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Hypercoagulable disorders associated with malignancyAuthorKenneth A Bauer, MDSection EditorLawrence LK Leung, MDDeputy EditorJennifer S Tirnauer, MDAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through:Jun 2013.|This topic last updated:Mar 01, 2013.INTRODUCTIONPatients with cancer are in a hypercoagulable state. The spectrum of hemostatic abnormalities ranges from abnormal coagulation tests in the absence of clinical manifestations to massive, fatal thromboembolism [1,2]. Thrombotic episodes may precede the diagnosis of malignancy by months or years and can present in one of the following ways [3]: Migratory superficial thrombophlebitis (Trousseau's syndrome) Idiopathic deep venous thrombosis and other venous thrombosis Nonbacterial thrombotic endocarditis (marantic endocarditis) Disseminated intravascular coagulation (DIC) Thrombotic microangiopathy Arterial thrombosisIn addition to hypercoagulability, tumors can also lead to venous thrombosis by external compression of vessels or by vascular invasion. As examples, renal cell carcinoma infiltrates the inferior vena cava in 5 to 9 percent of patients [4], hepatocellular carcinoma can compress or invade the hepatic vein(s), and a large mediastinal tumor or bulky axillary lymphadenopathy can lead to upper extremity venous thrombosis.The clinical features of the hypercoagulable syndromes that can be associated with malignancy will be discussed here. The pathogenesis of these disorders as well as drug-induced thrombosis and vascular disease in patients with malignancy are discussed separately. (See "Pathogenesis of the hypercoagulable state associated with malignancy".) (See "Drug-induced thrombosis and vascular disease in patients with malignancy".) (See "Catheter-induced upper extremity venous thrombosis".)Treatment of VTE in patients with malignancy is discussed separately.TROUSSEAU'S SYNDROMEAn association between venous thrombosis and malignancy was first suggested in 1865 by Trousseau. Of interest, Trousseau subsequently developed unexplained deep venous thrombosis, followed a year later by the development of gastric carcinoma [5].Trousseau's syndrome (migratory superficial thrombophlebitis, phlegmasia alba dolens) is a rare variant of venous thrombosis characterized by a recurrent and migratory pattern and involvement of superficial veins, frequently in unusual sites such as the arm or chest. The patient with Trousseau's syndrome usually has an occult tumor which is not always detectable at the time of presentation. If a tumor is discovered, it is usually an adenocarcinoma. In one review of patients with Trousseau's syndrome, the following associated tumors were seen [6]: Pancreas 24 percent Lung 20 percent Prostate 13 percent Stomach 12 percent Acute leukemia 9 percent Colon 5 percentThis syndrome occurs in up to 10 percent of patients with pancreatic carcinoma. Treatment is difficult; heparin can relieve some of the manifestations, while warfarin appears to be without effect [7,8].MucinMucins produced by adenocarcinomas may trigger this syndrome by reacting with leukocyte and platelet selectins, resulting in the production of platelet-rich microthrombi [9-11]. As an example, one study has shown that, while thrombotic risk was increased 20-fold in patients with lung cancer, the relative risk of venous thrombosis was significantly higher in those with mucin-expressing tumors (eg, adenocarcinomas) than in the those with squamous cell tumors (hazard ratio 3.1; 95% CI 1.4-6.9) [12]. (See "Pathology of lung malignancies", section on 'Adenocarcinoma'.)Heparin has the property of blocking selectin recognition of ligands, a property not shared by vitamin K antagonists. This may explain the superior efficacy of heparin in this setting [10]. This phenomenon was illustrated in a murine model of Trousseau syndrome, in which microthrombi formed independent of fluid-phase coagulation [11]. Mucins triggered reciprocal activation of platelets and neutrophils, and heparin was able to block mucin binding to P- and L-selectin. Of interest, these thrombi did not depend on the generation of thrombin to form, and their formation was blocked by a non-anticoagulant activity of heparin. (See "Treatment of venous thromboembolism in patients with malignancy", section on 'LMW heparin versus warfarin'.)VENOUS THROMBOEMBOLISMThe majority of cancers associated with thromboembolic events are clinically evident and have been previously diagnosed at the time of the event. However, some patients with venous thromboembolism (VTE) have an occult malignancy that is not diagnosed until many months following the event. While the incidence of VTE is increased in most patients with cancer, and anticoagulation can decrease this risk, there is a lack of convincing data that shows a survival benefit from anticoagulation. (See 'Prolongation of survival' below.)Incidence of VTEKnown malignancyOverall riskClinical thromboembolism occurs in as many as 11 percent of patients with cancer [6] and is the second leading cause of death in patients with overt malignant disease [13]. Autopsy series have described even higher rates of thrombosis for certain tumor types. One study, for example, found evidence of thrombosis in 30 percent of patients who died of pancreatic cancer; the incidence was over 50 percent in those with tumors in the body or tail of the pancreas [14]. Other tumor types commonly associated with thromboembolic complications are carcinomas of the gastrointestinal tract, ovary, prostate, and lung. By virtue of its prevalence, lung cancer accounts for the largest number of thromboembolic events [15].An estimate of the magnitude of this problem was obtained from a study of the records of more than eight million Medicare patients admitted to a hospital between 1988 and 1990 [16]: The percent of patients with a diagnosis of deep vein thrombosis (DVT)and/orpulmonary embolus (PE) at the initial hospitalization was higher for those with malignancy, compared with those with nonmalignant disease (0.60 versus 0.57 percent). The probability of readmission withrecurrentDVT/PEwithin 183 days of initial hospitalization for patients with or without malignancy was 22 and 6.5 percent, respectively. The probability of death within 183 days of initial hospitalization forDVT/PEamong those with or without malignancy was 94 versus 29 percent, respectively. The adverse influence of venous thromboembolism on prognosis in cancer patients (particularly those with pancreatic cancer) has been shown by others [17-20]. Those malignancies causing the greatestabsolute numberof episodes ofDVT/PEduring this time period were lung, colon, and prostate, while those cancers with the highestratesofDVT/PE(number of episodes per 10,000 patients with a specific malignancy) were ovary, brain, pancreas, and lymphoma.In addition to hypercoagulability, tumors can also lead to venous thrombosis by external compression of vessels or by vascular invasion. As examples, renal cell carcinoma infiltrates the inferior vena cava in 5 to 9 percent of patients [4], hepatocellular carcinoma can compress or invade the hepatic vein(s), and a large mediastinal tumor or bulky axillary lymphadenopathy can lead to upper extremity venous thrombosis. (See "Clinical manifestations, evaluation, and staging of renal cell carcinoma" and "Clinical features and diagnosis of primary hepatocellular carcinoma" and "Primary (spontaneous) upper extremity deep vein thrombosis".)Tumor-specific factorsThe risk factors for VTE in patients with known malignancy have been evaluated in a number of large population-based, case-control studies [21-26]. A number of these are discussed below.In a Danish cohort study of 57,591 cancer patients and a comparison control of 287,476 general population subjects, the following observations were made [24]: Throughout nine years of subject accrual and follow-up, the incidence rates of VTE were higher among the cancer patients (IR 8.0; 95% CI 7.6-8.5) than among the