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خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : -24 مورد

Overview of the causes of venous thrombosis in adults

Overview of the causes of venous thrombosis in adults
Authors:
Kenneth A Bauer, MD
Gregory YH Lip, MD, FRCPE, FESC, FACC
Section Editors:
Jess Mandel, MD, MACP, ATSF, FRCP
James D Douketis, MD, FRCPC, FACP, FCCP
Deputy Editor:
Geraldine Finlay, MD
Literature review current through: Apr 2025. | This topic last updated: Apr 24, 2025.

INTRODUCTION — 

The most common presentations of venous thrombosis are deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism (PE). The causes of venous thrombosis can be inherited or acquired and are often multiple in a given patient.

The causes and risk factors for venous thrombosis will be reviewed here (table 1) [1,2]. The diagnostic approach to DVT and PE, the evaluation for risk factors in patients with documented venous thrombosis, and etiologies of upper extremity venous thrombosis are discussed separately.

●(See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".)

●(See "Clinical presentation and diagnostic evaluation of the nonpregnant adult with suspected acute pulmonary embolism".)

●(See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

●(See "Primary (spontaneous) upper extremity deep vein thrombosis".)

●(See "Catheter-related upper extremity venous thrombosis in adults".)

VIRCHOW'S TRIAD AND RISK FACTOR PREVALENCE — 

Identifying risk factors raises clinical suspicion for thrombosis and may influence treatment.

Virchow's triad — Virchow's triad is the underlying pathophysiology of thrombosis formation [3] and includes the following:

●Blood flow stasis

●Vascular endothelial injury

●Hypercoagulable state

Risk factor prevalence in VTE — A risk factor (table 1) can be identified in >80 percent of patients with venous thromboembolism (VTE). Furthermore, more than one factor is often present in a given patient. As examples:

●Many patients with an episode of VTE have more than one acquired risk factor for thrombosis [4-6]. In one study, over one-third of patients had one to two risk factors and 53 percent had three or more risk factors [4]. In another study, the combination of a major medical illness plus immobilization increased the risk of VTE 11-fold [6].

●Patients may also have combinations of both inherited and acquired thrombophilic defects, driving up the overall risk of thrombosis (table 2). One-half of thrombotic events in patients with inherited thrombophilia are associated with the additional presence of an acquired risk factor (eg, surgery) [7].

●Some patients with VTE have more than one type of inherited thrombophilia, which leads to a significant increase in the risk of developing VTE. This has been shown in the general population in individuals who are heterozygous for both the factor V Leiden and prothrombin G20210A mutations [8]. (See 'Common inherited hypercoagulable states' below.)

ACQUIRED RISK FACTORS — 

There are many acquired risk factors for thrombosis (table 1). Common risk factors include prior thromboembolism, active malignancy (including myeloproliferative neoplasms [MPNs]), recent major surgery, trauma, immobilization, heart failure, older age (≥65 years), pregnancy, inflammatory bowel disease (IBD), exogenous estrogens, and antiphospholipid antibodies (aPL) (table 1).

Previous thromboembolism — Previous venous thromboembolism (VTE) is a risk factor for recurrence. The risk is cumulative and dependent upon patient-specific factors. Assessing this risk, which can range from low to high, is discussed separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Assessing risk of recurrence'.)

The site of the first VTE appears to predict future sites of recurrence. Patients presenting with pulmonary embolism (PE) are more likely to recur with PE than deep vein thrombosis (DVT) [9,10]. Similarly, patients who present with DVT are more likely to recur with DVT, although DVT often occurs in the contralateral leg [11].

Active malignancy — VTE occurs in approximately 15 percent of patients with active malignancy, especially those with advanced disease at the time of diagnosis (eg, pancreatic cancer) and those with MPNs. The risk is increased further by major surgery, chemotherapy, hospitalization, and the presence of intravenous catheters (eg, peripherally inserted central catheters [PICCs], port-a-cath, Hickman line). Studies have reported unprovoked VTE can precede the diagnosis of malignancy in older individuals [12-14], but this is less commonly seen in the era of age-appropriate cancer screening [15]. This risk is discussed in detail separately. (See "Cancer-associated hypercoagulable state: Causes and mechanisms" and "Multiple myeloma: Prevention of venous thromboembolism" and "Cancer-associated hypercoagulable state: Causes and mechanisms", section on 'Therapy-related factors' and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Evaluation for occult malignancy'.)

The impact of hyperviscosity in myeloproliferative syndromes is discussed below. (See 'Hematologic conditions' below.)

Surgery — Thrombotic risk increases during surgery, particularly orthopedic and major vascular, pelvic, neuro-, and cancer surgery [16-19]. The risk of thrombosis in nonorthopedic and orthopedic surgery is discussed separately.

●(See "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement", section on 'Risk of thrombosis'.)

●(See "Prevention of venous thromboembolism (VTE) in adults with non-major extremity orthopedic injury with or without surgical repair", section on 'Risk of thrombosis'.)

●(See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Baseline thrombosis risk'.)

Trauma — The risk of thrombosis is increased in all forms of major injury, especially spinal cord injury [20-23], and possibly in mild trauma, especially if an inherited thrombophilia is present (eg, trauma not requiring surgery, a plaster cast, hospitalization, or extended bed rest at home for at least four days) [24]. VTE risk in trauma patients is discussed separately. (See "Venous thromboembolism risk and prevention in the severely injured trauma patient", section on 'Pathophysiology and risk factors'.)

Immobilization (including hospitalization) — Venous stasis associated with bed rest, hospitalization, or prolonged immobilization (eg, intensive care unit admission, heart failure, stroke, myocardial infarction, leg injury) is an important risk factor for venous thrombosis [25,26]. VTE following stroke, hospitalization, and lower extremity injury are discussed separately. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke" and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Epidemiology' and "Prevention of venous thromboembolism (VTE) in adults with non-major extremity orthopedic injury with or without surgical repair", section on 'Risk of thrombosis'.)

Prolonged travel, especially by air, appears to confer a small increase in VTE risk (termed the "economy class syndrome"). This subject, including possible preventive measures, is discussed in detail separately. (See "Pathogenesis, risk factors, and prevention of venous thromboembolism in adult travelers", section on 'Epidemiology' and "Pathogenesis, risk factors, and prevention of venous thromboembolism in adult travelers", section on 'Risk factors'.)

Older age (≥65 years) — Data supporting age as a risk factor for DVT include the following:

●One observational study reported that the annual incidence of DVT increased from 17 per 100,000 persons/year for those between the ages of 40 and 49 to 232 per 100,000 persons/year for those between the ages of 70 and 79 [27].

●Another study reported an increasing incidence of VTE with age (hazard ratio [HR] 1.7 for every decade of life after 55 years) [28].

Pregnancy — The risk of thrombosis during pregnancy is approximately four times higher than in nonpregnant female patients. This subject is discussed in depth separately. (See "Venous thromboembolism in pregnancy: Epidemiology, pathogenesis, and risk factors", section on 'Epidemiology'.)

The risk of thrombosis is further accentuated when inherited thrombophilia is present. Details regarding inherited thrombophilias and VTE risk in pregnancy are described separately. (See "Inherited thrombophilias in pregnancy" and "Venous thromboembolism in pregnancy: Prevention".)

