Approach To The Diagnosis and Therapy of Lower Extremity Deep Vein Thrombosis

4/27/2014 Approach to the diagnosis and therapy of lower extremity deep vein thrombosis
Official reprint from UpToDate®

www.uptodate.com ©2014 UpToDate®
Approach to the diagnosis and therapy of lower extremity deep vein thrombosis
Authors Section Editors Deputy Editor

Stephen A Landaw, MD, PhD Lawrence LK Leung, MD Geraldine Finlay, MD
Kenneth A Bauer, MD Jess Mandel, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2014. | This topic last updated: Jan 09, 2014.
INTRODUCTION — Deep vein thrombosis (DVT) and acute pulmonary embolism (PE) are two manifestations of
the same disorder, venous thromboembolism (VTE). DVT of the lower extremity is subdivided into two
categories:
● Distal (calf) vein thrombosis, in which thrombi remain confined to the deep calf veins
● Proximal vein thrombosis, in which thrombosis involves the popliteal, femoral, or iliac veins
Proximal vein thrombosis is of greater importance clinically, since it is more commonly associated with the
development of pulmonary emboli. (See "Treatment of lower extremity deep vein thrombosis", section on
'Introduction'.)
There are a number of questions that arise when a patient is suspected of having deep vein thrombosis (DVT) of
the lower extremity. These include:
● What is the differential diagnosis and what are the possible risk factors for DVT?
● What is the best way to diagnose or exclude DVT?
● What is the appropriate initial therapy for DVT; when is hospitalization not required?
● What is the recommended long-term treatment for DVT (eg, agents to use, monitoring the degree of
anticoagulation, length of time treatment is needed)?
● When should one screen for the presence of a hypercoagulable state, not only in the patient, but also in
family members?
This topic review will serve as a guide for answering the above questions in a patient suspected of having DVT of
the lower extremity [1]. Each section will provide links to UpToDate reviews in which extended discussions of
that subject can be found. Patient information documents covering these issues are also available. (See
"Patient information: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient information: Warfarin
(Coumadin) (Beyond the Basics)".)
The pathogenesis, clinical manifestations, diagnosis, and treatment of DVT in infants and children are presented
separately. (See "Pathogenesis and clinical manifestations of venous thrombosis and thromboembolism in
infants and children" and "Diagnosis and treatment of venous thrombosis and thromboembolism in infants and
children".)
Upper extremity DVT, the pathogenesis and natural course of which differs considerably from that of lower
extremity DVT [2], is discussed separately. (See "Primary (spontaneous) upper extremity deep vein
thrombosis" and "Catheter-related upper extremity venous thrombosis".)
EPIDEMIOLOGY — The Longitudinal Investigation of Thromboembolism Etiology (LITE), which combined

information from two prospective cohort studies, the Atherosclerosis Risk in Communities (ARIC) and the
Cardiovascular Health Study (CHS), determined the incidence of symptomatic DVT and pulmonary embolism in
21,680 participants aged ≥45 years who were followed for 7.6 years [3]. The following observations were made:
● The age-standardized incidence of first-time venous thromboembolism (VTE) was 1.92 per 1000 person-
years. Rates were higher in men than women, and increased with age in both sexes. (See "Overview of the
http://www.uptodate.com/contents/approach-to-the-diagnosis-and-therapy-of-lower-extremity-deep-vein-thrombosis?topicKey=PULM%2F1322&elapsedTim… 1/20
causes of venous thrombosis", section on 'Cardiovascular diseases'.)
● Of the 366 VTE events, most of the 191 cases of secondary VTE were associated with more than one
underlying condition. These included cancer (48 percent), hospitalization (52 percent), surgery (42
percent), and major trauma (6 percent). There was no antecedent trauma, surgery, immobilization, or
diagnosis of cancer in 48 percent of cases. (See "Overview of the causes of venous thrombosis", section
on 'Acquired risk factors'.)
Among 1102 acutely ill, immobilized general medical patients enrolled in the MEDENOX study, multiple logistic
regression analysis found the following factors to be significantly and independently associated with an
increased risk for VTE, most of which were asymptomatic and diagnosed by venography of both lower
extremities [4]:
● Presence of an acute infectious disease

● Age >75 years
● Cancer
● History of prior VTE
INITIAL APPROACH — When approaching the patient with suspected DVT of the lower extremity, it is
important to appreciate that only a minority of patients actually have the disease and will require
anticoagulation. This illustrates the importance of using validated algorithms to evaluate patients with suspected
DVT, along with objective testing to establish the diagnosis. Given the potential risks associated with proximal
lower extremity DVT that is not treated (eg, fatal pulmonary emboli) and the potential risk of anticoagulating a
patient who does not have a DVT (eg, life-threatening bleeding), accurate diagnosis is essential.