general population (IR 4.7; 95% CI 4.3-5.1), especially in the first year after cancer diagnosis (IR 15.0 versus 8.6). Incidence rates were highest in patients with cancer of the pancreas (IR 41), brain (18), liver (20), multiple myeloma (23), and among those with advanced-stage cancer (28).Similar results were obtained from a California study that linked cases from its cancer registry to the subsequent diagnosis of VTE from a patient discharge data set. The following results were obtained [22]: Among 235,149 cancer cases, 3775 (1.6 percent) were diagnosed with definite or probable VTE within two years; 12 percent occurred at the time of diagnosis, and the remainder subsequently. The incidence rate of VTE was higher during the first year of follow-up than the second year for virtually all types and stages of cancer. Metastatic disease at the time of diagnosis was the strongest predictor for the development of VTE. The diagnosis of VTE was a significant predictor for decreased survival during the first follow-up year for all cancer types (median overall relative risk 3.7). Expressed as events per 100 patient-years, the highest incidences of VTE occurred during the first year of follow-up among cases with metastatic-stage cancer of the pancreas (20), stomach (10.7), bladder (7.9), uterus (6.4), kidney (6.0), and lung (5.0).A third study evaluated the incidence and effect of VTE on survival in 68,142 patients with colorectal cancer [23]. The two-year cumulative incidence of VTE was 3.1 percent, with rates of 5.0, 1.4, and 0.6events/100patient-years for months zero to 6, months 7 to 12, and during the second year following diagnosis, respectively. Other findings included: Significant predictors of VTE included metastatic stage disease and the presence of three or more comorbid conditions. In risk-adjusted models, VTE was a significant predictor of death within one year of cancer diagnosis among patients with local or regional-stage disease, but not among those with metastatic disease.Patient factorsWhile the presence of a malignancy is associated with an increased risk for VTE, and some malignancies and their associated operations are associated with a higher risk of VTE than others (eg, prostate, esophagus, uterus, liver, pancreas, lung, gastrointestinal tract, brain) [26], cancer patients often have multiple co-morbidities that contribute to an increased risk for VTE. In addition to the risks attendant to hospitalization, immobilization, and surgery, these include advanced age, widespread or metastatic disease, presence of circulating tumor cells, tumor grade, presence of a central venous catheter, active chemotherapyand/orradiation therapy, presence of inherited thrombophiliaand/orthrombocytosis, as well as transfusion of red cells or platelets [21,27-39].As an example, in a retrospective review of 43,808 patients undergoing one of 11 cancer surgical operations (breast resection, hysterectomy, prostatectomy, colectomy, gastrectomy, lung resection, hepatectomy, pancreatectomy, cystectomy, esophagectomy, nephrectomy), the following factors were significant predictors for development of VTE on multivariate analysis [26]. (See "Overview of the causes of venous thrombosis", section on 'Acquired thrombophilia'.) Increased age Recent steroid usage BMI 35kg/m2 Postoperative complications (eg, wound infection, reintubation, cardiac arrest, sepsis) Longer hospitalization (>1 week)Therapy-related factorsA number of drugs employed in cancer therapy have been associated with venous and arterial thrombosis (eg, thalidomide, lenalidomide, l-asparaginase, tamoxifen, bevacizumab). This subject is discussed in detail separately. (See "Drug-induced thrombosis and vascular disease in patients with malignancy" and "Thrombotic complications following treatment of multiple myeloma with thalidomide and its analogues", section on 'Venous thromboembolism prophylaxis'.)VTE risk assessment scoresSeveral risk assessment scores for predicting the risk of VTE have been developed in patients with cancer [40-47]. Among these, the Khorana score has been validated in large cohorts of patients with malignancy; it is also simple to calculate. The Khorana score estimates risk of VTE by assigning points based on the site of primary malignancy, hematologic parameters, and body mass index (BMI) (table 1) [40]. Patients were stratified according to the number of points into three risk groups to predict the development of VTE. The cumulative incidence of VTE at 2.5 months ranged from 0.3 percent to 6.7 percent in patients with the fewest and most risk factors, respectively.

The Khorana score was also validated in an independent study of 1415 patients with advanced malignancy enrolled in phase I chemotherapy trials (table 1) [48]. The Khorana score was modified in an observational cohort study (the Vienna Cancer and Thrombosis Study) to include additional high risk tumor types (brain, myeloma, kidney) and two additional variables: soluble P-selectin and D-dimer levels [49]. In a retrospective analysis of this cohort, the cumulative incidences of VTE at six months were 1 percent for the lowest risk group (0 points) and 35 percent for the highest risk group (5 points).Additional studies of patients with cancer have demonstrated that the incidence of VTE was higher in patients with elevated D-dimer levels, as well as other coagulation parameters (eg, peak thrombin, prothrombin fragment 1+2, tissue factor, fibrinogen) [41,42,50]. In a retrospective study of 497,180 Taiwanese patients with cancer, VTE risk was over 10-fold higher than the reported incidence in the general Taiwanese population (185 versus 15.9 cases per 100,000 person years, respectively) [47]. The following factors were associated with an increased risk of VTE: prior history of VTE; primary site myeloma, prostate cancer, lung cancer, gynecologic cancer, sarcoma, or metastasis of unknown origin, and female sex in a patient age 40 to 80 years. VTE risk was lower among patients >80 years, those with head and neck, endocrine, esophageal or breast cancer.Occult malignancyA number of uncontrolled or retrospective studies of patients with venous thromboembolism have indicated a clinically significant incidence of malignancy, diagnosed within the first 6 to 12 months after presentation with thrombosis [51-55]. In one of these studies, investigators reviewed the outcome of 4399 patients who had venography for suspected venous thrombosis. The subsequent incidence of malignancy was higher in the 1383 patients with thrombosis than in the 2412 patients without thrombosis (11 versus 7.5 percent) [51]. The cancers in the group with thrombosis were more likely to have occurred within six months of the study (44 versus 20 percent). In a study of all patients in Denmark from 1994 to 2009, the standardized incidence ratios for the development of cancer within one year of a diagnosis of superficial venous thrombosis, DVT of the legs, or PE were 2.46, 2.75, and 3.27, respectively [55]. After one year, the SIRs declined to 1.05, 1.11, and 1.14, respectively. For all three cohorts, strong associations were found for cancers of the liver, lung, ovaries, pancreas, and non-Hodgkin lymphoma.Malignancies developing within the first two years after a diagnosis of VTE are also associated with a significantly poorer prognosis. This was shown in a retrospective study comparing overall survival in 4322 patients diagnosed with a first malignancy occurring within five years after a diagnosis of VTE to a group of 299,714 patients with malignancy but without VTE. Hazard ratios for death were 2.48, 1.21, 1.26, and 1.07 for malignancies diagnosed within six months, >6 to 12 months, >1 to 2 years, and >2 to 5 years after the diagnosis of VTE, respectively [20].A less prominent association was noted in a Danish nationwide study of almost 27,000 patients with DVT or pulmonary embolism; the occurrence of cancer in this cohort was determined by linkage to the Danish Cancer Registry [52]. The standardized incidence