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Hypercoagulable disorders associated with malignancy
Author
Kenneth A Bauer, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD
All 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.
INTRODUCTION Patients 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 thrombosis
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.
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 SYNDROME An 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 percent
This 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].
Mucin Mucins 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 THROMBOEMBOLISM The 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 VTE
Known malignancy
Overall risk Clinical 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/or pulmonary
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 with recurrent DVT/PE within 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 for DVT/PE among 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 greatest absolute number of episodes of DVT/PE during
this time period were lung, colon, and prostate, while those cancers with the
highest rates ofDVT/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 factors The 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 0.6 events/100 patient-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 factors While 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
chemotherapy and/or radiation therapy, presence of inherited
thrombophilia and/or thrombocytosis, 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 35 kg/m
2

Postoperative complications (eg, wound infection, reintubation, cardiac arrest, sepsis)
Longer hospitalization (>1 week)
Therapy-related factors A 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 scores Several 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 malignancy A 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 screening The 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 thrombosis Thrombosis 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 VTE
Surgical patients Postoperative 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 25 kg/m
2

Platelet count >400,000/microL
Serum albumin <3.0 g/dL
Operation duration >2 hours
Overall VTE was significantly more likely after gastrointestinal, lung, prostate,
and ovarian/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 patients Acutely 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 count <50,000/microL, coagulopathy) [81,85-
87].
Recommendations for the prevention of VTE in hospitalized cancer patients, consistent with
these ASCO guidelines, are discussed separately. (See "Prevention of venous thromboembolic
disease in medical patients", section on 'Overview'.)
Patients with a central venous catheter Although the presence of a central venous catheter
is a risk factor for VTE in cancer patients, there is no evidence to support the routine use of
VTE prophylaxis to prevent central venous catheter thrombosis. This issue is discussed
separately. (See "Catheter-induced upper extremity venous thrombosis", section on
'Thrombosis prevention'.)
Ambulatory and postoperative cancer patients The ambulatory cancer patient has an
increased risk for the development of VTE. The development of VTE, even after complete
surgical resection for a primary tumor [90], is a risk factor for reduced survival in these
patients, and may also compromise the patient's ability to receive and respond to definitive
treatment [17-19]. This is especially true for exocrine pancreatic cancer, with most modern
studies reporting an incidence of thrombosis ranging from 5 to 27 percent [91].
This issue was addressed in an analysis of data from the National Cancer Institute of Canada
Clinical Trials Group PA3 randomized trial of chemotherapy in ambulatory patients with
advanced pancreatic cancer [19]. Patients with VTE either at the time of randomization or
during the study had a significantly higher risk of disease progression, a lower chance of
achieving a response to treatment, and shorter overall survival than patients without VTE.
Similar conclusions were made in a report of a single institution study of 1915 patients with
pancreatic carcinoma treated with chemotherapy, in whom 690 (36 percent) developed a
thrombotic event [92]. The development of a thrombotic event, especially within 1.5 months
of diagnosis, conferred a significantly worse prognosis.
Efficacy of anticoagulation We do not advocate the use of prophylactic anticoagulation for
ambulatory patients with cancer receiving or about to receive chemotherapy, as there is not
enough evidence available at this time to support its use. The 2007 ASCO guidelines, the 2012
ACCP Clinical Practice Guidelines, a 2009 Consensus Statement of major guidelines panels, and
the 2012 Clinical Practice Guidelines in Oncology from the NCCN do not recommend routine
VTE prophylaxis in ambulatory patients with cancer, except for those with multiple myeloma
receiving thalidomide or lenalidomide plus chemotherapy or dexamethasone
[36,81,85,87,93,94].
The 2012 guidelines from the NCCN, however, suggest that VTE prophylaxis might be
appropriate for those with a Khorana score 3 (table 1) who put a higher value on avoiding
VTE than on the increased risk of bleeding associated with anticoagulation [36]. Prophylactic
anticoagulation might also be considered on an individualized basis in patients who develop
cancer and have a prior history of unprovoked venous thromboembolism if they are not
chronically anticoagulated. (See "Thrombotic complications following treatment of multiple
myeloma with thalidomide and its analogues", section on 'Incidence and risk factors'.)
A number of randomized studies comparing various LMW heparins to placebo in cancer
patients receiving chemotherapy without VTE have been performed providing data on the
risks (eg, bleeding) and benefits (eg, reduction in the incidence of VTE, prolongation of
survival) of such anticoagulation. Results from a number of these studies are presented below.
(See 'Prolongation of survival' below.)