Chronic inflammatory bowel (and liver) disease — Despite an elevated international normalized ratio, patients with chronic liver disease are at increased risk of VTE. Further details are provided separately. (See "Hemostatic abnormalities in patients with liver disease".)

VTE is a known complication of IBD (ie, Crohn disease, ulcerative colitis). This subject is discussed further separately. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults", section on 'Extraintestinal manifestations' and "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults".)

Cardiovascular

Heart failure — Heart failure is a hypercoagulable state [29] that can result in intracardiac thrombus and DVT. The risk of DVT may be greatest in patients with right heart failure (eg, those with peripheral edema) and those who are hospitalized for heart failure (adjusted HR 3.13) [30].

Established atherosclerotic heart disease — Patients with established atherosclerotic heart disease are at increased risk of VTE [31-33]. For example, an observational study reported that myocardial infarction or stroke was associated with a fourfold increased risk of VTE within three months of the event [31]. Another study suggested that those at greatest risk were older, Black, and female patients [33].

Conversely, patients with DVT may be at increased risk of atherosclerotic disease [34-39]. In one cohort study, patients with VTE had a twofold risk of having asymptomatic atherosclerotic disease compared with those who did not have VTE [32]. In other studies, patients with VTE had a 1.5- to threefold risk of an acute myocardial infarction or stroke [34,37].

Cardiovascular risk factors — Patients with risk factors for cardiovascular disease are also at risk for VTE [28,40], especially age (see 'Older age (≥65 years)' above), obesity, and smoking:

●Obesity – Several studies have found an increased risk for VTE (two- to threefold) and VTE recurrence in patients with obesity [28,41-44] and a reduced risk for underweight patients [45]. In one study, the greatest impact was seen in those below the age of 40 [44].

Obesity further increases the risk of VTE when patients have factor V Leiden or the prothrombin gene mutation, undergo extended travel, or are taking hormonal contraceptives [43,46,47]

●Smoking – Most studies report a relationship between smoking and VTE risk with relative risks ranging from 1.3 to 3.3 [48-50]. In one meta-analysis of 32 observational studies, compared with "never smokers," the relative risk (RR) of VTE was 1.17 ("ever smokers"), 1.23 (current smokers), and 1.1 (former smokers). The risk increased by 10 percent for every additional ten cigarettes smoked per day or by 6.1 percent for every additional ten pack-years [50]. Additional risk factors, such as obesity or contraceptive use, increased the risk further [50,51].

●Others – Other factors that may be associated with an increased risk of VTE include male sex, diabetes, and possibly hypertension and hypercholesterolemia [41,52,53].

In a cohort study of 40,000 female patients, those who were nonsmokers were physically active, and consumed alcohol in moderation were at a lower risk of developing VTE [54].

Drugs — Several drugs have been associated with an increased risk of venous thrombosis. Statin use may be associated with a reduced risk of recurrence after a first episode of VTE [55].

Hormonal — Several hormonal therapies are associated with an increased risk of VTE:

●Contraceptives – Oral and transdermal contraceptive use (which contain estrogen) is a cause of thrombosis in young female patients [56-59].

The risk of thrombosis increases within the first 6 to 12 months of therapy [60] and is unaffected by duration of use. The risk likely returns to previous levels within one to three months of cessation [59].

Whether there is an additive risk with contraceptives and nonsteroidal anti-inflammatory agents is unclear [61].

Further information on VTE risk and contraceptives are provided separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism' and "Contraception: Transdermal contraceptive patches", section on 'Risk of venous thrombotic events' and "Transgender women: Evaluation and management", section on 'Estrogen therapy'.)

●Hormone replacement therapy – Data support an increased risk of VTE in female patients who take oral, but not transdermal, estrogen as part of menopausal hormone therapy. This subject is discussed in detail separately. (See "Menopausal hormone therapy: Benefits and risks", section on 'Venous thromboembolism'.)

●Testosterone – It is controversial as to whether there is an increased risk of VTE in some individuals taking testosterone, most commonly in those who develop erythrocytosis. However, a systematic review and meta-analysis did not find a statistically significant association between VTE and testosterone [62]. (See "Testosterone treatment of male hypogonadism", section on 'Venous thromboembolism'.)

●Tamoxifen – Tamoxifen is associated with an increased risk of VTE, especially when additional risk factors are present (eg, surgery, cancer, fracture). (See "Managing the side effects of tamoxifen and aromatase inhibitors", section on 'Venous thromboembolism'.)

Cancer therapy — Several chemotherapeutic agents (eg, cisplatin, asparaginase), immunomodulatory agents (eg, thalidomide, lenalidomide), antiangiogenic drugs (eg, bevacizumab), and cyclin-dependent kinase inhibitors used to treat cancer have been associated with an increased risk of thrombosis. The use of erythropoiesis-stimulating drugs has also been shown to increase the risk of thrombosis in cancer patients receiving chemotherapy. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".)

Antiphospholipid antibodies — Patients with aPL are at risk of developing venous or arterial thrombosis. They are given the diagnosis of antiphospholipid syndrome (APS) when they develop thrombosis or recurrent fetal loss. The risk of thrombosis in those with aPL and APS manifestations are discussed separately. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Thrombotic events'.)

Kidney diseases — Patients with end-stage kidney disease, nephrotic syndrome, and kidney transplant are at increased risk for VTE [63-67]. Data supporting this risk include the following:

●One study reported a higher annual frequency of PE in adults with end-stage kidney disease and chronic kidney disease compared with those who had normal kidney function (527, 204, and 66 per 100,000 persons, respectively) [68].

●Other observational data reported a relative VTE risk of 1.7 for patients with stage 3/4 chronic kidney disease compared with patients with nonimpaired kidney function [66].

●Patients with the nephrotic syndrome have an increased prevalence of both arterial thromboembolism and VTE (10 to 40 percent), particularly DVT and renal vein thrombosis. These data are discussed separately. (See "Hypercoagulability in nephrotic syndrome", section on 'Pathogenesis' and "Hypercoagulability in nephrotic syndrome", section on 'Epidemiology' and "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Other venous thrombosis'.)

●The prevalence of VTE following kidney transplantation is in the range of 5 to 8 percent, with PE being a common cause of death [69,70]. In one study of 484 kidney transplantation patients, 7 percent developed VTE at a median time of 6.5 months post-kidney transplantation (range 1 to 81 months) and 50 percent had recurrence following cessation of oral anticoagulants [69].

Risk factors for VTE in stages 1 to 3 chronic kidney disease include albuminuria (urinary albumin ≥30 mg/24 hours) and a low estimated glomerular filtration rate (<75 mL/minute per 1.73 m2) [71,72].

The reason for the increased risk is unknown but may relate to elevated levels of factor VIII and Von Willebrand factor in this population [73].

Hematologic conditions

●Heparin-induced thrombocytopenia – Venous and arterial thrombosis is the major clinical problem associated with heparin-induced thrombocytopenia (HIT). The risk of thrombosis in HIT is described separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia", section on 'Incidence and risk factors'.)