ratio for cancer was 1.3 compared with those without DVT or pulmonary embolism. The risk of cancer was substantially elevated only during the first six months of follow-up and declined rapidly thereafter to a constant level slightly above 1.0 one year after the thrombotic event.A study linking over 500,000 cases in the California Cancer Registry with a hospital discharge database for VTE found a SIR for unprovoked VTE of 1.3 (95% CI 1.2-1.5) within one year prior to the diagnosis of cancer [56]. The incidence of preceding VTE was significantly increased over that expected only during the four-month period immediately preceding the date of cancer diagnosis; almost all of these were in patients with an ultimate diagnosis of metastatic disease. Seven cancer types were associated with a significantly increased SIR: acute myeloid leukemia, non-Hodgkin lymphoma, and renal cell, ovarian, pancreatic, stomach, and lung cancer.A meta-analysis of 40 reports published between 1982 and 2007 found a threefold excess risk of occult cancer in patients with VTE when compared with subjects without VTE (RR 3.2; 95% CI 2.4-4.5) [57]. Risks were highest for occult cancers developing in the ovary (RR 7.0), pancreas (6.1), and liver (5.6).Several prospective studies have provided further data on this association. In one report, 250 consecutive patients with symptomatic DVT were evaluated [58]. A cause or risk factor for the thrombosis was identified in 105 patients. Malignancy was identified at the time of diagnosis of the thrombotic event in 5 of 153 patients (3.3 percent) with no other identifiable risk factor. During a two-year follow-up, there was an increased incidence of cancer in the patients with idiopathic 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.In another series of 400 patients with DVT, 70 (18 percent) already had been diagnosed with malignancy at the time of presentation [59]. Of the remaining 326 patients, 10 new malignancies were diagnosed among 137 patients (7.3 percent) with idiopathic DVT, compared with only three malignancies in 189 patients (1.6 percent) with secondary DVT.Other studies have reported a higher incidence of occult malignancy (up to 25 percent) among patients with idiopathic DVT or pulmonary embolism [60-63]. This may be explained in part by the use of a more aggressive diagnostic approach for cancer, which included measurement of serum carcinoembryonic antigen and prostate specific antigen, chest radiography, upper gastrointestinal endoscopy, abdominal ultrasound, and computed tomography scanning.Venous thromboembolism appears more likely to be the presenting sign of pancreatic and prostate cancer, whereas it more frequently occurs late in the course of patients with breast, lung, ovarian, uterine, or brain cancer [64,65].VTE at least one year after the diagnosis of a malignancy may be indicative of a second malignancy. In a case-control population-based cohort study of 6285 patients with cancer and an episode of VTE, the relative risk of developing a second malignancy was 1.0 if the thrombotic episode occurred within one year following the diagnosis of the first cancer, but rose to 1.4 (95% CI 1.2-1.7) if the episode of VTE occurred more than one year after the diagnosis of the initial cancer [66].Use of cancer screeningThe increased incidence of subsequent malignancy among patients presenting with idiopathic DVT or pulmonary embolism has raised the question of whether extensive screening for cancer would be beneficial. The recommendations are varied [67-69]. The use of extensive screening in two studies [60,62], as discussed above, as well as in a 2008 meta-analysis [70], appears to increase the incidence of detected malignancies. However, the incidence of cancer was also increased in the patients with secondary DVT in these studies, so that the relative risk of diagnosing malignancy among patients with unexplained DVT and secondary thrombosis was comparable to other studies.Several investigators have attempted to define risk factors to identify the subset of patients likely to benefit from extensive screening for malignancy. In one study, cancer was diagnosed in 16 of 136 patients (12 percent) with idiopathic DVT during the index hospitalization [71]. All 16 had one or more abnormalities suggestive of possible malignancy on at least one of the four components of the initial investigation: history, physical examination, basic laboratory testing, or chest X-ray. During follow-up at a median of 34 months, cancer was diagnosed in 3 of 122 patients (2.5 percent), similar to the age- and sex-matched United States population. In a second series, 13 new malignancies were diagnosed among 326 patients with DVT during a six-month follow-up period [59]. Ten of the 13 had some type of clinical abnormality at presentation, and seven were diagnosed within the first 16 days based upon patient characteristics and clinical findings on initial routine examination and laboratory testing. In an analysis of patients with symptomatic acute VTE enrolled in the RIETE registry, those in whom cancer was diagnosed within the next three months ("hidden cancer"), when compared with those who were not so diagnosed during this period, had an increased incidence of recurrent VTE, major bleeding, and mortality [72]. On multivariate analysis, risk factors for such "hidden cancer" were age 60 to 75 years, presence of anemia, presence of bilateral DVT, and idiopathic (rather than secondary) VTE.In the absence of prospective studies demonstrating either cost-effectiveness or improved survival with aggressive diagnostic testing for malignancy [70,73-76], we believe that the evaluation of patients with idiopathic DVT should be limited to a careful history, a complete physical examination (including digital rectal examination and testing for fecal occult blood, pelvic examination in women), and routine laboratory testing (complete blood count, chemistry panel including electrolytes, calcium, creatinine, and liver function tests, urinalysis, chest radiograph, and, in men over the age of 50, prostate-specific antigen). Any abnormality observed on initial testing should then be investigated aggressively. A routine aggressive search for malignancy in all patients does not appear to be warranted [52,69,74,76], except in patients with recurrent idiopathic DVT who represent a high-risk group [58,59,67,72].Hepatic vein and portal vein thrombosisThrombosis of the hepatic vein (the Budd-Chiari syndrome) or portal vein may be associated with myeloproliferative neoplasms (eg, polycythemia vera), the clonal disorder paroxysmal nocturnal hemoglobinuria, as well as renal cell and adrenal carcinomas, hepatomas, and other gastrointestinal malignancies [77].The most common clinical findings of hepatic vein thrombosis are abdominal pain, hepatomegaly, and ascites. Splenomegaly and esophagogastric varices are seen with portal vein thrombosis. Laboratory and in vitro studies (eg, presence of the JAK2 mutation, spontaneous erythroid colony growth in the absence of erythropoietin) suggest that an occult myeloproliferative disorder may be present in as many as 75 percent of patients with apparently idiopathic hepatic or portal vein thrombosis. (See "Etiology of the Budd-Chiari syndrome".)Prevention of VTESurgical patientsPostoperative deep vein thrombosis is more frequent in patients with known malignant disease than in the general population, occurring in as many as 40 percent of patients in clinical trials employing bilateral venography of the lower extremities. As a result, these patients should be considered as being at high risk for development of postoperative VTE, with 33 to 53 percent of VTE episodes occurring after hospital discharge [78-83].In one prospective observational study of 44,656 patients undergoing surgery for one of nine different malignancies, significant risk factors for the development of postoperative VTE included the following [83]: Age 65 Presence of metastatic disease Ascites Presence of congestive failure