Overview of the causes of venous thrombosis - UpToDate
64 Pages • 23,283 Words • PDF • 715.8 KB
Uploaded at 2021-09-24 10:43
This document was submitted by our user and they confirm that they have the consent to share it. Assuming that you are writer or own the copyright of this document, report to us by using this DMCA report button.
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Official reprint from UpToDate® www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Overview of the causes of venous thrombosis Authors: Kenneth A Bauer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC Section Editors: Lawrence LK Leung, MD, Jess Mandel, MD Deputy Editor: Geraldine Finlay, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2019. | This topic last updated: Sep 09, 2019.
INTRODUCTION The most common presentations of venous thrombosis are deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism. The causes of venous thrombosis can be divided into two groups: hereditary and acquired, and are often multiple in a given patient. The inherited and acquired causes of venous thrombosis will be reviewed here (table 1) [1,2]. The diagnostic approach to the patient with suspected venous thrombosis, the evaluation and treatment of patients with documented venous thrombosis, and the various causes 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" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Primary (spontaneous) upper extremity deep vein thrombosis" and "Brachial plexus syndromes" and "Catheter-related upper extremity venous thrombosis".)
VIRCHOW'S TRIAD A major theory delineating the pathogenesis of venous thromboembolism (VTE), often called Virchow's triad [3,4], proposes that VTE occurs as a result of: ●
Alterations in blood flow (ie, stasis)
●
Vascular endothelial injury
●
Alterations in the constituents of the blood (ie, inherited or acquired hypercoagulable state)
A risk factor for thrombosis can now be identified in over 80 percent of patients with venous thrombosis. Furthermore, there is often more than one factor at play in a given patient. As https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
1/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
examples: ●
Fifty percent of thrombotic events in patients with inherited thrombophilia are associated with the additional presence of an acquired risk factor (eg, surgery, prolonged bed rest, pregnancy, oral contraceptives). Some patients have more than one form of inherited thrombophilia or more than one form of acquired thrombophilia and appear to be at even greater risk for thrombosis (see 'Multiple inherited thrombotic defects' below) [5].
●
In a population-based study of the prevalence of venous thromboembolism (VTE), 56 percent of the patients had three or more of the following six risk factors present at the time of VTE: >48 hours of immobility in the preceding month; hospital admission, surgery, malignancy, or infection in the past three months; or current hospitalization (see 'Multiple acquired risk factors' below) [6].
Accordingly, many patients with VTE fulfill most or all of Virchow's triad of stasis, endothelial injury, and hypercoagulability [7-9].
SUPERFICIAL VEIN THROMBOSIS Superficial vein thrombosis (SVT), a less severe disorder than deep vein thrombosis (DVT), occurs in both inherited and acquired thrombophilic states and may progress to DVT and/or pulmonary embolism (PE) [10-13]. In 63 patients presenting with ultrasonically-confirmed SVT of the lower extremities as a first thrombotic episode, and in whom DVT, varicose veins, malignancy, and autoimmune disorders were absent, the following observations were made [14]: ●
Twenty patients (32 percent) developed DVT at a median elapsed interval of four years.
●
Fifteen patients (24 percent) had recurrent episodes of SVT.
●
The odds ratios for the development of SVT in patients with factor V Leiden, the prothrombin G20210A mutation, or a deficiency of antithrombin, protein S or C were 6.1, 4.3, and 12.9, respectively.
In another meta-analysis of 21 studies of patients with SVT, the prevalence of DVT was 18 percent and PE was 7 percent [15]. This subject is discussed in depth separately. (See "Phlebitis and thrombosis of the superficial lower extremity veins".)
INHERITED THROMBOPHILIA Common inherited hypercoagulable states — Inherited thrombophilia is a genetic tendency to venous thromboembolism. The most frequent causes of an inherited (primary) hypercoagulable https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
2/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
state are the factor V Leiden mutation and the prothrombin gene mutation, which together account for 50 to 60 percent of cases. Defects in protein S, protein C, and antithrombin (formerly known as antithrombin III) account for most of the remaining cases (table 1) [16-19]. Each of these is discussed separately, as follows: ●
Factor V Leiden mutation (see "Factor V Leiden and activated protein C resistance")
●
Prothrombin gene mutation (see "Prothrombin G20210A mutation")
●
Protein S deficiency (see "Protein S deficiency")
●
Protein C deficiency (see "Protein C deficiency")
●
Antithrombin deficiency (see "Antithrombin deficiency")
Deep vein thrombosis — The thrombotic risk associated with the inherited thrombophilias has been assessed in two ways: evaluation of patients with DVT (table 2) and evaluation of families with thrombophilia. In a Spanish study of 2132 consecutive unselected patients with venous thromboembolism, for example, 12.9 percent had an anticoagulant protein deficiency (7.3 percent with protein S, 3.2 percent with protein C, and 0.5 percent with antithrombin). An additional 4.1 percent had elevated levels of antiphospholipid antibodies (aPL) [16]. Similar findings were noted in a series of 277 Dutch outpatients with deep vein thrombosis: 8.3 percent had an isolated deficiency of antithrombin, protein C, protein S, or plasminogen compared with 2.2 percent of controls [20]. The prevalence of a protein deficiency was only modestly greater in "high risk" patients with recurrent, familial, or juvenile onset deep vein thrombosis (9, 16, and 12 percent respectively). A higher frequency of inherited thrombophilia has also been noted in patients with thrombosis of visceral or cerebral vessels [21]. The overall 8 to 13 percent prevalence of an isolated anticoagulant protein deficiency in patients with deep vein thrombosis does not include the contribution of factor V Leiden or the prothrombin gene mutation, now considered to be the most common causes of inherited thrombophilia. ●
The Physicians' Health Study and the Leiden Thrombophilia Study found a 12 to 19 percent prevalence of heterozygosity for the factor V Leiden mutation in patients with a first DVT (or pulmonary embolism in the Physicians' Health Study) compared with 3 to 6 percent in controls [22,23]. The prevalence reached 26 percent in the Physicians' Health Study in 31 men over the age of 60 with no identifiable precipitating factors [22]. (See "Factor V Leiden and activated protein C resistance".)
●
The prevalence of the prothrombin gene mutation is approximately 6 to 8 percent in patients with deep vein thrombosis compared with 2 to 2.5 percent in controls [17,24]. (See "Prothrombin G20210A mutation".)