Risk factors for DVT should be sought in all patients. These include the following (table 1) (see "Overview of the
causes of venous thrombosis"):
● History of immobilization or prolonged hospitalization/bed rest

● Recent surgery
● Obesity
● Prior episode(s) of venous thromboembolism
● Lower extremity trauma
● Malignancy
● Use of oral contraceptives or hormone replacement therapy
● Pregnancy or postpartum status
● Stroke
History — Classic symptoms of DVT include swelling, pain, and erythema of the involved extremity. There is
not necessarily a correlation between the location of symptoms and the site of thrombosis. Symptoms in the
calf alone are often the presenting manifestation of significant proximal vein involvement, while some patients
with whole leg symptoms are found to have isolated calf vein DVT.
A complete thrombosis history includes the age of onset, location of prior thromboses, and results of objective
diagnostic studies documenting thrombotic episodes in the patient. The patient should be carefully questioned
concerning recent potential precipitating conditions prior to the time of thrombosis, such as surgical procedures,
hospitalization, trauma, pregnancy, heart failure, and immobility. Women should be carefully questioned
regarding use of oral contraceptives or hormone replacement therapy as well as their obstetric history. The
presence of recurrent fetal loss in the second or third trimester suggests the possible presence of an inherited
thrombophilia or antiphospholipid antibodies. (See "Pregnancy in women with antiphospholipid syndrome".)
In addition to events proximate to the time of thrombosis, patients should also be questioned about previous
exposure and outcome in situations that predispose to thrombosis, such as pregnancy, cesarean section, and
surgery.
Questions should include the presence of significant disorders, such as collagen-vascular disease,
myeloproliferative disease, atherosclerotic disease, or nephrotic syndrome and about the use of drugs which
can induce antiphospholipid antibodies such as hydralazine, procainamide, and phenothiazines.
The patient should also be questioned about a past history of cancer, and the results, if any, of regular
screening examinations for cancer (eg, mammography, colonoscopy, pelvic examinations) since recurrent
thrombosis in spite of therapeutic anticoagulation with oral anticoagulants is more frequent in patients with VTE
in association with active cancer or an occult neoplasm. Other findings that may suggest an underlying
malignancy are constitutional symptoms such as loss of appetite, weight loss, fatigue, pain, hematochezia,
hemoptysis, and hematuria. (See "Risk and prevention of venous thromboembolism in adults with cancer",
section on 'Incidence and risk factors'.)
Family history — A positive family history of VTE is particularly important, since a well documented history
of VTE in one or more first-degree relatives under age 50 suggests the presence of a hereditary defect and/or an
increased susceptibility for venous thromboembolic disease [5]. This was most conclusively shown in a
population-based study of the incidence of VTE according to the presence or absence of VTE in a sibling [6].
Standard incidence ratios for VTE were 2.27, 51.9, and 53.7 for patients with one, two, or three or more affected
siblings, respectively.
Special clinical settings — There a number of clinical settings which may suggest the presence of a
specific risk factor for DVT. As examples:
● Recurrent unprovoked DVT in a young patient (age <50) may suggest either the presence of an inherited
hypercoagulable state or a congenital anomaly of the inferior vena cava. (See "Overview of the causes of
venous thrombosis", section on 'Inferior vena cava abnormalities'.)
● Recurrent left lower extremity DVT of the left lower extremity may indicate the presence of the May-
Thurner syndrome with thrombosis of the left iliac vein due to compression of this vein between the
overlying right iliac artery and the vertebral column. (See "Overview of the causes of venous thrombosis",
section on 'May-Thurner syndrome'.)
Physical examination — Physical examination may reveal a palpable cord (reflecting a thrombosed vein), calf
or thigh pain, unilateral edema or swelling with a difference in calf diameters, warmth, tenderness, erythema,
and/or superficial venous dilation.