Body mass index 25kg/m2 Platelet count>400,000/microL Serum albumin 2 hoursOverall VTE was significantly more likely after gastrointestinal, lung, prostate, andovarian/uterineoperations. In those experiencing an episode of VTE, 30-day mortality increased more than sixfold over those not experiencing VTE (8.0 versus 1.2 percent, respectively). Details on the use and duration of prophylactic anticoagulation were not provided, but the involved hospitals had a high compliance rate (93 percent) for in-hospital prophylactic anticoagulation. A high percentage of the patients developed VTE post-discharge, suggesting that more prolonged prophylactic anticoagulation may be warranted following major cancer surgery [84].Specific recommendations for the prevention of VTE in cancer patients undergoing surgery, consistent with the 2007 guidelines from the American Society of Clinical Oncology (ASCO) [85-87], are discussed separately. (See "Prevention of venous thromboembolic disease in surgical patients".)Hospitalized medical patientsAcutely ill hospitalized medical patients who are confined to bed and have active malignancy are at high risk for development of VTE, both symptomatic as well as asymptomatic [82,88,89]. The 2007 ASCO guidelines recommend that hospitalized patients with cancer should be considered for anticoagulation for prevention of VTE if there is no active bleeding and there are no other contraindications to anticoagulant use (eg, recent surgery, preexisting bleeding diathesis, platelet count60 years odds ratio (OR): 5.1 Male sex OR: 4.3 Breast cancer OR: 4.0 Tumor necrosis OR: 3.4 Advanced stage disease OR: 2.6Median survival for patients with early stage tumors (stages I and II: 16 versus 44 months) as well as advanced stage tumors (stages III and IV: 9 versus 14 months) were significantly reduced in subjects with DIC, as compared with those without DIC, respectively.THROMBOTIC MICROANGIOPATHYThrombotic microangiopathy (TMA) describes a syndrome characterized by a microangiopathic hemolytic anemia (MAHA) (picture 1), thrombocytopenia, microvascular thrombotic lesions, and the involvement of various specific organs. The two major TMA syndromes, which are thought to be pathogenetically similar, are thrombotic thrombocytopenic purpura (TTP) and the hemolytic-uremic syndrome (HUS) [122].TMA can also be seen as a complication of chemotherapy. This primarily occurs with one of four regimens: mitomycin C; cisplatin with or without bleomycin; gemcitabine; and the use of radiation and high dose chemotherapy prior to hematopoietic cell transplantation (HCT). (See "Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults", section on 'Chemotherapy agents' and "Kidney disease following hematopoietic cell transplantation" and "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency".)TMA is thought to reflect direct platelet consumption, due to endothelial injury or primary platelet activation resulting in some cases from accumulation of unusually large von Willebrand factor multimers [122-124]. (See "Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults", section on 'Pathogenesis'.)This is different from the direct activation of the coagulation pathway in DIC. As a result, TMA is characterized by thrombocytopenia, increased turnover of platelets but not fibrin, and usually normal levels of the coagulation components and little or no prolongation of the prothrombin time or activated partial thromboplastin time [122].Disseminated malignancyCases of TMA with thrombocytopenia mimicking TTP have been reported in association with disseminated, occasionally occult, mucin-producing adenocarcinoma of the breast, gastrointestinal tract, pancreas, lung, or prostate [123,125-129]. Neurologic abnormalities, such as headache, confusion, or paresis, can be seen, but renal failure is uncommon in carcinoma-associated TMA. This complication can occur in as many as 6 percent of patients with metastatic carcinoma. There are two main differences between these patients and those with TTP: Levels of the von Willebrand factor cleaving protease (ADAMTS13) are normal or only mildly reduced and antibodies to ADAMTS13 are not present [130-132]. This is in contrast to the marked reduction of, and presence of autoantibodies to, ADAMTS13 seen in TTP. (See "Diagnosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults".) Patients respond poorly, if at all, to plasma exchange [126], which is the standard of care in TTP. (See "Treatment and prognosis of thrombotic thrombocytopenic purpura-hemolytic uremic syndromes in adults".)A search for systemic malignancy, including a bone marrow biopsy, is appropriate when patients with apparent TTP have atypical clinical features or fail to respond to plasma exchange. (See "Causes of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults", section on 'Disseminated malignancy'.)Patients presenting with this complication usually die within days to weeks of diagnosis unless the underlying malignancy can be controlled [126-128,130,133-136].ACTIVATION OF COAGULATION PRIOR TO THE CLINICAL DIAGNOSIS OF MALIGNANCYA number of studies have documented an increased incidence of malignancy subsequent to the diagnosis of idiopathic VTE. (See 'Venous thromboembolism' above.)In addition, increased thrombin generation may be associated with an increase in cancer mortality even in the absence of symptomatic thrombosis [137,138]. This issue was addressed in the Second Northwick Park Study, which evaluated 3053 middle-aged men clinically free of malignancy to determine whether activation of coagulation had an impact on subsequent mortality [137]. Subjects with persistent activation of coagulation (ie, prothrombin fragment 1+2 and fibrinopeptide A concentrations in the upper quartile of the population distribution in two consecutive annual examinations) had an increased total mortality due to a higher mortality from all cancers, especially those of the gastrointestinal tract.Two explanations for these observations are that the underlying malignancy produced a hypercoagulable state or that increased thrombin generation and activity might predispose to enhanced growth of malignant cells through promotion of angiogenesis and tumor cell proliferation.INFORMATION FOR PATIENTSUpToDate 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 5thto 6thgrade 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 10thto 12thgrade 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.) Basics topic (see "Patient information: Disseminated intravascular coagulation (The Basics)")SUMMARY Clinical thromboembolism occurs in as many as 11 percent of patients with cancer and is the second leading cause of death in patients with overt malignant disease. Thrombotic episodes may precede the diagnosis of malignancy by months or years and can present in one or more of the following ways: Migratory superficial thrombophlebitis (Trousseau's syndrome) (see 'Trousseau's syndrome' above) Idiopathic deep venous thrombosis and other venous thrombosis (see 'Venous thromboembolism' above) Nonbacterial thrombotic endocarditis (marantic endocarditis) (see 'Nonbacterial thrombotic endocarditis' above) Disseminated intravascular coagulation (DIC) (see 'Disseminated intravascular coagulation' above) Thrombotic microangiopathy (see 'Thrombotic microangiopathy' above) Arterial thrombosis (see 'Arterial thrombosis' above) The high incidence of hypercoagulable states in patients with cancer doesNOTimply that all patients with a hypercoagulable state should be extensively screened for malignancy; however, it is important to pursue clinical symptoms and to perform age-appropriate cancer screening. (See 'Occult malignancy' above.) Risk prediction scores for the development of thromboembolic disease for patients with malignancy have been developed (table 1). (See 'VTE risk assessment scores' above.) Specific recommendations for the prevention of VTE in medical and surgical patients with cancer are discussed separately. (See "Prevention of venous thromboembolic disease in surgical patients" and "Prevention of venous thromboembolic disease in medical patients".) The pathogenesis of thromboembolic disease in patients with cancer and the treatment of cancer patients with established VTE are discussed separately. (See "Pathogenesis of the hypercoagulable state associated with malignancy" and "Treatment of venous thromboembolism in patients with malignancy".)Use of UpToDate is subject to theSubscription and License Agreement.REFERENCES1Goldenberg N, Kahn SR, Solymoss S. Markers of coagulation and angiogenesis in cancer-associated venous thromboembolism. J Clin Oncol 2003; 21:4194.