Thus, the total prevalence of an inherited thrombophilia in subjects with a deep vein thrombosis ranges from 24 to 37 percent overall compared with about 10 percent in controls. https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
3/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Thrombotic risk in families — The absolute risk of thrombosis among patients with inherited thrombophilia was evaluated in a report of 150 pedigrees, which compared the risk for thrombosis in individuals with inherited thrombophilia due to factor V Leiden or to antithrombin, protein C, or protein S deficiency (table 3) [12]. The lifetime probability of developing thrombosis compared with those with no defect was 8.5 times higher for carriers of protein S deficiency, 8.1 for antithrombin deficiency, 7.3 for protein C deficiency, and 2.2 for factor V Leiden. The thrombosis risk in affected women was also increased during pregnancy and the use of oral contraceptives (see 'Pregnancy' below). Multiple inherited thrombotic defects — A second thrombotic defect can occur among patients with any of the causes of familial thrombophilia, particularly factor V Leiden [25-28]. (See "Factor V Leiden and activated protein C resistance", section on 'Venous thromboembolism'.) In one series, factor V Leiden was present in 4 of 14 patients with protein S deficiency and 6 of 15 with protein C deficiency [26]. Carriers of two (or more) defects seem to be at a higher risk for thrombosis than their relatives with a single defect. In one review of four studies, approximately 75 percent of the family members who were carriers of two defects had experienced thrombosis compared with 10 to 30 percent of the carriers of a single defect [25]. Inherited thrombophilia also may interact to increase the risk of venous thrombosis in patients with acquired causes of hypercoagulability, such as oral contraceptive use (table 2) [29] and pregnancy (see 'Combined acquired plus inherited risk factors' below). The clinical characteristics and diagnosis of the five major causes of inherited thrombophilia: the factor V Leiden mutation, antithrombin deficiency, protein S and protein C deficiency, and the prothrombin gene mutation, are discussed in detail separately. (See "Factor V Leiden and activated protein C resistance" and "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency" and "Prothrombin G20210A mutation".) Other alleged inherited thrombophilias — The remainder of this section will briefly review other alleged causes of inherited thrombophilia. As will be seen, it remains unclear whether some of these disorders are actually associated with an increased risk of venous thrombosis. Heparin cofactor II deficiency — Heparin cofactor II (antithrombin is heparin cofactor I) is a heparin-dependent glycoprotein that acts as a thrombin inhibitor. Several families have been described with quantitative 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 not clear if heparin cofactor II deficiency is a significant risk factor for thrombosis [30,31]. In one series of 305 patients with juvenile thromboembolic episodes, two patients had heparin cofactor II deficiency [31]. However, each of these patients had a second defect: the factor V Leiden mutation and protein C deficiency. https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
4/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Plasminogen deficiency — Congenital plasminogen deficiency is usually inherited as an autosomal dominant trait. There are both quantitative defects (type I, hypoplasminogenemia in the heterozygote and aplasminogenemia in the homozygote) and functional defects (type 2, dysplasminogenemia). Venous thrombosis has been reported in some patients identified with plasminogen deficiency, but a familial predisposition is usually absent. The clinical importance of plasminogen deficiency as a risk factor for thrombosis is uncertain. In a Spanish study of 2132 consecutive patients with thrombosis, plasminogen deficiency was seen in 0.75 percent [16]. However, this prevalence may not be significantly higher than that seen in the general population. In a cohort of 9611 blood donors, for example, 0.29 percent had asymptomatic familial plasminogen deficiency [32]. Additional clinical findings associated with plasminogen deficiency (eg, ligneous conjunctivitis) are discussed separately. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".) Other rare fibrinolytic defects such as impaired tissue plasminogen activator release or increased plasminogen activator inhibitor levels have been linked to thrombosis in isolated families [33], and may increase the risk of venous thrombosis in subjects with other thrombophilic defects [34]. In one of these kindreds, six of the seven subjects with a history of thrombosis were also deficient in total and free protein S [35]. Once again, the pathogenetic importance of these defects is uncertain. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Plasminogen activator inhibitor'.) Dysfibrinogenemia — Patients with dysfibrinogenemia have structural defects that cause alterations in the conversion of fibrinogen to fibrin. Approximately 300 abnormal fibrinogens have been reported, and more than 80 structural defects have been identified [36,37]. The most common structural defects involve the fibrinopeptides and their cleavage sites, and the second most common involves the gamma-chain polymerization region. Approximately one-half of the mutants are clinically silent, whereas hemorrhage and thrombosis occur in almost equal numbers of symptomatic patients. (See "Disorders of fibrinogen".) Factor XII deficiency — Factor XII, Hageman factor, is the zymogen of a serine protease that initiates the contact activation reactions and intrinsic blood coagulation in vitro. Severe factor XII deficiency (factor XII activity less than 1 percent of normal) is inherited as an autosomal recessive trait; affected patients have marked prolongation in the activated partial thromboplastin time (aPTT) but do not exhibit a bleeding diathesis [38]. To the contrary, venous thromboembolism and myocardial infarction have been reported in a number of factor XII-deficient patients [39], including John Hageman, the initial patient described with this abnormality [40]. This thrombophilic tendency has been attributed to reduced plasma fibrinolytic activity [41]. The frequency with which severe factor XII deficiency leads to thrombosis is uncertain. One review found that 8 percent had a history of thromboembolism [39]. However, interpretation of this type of
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
5/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
data is difficult, since patients with complications are more likely to be reported than those who are asymptomatic. This led to cross-sectional analyses of thromboembolic events in larger numbers of unselected families with factor XII deficiency. In a study of 14 Swiss families with factor XII deficiency, 2 of 18 homozygous or doubly heterozygous patients had sustained deep venous thrombosis; however, each episode occurred at a time when other predisposing thrombotic risk factors were present [42]. Only one of 45 heterozygotes in these families had a possible history of venous thrombosis. However, other groups have found a more pronounced association with thrombosis [43,44]. Thus, it remains unproven if factor XII deficiency is associated with an increased risk of thrombosis.
ACQUIRED RISK FACTORS Overview — Acquired risk factors or predisposing conditions for thrombosis include a prior thrombotic event, recent major surgery, presence of a central venous catheter , trauma, immobilization, malignancy, pregnancy, the use of oral contraceptives or heparin, myeloproliferative disorders, antiphospholipid syndrome (APS), and a number of other major medical illnesses (table 1) [2,45-49]. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Assess risk'.) While upper extremity DVT is less common than lower extremity DVT, some of the same risk factors are present [50,51]. As an example, in a study of 512 patients with acute symptomatic upper extremity DVT with or without pulmonary embolism, 38 percent had cancer; 45 percent had central venous catheter-related DVT [50]. (See "Catheter-related upper extremity venous thrombosis".) Multiple acquired risk factors — Many patients with an episode of VTE have more than one acquired risk factor for thrombosis. This was shown in a population-based study of the incidence of VTE in residents of Worcester, MA during 1999. The six most prevalent pre-existing medical characteristics of patients in this study were [6]: ●
More than 48 hours of immobility in the preceding month – 45 percent
●
Hospital admission in the past three months – 39 percent
●
Surgery in the past three months – 34 percent
●
Malignancy in the past three months – 34 percent
●
Infection in the past three months – 34 percent
●
Current hospitalization – 26 percent
Only 11 percent of the 587 episodes of VTE had none of these six characteristics present, while 36 and 53 percent had 1 to 2 and ≥3 risk factors, respectively.
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
6/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Triggers of hospitalization for VTE were evaluated in a case-crossover study of 16,781 participants in the Health and Retirement Study, a nationally representative sample of older Americans. Exposures to triggering events during the 90-day period prior to 399 hospitalizations for VTE were compared with exposures occurring during four 90-day comparison periods that did not result in hospitalization for VTE. Results included [52]: ●
Infections, especially for those associated with a previous hospital or skilled nursing facility stay, were the most common trigger of hospitalization for VTE, occurring in 52.4 percent of the risk periods before hospitalization, as compared with 28 percent for the four comparison periods.
●
Other significant triggers included use of erythropoiesis-stimulating agents, blood transfusion, major surgery, fractures, immobility, and chemotherapy.
●
These triggers, when combined, accounted for 70 percent of exposures before VTE hospitalization, as opposed to 35 percent in the comparison periods.
Combined acquired plus inherited risk factors — As noted above, patients with VTE may have multiple inherited defects or multiple acquired risk factors for VTE. In addition, they may also have combinations of both inherited and acquired thrombophilic defects. This was best shown in the MEGA case-control study in 4311 consecutive subjects with a first episode of VTE and 5768 controls, in which the following observations were made [49]: ●
Subjects with self-reported major medical illnesses (ie, liver or kidney disease, rheumatoid arthritis, multiple sclerosis, heart failure, hemorrhagic stroke, arterial thrombosis) had increased venous thrombotic risk, with odds ratios in the range of 1.5 to 4.9.
●
The combination of a major medical illness, as defined above, plus immobilization increased the odds ratio for development of venous thrombosis to 10.9 (95% CI 4.2-28).
●
The combination of a major medical illness along with immobilization plus an thrombophilic defect increased the risk of venous thrombosis even further, with odds ratios of 80, 35, 88, 84, and 53 for increased factor VIII levels, increased factor IX levels, increased von Willebrand factor levels, presence of factor V Leiden, or the presence of non-O blood groups, respectively.
Regardless of whether the patient has a genetic and/or an environmental risk factor for VTE, the presence of a positive family history of VTE has been found to be a strong additional risk factor for VTE [53]. Previous thromboembolism — Previous thrombotic episodes are a major risk factor for recurrent VTE. In an outpatient prospective cohort study, the risk of recurrence after an acute episode of venous thrombosis was 18, 25, and 30 percent at two, five, and eight years,
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
7/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
respectively [54]. In a community-based epidemiologic study, a previous history of VTE conferred a relative risk (RR) of 7.9 for VTE recurrence [55]. The magnitude of this risk is highly dependent upon patient-specific factors. Those with an episode of thrombosis in the absence of known risk factors (ie, idiopathic VTE), or in association with permanent risk factors (eg, cancer) have a higher rate of recurrence than those with timelimited, reversible risk factors (eg, recent major surgery, immobilization) [54,56,57]. In one study, for example, the influence of these risk factors on the two-year cumulative incidence of VTE recurrence was as follows [58]: ●
Patients with surgery in the six weeks prior to a first VTE – zero percent recurrence; a much lower risk for recurrence in patients with surgery associated VTE (hazard ratio 0.36) was also noted in another study [54].