In the general physical examination, special attention should be directed to the vascular system, extremities
(eg, looking for signs of superficial or deep vein thrombosis), chest, heart, abdominal organs, and skin (eg, skin
necrosis, livedo reticularis). There may be pain and tenderness in the thigh along the course of the major veins
("painful deep vein syndrome"). Tenderness on deep palpation of the calf muscles is suggestive, but not
diagnostic. Homans’ sign is also unreliable. (See "Evaluation of the patient with established venous
thrombosis", section on 'Physical exam'.)
However, each of the above signs and symptoms is nonspecific and has low accuracy for making the diagnosis
of DVT. A 2005 meta-analysis of diagnostic cohort studies of patients with suspected DVT concluded the
following concerning these physical findings [7]:
● Only a difference in calf diameters (likelihood ratio, LR 1.8; 95% CI 1.5-2.2) was of potential value for ruling
in DVT.
● Only absence of calf swelling (LR 0.67; 95% CI 0.58-0.78) and absence of a difference in calf diameters
(LR 0.57; 95% CI 0.44-0.72) were of potential value for ruling out DVT.
● Individual clinical features are poorly predictive of DVT when not combined in a formal prediction rule (eg,
Wells score, see below) [8].
Accordingly, further diagnostic testing is required to confirm or exclude the diagnosis of DVT (see 'Diagnosis of
DVT' below).
Venous thromboembolism may also be associated with other clinical disorders such as heart failure and the
myeloproliferative neoplasms. The presence or absence of relevant physical exam findings (eg, splenomegaly in
polycythemia vera) should be ascertained.
The physical examination may also reveal signs of hepatic vein thrombosis (Budd-Chiari syndrome), such as
ascites and hepatomegaly, or edema due to the nephrotic syndrome. The hypercoagulable state associated
with the nephrotic syndrome may manifest as renal vein thrombosis, which is usually asymptomatic unless
associated with pulmonary embolism. (See "Renal vein thrombosis and hypercoagulable state in nephrotic
syndrome".)
Phlegmasia cerulea dolens — Phlegmasia cerulea dolens is an uncommon form of massive proximal (eg,
iliofemoral) venous thrombosis of the lower extremities associated with a high degree of morbidity and mortality.
Signs and symptoms include sudden severe leg pain with swelling, cyanosis, edema, venous gangrene,
compartment syndrome, and arterial compromise, often followed by followed by circulatory collapse and shock.
Delay in treatment may result in death or loss of the patient's limb. (See "Treatment of lower extremity deep vein
thrombosis", section on 'Phlegmasia cerulea dolens'.)
Screening for malignancy — Malignancy is a risk factor for the development of venous thromboembolism.
However, prospective studies do not demonstrate improved survival with aggressive diagnostic testing for cancer
in those with a first idiopathic DVT.
While available data do not support an extensive search for occult malignancy, it is important to pursue
symptoms or signs which suggest an underlying malignancy and to ensure that age- and sex-appropriate
screening tests have been performed. This issue is discussed in more detail separately. (See "Overview of
preventive medicine in adults" and "Evaluation of the patient with established venous thrombosis", section on
'Screening for malignancy'.)
Laboratory testing — The initial laboratory evaluation in patients with venous thrombosis should include a
complete blood count and platelet count, coagulation studies (eg, prothrombin time, activated partial
thromboplastin time), renal and liver function tests, and urinalysis. Any abnormality observed on initial testing
should be investigated aggressively. (See "Evaluation of the patient with established venous thrombosis",
section on 'Laboratory tests'.)
DIFFERENTIAL DIAGNOSIS — When approaching the patient with suspected DVT of the lower extremity, it is
important to appreciate that only a minority of patients (17 and 32 percent in two large series) actually have the
disease [9,10].
The differential diagnosis in patients with suspected DVT includes a variety of disorders, including
musculoskeletal injury and venous insufficiency [11,12]. The range of disorders that can mimic DVT was
illustrated in a study of 160 consecutive patients with suspected DVT who had negative venograms; the following
causes of the leg pain were identified [11]:
● Muscle strain, tear, or twisting injury to the leg — 40 percent

● Leg swelling in a paralyzed limb — 9 percent
● Lymphangitis or lymph obstruction — 7 percent
● Venous insufficiency — 7 percent
● Popliteal (Baker's) cyst — 5 percent
● Cellulitis — 3 percent
● Knee abnormality — 2 percent
● Unknown — 26 percent
Cellulitis — Bacterial cellulitis is a frequent complication in the leg with chronic swelling due to venous
insufficiency or lymphedema. The warmth and redness often skip areas, leading to the erroneous clinical
diagnosis of superficial phlebitis. Some patients with venous insufficiency develop a low-grade "chemical"
cellulitis, which resembles bacterial cellulitis but without constitutional symptoms. (See "Cellulitis and
erysipelas".)