Very rarely, patients can develop a HIT-like syndrome in the absence of heparin exposure, referred to as autoimmune HIT or spontaneous HIT. Coronavirus disease 2019 (COVID-19) virus-induced immune thrombotic thrombocytopenia is one such syndrome. (See "Virus-induced immune thrombotic thrombocytopenia (VITT) and VITT-like disorders".)

●Hyperviscosity – Thrombosis is a complication of hyperviscosity (ie, increased plasma viscosity, number of red or white blood cells, or decreased cell deformability).

•Hyperfibrinogenemia and hypergammaglobulinemia – Increased plasma viscosity can result from hyperfibrinogenemia or hypergammaglobulinemia. Hyperviscosity-associated hypergammaglobulinemia is most commonly encountered in Waldenstrom macroglobulinemia or multiple myeloma. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome' and "Multiple myeloma: Prevention of venous thromboembolism", section on 'VTE incidence and risk factors' and "Disorders of fibrinogen".)

•Myeloproliferative neoplasms (MPNs) – Increased whole blood viscosity (and platelet defects) play an important role in the pathogenesis of thrombosis in polycythemia vera. Common thrombotic complications include cerebrovascular accidents, myocardial infarction, peripheral arterial occlusion, DVT, PE, and portal and hepatic vein thrombosis (Budd-Chiari syndrome).

Essential thrombocythemia is also associated with an increased risk of thrombotic complications, particularly in association with the presence of the JAK2 V617F mutation; it can also lead to hemorrhagic complications when the platelet count is very elevated.

A high percentage of patients with idiopathic hepatic vein thrombosis (eg, Budd-Chiari syndrome) or portal vein thrombosis, but not those with idiopathic lower extremity DVT [74-77], have evidence of an occult MPN (lack of an elevated hematocrit or platelet count in association with the presence of the JAK2 V617F, CALR, or MPL mutations) [78-81]. (See "Etiology of the Budd-Chiari syndrome", section on 'Myeloproliferative disorders' and "Clinical manifestations and diagnosis of polycythemia vera", section on 'Thrombosis and hemorrhage' and "Essential thrombocythemia: Clinical manifestations and diagnosis", section on 'Thrombosis and hemorrhage'.)

•Hyperleukocytosis and leukostasis – Increased whole blood viscosity also occurs in occasional patients with myeloid and monocytic leukemias who have markedly elevated white blood cell counts (generally >100,000/microL). Small vessels in the lungs, brain, and (less commonly) other organs can be obstructed by high levels of immature leukocytes. (See "Hyperleukocytosis and leukostasis in hematologic malignancies".)

•Sickle cell disease – Increased whole blood viscosity in sickle cell disease is primarily due to decreased deformability of sickled erythrocytes and may contribute to the occlusion of small blood vessels. Other factors that may play a role in this complication include enhanced adhesion of sickle erythrocytes to vascular endothelium and increased coagulation and platelet activation [82-84]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Venous thromboembolism' and "Overview of the pulmonary complications of sickle cell disease", section on 'Venous thromboembolism and pulmonary thrombosis'.)

●Paroxysmal nocturnal hemoglobinuria (PNH) – PNH is a rare acquired clonal disorder of bone marrow stem cells. Approximately 40 percent of patients develop thrombosis, typically in the intraabdominal venous network (mesenteric, hepatic, portal, splenic, and renal veins) and cerebral vessels as opposed to a lower extremity or lung [85]. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Thrombosis'.)

Miscellaneous — Several other conditions are associated with an increased risk of VTE [45,86-109], most of which are discussed separately:

●Hyperhomocysteinemia – (See "Overview of homocysteine".)

●Polycystic ovary syndrome – (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Venous thromboembolism'.)

●Ovarian hyperstimulation syndrome – (See "Pathogenesis, clinical manifestations, and diagnosis of ovarian hyperstimulation syndrome", section on 'Specific complications'.)

●Central venous lines and PICCs – (See "Central venous catheters: Overview of complications and prevention in adults" and "Central venous catheters: Overview of complications and prevention in adults", section on 'Catheter malfunction'.)

●Superficial vein thrombosis – (See "Superficial vein thrombosis and phlebitis of the lower extremity veins".)

●COVID-19 and COVID-19 vaccination – (See "COVID-19: Hypercoagulability" and "Virus-induced immune thrombotic thrombocytopenia (VITT) and VITT-like disorders" and "COVID-19: Vaccines".)

●Rheumatoid arthritis – (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Venous thromboembolic disease'.)

●Active tuberculosis – (See "Pulmonary tuberculosis disease in adults: Clinical manifestations and complications", section on 'Venous thromboembolism'.)

●Sepsis – (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Intensive care unit patients'.)

●Klinefelter syndrome – (See "Clinical features, diagnosis, and management of Klinefelter syndrome", section on 'Comorbidities'.)

●Chronic psoriasis – (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

●Obstructive sleep apnea – (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Complications'.)

●Antineutrophil cytoplasmic antibodies-associated vasculitis – (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement".)

●Microalbuminuria – (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease".)

●Anemia (in acutely ill hospitalized patients) – (See "Diagnostic approach to anemia in adults".)

●Sarcoidosis – (See "Sarcoidosis-associated pulmonary hypertension: Diagnostic evaluation in adults", section on 'Pulmonary vascular disease'.)

●Hereditary angioedema – (See "Hereditary angioedema (due to C1 inhibitor deficiency): Epidemiology, clinical manifestations, exacerbating factors, and prognosis".)

●Intravenous drug use

●Asthma (the contribution of glucocorticoid use is unknown)

●Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome – VEXAS syndrome, due to somatic mutations in UBA1, is a rare acquired autoinflammatory disorder with systemic manifestations including thrombosis. In one observational study of 119 patients with VEXAS syndrome, almost one-half had thrombosis, 80 percent of which was venous (cumulatively 40 percent at 5 years) and the remainder arterial (cumulatively 11 percent at 5 years) [110]. Among those with VTE, two-thirds were unprovoked. Further details regarding VEXAS syndrome are provided separately. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome'.)

There is conflicting evidence concerning whether air pollution is [111-113] or is not [114,115] causally related to VTE development. (See "Overview of possible risk factors for cardiovascular disease", section on 'Air pollution'.)

Hospital admission rates for VTE are highest during the winter months and lowest during the summer months [116,117]. Possible explanations include vasoconstriction due to reduced activity or cold weather; superimposed infection; or seasonal variation in thrombogenic factors, including fibrinogen and factor VII activity [118], and active sun exposure [117].

The higher rate of VTE in Black Americans compared with White Americans is thought to be mostly explained by the higher prevalence of risk factors in Black Americans [119].

INHERITED THROMBOPHILIA — 

A positive family history of venous thromboembolism (VTE) is a strong VTE risk factor (table 3) [120].

Common inherited hypercoagulable states — Among the inheritable deficiencies, the factor V Leiden and the prothrombin gene mutations together account for 50 to 60 percent of cases in White populations. Defects in protein S, protein C, and antithrombin (formerly known as antithrombin III) account for most of the remaining cases [121-124]. The relative risk for developing VTE is increased in people with the factor V Leiden (four- to fivefold) and prothrombin G20210A mutations (three- to fourfold) and those with deficiencies of antithrombin (16-fold), protein C (sevenfold), and protein S (fivefold) (table 3).