●
Pregnancy-associated VTE – zero percent recurrence
●
Patients with nonsurgical risk factors (eg, oral contraceptive use, fracture or application of plaster cast, immobilization) – 8.8 percent
●
Patients with an unprovoked VTE in whom there was no identifiable clinical risk factor – 19.4 percent
The presence or absence of these risk factors (eg, pregnancy, surgery) becomes important in the therapeutic approach to patients with a first or recurrent episode of VTE. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Summary and recommendations'.) In addition, the site of the first VTE appears to be a predictor of the site and perhaps frequency of future episodes of VTE: ●
Patients with a PE during the first episode of VTE are much more likely to have a PE during recurrence. One study followed 436 patients recovering from a first episode of idiopathic VTE [59]. When compared with subjects with DVT and no symptoms of PE, those with symptomatic PE had a significantly higher risk of VTE recurrence (RR 2.2) and a higher risk of developing symptomatic PE at recurrence (RR 4.0). In another report of 165 patients presenting with PE, approximately 60 percent of the recurrences were a second episode of PE [56].
●
Patients with a DVT during the first episode of VTE are highly likely to have a DVT during recurrence. This was illustrated in a study of 267 patients with a first episode of idiopathic DVT; 34 of the 42 recurrences were DVTs, with the most common site of recurrence being in the contralateral leg [57].
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
8/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Malignancy — Patients with cancer often have a hypercoagulable state due to the production of substances with procoagulant activity (eg, tissue factor and cancer procoagulant). Clinical venous thromboembolism occurs in approximately 15 percent of such patients and is a common cause of serious clinical outcomes, including major hemorrhage and death, especially in older patients as well as in those malignancies associated with advanced disease at the time of diagnosis (eg, pancreatic cancer) and myeloproliferative neoplasms (MPNs) [60-65]. The risk of VTE in such patients appears to be highest during the initial hospitalization, time of diagnosis, onset of chemotherapy, as well as at the time of disease progression [66]. MPNs have a higher rate of both venous (10 percent) and arterial thrombosis (3 percent) [65]. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Hospitalized medical patients'.) The risk of thrombosis may be further increased in patients with malignancy and a central venous catheter, in which situation the prevalence of a venous thrombotic event may be as high as 12 percent [67-70]. The use of certain drugs may also increase the risk of VTE in these patients. (See "Pathogenesis of the hypercoagulable state associated with malignancy" and "Drug-induced thrombosis in patients with malignancy" and "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".) Approximately 20 percent of patients with symptomatic deep venous thrombosis have a known active malignancy [46,71]. In a retrospective study of over 63,000 patients admitted to Danish nonpsychiatric hospitals from 1977 through 1992 for a diagnosis of VTE, 18 percent had received a diagnosis of cancer (other than non-melanoma skin cancer) prior to the thromboembolic event [72]. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Incidence and risk factors'.) The majority of cancers associated with thromboembolic events are clinically evident and have been previously diagnosed at the time of the event. In the Danish study, 78 percent of the cancers were diagnosed before the event [72]. The five most common sites for cancer diagnosed AT THE TIME OF VTE included: ●
Lung – 17 percent
●
Pancreas – 10 percent
●
Colon and rectum – 8 percent
●
Kidney – 8 percent
●
Prostate – 7 percent
However, thromboembolism can precede the diagnosis of malignancy [73-75]. In one report, for example, 250 consecutive patients with symptomatic DVT were evaluated, 105 of whom had an identified cause or risk factor for the thrombosis [73]. Malignancy was identified at the time of the thrombotic event in five (3.3 percent) of 153 patients with no other identifiable risk factor. During a two-year follow-up, there was an increased incidence of cancer in the patients with idiopathic https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
9/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
thrombosis compared with the 105 patients with secondary thrombosis (8 versus 2 percent). The incidence of cancer was considerably higher (17 percent) among the 35 patients with recurrent idiopathic venous thrombosis. Other studies have noted a less prominent association of venous thromboembolism with previously undiagnosed cancer. A Danish study evaluated almost 27,000 patients with VTE; the standardized incidence ratio for cancer was only 1.3 compared with those without DVT or pulmonary embolism [74]. When compared with a group of patients with cancer who did not have VTE, matched in terms of type of cancer, age, sex, and year of diagnosis, the group with VTE tended to have a higher prevalence of distant metastasis (44 versus 35 percent) and a lower one-year survival (12 versus 36 percent). Similar results were obtained in those patients in whom cancer was diagnosed within one year after an episode of VTE. The role of screening for malignancy in patients with venous thromboembolism is discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Evaluation for occult malignancy'.) Surgery — Thrombotic risk is greatly increased during surgery, particularly orthopedic, major vascular, neurosurgery, and cancer surgery [76-79]. Risk factors in this group include older age, previous venous thromboembolism, the coexistence of malignancy or medical illness (eg, cardiac disease), thrombophilia, and longer surgical, anesthesia, and immobilization times [76,78,80-84]. Without prophylaxis, there is a markedly increased risk of both venous thrombosis and pulmonary embolism. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".) According to the older 2004 ACCP Anticoagulation Guidelines, patients undergoing surgical procedures were divided into the following risk categories (table 4) [85]: ●
Low risk patients are under the age of 40, have none of the risk factors listed above, will require general anesthesia for less than 30 minutes, and are undergoing minor elective, abdominal, or thoracic surgery. Without prophylaxis their risk of proximal vein thrombosis is less than 1.0 percent, and risk of fatal pulmonary embolism is less than 0.01 percent.
●
Moderate risk patients are over the age of 40, will require general anesthesia for more than 30 minutes, and have one or more of the above risk factors. Without prophylaxis, their risk of proximal vein thrombosis is 2 to 10 percent, and their risk of fatal pulmonary embolism is 0.1 to 0.7 percent.
●
High risk patients include those over the age of 40 who are having surgery for malignancy or an orthopedic procedure of the lower extremity lasting more than 30 minutes, and those who have an inhibitor deficiency state or other risk factors. The risk of proximal vein thrombosis
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
10/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
and fatal pulmonary embolism in this group is 10 to 20 percent and 1.0 to 5.0 percent, respectively. These risk groups have been re-defined in the 2012 ACCP Guidelines. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Assess risk for thrombosis'.) Thromboprophylaxis significantly reduces the incidence of symptomatic DVT or pulmonary embolism in the immediate postoperative period. However, there is a continued risk of DVT following hospital discharge in those who have had total knee or hip arthroplasty after the usual 7 to 10 days of thromboprophylaxis [86-89]. In patients so treated, who did not develop a symptomatic venous thromboembolism during hospitalization, the incidence of symptomatic non-fatal venous thromboembolism (VTE) or fatal pulmonary embolism in the subsequent three months has been estimated at 2.2 percent (95% CI: 1.4-3.0) and 0.05 percent (95% CI: 0.0-0.12), respectively [90]. The estimated 30-day risk of symptomatic non-fatal VTE was higher for those undergoing total hip replacement than total knee replacement (2.5 versus 1.4 percent), in agreement with other studies [80,91]. Trauma Major trauma — The risk of thrombosis is increased in all forms of major injury [92-95]. In one study of 716 patients admitted to a regional trauma unit, DVT in the lower extremities was found in 58 percent of patients with adequate venographic studies; 18 percent had proximal vein thrombosis [92]. Thrombi were detected in 54 percent of patients with major head injuries, 61 percent of patients with pelvic fracture, 77 percent of patients with tibial fracture, and 80 percent of those with femoral fracture. The mechanisms of activation of the coagulation system following surgery or trauma are incompletely understood, but may include decreased venous blood flow in the lower extremities, diminished fibrinolysis, immobilization (see 'Immobilization' below), the release or exposure of tissue factor, and depletion of endogenous anticoagulants such as antithrombin [96]. In addition, the femoral vein in the operated leg may kink after hip replacement surgery, thereby increasing the risk of proximal venous thrombosis in the absence of calf vein thrombosis [97]. Other VTE risk factors in trauma patients may include spinal cord injury, lower extremity or pelvic fracture, need for a surgical procedure, insertion of a femoral venous line or repair of a major vein, increasing age, delayed initiation of thromboprophylaxis, or prolonged immobility either in the hospital or entrapment at the scene of the trauma [92,98-101]. (See "Overview of inpatient management of the adult trauma patient", section on 'Thromboprophylaxis' and "Thromboembolism and prevention in the severely injured trauma patient", section on 'Thromboprophylaxis'.)