Superficial thrombophlebitis — Superficial vein phlebitis is most likely in the presence of palpable, tender
superficial veins. (See "Superficial thrombophlebitis of the lower extremity".)
Venous valvular insufficiency — Chronic venous insufficiency is the most common cause of chronic
unilateral leg edema (picture 1) and is usually associated with a past history of DVT. (See "Diagnostic
evaluation of chronic venous insufficiency" and "Clinical manifestations of lower extremity chronic venous
disease".)
Lymphedema — Lymphedema is an important cause of chronic, rather than acute, edema of the extremities.
(See "Clinical manifestations and diagnosis of lymphedema".)
Popliteal (Baker's) cyst — The majority of popliteal cysts in adults are due to either distention of a bursa by
fluid originating from a knee joint lesion or posterior herniation of the joint capsule due to increased intraarticular
pressure. A popliteal cyst that causes calf symptoms is usually leaking or has ruptured. It can cause leg
swelling via compression of the popliteal vein and may result in DVT if the vein is compressed sufficiently. (See
"General evaluation of the adult with knee pain", section on 'Popliteal cyst'.)
Internal derangement of the knee — Pain, inflammation, and swelling can accompany knee joint pathology.
(See "General evaluation of the adult with knee pain".)
Drug-induced edema — Leg swelling is a side effect of some drugs, such as calcium channel blockers. The
edema is usually bilateral but can be asymmetric if there is underlying venous pathology; signs of inflammation
are not present. (See "Clinical manifestations and diagnosis of edema in adults", section on 'Venous
insufficiency or thrombosis'.)
Calf muscle pull or tear — A calf muscle pull or tear is frequently induced by unaccustomed physical activity.
There may be signs of bleeding within muscle compartments of the affected leg. (See "Non-Achilles ankle
tendinopathy".)
DIAGNOSIS OF DVT
Overview — A number of invasive and non-invasive approaches are possible (eg, contrast venography,
impedance plethysmography, compression ultrasonography, D-dimer testing). In most circumstances,
compression ultrasonography is the noninvasive approach of choice for the diagnosis of symptomatic patients
with a first episode of suspected DVT (algorithm 1). (See "Diagnosis of suspected deep vein thrombosis of the
lower extremity".)
A negative D-dimer assay may be insufficient to rule out DVT as a stand-alone test in patient populations with a
high prevalence of venous thromboembolism, and not all D-dimer assays are validated for this application.
However, a D-dimer level <500 ng/mL by ELISA or a negative SimpliRED assay in conjunction with a low clinical
probability (ie, Wells score) (table 2) (calculator 1) or other negative noninvasive tests may be useful in
excluding DVT, without the need for ultrasound testing. (See "Diagnosis of suspected deep vein thrombosis of
the lower extremity", section on 'D-dimer'.)
A positive noninvasive study in patients with a first episode of DVT usually establishes the diagnosis, with a
positive predictive value for compression ultrasonography of 94 percent (95% CI: 87-98 percent). If the initial
study is negative and the clinical suspicion of DVT is high, a repeat study should be obtained on day 5 to 7.
Use of a single study via extended (complete) lower extremity ultrasonography may obviate the need for repeat
testing. However, this technique requires specialized instrumentation and is highly dependent on user expertise.
(See "Diagnosis of suspected deep vein thrombosis of the lower extremity", section on 'Extended (complete)
lower extremity ultrasound'.)
Venography is currently used only when noninvasive testing is not clinically feasible or the results are equivocal.
Pretest probability — Ultrasonography and D-dimer tests for DVT are most useful when the results are
combined with an assessment of pretest probability of DVT. One report of 593 patients with suspected DVT
validated a measure of pretest probability (Wells score) (table 2) (calculator 1) [13]. DVT was documented in 3,
17, and 75 percent of patients with low, moderate, or high pretest probabilities, respectively. (See "Diagnosis of
suspected deep vein thrombosis of the lower extremity", section on 'Addition of pretest probability (Wells
score)'.)