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Primary (spontaneous) upper extremity deep vein thrombosisAuthorKaoru Goshima, MDSection EditorsJohn F Eidt, MDJoseph L Mills, Sr, MDDeputy EditorKathryn A Collins, MD, PhD, FACSAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through:Jun 2013.|This topic last updated:Mar 28, 2013.INTRODUCTIONPrimary, "spontaneous" upper extremity deep vein thrombosis is rare and is defined as thrombosis of the deep veins draining the upper extremity due to anatomic abnormalities of the thoracic outlet causing axillosubclavian compression and subsequent thrombosis. The syndrome is appropriately termed venous thoracic outlet syndrome, but is also referred to as Paget-Schroetter syndrome, and alternatively as effort thrombosis [1]. It typically presents in young, otherwise healthy individuals as sudden, severe upper extremity pain and swelling following vigorous upper extremity activity. An aggressive treatment approach that includes anticoagulation, catheter-directed thrombolysis and thoracic outlet decompression is aimed at relieving acute symptoms, and minimizing complications including recurrent thromboembolism and post-thrombotic syndrome.The epidemiology, risk factors, pathophysiology, clinical features, diagnosis and treatment of primary (spontaneous) upper extremity venous thrombosis will be reviewed here. Catheter-induced upper extremity venous thrombosis and lower extremity deep vein thrombosis are discussed elsewhere. (See "Catheter-induced upper extremity venous thrombosis" and "Approach to the diagnosis and therapy of lower extremity deep vein thrombosis".)UPPER EXTREMITY ANATOMYThe upper extremity veins are divided into the superficial and deep venous systems (figure 1).Superficial veinsThe main superficial veins of the upper extremity include the cephalic, basilic, median cubital, and accessory cephalic veins (figure 1). The basilic vein is a common access site for performing digital subtraction venography.Deep veinsThe deep veins of the upper extremity include the paired ulnar, radial and interosseous veins in the forearm, paired brachial veins of the upper arm, and axillary vein. The axillary vein becomes the subclavian vein at the lower border of the teres major muscle (figure 2).Thoracic outlet anatomyThe thoracic outlet is bounded by the bony structures of the spinal column, first ribs, and sternum (figure 3A). Compression of the venous structures that traverse the thoracic outlet occurs in two distinct spaces: the scalene triangle and the costoclavicular space. Scalene triangle The anterior border of the scalene triangle is formed by the anterior scalene muscle, which originates from the transverse processes of the third through sixth cervical vertebrae (C3-C6) and inserts on the inner borders and superior surfaces of the first rib. The posterior wall of the scalene triangle is formed by the middle scalene muscle, which arises from the transverse processes of the second through seventh cervical vertebrae (C2-C7) and inserts broadly onto the posterior aspects of the first rib. The superior border of the first rib forms the base of the scalene triangle. The trunks of the brachial plexus and the subclavian artery pass between the anterior and middle scalene muscles, while the subclavian vein courses anteromedial to the scalene triangle (figure 3B). Costoclavicular space The costoclavicular space comprises the area between the first rib and the clavicle. The brachial plexus, subclavian artery and subclavian vein pass through this space. The subclavian vein is most likely to be compressed at this site.PATHOGENESISPrimary upper extremity deep vein thrombosis is defined as thrombosis of the deep veins draining the upper extremity due to an underlying anatomic anomaly at the thoracic outlet causing compression or repetitive injury to the underlying axillosubclavian vein [2-5]. Primary upper extremity deep vein thrombosis is a manifestation of venous thoracic outlet syndrome (vTOS). (See "Overview of thoracic outlet syndromes", section on 'Venous TOS'.)Thrombosis of the veins draining the upper extremity was originally postulated to be the cause of acute arm pain and swelling by Paget [6], and later Von Schroetter related the clinical syndrome specifically to the axillary and subclavian veins [7]. This clinical entity was referred to as Paget-Schroetter syndrome [8]. In the mid-20th century, the term effort thrombosis was coined [9], due to the fact that the syndrome often occurred in physically active individuals after unusually strenuous use of the arm and shoulder [10-12]. The term "spontaneous" upper extremity venous thrombosis has also been used highlighting the often dramatic presentation in an otherwise healthy, young individual. For the purposes of our discussion, we will refer to the syndrome as primary upper extremity deep vein thrombosis to distinguish it from secondary causes, which are associated with inciting factors such as indwelling catheters or prothrombotic states. (See "Catheter-induced upper extremity venous thrombosis".)Anatomic abnormalities of the thoracic outlet that result in compression of the vein can be congenital or acquired. Congenital anomalies consist of cervical ribs, supernumerary muscles, abnormal tendon insertions or abnormal muscular or tendinous bands [13,14]. Acquired abnormalities include bony overgrowth due to bony fracture (eg, clavicle, first rib) [15-18], or hypertrophy of anterior scalene muscle or subclavius muscles, often related to repetitive lifting. The abnormalities of the thoracic outlet are often bilateral, and bilateral primary upper extremity deep vein thrombosis has been reported [19,20]. Anatomic abnormalities narrow the scalene triangle, or more commonly the costoclavicular space, predisposing the vein to compression between the first rib and muscle or tendon (figure 3A-B), or between anomalous tendon insertions. Less commonly, compression of the vein between the clavicle and a cervical rib can occur, and partial occlusion of the vein by a congenital web has also been reported [13,14]. (See 'Thoracic outlet anatomy' above.)Under some circumstances, it appears that an anatomic abnormality is not necessary to produce injury to the vein. Extremes in range of motion of the upper extremity can lead to movement of the clavicle relative to the first rib sufficient to cause venous compression. Repetitive overhead arm movements or hyperabduction and external rotation of the shoulder are most often implicated [21-23]. Repetitive injury causes perivenous fibrosis, which eventually leads to thrombosis. It is important to recognize that the patient often presents with acute onset of symptoms related to the thrombosis, but the underlining problem may be a chronic repetitive injury that had narrowed the vein.EPIDEMIOLOGY AND RISK FACTORSUpper extremity deep vein thrombosis (all causes) represents 1 to 4 percent of all cases of deep vein thrombosis [24]. Primary upper extremity deep vein thrombosis is rare with an estimated annual incidence of 1 to 2 cases per 100,000 population [10,24]. The majority of cases of upper extremity deep vein thrombosis are secondary and related to central venous cannulation (eg, central line, pacemaker) or prothrombotic states (eg, thrombophilia, malignancy) [1,10,25,26] (See "Catheter-induced upper extremity venous thrombosis".)Between 60 and 80 