The PROTECHT study The PROTECHT study randomized 1150 patients to the LMW
heparin nadroparin (3800 anti-Xa IU subcutaneously once daily; 769 patients) versus placebo
(381 patients) and evaluated prevention of thromboembolic events. Patients had metastatic
or locally advanced lung, breast, gastrointestinal, ovarian, or head and neck cancer, an ECOG
performance status of 2, and were receiving active chemotherapy. Study treatment was
given for the duration of chemotherapy, up to a maximum of four months. Results included
[95]:
The incidence of symptomatic venous and arterial thromboembolic events, the primary
study outcome, was significantly lower in the nadroparin-treated patients when compared
with those receiving placebo (2.0 versus 3.9 percent).
The rates of minor bleeding (7.4 versus 7.9 percent, respectively) and major bleeding (0.7
versus zero percent, respectively) were similar in the LMW heparin and placebo-treated
groups. The rates of other serious adverse events thought to be related to the
investigational drug were also similar (1.2 versus 1.6 percent, respectively).
Thromboembolic rates in the placebo-treated patients were highest in those with cancers
of the lung (8.8 percent) and pancreas (5.9 percent), suggesting that future studies should
concentrate on these high-risk groups. (See 'VTE risk assessment scores' above.)
The CONKO 004 trial A prospective, randomized study of the efficacy and safety of adding
the LMW heparin enoxaparin (1 mg/kg subcutaneously once daily) to chemotherapy in 312
patients with advanced pancreatic cancer (the CONKO 004 trial) has been presented in
abstract form [96]. Initial results include the following:
On an intent-to-treat analysis, there was a 65 percent relative risk reduction of
symptomatic VTE following the use of LMW heparin (14.5 percent for the observation
group versus 5.0 percent for the enoxaparin-treated group).
Major bleeding events were noted in 6.3 and 9.9 percent of those receiving enoxaparin or
observation, respectively.
Preliminary data showed no differences in time to progression or overall survival.
The FRAGEM study The FRAGEM study randomized 123 patients with advanced or
metastatic pancreatic cancer treated with gemcitabine (1000 mg/m
2
) to receive or not receive
full therapeutic doses of the LMW heparin dalteparin (200 units/kg once daily for four weeks
followed by 150 units/kg once daily for a further eight weeks) [97,98]. Results included the
following:
The incidence of VTE during the initial treatment period (ie, <100 days), the primary efficacy
endpoint, was significantly reduced in those receiving dalteparin (23 percent in those
treated with chemotherapy alone versus 3.4 percent in those also treated with dalteparin;
RR 0.145; 95% CI 0.035-0.612).
The incidence of all-type VTE during the entire follow-up period was also significantly
reduced in those receiving dalteparin (28 percent in those treated with chemotherapy
alone versus 12 percent in those also treated with dalteparin; RR 0.419; 95% CI 0.187-
0.935).
There were five lethal episodes of VTE during the first 100 days of observation, which were
seen only in the chemotherapy alone group. This difference was not statistically significant
(8.3 versus 0 percent; RR 0.092; 95% CI 0.005-1.635).
There were no significant differences in the secondary endpoints of overall survival (9.7
versus 8.7 months), time to progression (5.3 versus 5.5 months), or incidence of severe
hemorrhage (3.2 versus 3.4 percent) between the two treatment arms.
The SAVE-ONCO trial This trial evaluated the efficacy and safety of the ultra LMW heparin
semuloparin (20 mg once daily by subcutaneous injection) versus placebo for the prevention
of VTE in patients with metastatic or locally advanced solid tumors who were beginning a
course of chemotherapy. Findings during the 3.5-month treatment period included [99]:
VTE occurred significantly less often in those treated with semuloparin than in those
treated with placebo (1.2 versus 3.4 percent, respectively; HR 0.36; 95% CI 0.21-0.60).
Efficacy of semuloparin was similar among subgroups defined according to the origin and
stage of cancer and the baseline risk of VTE.
Seven risk factors for VTE were evaluated, including presence of a central venous line,
obesity, age >75, chronic respiratory failure, chronic heart failure,
venousinsufficiency/varicose veins, and a history of prior VTE [99]. The incidence of VTE in
those with none of these risk factors (placebo treated group only) was 2.5 percent, while it
was 12.5 percent in those with three or more of these risk factors.
The incidences of clinically relevant bleeding (2.8 versus 2.0 percent) and major bleeding
(1.2 versus 1.0 percent) were similar in the two treatment arms.
Overall survival, assessed either at one year following randomization or seven months after
randomization of the last subject, was similar in the two treatment arms (43.4 versus 44.5
percent, respectively; HR 0.96; 95% CI 0.86-1.06). [40-49]
Use of statins A number of studies have suggested that the use of statins decreases the risk
of VTE in several groups of medical patients (eg, healthy adults, subjects with atherosclerosis).
