4 (PF4). Antibody binding to heparin/PF4 complex results in platelet activation, microparticle formation, platelet consumption, thrombocytopenia, and a subsequent increase in thrombin generation.[74] Should be suspected in any patient who develops thrombocytopenia or new thrombosis soon after starting heparin therapy.[75][76] Risk is lowest in medical/obstetric patients treated with low molecular weight heparin (<0.1%) and increases in postoperative cardiac and orthopaedic surgery patients treated with unfractionated heparin (1% to 5%).[75][77]
Oestrogen-containing oral contraceptive pill/hormone replacement therapy (HRT)/selective oestrogen receptor modulator therapy: these hormone therapies increase the risk of VTE.[78][79] [
]
Absolute risk of VTE following oral contraceptive pill use in young women without personal/family history of venous thrombosis remains low. Combined oral contraceptive pill and HRT can lead to decreased levels of protein S, increased levels of coagulation factors VII and VIII, increased fibrinolysis, and APC resistance.[80][81][82][83][84] Transdermal HRT preparations are associated with a lower risk than oral formulations.[85][86][87][88] Incidence of VTE is highest in first 12 months of starting oral contraceptive pill or HRT.[78][83] Tamoxifen use is associated with an increased risk of VTE.[89] Among women taking adjuvant tamoxifen for early-stage breast cancer, prevalence of factor V Leiden mutation may be approximately five times greater in those who experience a thromboembolic event than in those who do not.[90]Chemotherapy: the overall rate of VTE for patients receiving chemotherapy for cancer is 6%. Regimens that incorporate thalidomide or lenalidomide, in addition to high-dose dexamethasone, are associated with a higher incidence of VTE (8% to 75% in patients with newly diagnosed myeloma, compared with 3% when thalidomide or lenalidomide is used as a single agent).[91] Asparaginase therapy results in a near fivefold increase in rate of VTE in patients with acute lymphoblastic leukemia.[92]
Surgery: risk for VTE varies with type of surgery and other underlying risk factors. In patients not receiving prophylaxis, the baseline risk of symptomatic VTE following major orthopaedic surgery is estimated to be 4.3%.[93] Possibly due to postoperative prothrombotic state. Surgical trauma may result in tissue factor exposure and subsequent activation of coagulation.[94]
Obesity: pathogenesis is multifactorial and includes increased coagulation factors and impaired fibrinolysis. Tissue factor, factors VII and VIII, and plasminogen activator inhibitor-1 are all increased in obesity and may contribute to the prothrombotic state.[95][96] Adipocytokines may also be involved.[97] Obesity is associated with increased risk for both first and recurrent VTE, with greater risk conferred by increasing body mass index.[27][98][99]
Smoking: a weak risk factor for VTE, which remits on cessation of smoking.[100][101] Hypercoagulability may result from activation of coagulation and increased levels of fibrinogen and factors VII, IX, and X in current smokers compared with non-smokers.[102]
HIV infection: the incidence of VTE is higher in patients with HIV infection than in age- and sex-matched controls.[103] The mechanism leading to the prothrombotic state is uncertain.
Long-haul flight (>4 hours): the risk of VTE in a cohort of healthy people taking a flight of ≥4 hours is 1 in 6000.[104] Activation of coagulation and fibrinolysis with increased markers of thrombin generation has been observed in a subset of healthy volunteers after an 8-hour flight. These findings suggest that hypercoagulability acquired in-flight (rather than from immobilisation) contributes to VTE risk.[104][105] The risk of VTE increases with the presence of additional risk factors.[104][106][107]
Pathophysiology
The pathophysiology of the hypercoagulable state is not entirely understood. It is clear that a cumulative effect of multiple risk factors is important in its manifestation as venous thromboembolism (VTE), and such factors may be inherited and/or acquired.
An imbalance in the natural anticoagulant and procoagulant systems, and impaired fibrinolysis, lead to hypercoagulability. The underlying mechanisms will depend on the predisposing factors. Multiple risk factors can act synergistically, lowering the threshold for thrombosis. The trigger for a discrete clinical thrombotic event is often the development of one of the acquired secondary hypercoagulable states superimposed on an inherited state of hypercoagulability.
Classification
Types of inherited thrombophilia[3]
Group 1: reduced levels of inhibitors of the coagulation cascade
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Plasminogen deficiency
Dysfibrinolysis
Group 2: increased levels or function of coagulation factors
Factor V Leiden
Prothrombin gene mutation
Sickle cell disease
Group 3: mixed or unknown aetiology
Elevated fibrinogen levels
Elevated levels of factors VIII, IX, and XI
Hyperhomocysteinemia
Causes of acquired thrombophilia
Paroxysmal nocturnal haemoglobinuria
Nephrotic syndrome
Malignancy
Myeloproliferative disorders
Disseminated intravascular coagulation
Pregnancy/postpartum
Acute inflammatory state
Behcet's disease
Antiphospholipid antibodies (e.g., lupus anticoagulants, anticardiolipin antibodies, anti-beta-2 glycoprotein 1 antibodies)
Chemotherapy
Surgery
Heparin-induced thrombocytopenia
Oral contraceptive pills, oestrogen therapy (e.g., hormone replacement therapy, selective oestrogen receptor modulator therapy)
Smoking
Obesity
HIV infection
Long-haul flight (>4 hours)
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