percent of patients with primary upper extremity deep vein thrombosis report a history of exercise or strenuous activity involving usually the dominant upper extremity prior to the onset of symptoms. Strenuous activities include weight-lifting, rowing, or activities involving repetitive overhead arm movements, particularly hyperabduction, such as pitching [1,27,28]. The average age at presentation is in the early thirties and the male to female ratio is 2:1 [1]. A predominance of right-handed individuals may explain why the right axillosubclavian vein is more commonly affected. (See 'Pathogenesis' above.)Risk factorsRisk factors for primary upper extremity deep vein thrombosis include the following [1,10,25-28]: Younger age Athletic muscular male Strenuous upper extremity activity Repetitive overarm hyperabduction Anatomic abnormalities of the thoracic outlet (congenital, acquired)CLINICAL PRESENTATIONSPrimary upper extremity deep vein thrombosis can present acutely with symptoms and signs of upper extremity deep vein thrombosis or pulmonary embolism, or with chronic or intermittent symptoms.Acute upper extremity deep vein thrombosisAcute presentations are due to sudden thrombosis of the axillosubclavian vein.The classic presentation is that of a young, athletic male presenting with acute onset of upper extremity pain and swelling in the dominant arm following a particularly strenuous activity [1,27,28]. Strenuous use of the arm prior to the onset of extremity swelling or pain is recalled in 40 to 80 percent of patients, and symptoms are generally noticed within 24 hours of the strenuous activity [10,11,23,29]. The majority of patients (70 to 80 percent) manifest with variable degrees of neck, shoulder, or axillary discomfort, arm heaviness and pain associated with complaints of upper extremity swelling [30,31]. Swelling and pain typically improve with rest and elevation of the arm to the level of the heart, whereas elevation of the extremity overhead may aggravate the symptoms [32].Physical examination generally reveals edema of the affected extremity, often accompanied by cyanosis of the hand and fingers. The patient may also have a low-grade fever. A palpable venous cord (superficial thrombophlebitis) may be apparent in associated superficial veins (eg, proximal cephalic vein). Dilated subcutaneous collateral veins, also known as Urschels sign, may be noticeable over the upper chest and proximal upper extremity, particularly in those with an underlying chronic venous stenosis [11,27,30].The upper extremity arterial vascular examination should be normal. Reduced arterial blood flow due to venous congestion (phlegmasia cerulea dolens) is rare in the lower extremity and even more so in the upper extremity [33,34]. However, if present, it represents an emergency and indicates the need for emergent treatment. (See 'Thrombolytic therapy' below.)Coexistent signs related to brachial plexus compression (ie, neurogenic thoracic outlet syndrome) may be present, manifesting as paraesthesias or pain in the ulnar nerve distribution, tenderness over the supraclavicular fossa, and wasting of the intrinsic hand muscles. (See "Overview of thoracic outlet syndromes", section on 'Clinical evaluation'.)Acute pulmonary embolismIn addition to upper extremity swelling and pain, upper extremity deep vein thrombosis can initially present as symptomatic or asymptomatic pulmonary embolism [12,28,31,35-39]. The clinical features, diagnosis and treatment of pulmonary embolism are discussed in detail elsewhere. (See "Overview of acute pulmonary embolism".)Chronic or intermittent symptomsIn patients with partial thrombosis or chronic venous stenosis due to repetitive injury that causes activity-related obstruction, symptoms may be intermittent and less severe. If venous occlusion develops over a protracted period of time, edema or pain may be minimal, and increased venous collateral flow over the chest (Urschels sign) may be the only clinical sign that is apparent [11,27,30,40].DIAGNOSISA diagnosis of upper extremity venous outflow obstruction (ie, deep vein thrombosis or venous stenosis) may be suspected based upon the clinical presentation, but should be confirmed with imaging, typically initially using ultrasound. D-dimer is useful for excluding thrombosis as an etiology, but will not exclude venous stenosis without thrombosis as a source of symptoms. Once a diagnosis of venous outflow obstruction is established, a primary etiology should be sought to identify the underlying anatomic abnormality that is the source of the obstruction. We obtain a plain chest radiograph on all patients to identify any obvious bony abnormalities; however, more advanced imaging may be needed to demonstrate abnormal muscular attachments. It is important to assess contralateral limb involvement because about half of patients will have some degree of contralateral venous obstruction, even in the absence of symptoms. (See 'Pathogenesis' above.)D-dimerPlasma D-dimer, which is a degradation product of cross-linked fibrin, may be elevated in patients with upper extremity deep vein thrombosis, as in those with other lower extremity deep vein thrombosis or pulmonary embolism. However, although a plasma D-dimer >500g/Lis sensitive for thrombosis, and has a high negative predictive value, it is not specific for the anatomic location of the thrombosis, and will not exclude veincompression/stenosisas a source for symptoms [41].Venous outflow obstructionB-mode ultrasound, color Doppler ultrasound, and duplex ultrasound have been used extensively in the diagnosis of deep vein obstruction. Noncompressibility of the vein on B-mode ultrasound with or without visible intraluminal thrombus is the major criterion for the diagnosis of venous thrombosis. We use duplex ultrasound as the initial test for diagnosing upper extremity venous outflow obstruction because it is noninvasive, inexpensive, and in observational studies, has an acceptable sensitivity and specificity for the diagnosis of upper extremity deep vein thrombosis [31,42-49]. A systematic review evaluated 17 studies, concluding that compression ultrasonography is an acceptable alternative to standard contrast venography [42]. The summary estimates of the sensitivity of compression, Doppler ultrasound, and Doppler ultrasound with compression were 97, 84, and 81 percent, respectively, and specificities were 96, 94, and 93 percent, respectively. Disadvantages of ultrasound are that it is technician-dependent, and that nonocclusive mural thrombus and thrombus in the proximal subclavian or innominate veins may not be adequately seen as a result of acoustic shadowing by the overlying clavicle and sternum [48,50,51]. However, proximal subclavian vein obstruction is less typical of primary causes of upper extremity venous outflow obstruction, which tend to affect the mid- to distalsubclavian/proximalaxillary vein at the thoracic outlet. When acoustic shadowing is a problem, venous thrombus or stenosis more proximal to the placement of the ultrasound probe can be inferred from abnormal respiratory variation, abnormal augmentation, and abnormal Doppler flow.Although standard catheter-based (digital subtraction) venography provides the best definition of abnormal venous anatomy and is the standard with which other modalities are compared [42,52], it is generally not needed to establish a diagnosis of upper extremity deep vein thrombosis. Venography requires cannulation of a peripheral vein of the affected upper extremity, which can be challenging in the face of significant extremity edema, and the study requires a substantial intravenous contrast load. As such, catheter-based venography is generally reserved for situations where noninvasive studies are equivocal, but clinical suspicion remains high for a primary cause of venous outlet obstruction [1]. For patients with intermittent or chronic symptoms, extrinsic compression of the vein can be demonstrated during catheter-based venography by performing dynamic