Each of these conditions is discussed separately:

●Factor V Leiden mutation (see "Factor V Leiden and activated protein C resistance")

●Prothrombin gene mutation (see "Prothrombin G20210A")

●Protein S deficiency (see "Protein S deficiency")

●Protein C deficiency (see "Protein C deficiency")

●Antithrombin deficiency (see "Antithrombin deficiency")

The evaluation of patients with established VTE for inherited thrombophilia is discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Other genetic abnormalities of no or uncertain VTE risk — These disorders include the following:

●Heparin cofactor II deficiency – Heparin cofactor II is a thrombin inhibitor. Several families have been described with deficiency in this protein inherited as an autosomal dominant trait. Heterozygous individuals have plasma heparin cofactor II concentrations that are approximately 50 percent of normal values.

It is unclear if heparin cofactor II deficiency is a significant risk factor for thrombosis [125,126]. In one series of 305 patients with juvenile thromboembolic episodes, two patients had heparin cofactor II deficiency [126]. However, each patient had a second defect: the factor V Leiden mutation or protein C deficiency.

●Dysfibrinogenemia – Patients with dysfibrinogenemia have structural defects that cause alterations in converting fibrinogen to fibrin. Defects can be inherited or acquired. These disorders are discussed separately. (See "Disorders of fibrinogen".)

●Factor XII deficiency – Severe factor XII deficiency (factor XII activity <1 percent of normal) is inherited as an autosomal recessive trait. It prolongs the activated partial thromboplastin time, but is not associated with bleeding [127]. However, patients exhibit a thrombophilic tendency attributed to reduced plasma fibrinolytic activity [128]. Further information on factor XII deficiency is provided separately. (See "Rare inherited coagulation disorders".)

●Other genetic variants – Several genetic variants associated with an increased VTE risk have been found by candidate and genome-wide screens with odds ratios generally <1.5 [129-131]. These include variants in the genes for fibrinogen and factor XI. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors".)

Similarly, adults with supernumerary sex chromosome aneuploidies (ie, more than two sex chromosomes) are at increased risk of VTE compared with patients who have two sex chromosomes (1.3 versus 0.25 percent per person year; 10-year risk difference 8.8 percent) [132].

●Plasminogen and plasminogen activator inhibitor-1 (PAI-1) – Plasminogen deficiency has not been shown to be a risk factor for venous thrombosis. However, a 4G polymorphism in the PAI-1 promoter (designated 4G/5G) may be a weak risk factor when combined with other thrombophilic defects. (See "Plasminogen deficiency" and "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".)

ANATOMIC RISK FACTORS FOR DEEP VEIN THROMBOSIS — 

Several anatomic factors increase the risk of deep vein thrombosis (DVT) in the upper or lower extremities.

Varicose veins — Varicose veins are associated with an increased risk of DVT [133-135]. In one observational study, patients with varicose veins had an increased rate of DVT and pulmonary embolism (PE) compared with patients without varicose veins (6.6 versus 1.2 per 1000 person-years, hazard ratio [HR] 5.3 [DVT]; 0.48 versus 0.28 per 1000 person-years, HR 1.73 [PE]) [133]. Further studies are required to confirm this association and ensure that it is not due to confounding variables, such as smoking or obesity. (See "Approach to treating symptomatic superficial venous insufficiency".)

Paget-Schroetter syndrome — Paget-Schroetter syndrome, also called spontaneous upper extremity venous thrombosis, is usually due to an underlying compressive anomaly at the thoracic outlet. This subject is discussed separately. (See "Primary (spontaneous) upper extremity deep vein thrombosis" and "Brachial plexus syndromes", section on 'Thoracic outlet syndrome'.)

May-Thurner syndrome — May-Thurner syndrome (MTS; also known as iliac vein compression syndrome) is due to compression of the left common iliac vein between the overlying right common iliac artery and the underlying vertebral body. MTS has been associated with unprovoked left iliofemoral DVT or chronic venous insufficiency. MTS is discussed separately. (See "May-Thurner syndrome".)

Inferior vena cava abnormalities — Congenital venous malformations of the inferior vena cava (IVC), including agenesis, hypoplasia, or malformation, may lead to DVT [136-143]. In such cases, DVT primarily occurs in young patients and may be bilateral or recurrent or involve the iliac veins, a clinical picture similar to that of the inherited thrombophilias.

●In a series of 97 consecutive patients presenting with confirmed DVT of the lower extremities, 5 of the 31 with thrombotic occlusion of the iliac veins had an anomaly of the IVC. Thrombosis was bilateral in one and recurrent in two patients [140]. Patients with IVC abnormalities were younger at the time of presentation compared with those who did not have an IVC abnormality (25 versus 53 years).

●In one report of 10 cases of IVC agenesis-associated DVT (mean age 25 years), DVT followed intense and unusual physical activity in eight, was bilateral in six, and was localized to iliofemoral veins in nine [141].

ABNORMAL LEVELS OF CLOTTING FACTORS AND CHEMOKINES — 

Elevated levels of select clotting factors and chemokines have been associated with an increased thrombotic risk (table 4). These measurements in patients with venous thromboembolism (VTE) have generally been made following a thrombotic event, so a post-thrombotic phenomenon cannot be entirely excluded. The basis for the elevated levels of these factors remains unclear and is rarely genetically based.

●Elevated factor VIII – Elevated plasma factor VIII coagulant activity (VIII:C) is an independent marker of increased thrombotic risk [144-148]. In one study, factor VIII:C levels >150 percent of normal had a fivefold increased risk of VTE compared with individuals with levels <100 percent [149].

Another study reported that the prevalence of elevated factor VIII:C levels in patients with unexplained thrombosis is approximately 25 percent [150].

An elevated factor VIII level may also be a strong thrombotic risk factor in Black patients. In a study of 100 Black patients with VTE, only 9 percent had an underlying genetic cause (eg, protein C or S deficiency, antithrombin deficiency) while 34 percent had VIII:C levels higher than the 90th percentile [151].

High factor VIII levels are not acute phase reactants and persist over time [152,153]. Elevated factor VIII levels appear to be constitutional with a heritable contribution [154-156], although the genetic determinant responsible for them has not been identified [157-159].

A rare partial duplication in the gene for factor VIII has been associated with markedly elevated factor VIII levels and venous thrombosis in two Italian families [160]. This duplication contains transcriptional activators that may upregulate messenger ribonucleic acid (mRNA) and protein expression.

●Other plasma components – A two- to threefold increased risk for VTE has been reported for altered levels of several plasma components, coagulant factors, anticoagulant factors, and inflammatory chemokines (table 4). Assays for some of these proteins are not widely available and the clinical utility of these abnormalities is uncertain. (See "Clinical use of coagulation tests", section on 'Shortened PT and/or aPTT'.)