(See "Prevention of venous thromboembolic disease in medical patients", section on 'Statins'.)
The effect of statin use on the risk of VTE in cancer patients was explored in a retrospective,
case control study in 740 consecutive patients with a diagnosis of solid organ tumor, who
were followed for an average duration of 10.2 months (range: 2 to 41 months) [100]. Findings
included:
Multivariate analysis indicated that statin use was associated with a significant reduction in
the risk of VTE (OR 0.33; 95% CI 0.18-0.59).
As expected, the same analysis confirmed the presence of known factors that increase the
risk of VTE, such as immobilization (OR 2.88), presence of metastatic disease (OR 2.07), and
current chemotherapy (OR 1.77).
Prolongation of survival There is limited information on the use of anticoagulation to
prolong survival in cancer patients without VTE. Available results are mixed, as noted below:
A meta-analysis of 11 randomized controlled studies has concluded that anticoagulation
significantly reduced one-year overall mortality in cancer patients WITHOUT VTE by 8
percent for LMW heparin and 3 percent for warfarin, while increasing the risk for bleeding
complications [101]. Available trials did not permit subgroup analyses of the influence of
cancer type and stage.
A 2007 Cochrane review of five randomized controlled trials concluded that therapy with
unfractionated or LMW heparin was associated with a clinically significant survival benefit
(hazard ratio 0.77; 95% CI 0.65-0.91) in cancer patients without another reason for
anticoagulation [102]. In a subgroup analysis, patients with limited small cell lung cancer
experienced a clear survival benefit (HR 0.56; 95% CI 0.38-0.83) which was not seen in
patients with advanced cancer of any site. The analysis could not rule out an increased risk
of bleeding with heparin in these patients (RR 1.8; 95% CI 0.73-4.4).
Results from a multicenter randomized study have indicated that use of the LMW
heparin nadroparin did not significantly improve median overall survival in 244 patients
with advanced cancer (prostate, pancreas, non-small cell lung cancer) when compared with
the 259 not receiving this agent (13.1 versus 11.9 months, respectively; adjusted hazard
ratio 0.94; 95% CI 0.75-1.18) [103]. In addition, no difference in time to progression was
observed between the two study arms. Major bleeding events were comparable between
the two groups (4.1 versus 3.5 percent).
In the absence of consistent data indicating a survival benefit, we agree with the 2007 ASCO
guidelines, the 2008 ACCP guidelines, and the 2011 ESMO guidelines, which recommended
against the use of anticoagulants for the purpose of improving survival in cancer patients
without VTE [85,104,105].
Treatment of VTE The treatment of VTE in patients with cancer is discussed separately. (See
"Treatment of venous thromboembolism in patients with malignancy".)
ARTERIAL THROMBOSIS Arterial thrombosis is less common than venous thrombosis in
cancer patients.
In a retrospective cohort study, the incidence of arterial and venous thromboembolism
among 66,106 hospitalized adult neutropenic cancer patients was 1.5 and 5.4 percent,
respectively [106].
In a retrospective cohort study of 504,208 hospitalized cancer patients who did not receive
blood transfusions and were admitted between 1995 and 2003 at 60 medical centers, the
overall rates of arterial and venous thromboembolism were 3.0 and 3.7 percent,
respectively [30]. These rates were as high as 5.2 and 7.2 percent, respectively in those who
did receive blood transfusions during their hospitalization.
Such episodes of arterial thromboembolism are most frequently due to nonbacterial
thrombotic endocarditis (see below), but some cases of acute ischemic stroke in patients with
malignancy may be due to paradoxical brain embolism arising from deep vein thrombosis and
a right-to-left shunt [107].
Thrombosis of the arterioles of the central nervous system and extremities may be associated
with the myeloproliferative disorders, particularly essential thrombocythemia and
polycythemia vera [108]. Digital ischemia may be a paraneoplastic phenomenon in solid
tumors [109].
NONBACTERIAL THROMBOTIC ENDOCARDITIS The term nonbacterial thrombotic
endocarditis (NBTE, marantic endocarditis, Libman-Sacks endocarditis, verrucous endocarditis)
refers to a spectrum of lesions on the heart valves (most often aortic and mitral), usually in
patients with advanced malignancy. In autopsy series, cancer has been found in as many as 75
percent of cases [110]. The majority of NBTE is seen in patients with adenocarcinomas (eg, of
the pancreas, lung, colon, or prostate); the incidence among patients with lung cancer may be
as high as 7 percent [111,112]. (See "Echocardiography in detection of intracardiac sources of
embolism", section on 'Nonbacterial thrombotic endocarditis'.)