studies that place the arm in various positions during the study. The venogram may be normal at rest but abnormal (varying degrees of extrinsic compression with new venous collaterals) with arm abduction; however, vein compression with arm abduction can be a normal variant [53] Bony abnormalities may also be seen with fluoroscopic imaging during catheter-based venography, but abnormal fibrous bands or muscle insertions will not.Less invasive methods of venography include computed tomographic (CT) and magnetic resonance (MR) venography [51,54-56]. These modalities are not typically used to establish a diagnosis of upper extremity venous outflow obstruction. Rather, these studies are more useful for identifying anatomic abnormalities and other secondary causes for deep vein thrombosis (eg, tumor). (See 'Anatomic abnormalities of the thoracic outlet' below.) CT venography can be used to confirm or exclude central vein thrombus; however, like catheter-based venography, substantial contrast loads are required. CT venography has not been studied sufficiently to determine its sensitivity and specificity. A small study of 18 patients compared CT venography and digital subtraction venography for their ability to discriminate the severity and extent of venous obstruction, the cause of upper extremity deep vein thrombosis, and implications for the planning of treatment [56]. CT venography was felt to provide more information than digital subtraction venography, and in half of the patients, the findings of CT venography changed the treatment plan. Magnetic resonance imaging is very specific in its ability to image subclavian vein thrombosis, but its sensitivity for thrombosis is too low to be a useful screening modality [51]. In one study comparing standard catheter-based venography to time of flight (TOF) magnetic resonance (MR) venography and gadolinium 3-D MR venography in 31 patients, sensitivities and specificities were 71 and 89 percent for TOF MRV, and 50 and 80 percent gadolinium 3D MRV, respectively. In this study, 10 of 21 patients were unable to undergo MR venography [55].Anatomic abnormalities of the thoracic outletOnce a diagnosis of upper extremity venous outflow obstruction is established, further imaging should be performed to identify a primary cause for thrombosis, such as cervical ribs, supernumerary ribs, abnormal bands or abnormal muscle insertions. For any patient suspected of having a primary cause for upper extremity deep vein thrombosis or stenosis, we obtain a plain chest film to identify any bony abnormalities [57]. Ideally, the anatomic abnormality should be identified prior to thoracic outlet decompression; however, this is not always possible. At times, the anatomic abnormality may not be apparent until the time of surgical exploration. (See 'Thoracic outlet decompression' below.)Although computed tomography (CT) and magnetic resonance (MR) imaging are less appropriate initial studies for screening patients suspected of having upper extremity deep vein thrombosis, these studies provide more anatomic detail and show the relationship of venous structures to the surrounding bone and muscle. CT and MRI also allow the assessment of central venous stenosis or occlusion, which can be missed by ultrasound due to acoustic shadowing from overlying bony structures. In addition, less obvious bony abnormalities can be seen on these studies, and at times, venous compression related to bony or muscular abnormalities can also be seen.In the absence of an obvious bony anatomic abnormality, a primary cause for the thrombosis or venous stenosis can be presumed in the young, otherwise healthy, active individual with a classic presentation who does not have a history of central venous instrumentation or other medical problems associated with secondary etiologies for venous outflow obstruction. The specific abnormality may not be determined until the time of surgical exploration. (See 'Approach to treatment' below.)DIFFERENTIAL DIAGNOSISThe differential diagnosis for upper extremity edema not related to primary upper extremity deep vein thrombosis includes edema related to other etiologies, secondary causes of venous thrombosis, and lymphedema.Primary upper extremity deep vein thrombosis can be distinguished from secondary causes by the absence of venous instrumentation, a young, otherwise healthy patient demographic, and a more typically sudden onset of symptoms. The clinical features of upper extremity deep vein thrombosis are otherwise similar and include upper extremity edema and pain, and cyanosis of the skin due to venous congestion. Upper extremity deep vein thrombosis that occurs in the absence of instrumentation and with no identifiable anatomic abnormalities or other risk factors for venous thrombosis (eg, oral contraceptives) raises a concern of occult malignancy. Up to 25 percent of patients will be diagnosed within one year of a venous thromboembolic event [31,58]. If a primary cause for upper extremity deep vein thrombosis is not immediately apparent on imaging studies, the patient has no history of instrumentation, and the patient has none of the risk factors listed above for primary upper extremity deep venous thrombosis, we suggest a more formal laboratory evaluation to rule out secondary causes for upper extremity deep vein thrombosis, including coagulation studies, which should be drawn prior to the initiation of anticoagulation. (See "Screening for inherited thrombophilia in asymptomatic populations" and "Hypercoagulable disorders associated with malignancy".)Patients with venous thrombosis due to compression of structures of the thoracic outlet may also have symptoms attributable to the arterial or neurologic structures that pass through this space. Distinguishing between neurogenic, arterial, and venous thoracic outlet syndrome is discussed elsewhere. (See "Overview of thoracic outlet syndromes", section on 'Clinical evaluation'.)There are many causes of extremity edema that are not related to venous obstruction. The medical history will usually give a clue as to the potential etiology for edema (eg, history of heart failure). Although systemic etiologies typically present with bilateral extremity edema, this feature is not helpful given that anatomic abnormalities of the thoracic outlet are common and patients with primary upper extremity deep vein thrombosis can present with bilateral symptoms. Routine laboratory studies typically important in the evaluation of patients with extremity edema include a complete blood count, electrolytes, and liver function tests. These studies may point to an alternative etiology for upper extremity edema. The general approach to the patient with edema is discussed in detail elsewhere. (See "Pathophysiology and etiology of edema in adults" and "Clinical manifestations and diagnosis of edema in adults".)Upper extremity arm swelling can be due to lymphedema; however, swelling from acute venous thrombosis has a more abrupt onset and an antecedent risk factor such as prior axillary lymph node dissection is lacking. (See "Clinical manifestations and diagnosis of lymphedema".)APPROACH TO TREATMENTThe goals of treatment of primary upper extremity deep vein thrombosis are relieving symptoms related to venous obstruction, preventing complications of deep vein thrombosis, and preventing recurrent thrombosis [59]. Treatment options include anticoagulation, thrombolysis, and surgical decompression of the thoracic outlet. No treatment or combination of treatments has been rigorously evaluated for the treatment of upper extremity deep vein thrombosis. As a result, recommendations are based upon available retrospective studies and indirect evidence provided from the experience with deep vein thrombosis of the lower extremity [1].Our approach to treatment is as follows: We agree with guidelines from the American College of Chest Physicians that recommend anticoagulation for a minimum of three months for all patients identified with upper extremity deep vein