Wells score — While other pretest probability scoring systems are available, such as the Hamilton score
[14] and the Primary Care Rule (AMUSE score) proposed for use in primary care patients [15], the Wells score
for DVT (ie, Wells criteria for DVT) appears to be most commonly used (table 2) (calculator 1). (See "Diagnosis
of suspected deep vein thrombosis of the lower extremity", section on 'Clinical decision rule for primary care
providers'.)
A review of 15 studies in which the Wells score was tested concluded the following [16]:
● Patients in the low pretest probability category had a median negative predictive value for DVT of 96
percent (range: 87 to 100 percent), indicating the usefulness of the Wells score for ruling out DVT.
● The median negative predictive value for DVT in patients with a low pretest probability was improved further
by the presence of a negative test for D-dimer (median value 99 percent, range: 96 to 100 percent).
● Positive predictive values for DVT rarely exceeded 75 percent for patients in the high pretest probability
category, indicating that these rules alone were not as useful for identifying patients who did have
thrombosis.
The value and limitations of the Wells score, with or without D-dimer testing, in identifying patients who may not
require further investigation in order to rule out deep vein thrombosis, are discussed in depth separately. (See
"Diagnosis of suspected deep vein thrombosis of the lower extremity", section on 'Limitations of the Wells
score'.)
SCREENING FOR A HYPERCOAGULABLE STATE
Inherited and acquired hypercoagulable states — A biologic risk factor for venous thrombosis can be
identified in over 60 percent of Caucasian patients under age 50 with a first idiopathic DVT. In addition, there is
often more than one factor at play in a given patient. As an example, 50 percent of thrombotic events in patients
with inherited thrombophilia are associated with an accompanying acquired risk factor (eg, surgery, pregnancy,
use of oral contraceptives).
Some patients have more than one form of inherited thrombophilia or may have combinations of inherited as well
as acquired thrombophilic states and are at even greater risk for thrombosis (table 3). (See "Overview of the
causes of venous thrombosis", section on 'Inherited thrombophilia'.)
A thrombophilic state leading to venous thrombosis can be inherited or acquired:
● Congenital/inherited (eg, factor V Leiden, protein C deficiency)

● Acquired (eg, following orthopedic surgery, antiphospholipid antibody)
● Associated with systemic disease (eg, malignancy)
Whom to test — There is currently no consensus regarding who to test for inherited thrombophilia. (See
"Evaluation of the patient with established venous thrombosis", section on 'Screening for inherited
thrombophilia'.)
However, the likelihood of identifying an inherited thrombophilia is increased several-fold by screening only
patients with one or more of the following:
● Initial thrombosis occurring prior to age 50 without an immediately identified risk factor (ie, idiopathic or
unprovoked venous thrombosis)
● A family history of venous thromboembolism (ie, first-degree relatives with VTE prior to age 50)
● Recurrent venous thrombosis
● Thrombosis occurring in unusual vascular beds such as portal, hepatic, mesenteric, or cerebral veins
● A history of warfarin-induced skin necrosis, which suggests protein C deficiency (see "Protein C
deficiency: Clinical manifestations and diagnosis")
Value of screening — Although we can identify patients at increased risk for inherited thrombophilia, there is
no clear clinical value to screening for the following reasons:
● Even if a hypercoagulable workup uncovers abnormalities predisposing to VTE, the strongest risk factor for
VTE recurrence is the prior VTE event itself, particularly if idiopathic.
● Patients with idiopathic VTE, whether or not they have an identifiable inherited thrombophilia, are at high
risk for recurrence (as high as 7 to 8 percent per year in some studies) after warfarin is discontinued, at
least for the first few years after the event. Thus, the presence or absence of an inherited thrombophilia will
usually not change the decision regarding length of warfarin therapy. (See "Treatment of lower extremity
deep vein thrombosis", section on 'Idiopathic VTE'.)
● Screening information can be used to identify family members with an inherited thrombophilia, but
anticoagulant prophylaxis is rarely recommended in asymptomatic affected family members outside of
high-risk situations. (See "Screening for inherited thrombophilia in asymptomatic individuals", section on
'Summary'.)
Screening test interference — A number of factors can interfere with screening tests for thrombophilia (table
4). Therefore, it is generally best not to undertake testing at the time of presentation with VTE. (See "Evaluation
of the patient with established venous thrombosis", section on 'Technical screening issues'.)