The vegetations consist of degenerating platelets interwoven with strands of fibrin. The
masses vary in size from microscopic to large and exuberant with a tendency to cause
extensive infarction if embolization occurs.
The initiating factor in the pathogenesis of NBTE is unknown. Endothelial damage caused by
circulating cytokines, such as tumor necrosis factor or interleukin-1, might trigger platelet
deposition, particularly in the presence of an activated coagulation system. Laboratory
evidence for disseminated intravascular coagulation (DIC) is often present.
The major clinical manifestations of NBTE result from systemic emboli rather than valvular
dysfunction. The vegetations are easily dislodged since there is little inflammatory reaction at
the site of attachment. Common sites of embolization include the spleen, kidney, and
extremities, but the most significant morbidity arises from emboli to the central nervous
system and coronary arteries [113,114]. Focal or diffuse neurologic abnormalities may be
seen.
Diagnosis The possibility of NBTE should be considered in all cancer patients who develop
an acute stroke syndrome as well as in patients presenting with cerebral embolism of
unknown etiology [113,115]. The diagnosis of NBTE can be difficult to establish antemortem.
Fewer than 50 percent of patients have audible cardiac murmurs, and small lesions (less than
3 mm) may not be identified by echocardiography.
The preferred diagnostic test is transesophageal echocardiography (TEE), which is more
sensitive than transthoracic echocardiography for the detection of vegetations. The potential
value of TEE in this setting was illustrated in a series of 51 consecutive cancer patients with
cerebrovascular events who were referred for TEE [115]. Almost one-half of patients had a
definite cardiac source of embolism. Nonbacterial vegetations were detected in nine (18
percent); transthoracic echocardiography was performed in seven of these patients and was
negative in four. Other sources of embolism included left atrial thrombus, complex aortic
atheroma, and a patent foramen ovale or atrial septal defect in the presence of venous
thromboembolism. (See "Echocardiography in detection of intracardiac sources of embolism",
section on 'Nonbacterial thrombotic endocarditis'.)
Treatment We use anticoagulation for patients with NBTE and systemic or pulmonary
emboli, if there is no contraindication to anticoagulation. These patients should receive full-
dose intravenous unfractionated heparin or subcutaneous low molecular weight (LMW)
heparin, rather than warfarin. This is in agreement with the American College of Chest
Physicians (ACCP) guidelines on antithrombotic therapy published in 2012 [116].
We also use anticoagulation with full dose intravenous heparin or subcutaneous LMW heparin
in patients with disseminated cancer who are found to have aseptic vegetations.
Anticoagulation should be continued indefinitely, since recurrent thromboembolism has
occurred in patients following its discontinuation [117]. Treatment of the underlying
malignancy, often metastatic at the time of diagnosis of NBTE, is generally unsatisfactory, but
should be attempted in appropriate patients.
DISSEMINATED INTRAVASCULAR COAGULATION Disseminated intravascular coagulation
(DIC), resulting from generalized activation of the coagulation system, is the most common
coagulopathy associated with malignancy. Malignancy is the third most frequent cause of DIC
after infection and trauma, accounting for approximately 7 percent of clinically evident cases.
DIC, which may be occult, has been reported in as many as 15 percent of patients with
advanced disease and in most patients with acute promyelocytic leukemia (APL).
Acute DIC Acute, overt DIC is rare in most malignancies, most often occurring with APL and
adenocarcinomas [118]. Two tumor cell procoagulants may be of primary importance in APL:
tissue factor which forms a complex with factor VII to activate factors X and IX; and cancer
procoagulant which activates factor X independent of factor VII [119,120]. (See "Pathogenesis
of the hypercoagulable state associated with malignancy".)
Symptomatic DIC is manifested by bleeding due to utilization of clotting factors by the
consumptive process. Affected patients may complain of minor bleeding from mucosal or
cutaneous surfaces and/or extensive life-threatening hemorrhage involving visceral sites.
Among patients with APL, DIC is often present at the time of diagnosis or soon after the
initiation of cytotoxic chemotherapy. It can cause pulmonary or cerebrovascular hemorrhage
in up to 40 percent of patients and some studies report a 10 to 20 percent incidence of early
hemorrhagic deaths. The induction of tumor cell differentiation with retinoic acid can lead to
rapid improvement in the coagulopathy associated with acute promyelocytic leukemia [119].
(See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic
leukemia in adults".)
Carcinoma of the prostate also may be associated with hemorrhagic symptoms. However, the
mechanism is different from DIC, being due to activation of fibrinolysis.