thrombosis [60]. (See 'Anticoagulation' below.) For patients with primary upper extremity axillosubclavian deep vein thrombosis with sudden onset, moderate-to-severe upper extremity symptoms of less than two weeks duration, we suggest thrombolysis to eliminate thrombus to the extent that is possible. Lysis is less effective when symptoms have been present for more than two weeks. (See 'Thrombolytic therapy' below.) For good-risk surgical patients identified with anatomic abnormalities of the thoracic outlet causing symptomatic venous compression, we suggest thoracic outlet decompression. The specific procedure is targeted to the type of abnormality identified. For those in whom a specific abnormality has not been identified, we perform first rib resection, provided that a secondary cause of upper extremity venous thrombosis is not present. Anticoagulation alone (no thrombolysis) with or without thoracic outlet decompression may be appropriate for patients with mild symptoms, intermittent symptoms, and those who present in a delayed manner (>2 weeks). The natural history of these patients is unclear. (See 'Symptomatic care' below and 'Anticoagulation' below.)Rationale for aggressive treatmentAn aggressive approach that includes a combination of thrombolysis and thoracic outlet decompression with or without venoplasty (percutaneous, open) appears to improve long-term outcomes in patients with primary upper extremity deep vein thrombosis, particularly those with acute, moderate-to-severe symptoms [61-82]. With an aggressive approach, success rates for re-establishing subclavian vein patency are nearly 100 percent provided that thrombolysis is performed within two weeks of the onset of symptoms [83-85]. Although early intervention is advocated, patients with primary upper extremity deep vein thrombosis who present later than two weeks may also benefit from thoracic outlet decompression (no thrombolysis) given the high rates of recurrent thrombosis and long-term morbidity associated with anticoagulation alone [3,22,86,87].In a worldwide clinical series of 606 patients with primary upper extremity deep vein thrombosis, early thrombolysis and first rib resection provided the best outcome, with 95 percent of the surgical cohort experiencing an excellent clinical outcome compared with 29 percent treated conservatively, which consisted of anticoagulation, arm elevation, and upper extremity compression [27]. Residual venous obstruction was present in 78 percent of patients. The clinical outcomes associated with anticoagulation alone were evaluated in a later series of 54 patients, nearly all of whom were treated with warfarin [21]. After a mean follow-up of five years, 22 percent had persistent severe venous outflow obstruction on follow-up ultrasound. About 50 percent of the patients were asymptomatic, but 13 percent had severe or disabling symptoms. Subsequent pulmonary embolism was documented in 26 percent and was symptomatic in one-third of the patients. By comparison, among patients treated with thrombolysis (without thoracic outlet decompression), 76 percent were asymptomatic after a mean follow-up of 55 months [21,83]. In other retrospective reviews, persistent symptoms and disability occurred in 41 to 91 percent of patients treated conservatively [1,27].First rib resection without preoperative thrombolysis has been proposed for the management of primary subacute venous thrombosis. In the retrospective review, 45 of 110 patients underwent preoperative thrombolysis alone or thrombolysis and balloon venoplasty prior to thoracic outlet decompression. The remaining 65 patients were treated with anticoagulation alone prior to thoracic outlet decompression. Up to 80 percent of occluded axillosubclavian veins recanalized during the follow-up period in the anticoagulation group, and the overall rates of venous patency were similar between the groups [86].Recommendations of othersOur recommendations are in general agreement with the guidelines from the American College of Chest Physicians (ACCP); however, the ACCP suggests anticoagulant therapy alone over thrombolysis for patients with acute upper extremity deep vein thrombosis that involves the axillary or more proximal veins [60]. They further state that patients are likely to choose thrombolytic therapy over anticoagulation alone if they are more likely to benefit from thrombolysis, have access to catheter-based therapy, attach a high value to the prevention of post-thrombotic syndrome, and attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy. This recommendation does not distinguish between primary and secondary causes of upper extremity deep vein thrombosis directly; however, given that patients with primary upper extremity deep vein thrombosis are more likely to benefit from thrombolysis compared with patients with secondary causes of deep vein thrombosis, we support a more aggressive treatment strategy. (See 'Rationale for aggressive treatment' above.)INITIAL MANAGEMENTPatients who are diagnosed with primary upper extremity deep vein thrombosis are initially managed with measures to improve their comfort and are anticoagulated. Anticoagulation helps to maintain patency of collateral veins and reduces propagation of thrombus. Anticoagulant therapy with heparin or warfarin is also effective in preventing pulmonary embolism with lower extremity venous thrombosis, and by extrapolation, may also prevent embolism from upper extremity deep vein thrombosis [28,60]. The decision to proceed with thrombolysis or thoracic outlet decompression is based upon symptom severity and the type of associated anatomic abnormality. (See 'Approach to treatment' above.)Symptomatic careSymptomatic care of phlebitic symptoms related to upper extremity deep vein thrombosis includes upper extremity elevation, and nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management.Arm elevation should help reduce upper extremity swelling. Graduated compression stockings have been shown to reduce the rate of post-thrombotic syndrome in patients with lower extremity deep vein thrombosis, and may also be beneficial in patients with upper extremity deep vein thrombosis [31]. However, compression is likely unnecessary in treated patients for whom the lesion is corrected and edema has resolved.AnticoagulationWe agree with guidelines from the American College of Chest Physicians that recommend parenteral anticoagulation (eg, low molecular-weight heparin, fondaparinux, intravenous unfractionated heparin, subcutaneous unfractionated heparin) for all patients with axillosubclavian vein thrombosis [60]. In our practice, we begin parenteral anticoagulation once a diagnosis of deep vein thrombosis is made but after any necessary laboratory tests to evaluate for hypercoagulable states have been obtained. The choice of initial parenteral agent for anticoagulation in patients with primary upper extremity deep vein thrombosis depends upon the need for further treatment in the form of thrombolysis or thoracic outlet decompression. For patients with mild, intermittent, or chronic symptoms who will be managed on an outpatient basis, low molecular-weight heparin (LMWH) or fondaparinux can be initiated to bridge to long-term therapy in a similar fashion as those with lower extremity deep vein thrombosis [60,88-90]. (See "Treatment of lower extremity deep vein thrombosis".)When thrombolysis is anticipated, we administer unfractionated heparin, and maintain therapeutic levels (aPTT 1.5 to 2.5 times control) until thrombolysis is initiated. During thrombolysis, the dose of heparin should be lowered to minimize bleeding complications, but once thrombolysis is completed, full anticoagulation can be resumed [91,92]. Similarly, the dose of heparin should be lowered around the time of surgical intervention. Once any necessary interventions are completed, bridging anticoagulation can be use to transition to long-term therapy in anticipation of discharge. (See "Management of anticoagulation before and after el