•Elevated levels of the following have been described:

-Plasma factor IX antigen [161,162]

-Plasma factor XI antigen [163,164]

-Thrombin-activatable fibrinolysis inhibitor [165-167]

-Plasminogen activator inhibitor-1 [167]

-Interleukin 8 [168,169]

-Factor VII levels [156]

-Plasma fibronectin levels [170]

-Von Willebrand factor (VWF) [156,171,172]

-Fibrinogen [153,173,174] (see "Disorders of fibrinogen")

-Altered fibrin clot structure and function [175]

•Reduced levels of the following have been described:

-Tissue factor pathway inhibitor [176]

-Plasma fibrinolytic activity [167,177]

-Thrombomodulin [178]

●Single nucleotide polymorphisms (SNPs) – SNPs variations of the nucleotide sequence in the genome occurring in at least 1 percent of the population) and other genetic variations have been implicated as potential genetic contributors to the risk of VTE [178-186]. (See "Genetic testing".)

Several such SNPs were identified, including two within the factor XI gene locus, that may explain VTE associated with elevated factor XI levels [179,180,186].

●Non-O blood type – Patients with the non-O blood group (ie, groups A, B, and AB) have been shown to have a higher VTE risk than those with blood group O (odds ratios of 1.79 and 1.84) [187-189]. This may be related to associated differences in VWF and factor VIII levels between patients with O and non-O blood groups. (See "Pathophysiology of von Willebrand disease", section on 'Clearance and control of plasma VWF levels'.)

●Stabilin-2 (STAB2) variants – Genetic analysis has shown rare variants in the STAB2 gene that increase the risk for VTE [190]. STAB2 encodes Stabilin-2, an endothelial cell surface scavenger receptor that may lead to reduced clearance and higher levels of VWF in the blood.

●Factor IX Padua – A rare gain-of-function mutation in factor IX (R338L or factor IX Padua) was associated with an episode of deep vein thrombosis in a previously healthy 23-year-old male from Italy [161]. The plasma level of factor IX antigen in the proband was normal, but factor IX activity was approximately eight times the normal level.

UPPER EXTREMITY THROMBOSIS — 

A major risk factor for developing deep vein thrombosis (DVT) of the upper extremity is the presence of indwelling venous catheters. A less common risk factor in patients with a spontaneous upper extremity DVT is anatomic abnormalities of the thoracic outlet causing axillosubclavian compression. These entities are discussed separately. (See "Catheter-related upper extremity venous thrombosis in adults" and "Primary (spontaneous) upper extremity deep vein thrombosis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Pulmonary embolism (Beyond the Basics)" and "Patient education: Antiphospholipid syndrome (Beyond the Basics)")

SUMMARY

●Pathogenesis and risk factors – Virchow's triad is the underlying pathophysiology of thrombosis formation (stasis, endothelial injury, hypercoagulable state). Risk factors are identified in 80 percent of patients with venous thromboembolism (VTE), can be acquired or hereditary, and are often multiple in a given patient (table 1). Identifying risk factors raises the clinical suspicion for thrombosis and may influence treatment. (See 'Virchow's triad and risk factor prevalence' above.)

●Acquired – The major acquired risk factors for VTE include prior thromboembolism, active malignancy, (including myeloproliferative neoplasms), recent major surgery, trauma, immobilization, heart failure, older age (≥65 years), pregnancy, inflammatory bowel disease, exogenous estrogens, and antiphospholipid antibodies (table 1). (See 'Acquired risk factors' above.)

Less common etiologies include kidney diseases, hematologic diseases associated with hyperviscosity and leukostasis, and paroxysmal nocturnal hemoglobinuria.

Other miscellaneous causes include hyperhomocysteinemia, polycystic ovarian syndrome, ovarian hyperstimulation syndrome venous catheters, superficial thrombophlebitis, and several other conditions.

●Inherited thrombophilia – Factor V Leiden and prothrombin gene mutations are the most common inherited thrombophilias while defects in protein S, protein C, and antithrombin are less common (table 2 and table 3). (See 'Common inherited hypercoagulable states' above.)

Inherited thrombophilias are discussed in detail separately.

•(See "Factor V Leiden and activated protein C resistance".)

•(See "Prothrombin G20210A".)

•(See "Protein S deficiency".)

•(See "Protein C deficiency".)

•(See "Antithrombin deficiency".)

In other inheritable disorders, the risk is unclear. This includes heparin cofactor II deficiency, dysfibrinogenemia, and factor XII deficiency. (See 'Other genetic abnormalities of no or uncertain VTE risk' above.)

●Anatomic abnormalities – Several anatomic factors increase the risk of deep vein thrombosis in the upper or lower extremities including varicose veins; Paget-Schroetter syndrome (thoracic outlet compression); May-Thurner syndrome (iliac vein compression); or inferior vena cava agenesis, hypoplasia, or malformation. (See 'Anatomic risk factors for deep vein thrombosis' above and "May-Thurner syndrome" and "Primary (spontaneous) upper extremity deep vein thrombosis".)

●Abnormal levels of clotting factors and chemokines – Abnormal levels of some clotting factors and chemokines, including elevated levels of factors VIII, IX, and XI, thrombin-activatable fibrinolysis inhibitor, plasminogen activator inhibitor-1, and interleukin 8 have been associated with an increased thrombotic risk (table 4). (See 'Abnormal levels of clotting factors and chemokines' above.)