Laboratory evaluation in DIC reveals a typical constellation of findings. These include
prolongation of the prothrombin time (PT), activated partial thromboplastin time (aPTT),
thrombin time and reptilase time; thrombocytopenia; and reductions in plasma
concentrations of fibrinogen and factors V and VIII. The most useful confirmatory test is the
demonstration of increased levels of fibrin degradation products (FDPs).
Chronic DIC Chronic forms of DIC are more common in patients with cancer, particularly
those with solid tumors. Most patients are asymptomatic while laboratory testing reveals low
grade activation of coagulation with secondary fibrinolysis. The most common manifestations
are modest reductions in plasma fibrinogen and the platelet count, elevated FDPs, and
minimal changes in the PT or aPTT. A minority of affected patients have more obvious
evidence of platelet, fibrinogen, and coagulation factor consumption. These patients often are
hypercoagulable, and can present with deep vein thrombosis, Trousseau's syndrome, or NBTE.
In one study of 1117 patients with solid tumors, DIC was present in 76 (6.8 percent); 50
patients presented with bleeding, while 31 presented with thrombosis [121]. On multivariate
analysis, significant risk factors for development of DIC included:
Age >60 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: 2.6
Median 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 MICROANGIOPATHY Thrombotic 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 malignancy Cases 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 MALIGNANCY A
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 PATIENTS UpToDate offers two types of patient education materials,
The Basics and Beyond the Basics. The Basics patient education pieces are written in plain
language, at the 5
th
to 6
th
grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10
th
to 12
th
grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles on
a variety of subjects by searching on patient info and the keyword(s) of interest.)
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 does NOT imply 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 the Subscription and License Agreement.
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Primary (spontaneous) upper extremity deep vein thrombosis
Author
Kaoru Goshima, MD
Section Editors
John F Eidt, MD
Joseph L Mills, Sr, MD
Deputy Editor
Kathryn A Collins, MD, PhD, FACS
All 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.
INTRODUCTION Primary, "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 ANATOMY The upper extremity veins are divided into the superficial and
deep venous systems (figure 1).
Superficial veins The 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 veins The 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 anatomy The 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.
PATHOGENESIS Primary 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 FACTORS Upper 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 factors Risk 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 PRESENTATIONS Primary 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 thrombosis Acute 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 embolism In 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 symptoms In 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].
DIAGNOSIS A 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-dimer Plasma 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 >500 g/L is 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
vein compression/stenosis as a source for symptoms [41].
Venous outflow obstruction B-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
distal subclavian/proximal axillary 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 outlet Once 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 DIAGNOSIS The 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 TREATMENT The 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 treatment An 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 others Our 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 MANAGEMENT Patients 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 care Symptomatic 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.
Anticoagulation We 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 elective surgery", section on 'Bridging anticoagulation'.)
Admission and referral Many patients with acute, severe symptoms related to primary
upper extremity deep vein thrombosis will require admission to manage symptoms and in
anticipation of thrombolytic therapy and/or surgical decompression.
There is no "one size fits all" approach to the treatment of primary upper extremity deep vein
thrombosis. Individualized care requires a team of specialists with sufficient experience and
readily available resources and ancillary personnel. Such teams are rare outside tertiary
referral centers, and thus, referral to a vascular center with such a team is appropriate
[66,93].
Initial outpatient anticoagulation and outpatient referral for possible further treatment may
be appropriate for patients with:
Minimal symptoms
Delayed presentation more than two weeks after the onset of symptoms
Intermittent symptoms due to venous obstruction without thrombosis
THROMBOLYTIC THERAPY The aim of thrombolytic therapy is prompt dissolution of
thrombus to minimize inflammation and endothelial injury and to restore vein patency, which
reduces extremity edema and associated symptoms [28,82,94,95]. Thrombolytic therapy
appears to have the most benefit for patients who present with acute, moderate-to-severe
symptoms related to sudden axillosubclavian thrombosis. In our experience, thrombi that
have been symptomatic for up to two weeks have a reasonable chance of lysis with catheter-
directed infusion of alteplase directed into the thrombus. Thrombolysis restores vein patency
in 64 to 84 percent of patients, with better patency rates associated with earlier initiation of
lytic therapy [82]. However, even after successful lysis that restores vein patency, up to one-
third of patients will re-occlude [1,82]. (See 'Rationale for aggressive treatment' above.)
The general contraindications to thrombolytic therapy are given in the table (table 1). We do
not perform thrombolysis in patients with only partial thrombosis, or those with mild acute or
chronic, intermittent symptoms. Symptomatic patients who present more than two weeks
after the onset of symptoms are less likely to benefit from thrombolysis due to the organized
nature of the clot and inflammatory changes in the vein.