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
11/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Minor injuries — A large population-based study investigated the VTE risk following a minor injury (ie, one not requiring surgery, a plaster cast, hospitalization, or extended bed rest at home for at least four days) [102]. A minor injury occurring in the preceding three to four weeks was associated with a three- to fivefold increase in DVT risk. In carriers of factor V Leiden, this risk was increased 50-fold. Intravenous drug use — Direct trauma, irritation, and infection may be responsible for the high prevalence of DVT noted in young drug users who inject these agents directly into their femoral veins [103-105]. Pregnancy — Pregnancy is associated with an increased risk of thrombosis that may be due in part to obstruction of venous return by the enlarged uterus, as well as the hypercoagulable state associated with pregnancy. Estimates of the age-adjusted incidence of VTE range from 5 to 50 times higher in pregnant versus non-pregnant women. This subject is discussed in depth separately. (See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis" and "Use of anticoagulants during pregnancy and postpartum".) Inherited thrombophilia — The risk of thrombosis is further accentuated in those women who have inherited thrombophilia, as illustrated by the following observations [106-109]: ●
In one series of 60 women with an inherited deficiency of a naturally occurring anticoagulant (antithrombin, protein C, or protein S), the risk of venous thrombosis during pregnancy or the postpartum period was increased eightfold (4.1 versus 0.5 percent in nondeficient women) [107].
●
The thrombotic risk for a woman with factor V Leiden during pregnancy or the puerperium has been estimated at approximately 1 in 400 to 500 compared with 1 in 1400 in the general population [106]. (See "Factor V Leiden and activated protein C resistance", section on 'Fetal loss and obstetric complications'.)
●
A case-control study looked for factor V Leiden and the prothrombin gene mutation in 190 women with a first history of venous thromboembolism during pregnancy or the postpartum period and 190 controls without a history of thrombosis [109]. Compared with the controls, the women with a positive history had a higher prevalence of factor V Leiden (30 versus 6 percent), the prothrombin gene mutation (9 versus 2 percent), or both (7 versus zero percent). Women with both mutations had a higher probability of thrombosis during pregnancy than those with only the factor V Leiden or only the prothrombin mutation (5.2 versus 0.3 and 0.4 percent, respectively).
The prevalence of selected thrombophilias in women with no history of thrombosis and the probability of thromboembolism during pregnancy in these carriers are shown in the table. The risk of thromboembolism during pregnancy is also higher among women with inherited thrombophilia who have a past history or family history of thromboembolic events. (See "Inherited thrombophilias https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
12/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
in pregnancy" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".) These data have been derived from essentially white Caucasian populations; there is a paucity of data on the prevalence and clinical significance of these states in non-white populations [110]. Drugs — A number of drugs have been associated with an increased risk of venous thrombosis, while statin use may be associated with a reduced risk of recurrence after a first episode [111] Oral and transdermal contraceptives — Because of their widespread use, oral contraceptives (OCs) are the most important cause of thrombosis in young women [112-114]. The risk of thrombosis increases within the first 6 to 12 months of the initiation of therapy [115] and is unaffected by duration of use; the risk is considered by most experts to return to previous levels within one to three months of cessation. An increased risk for VTE has also been found in women using contraceptive transdermal patches (Xulane). The use of OCs in older women to alleviate menopausal symptoms is also associated with a substantially increased risk of VTE, especially in those with inherited thrombophilia or a family history of VTE [116]. This subject is discussed in detail separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism' and "Transdermal contraceptive patch", section on 'Risk of venous thrombotic events'.) Hormone replacement therapy — Observational studies, the HERS trials, and a metaanalysis published before the Women's Health Initiative (WHI), evaluated the association between hormone replacement therapy (HRT) and venous thromboembolism (VTE), and suggested that HRT caused an approximately twofold increase in VTE risk, which appeared to be greatest in the first year of treatment [117-120]. The most definitive data come from the WHI and are consistent with previous estimates [121]. The risk for VTE following the use of HRT appears to be further increased in older women, as well as in those who are obese, have an underlying thrombophilia (eg, factor V Leiden, prothrombin gene mutation), or a past history of venous thromboembolism [116,121-125]. This subject is discussed in detail separately. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Venous thromboembolism'.) Testosterone — Postmarketing reports of VTE in men taking testosterone has led to the US Food and Drug Administration (FDA) requiring manufacturers to place a general warning in the labeling of all approved testosterone products regarding this risk [126]. (See "Testosterone treatment of male hypogonadism", section on 'Venous thromboembolism'.) Tamoxifen — A number of studies, including the large Breast Cancer Prevention Trials, have demonstrated that tamoxifen use is associated with an increased rate of venous thromboembolic events and that there is a significant additional procoagulant effect when tamoxifen is added to chemotherapy [127,128]. As an example, the role of tamoxifen in thromboembolic events was https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
13/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
assessed in seven Eastern Cooperative Oncology Group (ECOG) trials, three of which randomly allocated patients to receive or not receive tamoxifen as part of their design [129]. Each trial with a tamoxifen versus no tamoxifen randomization showed a trend toward more venous events in the tamoxifen-containing arm. Using data from all seven studies, premenopausal, but not postmenopausal, women who received chemotherapy and tamoxifen developed more venous thrombosis than those who received chemotherapy alone (3 versus 1 percent). (See "Druginduced thrombosis in patients with malignancy", section on 'Tamoxifen'.) Bevacizumab — Use of the monoclonal antibody bevacizumab has been associated with an increased risk for both arterial and venous thromboembolic events. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Arterial and venous thromboembolism'.) Glucocorticoids — Glucocorticoid administration is associated with an increased risk of VTE [48,130]. A population-based case-control study compared rates of glucocorticoid use in nearly 39,000 cases of VTE to rates in age- and sex-matched controls without VTE [130]. Compared to former use of glucocorticoids (>3 months prior to VTE), recent use (150 percent
25
11
4.8
XI:A >121 percent
19
10
2.2
IX:A >129 percent
20
10
2.8
TAFI >122 percent
14
9
1.7
Interleukin 8 >8.2 pg/mL*
14
5
3.3
VIII:C >150 percent and IX:A >129 percent
10
1.5
8.2
Adult subjects only. DVT: Deep vein thrombosis; C: Coagulant activity; A: Antigen concentration; TAFI: Thrombin-activatable fibrinolysis inhibitor. * Inflammatory chemokine; not a coagulation factor. Data from the Leiden Thrombophilia Study. Graphic 62182 Version 1.0
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
63/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Contributor Disclosures Kenneth A Bauer, MD Consultant/Advisory Boards: Janssen Pharmaceuticals [Anticoagulation (Rivaroxaban)]. Gregory YH Lip, MD, FRCPE, FESC, FACC Speaker's Bureau: Bayer [Atrial fibrillation and thrombosis (rivaroxaban)]; BMS/Pfizer [Atrial fibrillation and thrombosis (apixaban)]; Boehringer Ingelheim [Atrial fibrillation and thrombosis (dabigatran)]; Daiichi-Sankyo [Atrial fibrillation and thrombosis (edoxaban)]. Consultant/Advisory Boards: Bayer/Janssen [Atrial fibrillation and thrombosis (rivaroxaban)]; BMS/Pfizer [Atrial fibrillation and thrombosis (apixaban)]; Boehringer Ingelheim [Atrial fibrillation and thrombosis (dabigatran)]; Daiichi-Sankyo [Atrial fibrillation and thrombosis (edoxaban)]; Verseon [thrombosis (drug in development)]. Lawrence LK Leung, MD Nothing to disclose Jess Mandel, MD Nothing to disclose Geraldine Finlay, MD Consultant/Advisory Boards: LAM Board of directors, LAM scientific grant review committee for The LAM Foundation. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
64/64
Overview of the causes of venous thrombosis - UpToDate
Official reprint from UpToDate® www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Overview of the causes of venous thrombosis Authors: Kenneth A Bauer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC Section Editors: Lawrence LK Leung, MD, Jess Mandel, MD Deputy Editor: Geraldine Finlay, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Aug 2019. | This topic last updated: Sep 09, 2019.
INTRODUCTION The most common presentations of venous thrombosis are deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism. The causes of venous thrombosis can be divided into two groups: hereditary and acquired, and are often multiple in a given patient. The inherited and acquired causes of venous thrombosis will be reviewed here (table 1) [1,2]. The diagnostic approach to the patient with suspected venous thrombosis, the evaluation and treatment of patients with documented venous thrombosis, and the various causes 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" and "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Primary (spontaneous) upper extremity deep vein thrombosis" and "Brachial plexus syndromes" and "Catheter-related upper extremity venous thrombosis".)