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  130. Smith NL, Hindorff LA, Heckbert SR, et al. Association of genetic variations with nonfatal venous thrombosis in postmenopausal women. JAMA 2007; 297:489.
  131. Klarin D, Busenkell E, Judy R, et al. Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease. Nat Genet 2019; 51:1574.
  132. Berry ASF, Finucane BM, Myers SM, et al. Association of Supernumerary Sex Chromosome Aneuploidies With Venous Thromboembolism. JAMA 2023; 329:235.
  133. Chang SL, Huang YL, Lee MC, et al. Association of Varicose Veins With Incident Venous Thromboembolism and Peripheral Artery Disease. JAMA 2018; 319:807.
  134. Li R, Chen Z, Gui L, et al. Varicose Veins and Risk of Venous Thromboembolic Diseases: A Two-Sample-Based Mendelian Randomization Study. Front Cardiovasc Med 2022; 9:849027.
  135. Wei Q, Wei ZQ, Jing CQ, et al. Incidence, prevention, risk factors, and prediction of venous thromboembolism in Chinese patients after colorectal cancer surgery: a prospective, multicenter cohort study. Int J Surg 2023; 109:3003.
  136. Chee YL, Culligan DJ, Watson HG. Inferior vena cava malformation as a risk factor for deep venous thrombosis in the young. Br J Haematol 2001; 114:878.
  137. Ruggeri M, Tosetto A, Castaman G, Rodeghiero F. Congenital absence of the inferior vena cava: a rare risk factor for idiopathic deep-vein thrombosis. Lancet 2001; 357:441.
  138. Hamoud S, Nitecky S, Engel A, et al. Hypoplasia of the inferior vena cava with azygous continuation presenting as recurrent leg deep vein thrombosis. Am J Med Sci 2000; 319:414.
  139. Motwani J, Rose PE, Shatwell W. An unusual case of venous thromboembolism. Br J Haematol 2005; 128:1.
  140. Obernosterer A, Aschauer M, Schnedl W, Lipp RW. Anomalies of the inferior vena cava in patients with iliac venous thrombosis. Ann Intern Med 2002; 136:37.
  141. Lambert M, Marboeuf P, Midulla M, et al. Inferior vena cava agenesis and deep vein thrombosis: 10 patients and review of the literature. Vasc Med 2010; 15:451.
  142. Kim H, Labropoulos N, Blake AM, Desai K. Prevalence of Inferior Vena Cava Anomalies and Their Significance and Impact in Clinical Practice. Eur J Vasc Endovasc Surg 2022; 64:388.
  143. Protti G, Elia F, Bosco F, Aprà F. An Eminent Absence: Agenesis of Inferior Vena Cava Underlying Bilateral Iliac Vein Thrombosis. Eur J Case Rep Intern Med 2020; 7:001999.
  144. Kraaijenhagen RA, in't Anker PS, Koopman MM, et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83:5.
  145. Tsai AW, Cushman M, Rosamond WD, et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113:636.
  146. Jenkins PV, Rawley O, Smith OP, O'Donnell JS. Elevated factor VIII levels and risk of venous thrombosis. Br J Haematol 2012; 157:653.
  147. Bank I, van de Poel MH, Coppens M, et al. Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study. Thromb Haemost 2007; 98:1040.
  148. Lowe G, Wu O, van Hylckama Vlieg A, et al. Plasma levels of coagulation factors VIII and IX and risk of venous thromboembolism: Systematic review and meta-analysis. Thromb Res 2023; 229:31.
  149. Koster T, Blann AD, Briët E, et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345:152.
  150. O'Donnell J, Tuddenham EG, Manning R, et al. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77:825.
  151. Patel RK, Ford E, Thumpston J, Arya R. Risk factors for venous thrombosis in the black population. Thromb Haemost 2003; 90:835.
  152. O'Donnell J, Mumford AD, Manning RA, Laffan M. Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2000; 83:10.
  153. Kamphuisen PW, Eikenboom JC, Vos HL, et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost 1999; 81:680.
  154. de Lange M, Snieder H, Ariëns RA, et al. The genetics of haemostasis: a twin study. Lancet 2001; 357:101.
  155. Morange PE, Tregouet DA, Frere C, et al. Biological and genetic factors influencing plasma factor VIII levels in a healthy family population: results from the Stanislas cohort. Br J Haematol 2005; 128:91.
  156. Smith NL, Chen MH, Dehghan A, et al. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010; 121:1382.
  157. Kamphuisen PW, Eikenboom JC, Rosendaal FR, et al. High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. Br J Haematol 2001; 115:156.
  158. Berger M, Mattheisen M, Kulle B, et al. High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11. Blood 2005; 105:638.
  159. Viel KR, Machiah DK, Warren DM, et al. A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels. Blood 2007; 109:3713.
  160. Simioni P, Cagnin S, Sartorello F, et al. Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia. Blood 2021; 137:2383.
  161. Simioni P, Tormene D, Tognin G, et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009; 361:1671.
  162. van Hylckama Vlieg A, van der Linden IK, Bertina RM, Rosendaal FR. High levels of factor IX increase the risk of venous thrombosis. Blood 2000; 95:3678.
  163. Meijers JC, Tekelenburg WL, Bouma BN, et al. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342:696.
  164. Cushman M, O'Meara ES, Folsom AR, Heckbert SR. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood 2009; 114:2878.
  165. Martini CH, Brandts A, de Bruijne EL, et al. The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis. Br J Haematol 2006; 134:92.
  166. Folkeringa N, Coppens M, Veeger NJ, et al. Absolute risk of venous and arterial thromboembolism in thrombophilic families is not increased by high thrombin-activatable fibrinolysis inhibitor (TAFI) levels. Thromb Haemost 2008; 100:38.
  167. Meltzer ME, Lisman T, de Groot PG, et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood 2010; 116:113.
  168. van Aken BE, den Heijer M, Bos GM, et al. Recurrent venous thrombosis and markers of inflammation. Thromb Haemost 2000; 83:536.
  169. van Aken BE, Reitsma PH, Rosendaal FR. Interleukin 8 and venous thrombosis: evidence for a role of inflammation in thrombosis. Br J Haematol 2002; 116:173.
  170. Pecheniuk NM, Elias DJ, Deguchi H, et al. Elevated plasma fibronectin levels associated with venous thromboembolism. Thromb Haemost 2008; 100:224.
  171. Nossent AY, VAN Marion V, VAN Tilburg NH, et al. von Willebrand factor and its propeptide: the influence of secretion and clearance on protein levels and the risk of venous thrombosis. J Thromb Haemost 2006; 4:2556.
  172. Smith NL, Rice KM, Bovill EG, et al. Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis. Blood 2011; 117:6007.
  173. Koster T, Rosendaal FR, Reitsma PH, et al. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms--the Leiden Thrombophilia Study (LETS). Thromb Haemost 1994; 71:719.
  174. Machlus KR, Cardenas JC, Church FC, Wolberg AS. Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice. Blood 2011; 117:4953.
  175. Undas A, Zawilska K, Ciesla-Dul M, et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114:4272.
  176. Dahm A, Van Hylckama Vlieg A, Bendz B, et al. Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 2003; 101:4387.
  177. Lisman T, de Groot PG, Meijers JC, Rosendaal FR. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood 2005; 105:1102.
  178. Tang L, Wang HF, Lu X, et al. Common genetic risk factors for venous thrombosis in the Chinese population. Am J Hum Genet 2013; 92:177.
  179. Bezemer ID, Bare LA, Doggen CJ, et al. Gene variants associated with deep vein thrombosis. JAMA 2008; 299:1306.
  180. Li Y, Bezemer ID, Rowland CM, et al. Genetic variants associated with deep vein thrombosis: the F11 locus. J Thromb Haemost 2009; 7:1802.
  181. Reiner AP, Lange LA, Smith NL, et al. Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study. J Thromb Haemost 2009; 7:1499.
  182. Morange PE, Tregouet DA. Deciphering the molecular basis of venous thromboembolism: where are we and where should we go? Br J Haematol 2010; 148:495.
  183. Heit JA, Cunningham JM, Petterson TM, et al. Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism. J Thromb Haemost 2011; 9:1133.
  184. Dennis J, Johnson CY, Adediran AS, et al. The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies. Blood 2012; 119:2392.
  185. El-Galaly TC, Severinsen MT, Overvad K, et al. Single nucleotide polymorphisms and the risk of venous thrombosis: results from a Danish case-cohort study. Br J Haematol 2013; 160:838.
  186. Austin H, De Staercke C, Lally C, et al. New gene variants associated with venous thrombosis: a replication study in White and Black Americans. J Thromb Haemost 2011; 9:489.
  187. Wu O, Bayoumi N, Vickers MA, Clark P. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost 2008; 6:62.
  188. El-Galaly TC, Kristensen SR, Overvad K, et al. Interaction between blood type, smoking and factor V Leiden mutation and risk of venous thromboembolism: a Danish case-cohort study. J Thromb Haemost 2012; 10:2191.
  189. Gándara E, Kovacs MJ, Kahn SR, et al. Non-OO blood type influences the risk of recurrent venous thromboembolism. A cohort study. Thromb Haemost 2013; 110:1172.
  190. Desch KC, Ozel AB, Halvorsen M, et al. Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease. Blood 2020; 136:533.
Topic 1361 Version 119.0

References

1 : Risk factors for venous thrombosis - current understanding from an epidemiological point of view.