Observational studies have shown that catheter-directed pharmacologic thrombolysis, which
involves embedding an infusion catheter into the axillosubclavian vein thrombus, achieves
higher rates of clot dissolution compared with systemic infusion and requires an overall lower
dose and shorter duration of lysis, which reduces bleeding complications [28,82,95].
Catheter-directed pharmacologic upper extremity thrombolysis is performed in the following
manner:
The basilic vein of the affected limb is accessed using ultrasound guidance.
A guidewire and catheter are used to traverse the thrombosed axillosubclavian vein.
A multi sidehole infusion catheter is embedded within the thrombus and infusion of
alteplase initiated at 0.01 mg/kg/hour [82,96]. Alternatively, urokinase (not available in the
United States) can be used [97].
The catheter is sutured into position, and the patient transferred to a monitored setting to
monitor for any bleeding complications. The progress of thrombolysis is evaluated by
performing venography at 12 hours, and again at 24 hours if necessary. A total dose of 20
to 25 mg alteplase can be safely used in most cases.
For patients undergoing catheter-directed or systemic thrombolysis, aspirin should be
administered along with unfractionated heparin during infusion of the thrombolytic agent
to counteract platelet activation and potentially increased thrombogenicity that may be
induced with lytic therapy [31].
Mechanical thrombolysis (eg, Trellis, AngioJet, EKOS catheter) is often used in combination
with pharmacologic thrombolysis [98]. There are limited data involving the use of these
devices to treat upper extremity thrombosis. However, based upon available results for lower
extremity deep vein thrombosis, these treatments may be useful in upper extremity
thrombosis to rapidly extract a large burden of thrombus and reduce the overall dose and
duration of lytic therapy [99]. Mechanical thrombolysis may be more effective for patients
with acute, severe symptoms who present in a delayed manner (>2 weeks) after the initial
onset of symptoms.
Once venous patency has been re-established with catheter-directed thrombolysis, it is
important to evaluate the residual axillosubclavian vein for persistent compression or
stenosis. Occasionally, adjunctive percutaneous transluminal angioplasty (PTA) following
successful thrombolysis is needed to open the vein sufficiently so that anticoagulant
treatment can maintain patency until thoracic outlet decompression can be performed [1].
(See 'Venoplasty' below and 'Thoracic outlet decompression' below.)
THORACIC OUTLET DECOMPRESSION For patients with primary upper extremity
axillosubclavian deep vein thrombosis, and selected patients with axillosubclavian
venouscompression/stenosis, observational studies support surgical decompression of the
thoracic outlet, which provides the lower rates of recurrent (or future) thrombosis, and
reduced long-term morbidity compared with more conservative management [1,27]. (See
'Rationale for aggressive treatment' above.)
Thoracic outlet decompression, which may include any one of a combination of the
procedures discussed below, is indicated for good-risk surgical patients with any of the
following presentations [1,27,61,100,101]:
Patients who present with acute, moderate to severe symptoms due to primary upper
extremity axillosubclavian thrombosis, following thrombolysis.
Symptomatic patients (intermittent or recurrent) with a thoracic outlet anatomic
abnormality causing venous compression/stenosis. Objective evidence of venous
thrombosis may or may not be present.
Thoracic outlet decompression may be indicated for an asymptomatic limb with
venouscompression/stenosis contralateral to a symptomatic limb (current or prior
symptoms), if the asymptomatic extremity is the dominant limb, or thrombosis is likely due
to their occupation.
Following successful thrombolysis, some clinicians favor anticoagulation for one to three
months to allow endothelial healing and resolution of acute inflammation before thoracic
outlet decompression [61]. However, given the risk of re-thrombosis, we agree with the
majority of surgeons in advocating surgical decompression during the same hospitalization as
thrombolytic therapy [1,3,93]. Regardless of the timing of surgical decompression,
anticoagulation is maintained until the surgery can be performed. (See 'Anticoagulation'
above.)
For patients with residual thrombus following thrombolysis or those with chronic
axillosubclavian thrombosis, the axillosubclavian vein can be reconstructed concurrent with
thoracic outlet decompression or at a later time using open or endovascular techniques, if
needed. In a series of patients undergoing first rib resection for chronic symptoms related to
primary subclavian vein thrombosis, subclavian vein thrombus resolved in 14 of 16 patients
treated with ongoing anticoagulation [102]. (See 'Venoplasty' below.)
The aim of thoracic outlet decompression is to provide more space through which the
neurovascular structures of the upper extremity can pass. Thoracic outlet decompression may
include any one or a combination of the following procedures, the choice of which will depend
upon the specific anatomic abnormality identified [22,102]. (See "Overview of thoracic outlet
syndromes", section on 'Pathogenesis'.)