VIRCHOW'S TRIAD A major theory delineating the pathogenesis of venous thromboembolism (VTE), often called Virchow's triad [3,4], proposes that VTE occurs as a result of: ●
Alterations in blood flow (ie, stasis)
●
Vascular endothelial injury
●
Alterations in the constituents of the blood (ie, inherited or acquired hypercoagulable state)
A risk factor for thrombosis can now be identified in over 80 percent of patients with venous thrombosis. Furthermore, there is often more than one factor at play in a given patient. As https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
1/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
examples: ●
Fifty percent of thrombotic events in patients with inherited thrombophilia are associated with the additional presence of an acquired risk factor (eg, surgery, prolonged bed rest, pregnancy, oral contraceptives). Some patients have more than one form of inherited thrombophilia or more than one form of acquired thrombophilia and appear to be at even greater risk for thrombosis (see 'Multiple inherited thrombotic defects' below) [5].
●
In a population-based study of the prevalence of venous thromboembolism (VTE), 56 percent of the patients had three or more of the following six risk factors present at the time of VTE: >48 hours of immobility in the preceding month; hospital admission, surgery, malignancy, or infection in the past three months; or current hospitalization (see 'Multiple acquired risk factors' below) [6].
Accordingly, many patients with VTE fulfill most or all of Virchow's triad of stasis, endothelial injury, and hypercoagulability [7-9].
SUPERFICIAL VEIN THROMBOSIS Superficial vein thrombosis (SVT), a less severe disorder than deep vein thrombosis (DVT), occurs in both inherited and acquired thrombophilic states and may progress to DVT and/or pulmonary embolism (PE) [10-13]. In 63 patients presenting with ultrasonically-confirmed SVT of the lower extremities as a first thrombotic episode, and in whom DVT, varicose veins, malignancy, and autoimmune disorders were absent, the following observations were made [14]: ●
Twenty patients (32 percent) developed DVT at a median elapsed interval of four years.
●
Fifteen patients (24 percent) had recurrent episodes of SVT.
●
The odds ratios for the development of SVT in patients with factor V Leiden, the prothrombin G20210A mutation, or a deficiency of antithrombin, protein S or C were 6.1, 4.3, and 12.9, respectively.
In another meta-analysis of 21 studies of patients with SVT, the prevalence of DVT was 18 percent and PE was 7 percent [15]. This subject is discussed in depth separately. (See "Phlebitis and thrombosis of the superficial lower extremity veins".)
INHERITED THROMBOPHILIA Common inherited hypercoagulable states — Inherited thrombophilia is a genetic tendency to venous thromboembolism. The most frequent causes of an inherited (primary) hypercoagulable https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
2/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
state are the factor V Leiden mutation and the prothrombin gene mutation, which together account for 50 to 60 percent of cases. Defects in protein S, protein C, and antithrombin (formerly known as antithrombin III) account for most of the remaining cases (table 1) [16-19]. Each of these is discussed separately, as follows: ●
Factor V Leiden mutation (see "Factor V Leiden and activated protein C resistance")
●
Prothrombin gene mutation (see "Prothrombin G20210A mutation")
●
Protein S deficiency (see "Protein S deficiency")
●
Protein C deficiency (see "Protein C deficiency")
●
Antithrombin deficiency (see "Antithrombin deficiency")
Deep vein thrombosis — The thrombotic risk associated with the inherited thrombophilias has been assessed in two ways: evaluation of patients with DVT (table 2) and evaluation of families with thrombophilia. In a Spanish study of 2132 consecutive unselected patients with venous thromboembolism, for example, 12.9 percent had an anticoagulant protein deficiency (7.3 percent with protein S, 3.2 percent with protein C, and 0.5 percent with antithrombin). An additional 4.1 percent had elevated levels of antiphospholipid antibodies (aPL) [16]. Similar findings were noted in a series of 277 Dutch outpatients with deep vein thrombosis: 8.3 percent had an isolated deficiency of antithrombin, protein C, protein S, or plasminogen compared with 2.2 percent of controls [20]. The prevalence of a protein deficiency was only modestly greater in "high risk" patients with recurrent, familial, or juvenile onset deep vein thrombosis (9, 16, and 12 percent respectively). A higher frequency of inherited thrombophilia has also been noted in patients with thrombosis of visceral or cerebral vessels [21]. The overall 8 to 13 percent prevalence of an isolated anticoagulant protein deficiency in patients with deep vein thrombosis does not include the contribution of factor V Leiden or the prothrombin gene mutation, now considered to be the most common causes of inherited thrombophilia. ●
The Physicians' Health Study and the Leiden Thrombophilia Study found a 12 to 19 percent prevalence of heterozygosity for the factor V Leiden mutation in patients with a first DVT (or pulmonary embolism in the Physicians' Health Study) compared with 3 to 6 percent in controls [22,23]. The prevalence reached 26 percent in the Physicians' Health Study in 31 men over the age of 60 with no identifiable precipitating factors [22]. (See "Factor V Leiden and activated protein C resistance".)
●
The prevalence of the prothrombin gene mutation is approximately 6 to 8 percent in patients with deep vein thrombosis compared with 2 to 2.5 percent in controls [17,24]. (See "Prothrombin G20210A mutation".)
Thus, the total prevalence of an inherited thrombophilia in subjects with a deep vein thrombosis ranges from 24 to 37 percent overall compared with about 10 percent in controls. https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
3/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Thrombotic risk in families — The absolute risk of thrombosis among patients with inherited thrombophilia was evaluated in a report of 150 pedigrees, which compared the risk for thrombosis in individuals with inherited thrombophilia due to factor V Leiden or to antithrombin, protein C, or protein S deficiency (table 3) [12]. The lifetime probability of developing thrombosis compared with those with no defect was 8.5 times higher for carriers of protein S deficiency, 8.1 for antithrombin deficiency, 7.3 for protein C deficiency, and 2.2 for factor V Leiden. The thrombosis risk in affected women was also increased during pregnancy and the use of oral contraceptives (see 'Pregnancy' below). Multiple inherited thrombotic defects — A second thrombotic defect can occur among patients with any of the causes of familial thrombophilia, particularly factor V Leiden [25-28]. (See "Factor V Leiden and activated protein C resistance", section on 'Venous thromboembolism'.) In one series, factor V Leiden was present in 4 of 14 patients with protein S deficiency and 6 of 15 with protein C deficiency [26]. Carriers of two (or more) defects seem to be at a higher risk for thrombosis than their relatives with a single defect. In one review of four studies, approximately 75 percent of the family members who were carriers of two defects had experienced thrombosis compared with 10 to 30 percent of the carriers of a single defect [25]. Inherited thrombophilia also may interact to increase the risk of venous thrombosis in patients with acquired causes of hypercoagulability, such as oral contraceptive use (table 2) [29] and pregnancy (see 'Combined acquired plus inherited risk factors' below). The clinical characteristics and diagnosis of the five major causes of inherited thrombophilia: the factor V Leiden mutation, antithrombin deficiency, protein S and protein C deficiency, and the prothrombin gene mutation, are discussed in detail separately. (See "Factor V Leiden and activated protein C resistance" and "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency" and "Prothrombin G20210A mutation".) Other alleged inherited thrombophilias — The remainder of this section will briefly review other alleged causes of inherited thrombophilia. As will be seen, it remains unclear whether some of these disorders are actually associated with an increased risk of venous thrombosis. Heparin cofactor II deficiency — Heparin cofactor II (antithrombin is heparin cofactor I) is a heparin-dependent glycoprotein that acts as a thrombin inhibitor. Several families have been described with quantitative 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 not clear if heparin cofactor II deficiency is a significant risk factor for thrombosis [30,31]. In one series of 305 patients with juvenile thromboembolic episodes, two patients had heparin cofactor II deficiency [31]. However, each of these patients had a second defect: the factor V Leiden mutation and protein C deficiency. https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