2 : Risk factors for venous thromboembolism.

3 : Virchow and his triad: a question of attribution.

4 : The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism.

5 : Triggers of hospitalization for venous thromboembolism.

6 : Risk of venous thrombosis in patients with major illnesses: results from the MEGA study.

7 : Genetic approach to thrombophilia.

8 : Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank.

9 : Extended oral anticoagulant therapy after a first episode of pulmonary embolism.

10 : Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism.

11 : Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators.

12 : Deep-vein thrombosis and the incidence of subsequent symptomatic cancer.

13 : The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism.

14 : The long-term risk of cancer in patients with a first episode of venous thromboembolism.

15 : Screening for Occult Cancer in Unprovoked Venous Thromboembolism.

16 : Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures.

17 : Bilateral vs. ipsilateral venography as the primary efficacy outcome measure in thromboprophylaxis clinical trials: a systematic review.

18 : Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial.

19 : Variation in the risk of venous thromboembolism following colectomy.

20 : A prospective study of venous thromboembolism after major trauma.

21 : Thromboembolic complications in patients with pelvic trauma.

22 : A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma.

23 : Thromboembolic complications following trauma.

24 : Minor injuries as a risk factor for venous thrombosis.

25 : Incidence of deep vein thrombosis in bedridden non-surgical patients.

26 : Use of the low-molecular-weight heparin reviparin to prevent deep-vein thrombosis after leg injury requiring immobilization.

27 : A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study.

28 : Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology.

29 : Does heart failure confer a hypercoagulable state? Virchow's triad revisited.

30 : Incident heart failure and long-term risk for venous thromboembolism

31 : Arterial cardiovascular events, statins, low-dose aspirin and subsequent risk of venous thromboembolism: a population-based case-control study.

32 : An association between atherosclerosis and venous thrombosis.

33 : Rate and impact of venous thromboembolism in patients with ST-segment elevation myocardial infarction: Analysis of the Nationwide Inpatient Sample database 2003-2013.

34 : Venous thromboembolism and subsequent hospitalisation due to acute arterial cardiovascular events: a 20-year cohort study.

35 : Risk of arterial cardiovascular events in patients after pulmonary embolism.

36 : Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta-analysis.

37 : Increased risk of arterial thromboembolism after a prior episode of venous thromboembolism: results from the Prevention of REnal and Vascular ENd stage Disease (PREVEND) Study.

38 : Impact of incident venous thromboembolism on risk of arterial thrombotic diseases.

39 : Long-Term Effects of Unprovoked Venous Thromboembolism on Mortality and Major Cardiovascular Events.

40 : Troponin T, NT-proBNP, and venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE).

41 : Cardiovascular risk factors and venous thromboembolism: a meta-analysis.

42 : Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study.

43 : Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations.

44 : Obesity as a risk factor in venous thromboembolism.

45 : Underweight is associated with a reduced risk of venous thromboembolism. Results from the EDITH case-control study.

46 : Genetic susceptibility, smoking, obesity and risk of venous thromboembolism.

47 : The relationship between body mass index, activated protein C resistance and risk of venous thrombosis.

48 : Smoking, surgery, and venous thromboembolism risk in women: United Kingdom cohort study.

49 : The association of smoking with venous thrombosis in women. A population-based, case-control study.

50 : Current and former smoking and risk for venous thromboembolism: a systematic review and meta-analysis.

51 : Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use.

52 : Family history of myocardial infarction is an independent risk factor for venous thromboembolism: the Tromsøstudy.

53 : Atrial fibrillation and future risk of venous thromboembolism:the Tromsøstudy.

54 : The relationship between lifestyle factors and venous thromboembolism among women: a report from the MISS study.

55 : The association of statin therapy with the risk of recurrent venous thrombosis.

56 : Hormones and pregnancy: thromboembolic risks for women.

57 : Risk of acute thromboembolic events with oral contraceptive use: a systematic review and meta-analysis.

58 : Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis.

59 : The risk of venous thrombosis in women over 50 years old using oral contraception or postmenopausal hormone therapy.

60 : Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects.

61 : Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study.

62 : Testosterone therapy and venous thromboembolism: A systematic review and meta-analysis.

63 : Prevalence of preterminal pulmonary thromboembolism among patients on maintenance hemodialysis treatment before and after introduction of recombinant erythropoietin.

64 : Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy.

65 : Chronic dialysis patients have high risk for pulmonary embolism.

66 : Chronic kidney disease increases risk for venous thromboembolism.

67 : Pulmonary Embolism in Patients with End-Stage Kidney Disease Starting Dialysis.

68 : Pulmonary embolism in patients with CKD and ESRD.

69 : High rate of recurrence in renal transplant recipients after a first episode of venous thromboembolism.

70 : Early renal insufficiency and late venous thromboembolism after renal transplantation in the United States.

71 : Chronic kidney disease stages 1-3 increase the risk of venous thrombosis.

72 : Association of mild to moderate chronic kidney disease with venous thromboembolism: Pooled analysis of five prospective general population cohorts

73 : Role of hemostatic factors on the risk of venous thrombosis in people with impaired kidney function.

74 : JAK2V617F mutation screening as part of the hypercoagulable work-up in the absence of splanchnic venous thrombosis or overt myeloproliferative neoplasm: assessment of value in a series of 664 consecutive patients.

75 : Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings.

76 : Prevalence of the JAK2 V617F mutation is low among unselected patients with a first episode of unprovoked venous thromboembolism.

77 : JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis.

78 : Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis.

79 : Etiology of portal vein thrombosis in adults. A prospective evaluation of primary myeloproliferative disorders.

80 : In vitro colony culture and chromosomal studies in hepatic and portal vein thrombosis--possible evidence of an occult myeloproliferative state.

81 : Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis.

82 : Erythrocyte adherence to endothelium in sickle-cell anemia. A possible determinant of disease severity.

83 : Thrombophilia in sickle cell disease: the red cell connection.

84 : Hypercoagulability in sickle cell disease: a curious paradox.

85 : Natural history of paroxysmal nocturnal hemoglobinuria.

86 : Infectious complications of central venous catheters increase the risk of catheter-related thrombosis in hematology patients: a prospective study.

87 : Incidence of thrombotic complications in patients with haematological malignancies with central venous catheters: a prospective multicentre study.

88 : Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis.

89 : Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003-2008.

90 : Risk of venous thromboembolism associated with peripherally inserted central catheters: a systematic review and meta-analysis.

91 : Risk of venous thromboembolism in patients with rheumatoid arthritis.

92 : Asthma increases pulmonary thromboembolism risk: a nationwide population cohort study.

93 : Use of oral glucocorticoids and the risk of pulmonary embolism: a population-based case-control study.

94 : Active tuberculosis and venous thromboembolism: association according to international classification of diseases, ninth revision hospital discharge diagnosis codes.

95 : Impact of sepsis on risk of postoperative arterial and venous thromboses: large prospective cohort study.

96 : Psoriasis and risk of venous thromboembolism: a systematic review and meta-analysis.