First rib resection
Cervical rib resection (less common for venous thoracic outlet syndrome)
Division of anomalous bands
Division of anomalous musculotendinous insertions
Scalenectomy
For patients identified with a cervical rib, cervical rib resection may be all that is required.
However, when a cervical rib is not present, first rib resection is combined with dissection and
division of structures identified at the time of surgical exploration as potentially causing
compression on the neurovascular structures of the thoracic outlet, whether or not these
were identified as a specific source of compression on prior imaging studies.
Three surgical approaches are used for thoracic outlet decompression: the transaxillary,
supraclavicular, and infraclavicular approaches, each with advantages and disadvantages.
There are no trials comparing surgical approaches for decompression, and there remains no
expert consensus as to which surgical approach or method of treating the injured venous
segment is better. As such, the surgical approach depends largely upon the type of anatomic
abnormalities identified and surgeon preference. These approaches and the complications
associated with them are discussed separately. (See "Overview of thoracic outlet syndromes",
section on 'Thoracic outlet decompression'.)
Complications of thoracic outlet decompression include hemopneumothorax, long thoracic
nerve injury, incomplete rib resection that can lead to recurrent symptoms, brachial plexus
injury, arterial injury, lymphatic leak, and surgical site infection.
VENOPLASTY Although there is uniform agreement that thoracic outlet decompression
should be performed early in patients with acute axillosubclavian thrombosis [1], debate exits
over the management of the vein. Concurrent with thoracic outlet decompression, some feel
that venolysis or venoplasty (percutaneous transluminal or open) is sufficient while others
advocate vein repair (patch venoplasty, interposition vein graft, vein bypass, jugular
turndown) [27,77,103]. There are insufficient data to support one approach over another.
Occasionally, percutaneous transluminal angioplasty (PTA) is needed to keep the vein open
following thrombolysis until thoracic outlet decompression can be accomplished [1]. However,
prior to thoracic outlet decompression, stenting should be avoided [40,83,104-106]. Shoulder
movements subject the stent to repetitive compression that can lead to stent fracture. In one
small observational study, stent use was found to be an independent risk factor for upper
extremity rethrombosis [83]. Once thoracic outlet decompression has been performed,
whether or not a vein patch repair or bypass was performed, residual or recurrent stenosis
may warrant PTA and possibly stenting, with acceptable clinical outcomes [1,22].
FOLLOW-UP We obtain a Duplex ultrasound in the postsurgical period to confirm patency
of axillosubclavian vein. If the patient experiences recurrent symptoms, we agree with others
in advocating an immediate venogram to evaluate the patency of the repaired venous
segment [102].
Duration of anticoagulation In patients with primary upper extremity deep vein thrombosis,
anticoagulation should be continued for a minimum of three to six months following the initial
thrombotic event, with a longer duration of therapy indicated for those who have had a
recurrent event [60,107]. We maintain anticoagulation regardless of whether intervention
(thrombolysis, thoracic outlet decompression) was performed.
PERIOPERATIVE MORBIDITY AND MORTALITY Mortality related to primary upper extremity
deep vein thrombosis is overall low, due to the relatively young population of patients who
are typically affected. By comparison, mortality related to secondary causes of upper
extremity deep vein thrombosis is higher, ranging from 15 to 50 percent reflecting underlying
co-morbidities such as malignancy, renal failure, and multi-organ failure [12].
Recurrent thromboembolism Recurrent upper extremity deep vein thrombosis (all causes)
occurs in 2 to 8 percent of patients following treatment [28,108,109]. These rates are
significantly lower than recurrence rates for lower extremity deep vein thrombosis, which in
one long term study was 30 percent at eight years [110].
A hypercoagulable state needs to be considered in patients who develop recurrent
thromboembolism [12]. Higher rates of thrombophilia have been reported in patients with
recurrent upper extremity deep vein thrombosis [111-115]. In one study, 90 percent of
postoperative complications were associated with some form of thrombophilia [112]. The
evaluation of thrombophilia is discussed elsewhere. (See "Evaluation of the patient with
established venous thrombosis".)
Post-thrombotic syndrome Post-thrombotic syndrome refers to the development of
symptoms or signs of chronic venous insufficiency related to a prior deep vein thrombosis.
Post-thrombotic syndrome is discussed in detail elsewhere. (See "Post-thrombotic
(postphlebitic) syndrome".)