4/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Plasminogen deficiency — Congenital plasminogen deficiency is usually inherited as an autosomal dominant trait. There are both quantitative defects (type I, hypoplasminogenemia in the heterozygote and aplasminogenemia in the homozygote) and functional defects (type 2, dysplasminogenemia). Venous thrombosis has been reported in some patients identified with plasminogen deficiency, but a familial predisposition is usually absent. The clinical importance of plasminogen deficiency as a risk factor for thrombosis is uncertain. In a Spanish study of 2132 consecutive patients with thrombosis, plasminogen deficiency was seen in 0.75 percent [16]. However, this prevalence may not be significantly higher than that seen in the general population. In a cohort of 9611 blood donors, for example, 0.29 percent had asymptomatic familial plasminogen deficiency [32]. Additional clinical findings associated with plasminogen deficiency (eg, ligneous conjunctivitis) are discussed separately. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".) Other rare fibrinolytic defects such as impaired tissue plasminogen activator release or increased plasminogen activator inhibitor levels have been linked to thrombosis in isolated families [33], and may increase the risk of venous thrombosis in subjects with other thrombophilic defects [34]. In one of these kindreds, six of the seven subjects with a history of thrombosis were also deficient in total and free protein S [35]. Once again, the pathogenetic importance of these defects is uncertain. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Plasminogen activator inhibitor'.) Dysfibrinogenemia — Patients with dysfibrinogenemia have structural defects that cause alterations in the conversion of fibrinogen to fibrin. Approximately 300 abnormal fibrinogens have been reported, and more than 80 structural defects have been identified [36,37]. The most common structural defects involve the fibrinopeptides and their cleavage sites, and the second most common involves the gamma-chain polymerization region. Approximately one-half of the mutants are clinically silent, whereas hemorrhage and thrombosis occur in almost equal numbers of symptomatic patients. (See "Disorders of fibrinogen".) Factor XII deficiency — Factor XII, Hageman factor, is the zymogen of a serine protease that initiates the contact activation reactions and intrinsic blood coagulation in vitro. Severe factor XII deficiency (factor XII activity less than 1 percent of normal) is inherited as an autosomal recessive trait; affected patients have marked prolongation in the activated partial thromboplastin time (aPTT) but do not exhibit a bleeding diathesis [38]. To the contrary, venous thromboembolism and myocardial infarction have been reported in a number of factor XII-deficient patients [39], including John Hageman, the initial patient described with this abnormality [40]. This thrombophilic tendency has been attributed to reduced plasma fibrinolytic activity [41]. The frequency with which severe factor XII deficiency leads to thrombosis is uncertain. One review found that 8 percent had a history of thromboembolism [39]. However, interpretation of this type of
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
5/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
data is difficult, since patients with complications are more likely to be reported than those who are asymptomatic. This led to cross-sectional analyses of thromboembolic events in larger numbers of unselected families with factor XII deficiency. In a study of 14 Swiss families with factor XII deficiency, 2 of 18 homozygous or doubly heterozygous patients had sustained deep venous thrombosis; however, each episode occurred at a time when other predisposing thrombotic risk factors were present [42]. Only one of 45 heterozygotes in these families had a possible history of venous thrombosis. However, other groups have found a more pronounced association with thrombosis [43,44]. Thus, it remains unproven if factor XII deficiency is associated with an increased risk of thrombosis.
ACQUIRED RISK FACTORS Overview — Acquired risk factors or predisposing conditions for thrombosis include a prior thrombotic event, recent major surgery, presence of a central venous catheter , trauma, immobilization, malignancy, pregnancy, the use of oral contraceptives or heparin, myeloproliferative disorders, antiphospholipid syndrome (APS), and a number of other major medical illnesses (table 1) [2,45-49]. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Assess risk'.) While upper extremity DVT is less common than lower extremity DVT, some of the same risk factors are present [50,51]. As an example, in a study of 512 patients with acute symptomatic upper extremity DVT with or without pulmonary embolism, 38 percent had cancer; 45 percent had central venous catheter-related DVT [50]. (See "Catheter-related upper extremity venous thrombosis".) Multiple acquired risk factors — Many patients with an episode of VTE have more than one acquired risk factor for thrombosis. This was shown in a population-based study of the incidence of VTE in residents of Worcester, MA during 1999. The six most prevalent pre-existing medical characteristics of patients in this study were [6]: ●
More than 48 hours of immobility in the preceding month – 45 percent
●
Hospital admission in the past three months – 39 percent
●
Surgery in the past three months – 34 percent
●
Malignancy in the past three months – 34 percent
●
Infection in the past three months – 34 percent
●
Current hospitalization – 26 percent
Only 11 percent of the 587 episodes of VTE had none of these six characteristics present, while 36 and 53 percent had 1 to 2 and ≥3 risk factors, respectively.
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
6/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Triggers of hospitalization for VTE were evaluated in a case-crossover study of 16,781 participants in the Health and Retirement Study, a nationally representative sample of older Americans. Exposures to triggering events during the 90-day period prior to 399 hospitalizations for VTE were compared with exposures occurring during four 90-day comparison periods that did not result in hospitalization for VTE. Results included [52]: ●
Infections, especially for those associated with a previous hospital or skilled nursing facility stay, were the most common trigger of hospitalization for VTE, occurring in 52.4 percent of the risk periods before hospitalization, as compared with 28 percent for the four comparison periods.
●
Other significant triggers included use of erythropoiesis-stimulating agents, blood transfusion, major surgery, fractures, immobility, and chemotherapy.
●
These triggers, when combined, accounted for 70 percent of exposures before VTE hospitalization, as opposed to 35 percent in the comparison periods.
Combined acquired plus inherited risk factors — As noted above, patients with VTE may have multiple inherited defects or multiple acquired risk factors for VTE. In addition, they may also have combinations of both inherited and acquired thrombophilic defects. This was best shown in the MEGA case-control study in 4311 consecutive subjects with a first episode of VTE and 5768 controls, in which the following observations were made [49]: ●
Subjects with self-reported major medical illnesses (ie, liver or kidney disease, rheumatoid arthritis, multiple sclerosis, heart failure, hemorrhagic stroke, arterial thrombosis) had increased venous thrombotic risk, with odds ratios in the range of 1.5 to 4.9.
●
The combination of a major medical illness, as defined above, plus immobilization increased the odds ratio for development of venous thrombosis to 10.9 (95% CI 4.2-28).
●
The combination of a major medical illness along with immobilization plus an thrombophilic defect increased the risk of venous thrombosis even further, with odds ratios of 80, 35, 88, 84, and 53 for increased factor VIII levels, increased factor IX levels, increased von Willebrand factor levels, presence of factor V Leiden, or the presence of non-O blood groups, respectively.
Regardless of whether the patient has a genetic and/or an environmental risk factor for VTE, the presence of a positive family history of VTE has been found to be a strong additional risk factor for VTE [53]. Previous thromboembolism — Previous thrombotic episodes are a major risk factor for recurrent VTE. In an outpatient prospective cohort study, the risk of recurrence after an acute episode of venous thrombosis was 18, 25, and 30 percent at two, five, and eight years,
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
7/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
respectively [54]. In a community-based epidemiologic study, a previous history of VTE conferred a relative risk (RR) of 7.9 for VTE recurrence [55]. The magnitude of this risk is highly dependent upon patient-specific factors. Those with an episode of thrombosis in the absence of known risk factors (ie, idiopathic VTE), or in association with permanent risk factors (eg, cancer) have a higher rate of recurrence than those with timelimited, reversible risk factors (eg, recent major surgery, immobilization) [54,56,57]. In one study, for example, the influence of these risk factors on the two-year cumulative incidence of VTE recurrence was as follows [58]: ●
Patients with surgery in the six weeks prior to a first VTE – zero percent recurrence; a much lower risk for recurrence in patients with surgery associated VTE (hazard ratio 0.36) was also noted in another study [54].
●
Pregnancy-associated VTE – zero percent recurrence
●
Patients with nonsurgical risk factors (eg, oral contraceptive use, fracture or application of plaster cast, immobilization) – 8.8 percent
●
Patients with an unprovoked VTE in whom there was no identifiable clinical risk factor – 19.4 percent
The presence or absence of these risk factors (eg, pregnancy, surgery) becomes important in the therapeutic approach to patients with a first or recurrent episode of VTE. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Summary and recommendations'.) In addition, the site of the first VTE appears to be a predictor of the site and perhaps frequency of future episodes of VTE: ●
Patients with a PE during the first episode of VTE are much more likely to have a PE during recurrence. One study followed 436 patients recovering from a first episode of idiopathic VTE [59]. When compared with subjects with DVT and no symptoms of PE, those with symptomatic PE had a significantly higher risk of VTE recurrence (RR 2.2) and a higher risk of developing symptomatic PE at recurrence (RR 4.0). In another report of 165 patients presenting with PE, approximately 60 percent of the recurrences were a second episode of PE [56].
●
Patients with a DVT during the first episode of VTE are highly likely to have a DVT during recurrence. This was illustrated in a study of 267 patients with a first episode of idiopathic DVT; 34 of the 42 recurrences were DVTs, with the most common site of recurrence being in the contralateral leg [57].