97 : Risk of venous and arterial thrombotic events in patients diagnosed with superficial vein thrombosis: a nationwide cohort study.

98 : VTE Incidence and Risk Factors in Patients With Severe Sepsis and Septic Shock.

99 : Sleep apnea and venous thromboembolism. A systematic review.

100 : High Risk of Venous Thromboembolism in Klinefelter Syndrome.

101 : Increased risks of venous thromboembolism in patients with psoriasis. A Nationwide Cohort Study.

102 : Risk of Cardiovascular Disease and Venous Thromboembolism Among Patients With Incident ANCA-Associated Vasculitis: A 20-Year Population-Based Cohort Study.

103 : Association of Anemia with Venous Thromboembolism in Acutely Ill Hospitalized Patients: An APEX Trial Substudy.

104 : The groin hit: complications of intravenous drug abuse.

105 : High prevalence of iliofemoral venous thrombosis with severe groin infection among injecting drug users in North East Scotland: successful use of low molecular weight heparin with antibiotics.

106 : Injecting drug use is a risk factor for deep vein thrombosis in women in Glasgow.

107 : Increased risk of venous thromboembolism in young and middle-aged individuals with hereditary angioedema: a family study.

108 : Exploring the Two-Way Link between Migraines and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

109 : The Association between Obstructive Sleep Apnea and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study.

110 : Venous and arterial thrombosis in patients with VEXAS syndrome.

111 : Exposure to particulate air pollution and risk of deep vein thrombosis.

112 : Living near major traffic roads and risk of deep vein thrombosis.

113 : Air pollution and hospitalization for venous thromboembolic disease in Chile.

114 : Ambient particulate matter air pollution and venous thromboembolism in the Women's Health Initiative Hormone Therapy trials.

115 : Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study.

116 : Seasonal variations in hospital admission for deep vein thrombosis and pulmonary embolism: analysis of discharge data.

117 : Does an active sun exposure habit lower the risk of venous thrombotic events? A D-lightful hypothesis.

118 : Seasonal variations of plasma fibrinogen and factor VII activity in the elderly: winter infections and death from cardiovascular disease.

119 : Reasons for Differences in the Incidence of Venous Thromboembolism in Black Versus White Americans.

120 : The value of family history as a risk indicator for venous thrombosis.

121 : Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism--results of the Spanish Multicentric Study on Thrombophilia (EMET-Study).

122 : Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant.

123 : Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system.

124 : Advances in understanding pathogenic mechanisms of thrombophilic disorders.

125 : Hereditary heparin cofactor II deficiency and the risk of development of thrombosis.

126 : A heparin cofactor II mutation (HCII Rimini) combined with factor V Leiden or type I protein C deficiency in two unrelated thrombophilic subjects.

127 : Contact factors in health and disease.

128 : Defective intrinsic fibrinolytic activity in a patient with severe factor XII-deficiency and myocardial infarction.

129 : Multiple SNP testing improves risk prediction of first venous thrombosis.

130 : Association of genetic variations with nonfatal venous thrombosis in postmenopausal women.

131 : Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease.

132 : Association of Supernumerary Sex Chromosome Aneuploidies With Venous Thromboembolism.

133 : Association of Varicose Veins With Incident Venous Thromboembolism and Peripheral Artery Disease.

134 : Varicose Veins and Risk of Venous Thromboembolic Diseases: A Two-Sample-Based Mendelian Randomization Study.

135 : Incidence, prevention, risk factors, and prediction of venous thromboembolism in Chinese patients after colorectal cancer surgery: a prospective, multicenter cohort study.

136 : Inferior vena cava malformation as a risk factor for deep venous thrombosis in the young.

137 : Congenital absence of the inferior vena cava: a rare risk factor for idiopathic deep-vein thrombosis.

138 : Hypoplasia of the inferior vena cava with azygous continuation presenting as recurrent leg deep vein thrombosis.

139 : An unusual case of venous thromboembolism.

140 : Anomalies of the inferior vena cava in patients with iliac venous thrombosis.

141 : Inferior vena cava agenesis and deep vein thrombosis: 10 patients and review of the literature.

142 : Prevalence of Inferior Vena Cava Anomalies and Their Significance and Impact in Clinical Practice.

143 : An Eminent Absence: Agenesis of Inferior Vena Cava Underlying Bilateral Iliac Vein Thrombosis.

144 : High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism.

145 : Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE).

146 : Elevated factor VIII levels and risk of venous thrombosis.

147 : Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study.

148 : Plasma levels of coagulation factors VIII and IX and risk of venous thromboembolism: Systematic review and meta-analysis.

149 : Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis.

150 : High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction.

151 : Risk factors for venous thrombosis in the black population.

152 : Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response.

153 : Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions.

154 : The genetics of haemostasis: a twin study.

155 : Biological and genetic factors influencing plasma factor VIII levels in a healthy family population: results from the Stanislas cohort.

156 : Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.

157 : High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene.

158 : High factor VIII levels in venous thromboembolism show linkage to imprinted loci on chromosomes 5 and 11.

159 : A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels.

160 : Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia.

161 : X-linked thrombophilia with a mutant factor IX (factor IX Padua).

162 : High levels of factor IX increase the risk of venous thrombosis.

163 : High levels of coagulation factor XI as a risk factor for venous thrombosis.

164 : Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology.

165 : The effect of genetic variants in the thrombin activatable fibrinolysis inhibitor (TAFI) gene on TAFI-antigen levels, clot lysis time and the risk of venous thrombosis.

166 : Absolute risk of venous and arterial thromboembolism in thrombophilic families is not increased by high thrombin-activatable fibrinolysis inhibitor (TAFI) levels.

167 : Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1.

168 : Recurrent venous thrombosis and markers of inflammation.

169 : Interleukin 8 and venous thrombosis: evidence for a role of inflammation in thrombosis.

170 : Elevated plasma fibronectin levels associated with venous thromboembolism.

171 : von Willebrand factor and its propeptide: the influence of secretion and clearance on protein levels and the risk of venous thrombosis.

172 : Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis.

173 : Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms--the Leiden Thrombophilia Study (LETS).

174 : Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice.

175 : Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives.

176 : Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis.

177 : Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis.

178 : Common genetic risk factors for venous thrombosis in the Chinese population.

179 : Gene variants associated with deep vein thrombosis.

180 : Genetic variants associated with deep vein thrombosis: the F11 locus.

181 : Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study.

182 : Deciphering the molecular basis of venous thromboembolism: where are we and where should we go?

183 : Genetic variation within the anticoagulant, procoagulant, fibrinolytic and innate immunity pathways as risk factors for venous thromboembolism.

184 : The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies.

185 : Single nucleotide polymorphisms and the risk of venous thrombosis: results from a Danish case-cohort study.

186 : New gene variants associated with venous thrombosis: a replication study in White and Black Americans.

187 : ABO(H) blood groups and vascular disease: a systematic review and meta-analysis.

188 : Interaction between blood type, smoking and factor V Leiden mutation and risk of venous thromboembolism: a Danish case-cohort study.

189 : Non-OO blood type influences the risk of recurrent venous thromboembolism. A cohort study.

190 : Whole-exome sequencing identifies rare variants in STAB2 associated with venous thromboembolic disease.