Quality of life is reduced in patients with post-thrombotic syndrome, particularly if the
dominant arm is affected. Severe upper extremity symptoms with skin ulceration are rare, but
post-thrombotic syndrome affecting the upper extremity can result in occupational disability
in patients whose job requires manual labor. Even in patients whose occupation does not
involve the vigorous use of the arms, symptoms of post-thrombotic syndrome can limit other
activities and adversely impact quality of life.
The incidence of post-thrombotic syndrome following upper extremity deep vein thrombosis
(all causes) ranges from 7 to 44 percent but appears to be more prevalent following primary
compared with secondary etiologies [12,28]. Since primary upper extremity deep vein
thrombosis generally affects young, otherwise healthy individuals with an active lifestyle and
long life expectancy, one of the aims of early aggressive treatment is minimizing symptoms of
post-thrombotic syndrome. (See 'Rationale for aggressive treatment' above.)
In patients with primary upper extremity deep vein thrombosis, up to 53 percent of patients
treated with anticoagulation alone historically developed post-thrombotic syndrome at 5
years [27,100]. With aggressive therapy that includes anticoagulation, thrombolysis, and
thoracic outlet decompression, the incidence of residual symptoms ranges from 12 to 25
percent [1,27]. The risk of developing post-thrombotic syndrome may be greater in patients
who have residual vein obstruction. However, in one study, no association between
ultrasound findings and the development of post-thrombotic syndrome was found [116].
SUMMARY AND RECOMMENDATIONS
Primary, "spontaneous" upper extremity deep vein thrombosis is estimated to represent
between 1 and 4 percent of all cases of upper extremity deep vein thrombosis, with
secondary causes of thrombosis related to central vein cannulation (eg, central line,
pacemaker) or prothrombotic states (eg, thrombophilia, malignancy) much more common.
(See 'Introduction' above.)
Primary upper extremity deep vein thrombosis is defined as thrombosis of the deep veins
draining the upper extremity (axillary, subclavian) due to an underlying anatomic anomaly
at the thoracic outlet causing compression or repetitive venous injury. The syndrome is
appropriately termed venous thoracic outlet syndrome, but is also referred to as Paget-
Schroetter syndrome and effort thrombosis. Anatomic abnormalities can be congenital or
acquired. Congenital anomalies consist of cervical ribs, supernumerary muscles, abnormal
tendon insertions, or abnormal muscular or tendinous bands. Acquired abnormalities
include bony overgrowth due to bony fracture (usually of the clavicle), or hypertrophy of
anterior scalene muscle or subclavius muscles, often related to repetitive lifting. (See
'Pathogenesis' above.)
Primary upper extremity deep vein thrombosis typically presents in young, otherwise
healthy individuals as sudden, severe arm swelling. Although more commonly associated
with lower extremity deep vein thrombosis, pulmonary embolism from upper extremity
deep vein thrombosis (primary and secondary) occurs in 4 to 10 percent of patients. The
clinician should have a high index of suspicion for this disorder when a young patient with
no inciting factors presents with signs of upper extremity venous thrombosis, or pulmonary
embolism in the absence of lower extremity symptoms. (See 'Clinical presentations' above.)
A 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 vein compression/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. More advanced imaging may be
necessary to demonstrate abnormal muscular attachments or dynamic venous
compression. (See 'Diagnosis' above.)
Treatment of primary upper extremity deep vein thrombosis is aimed at preventing
pulmonary embolism, recurrent venous thrombosis and post-thrombotic syndrome. For
patients with acutely symptomatic primary upper extremity deep vein thrombosis, we
recommend anticoagulation over no such therapy (Grade 1B). Anticoagulation helps to
maintain patency of collateral veins, reduces propagation of thrombus, and is effective for
preventing pulmonary embolism. We prefer to use unfractionated heparin to facilitate
rapid dose adjustment in patients who will undergo other interventions such as
thrombolysis and thoracic outlet decompression.
For patients with moderate to severe acute symptoms who are diagnosed with primary
upper extremity deep vein thrombosis, we suggest thrombolysis over anticoagulation alone
(Grade 2C). Following thrombolysis, we suggest thoracic outlet decompression, rather than
no decompression (Grade 2C). This approach decreases the risk for recurrent thrombosis
and post-thrombotic syndrome. Anticoagulation alone may be adequate for minimally
symptomatic or intermittently symptomatic patients, and for those who present in a
delayed manner (>2 weeks from the onset of symptoms). (See 'Approach to treatment'
above and 'Rationale for aggressive treatment' above.)
We agree with American College of Chest Physicians who recommend a minimum of three
months of anticoagulation following an initial thrombotic event. We maintain
anticoagulation for a minimum of three months regardless of whether intervention
(thrombolysis, thoracic outlet decompression) was performed. (See 'Approach to
treatment' above.)
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