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
8/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Malignancy — Patients with cancer often have a hypercoagulable state due to the production of substances with procoagulant activity (eg, tissue factor and cancer procoagulant). Clinical venous thromboembolism occurs in approximately 15 percent of such patients and is a common cause of serious clinical outcomes, including major hemorrhage and death, especially in older patients as well as in those malignancies associated with advanced disease at the time of diagnosis (eg, pancreatic cancer) and myeloproliferative neoplasms (MPNs) [60-65]. The risk of VTE in such patients appears to be highest during the initial hospitalization, time of diagnosis, onset of chemotherapy, as well as at the time of disease progression [66]. MPNs have a higher rate of both venous (10 percent) and arterial thrombosis (3 percent) [65]. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Hospitalized medical patients'.) The risk of thrombosis may be further increased in patients with malignancy and a central venous catheter, in which situation the prevalence of a venous thrombotic event may be as high as 12 percent [67-70]. The use of certain drugs may also increase the risk of VTE in these patients. (See "Pathogenesis of the hypercoagulable state associated with malignancy" and "Drug-induced thrombosis in patients with malignancy" and "Multiple myeloma: Prevention of venous thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".) Approximately 20 percent of patients with symptomatic deep venous thrombosis have a known active malignancy [46,71]. In a retrospective study of over 63,000 patients admitted to Danish nonpsychiatric hospitals from 1977 through 1992 for a diagnosis of VTE, 18 percent had received a diagnosis of cancer (other than non-melanoma skin cancer) prior to the thromboembolic event [72]. (See "Risk and prevention of venous thromboembolism in adults with cancer", section on 'Incidence and risk factors'.) The majority of cancers associated with thromboembolic events are clinically evident and have been previously diagnosed at the time of the event. In the Danish study, 78 percent of the cancers were diagnosed before the event [72]. The five most common sites for cancer diagnosed AT THE TIME OF VTE included: ●
Lung – 17 percent
●
Pancreas – 10 percent
●
Colon and rectum – 8 percent
●
Kidney – 8 percent
●
Prostate – 7 percent
However, thromboembolism can precede the diagnosis of malignancy [73-75]. In one report, for example, 250 consecutive patients with symptomatic DVT were evaluated, 105 of whom had an identified cause or risk factor for the thrombosis [73]. Malignancy was identified at the time of the thrombotic event in five (3.3 percent) of 153 patients with no other identifiable risk factor. During a two-year follow-up, there was an increased incidence of cancer in the patients with idiopathic https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&s…
9/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
thrombosis compared with the 105 patients with secondary thrombosis (8 versus 2 percent). The incidence of cancer was considerably higher (17 percent) among the 35 patients with recurrent idiopathic venous thrombosis. Other studies have noted a less prominent association of venous thromboembolism with previously undiagnosed cancer. A Danish study evaluated almost 27,000 patients with VTE; the standardized incidence ratio for cancer was only 1.3 compared with those without DVT or pulmonary embolism [74]. When compared with a group of patients with cancer who did not have VTE, matched in terms of type of cancer, age, sex, and year of diagnosis, the group with VTE tended to have a higher prevalence of distant metastasis (44 versus 35 percent) and a lower one-year survival (12 versus 36 percent). Similar results were obtained in those patients in whom cancer was diagnosed within one year after an episode of VTE. The role of screening for malignancy in patients with venous thromboembolism is discussed separately. (See "Evaluating adult patients with established venous thromboembolism for acquired and inherited risk factors", section on 'Evaluation for occult malignancy'.) Surgery — Thrombotic risk is greatly increased during surgery, particularly orthopedic, major vascular, neurosurgery, and cancer surgery [76-79]. Risk factors in this group include older age, previous venous thromboembolism, the coexistence of malignancy or medical illness (eg, cardiac disease), thrombophilia, and longer surgical, anesthesia, and immobilization times [76,78,80-84]. Without prophylaxis, there is a markedly increased risk of both venous thrombosis and pulmonary embolism. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".) According to the older 2004 ACCP Anticoagulation Guidelines, patients undergoing surgical procedures were divided into the following risk categories (table 4) [85]: ●
Low risk patients are under the age of 40, have none of the risk factors listed above, will require general anesthesia for less than 30 minutes, and are undergoing minor elective, abdominal, or thoracic surgery. Without prophylaxis their risk of proximal vein thrombosis is less than 1.0 percent, and risk of fatal pulmonary embolism is less than 0.01 percent.
●
Moderate risk patients are over the age of 40, will require general anesthesia for more than 30 minutes, and have one or more of the above risk factors. Without prophylaxis, their risk of proximal vein thrombosis is 2 to 10 percent, and their risk of fatal pulmonary embolism is 0.1 to 0.7 percent.
●
High risk patients include those over the age of 40 who are having surgery for malignancy or an orthopedic procedure of the lower extremity lasting more than 30 minutes, and those who have an inhibitor deficiency state or other risk factors. The risk of proximal vein thrombosis
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
10/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
and fatal pulmonary embolism in this group is 10 to 20 percent and 1.0 to 5.0 percent, respectively. These risk groups have been re-defined in the 2012 ACCP Guidelines. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Assess risk for thrombosis'.) Thromboprophylaxis significantly reduces the incidence of symptomatic DVT or pulmonary embolism in the immediate postoperative period. However, there is a continued risk of DVT following hospital discharge in those who have had total knee or hip arthroplasty after the usual 7 to 10 days of thromboprophylaxis [86-89]. In patients so treated, who did not develop a symptomatic venous thromboembolism during hospitalization, the incidence of symptomatic non-fatal venous thromboembolism (VTE) or fatal pulmonary embolism in the subsequent three months has been estimated at 2.2 percent (95% CI: 1.4-3.0) and 0.05 percent (95% CI: 0.0-0.12), respectively [90]. The estimated 30-day risk of symptomatic non-fatal VTE was higher for those undergoing total hip replacement than total knee replacement (2.5 versus 1.4 percent), in agreement with other studies [80,91]. Trauma Major trauma — The risk of thrombosis is increased in all forms of major injury [92-95]. In one study of 716 patients admitted to a regional trauma unit, DVT in the lower extremities was found in 58 percent of patients with adequate venographic studies; 18 percent had proximal vein thrombosis [92]. Thrombi were detected in 54 percent of patients with major head injuries, 61 percent of patients with pelvic fracture, 77 percent of patients with tibial fracture, and 80 percent of those with femoral fracture. The mechanisms of activation of the coagulation system following surgery or trauma are incompletely understood, but may include decreased venous blood flow in the lower extremities, diminished fibrinolysis, immobilization (see 'Immobilization' below), the release or exposure of tissue factor, and depletion of endogenous anticoagulants such as antithrombin [96]. In addition, the femoral vein in the operated leg may kink after hip replacement surgery, thereby increasing the risk of proximal venous thrombosis in the absence of calf vein thrombosis [97]. Other VTE risk factors in trauma patients may include spinal cord injury, lower extremity or pelvic fracture, need for a surgical procedure, insertion of a femoral venous line or repair of a major vein, increasing age, delayed initiation of thromboprophylaxis, or prolonged immobility either in the hospital or entrapment at the scene of the trauma [92,98-101]. (See "Overview of inpatient management of the adult trauma patient", section on 'Thromboprophylaxis' and "Thromboembolism and prevention in the severely injured trauma patient", section on 'Thromboprophylaxis'.)
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
11/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Minor injuries — A large population-based study investigated the VTE risk following a minor injury (ie, one not requiring surgery, a plaster cast, hospitalization, or extended bed rest at home for at least four days) [102]. A minor injury occurring in the preceding three to four weeks was associated with a three- to fivefold increase in DVT risk. In carriers of factor V Leiden, this risk was increased 50-fold. Intravenous drug use — Direct trauma, irritation, and infection may be responsible for the high prevalence of DVT noted in young drug users who inject these agents directly into their femoral veins [103-105]. Pregnancy — Pregnancy is associated with an increased risk of thrombosis that may be due in part to obstruction of venous return by the enlarged uterus, as well as the hypercoagulable state associated with pregnancy. Estimates of the age-adjusted incidence of VTE range from 5 to 50 times higher in pregnant versus non-pregnant women. This subject is discussed in depth separately. (See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis" and "Use of anticoagulants during pregnancy and postpartum".) Inherited thrombophilia — The risk of thrombosis is further accentuated in those women who have inherited thrombophilia, as illustrated by the following observations [106-109]: ●
In one series of 60 women with an inherited deficiency of a naturally occurring anticoagulant (antithrombin, protein C, or protein S), the risk of venous thrombosis during pregnancy or the postpartum period was increased eightfold (4.1 versus 0.5 percent in nondeficient women) [107].
●
The thrombotic risk for a woman with factor V Leiden during pregnancy or the puerperium has been estimated at approximately 1 in 400 to 500 compared with 1 in 1400 in the general population [106]. (See "Factor V Leiden and activated protein C resistance", section on 'Fetal loss and obstetric complications'.)
●
A case-control study looked for factor V Leiden and the prothrombin gene mutation in 190 women with a first history of venous thromboembolism during pregnancy or the postpartum period and 190 controls without a history of thrombosis [109]. Compared with the controls, the women with a positive history had a higher prevalence of factor V Leiden (30 versus 6 percent), the prothrombin gene mutation (9 versus 2 percent), or both (7 versus zero percent). Women with both mutations had a higher probability of thrombosis during pregnancy than those with only the factor V Leiden or only the prothrombin mutation (5.2 versus 0.3 and 0.4 percent, respectively).
The prevalence of selected thrombophilias in women with no history of thrombosis and the probability of thromboembolism during pregnancy in these carriers are shown in the table. The risk of thromboembolism during pregnancy is also higher among women with inherited thrombophilia who have a past history or family history of thromboembolic events. (See "Inherited thrombophilias https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
12/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
in pregnancy" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".) These data have been derived from essentially white Caucasian populations; there is a paucity of data on the prevalence and clinical significance of these states in non-white populations [110]. Drugs — A number of drugs have been associated with an increased risk of venous thrombosis, while statin use may be associated with a reduced risk of recurrence after a first episode [111] Oral and transdermal contraceptives — Because of their widespread use, oral contraceptives (OCs) are the most important cause of thrombosis in young women [112-114]. The risk of thrombosis increases within the first 6 to 12 months of the initiation of therapy [115] and is unaffected by duration of use; the risk is considered by most experts to return to previous levels within one to three months of cessation. An increased risk for VTE has also been found in women using contraceptive transdermal patches (Xulane). The use of OCs in older women to alleviate menopausal symptoms is also associated with a substantially increased risk of VTE, especially in those with inherited thrombophilia or a family history of VTE [116]. This subject is discussed in detail separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism' and "Transdermal contraceptive patch", section on 'Risk of venous thrombotic events'.) Hormone replacement therapy — Observational studies, the HERS trials, and a metaanalysis published before the Women's Health Initiative (WHI), evaluated the association between hormone replacement therapy (HRT) and venous thromboembolism (VTE), and suggested that HRT caused an approximately twofold increase in VTE risk, which appeared to be greatest in the first year of treatment [117-120]. The most definitive data come from the WHI and are consistent with previous estimates [121]. The risk for VTE following the use of HRT appears to be further increased in older women, as well as in those who are obese, have an underlying thrombophilia (eg, factor V Leiden, prothrombin gene mutation), or a past history of venous thromboembolism [116,121-125]. This subject is discussed in detail separately. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Venous thromboembolism'.) Testosterone — Postmarketing reports of VTE in men taking testosterone has led to the US Food and Drug Administration (FDA) requiring manufacturers to place a general warning in the labeling of all approved testosterone products regarding this risk [126]. (See "Testosterone treatment of male hypogonadism", section on 'Venous thromboembolism'.) Tamoxifen — A number of studies, including the large Breast Cancer Prevention Trials, have demonstrated that tamoxifen use is associated with an increased rate of venous thromboembolic events and that there is a significant additional procoagulant effect when tamoxifen is added to chemotherapy [127,128]. As an example, the role of tamoxifen in thromboembolic events was https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
13/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
assessed in seven Eastern Cooperative Oncology Group (ECOG) trials, three of which randomly allocated patients to receive or not receive tamoxifen as part of their design [129]. Each trial with a tamoxifen versus no tamoxifen randomization showed a trend toward more venous events in the tamoxifen-containing arm. Using data from all seven studies, premenopausal, but not postmenopausal, women who received chemotherapy and tamoxifen developed more venous thrombosis than those who received chemotherapy alone (3 versus 1 percent). (See "Druginduced thrombosis in patients with malignancy", section on 'Tamoxifen'.) Bevacizumab — Use of the monoclonal antibody bevacizumab has been associated with an increased risk for both arterial and venous thromboembolic events. (See "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects", section on 'Arterial and venous thromboembolism'.) Glucocorticoids — Glucocorticoid administration is associated with an increased risk of VTE [48,130]. A population-based case-control study compared rates of glucocorticoid use in nearly 39,000 cases of VTE to rates in age- and sex-matched controls without VTE [130]. Compared to former use of glucocorticoids (>3 months prior to VTE), recent use (150 percent
25
11
4.8
XI:A >121 percent
19
10
2.2
IX:A >129 percent
20
10
2.8
TAFI >122 percent
14
9
1.7
Interleukin 8 >8.2 pg/mL*
14
5
3.3
VIII:C >150 percent and IX:A >129 percent
10
1.5
8.2
Adult subjects only. DVT: Deep vein thrombosis; C: Coagulant activity; A: Antigen concentration; TAFI: Thrombin-activatable fibrinolysis inhibitor. * Inflammatory chemokine; not a coagulation factor. Data from the Leiden Thrombophilia Study. Graphic 62182 Version 1.0
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
63/64
18/09/2019
Overview of the causes of venous thrombosis - UpToDate
Contributor Disclosures Kenneth A Bauer, MD Consultant/Advisory Boards: Janssen Pharmaceuticals [Anticoagulation (Rivaroxaban)]. Gregory YH Lip, MD, FRCPE, FESC, FACC Speaker's Bureau: Bayer [Atrial fibrillation and thrombosis (rivaroxaban)]; BMS/Pfizer [Atrial fibrillation and thrombosis (apixaban)]; Boehringer Ingelheim [Atrial fibrillation and thrombosis (dabigatran)]; Daiichi-Sankyo [Atrial fibrillation and thrombosis (edoxaban)]. Consultant/Advisory Boards: Bayer/Janssen [Atrial fibrillation and thrombosis (rivaroxaban)]; BMS/Pfizer [Atrial fibrillation and thrombosis (apixaban)]; Boehringer Ingelheim [Atrial fibrillation and thrombosis (dabigatran)]; Daiichi-Sankyo [Atrial fibrillation and thrombosis (edoxaban)]; Verseon [thrombosis (drug in development)]. Lawrence LK Leung, MD Nothing to disclose Jess Mandel, MD Nothing to disclose Geraldine Finlay, MD Consultant/Advisory Boards: LAM Board of directors, LAM scientific grant review committee for The LAM Foundation. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy
https://www.uptodate.com/contents/overview-of-the-causes-of-venous-thrombosis/print?search=overview of the causes of venous thrombosis&…
64/64
Related documents
Overview of the causes of venous thrombosis - UpToDate
64 Pages • 23,283 Words • PDF • 715.8 KB
Overview of autoimmune hepatitis - UpToDate
31 Pages • 7,988 Words • PDF • 1.5 MB
Overview of the management of patients with variceal bleeding - UpToDate
14 Pages • 4,616 Words • PDF • 243.7 KB
Overview of The Mechanics of JustBeenPaid!
7 Pages • 1,926 Words • PDF • 593.7 KB
Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis) - UpToDate
26 Pages • 7,837 Words • PDF • 725.2 KB
Antimicrobial therapy of native valve endocarditis - UpToDate
38 Pages • 15,435 Words • PDF • 518.9 KB
Clinical manifestations and diagnosis of rhabdomyolysis - UpToDate
12 Pages • 4,220 Words • PDF • 251.7 KB
Definition, etiology, and evaluation of precocious puberty - UpToDate
42 Pages • 16,353 Words • PDF • 1.4 MB
Clinical manifestations and diagnosis of rheumatic heart disease - UpToDate
27 Pages • 9,625 Words • PDF • 381 KB
Clinical features and diagnosis of hemophagocytic lymphohistiocytosis - UpToDate
48 Pages • 16,289 Words • PDF • 708.3 KB
Central Venous Catheterization - Subclavian Vein (NEJM 2007)
2 Pages • 1,282 Words • PDF • 138.3 KB
Treatment and prognosis of common variable immunodeficiency - UpToDate
11 Pages • 5,878 Words • PDF • 269.8 KB