TREATMENT OF DVT
Rationale — The primary objectives of treatment of DVT are to prevent and/or treat the following complications:
● Prevent further clot extension

● Prevention of acute pulmonary embolism
● Reducing the risk of recurrent thrombosis
● Treatment of massive iliofemoral thrombosis with acute lower limb ischemia and/or venous gangrene (ie,
phlegmasia cerulea dolens)
● Limiting the development of late complications, such as the post-thrombotic syndrome, chronic venous
insufficiency, and chronic thromboembolic pulmonary hypertension.
Anticoagulant therapy is indicated for patients with symptomatic proximal DVT, since pulmonary embolism will
occur in approximately 50 percent of untreated individuals, most often within days or weeks of the event.
Initial therapy — The following recommendations for the treatment of acute venous thromboembolic disease
are in accord with the 2012 ACCP evidence-based clinical practice guidelines for antithrombotic and
thrombolytic therapy [17,18], as well as recommendations of the British Committee for Standards in
Haematology, the joint guidelines of the American College of Physicians and the American Academy of Family
Physicians, and the American Heart Association/American College of Cardiology. (See "Treatment of lower
extremity deep vein thrombosis", section on 'Summary and recommendations'.)
● Patients with DVT or pulmonary embolism should be treated acutely with LMW heparin, fondaparinux,
unfractionated intravenous heparin, or adjusted-dose subcutaneous heparin.
● Dosing requirements for LMW heparin are different for each LMW product. Minimal elements for early
discharge and/or outpatient therapy with LMW heparin or fondaparinux are shown in the table (table 5).
(See "Treatment of lower extremity deep vein thrombosis", section on 'Outpatient use'.)
● When unfractionated heparin is used, the dose should be sufficient to prolong the activated partial
thromboplastin time (aPTT) to 1.5 to 2.5 times the mean of the control value, or the upper limit of the
normal aPTT range. A survey of available weight-based nomograms supports the view that they represent a
safe and cost-effective strategy for unfractionated heparin dosing in a number of different health care
settings (table 6). (See "Therapeutic use of heparin and low molecular weight heparin", section on 'Heparin
monitoring' and "Therapeutic use of heparin and low molecular weight heparin", section on 'Administration
and efficacy'.)
● Treatment with LMW heparin, fondaparinux, or unfractionated heparin should be continued for at least five
days and oral anticoagulation with a vitamin K antagonist should be overlapped with LMW heparin,
fondaparinux, or unfractionated heparin for at least four to five days. No such overlap is required if
rivaroxaban is chosen.
● For most patients, warfarin should be initiated simultaneously with the heparin, at an initial oral dose of
approximately 5 mg/day. In elderly patients and in those at high risk of bleeding or who are
undernourished, debilitated, or have heart failure or liver disease, the starting dose should be reduced. The
heparin product can be discontinued on day five or six if the INR has been therapeutic for two consecutive
days. (See "Therapeutic use of warfarin and other vitamin K antagonists", section on 'Initial dose' and
"Therapeutic use of warfarin and other vitamin K antagonists", section on 'Maintenance therapy' and
"Anticoagulation in older adults", section on 'Increased sensitivity to warfarin'.)
● For patients receiving unfractionated heparin (UFH), ACCP Guidelines suggest that platelet counts be
obtained regularly to monitor for the development of thrombocytopenia. The frequency and timing of such
counts depends upon the clinical situation. (See "Therapeutic use of heparin and low molecular weight
heparin", section on 'Platelet count monitoring'.)
The heparin product should be stopped if any one of the following occurs: a precipitous or sustained fall in
the platelet count, or a platelet count <100,000/microL. (See "Management of heparin-induced
thrombocytopenia".)
● The use of thrombolytic agents, surgical thrombectomy, or percutaneous mechanical thrombectomy in the
treatment of venous thromboembolism must be individualized. Patients with hemodynamically unstable PE
or massive iliofemoral thrombosis (ie, phlegmasia cerulea dolens), and who are also at low risk to bleed,
are the most appropriate candidates for such treatment. (See "Fibrinolytic (thrombolytic) therapy in acute
pulmonary embolism and lower extremity deep vein thrombosis".)
● Inferior vena caval filter placement is recommended when there is a contraindication to, or a failure of,
anticoagulant therapy in an individual with, or at high risk for, proximal vein thrombosis or PE. It is also
recommended in patients with recurrent thromboembolism despite adequate anticoagulation, for chronic
recurrent embolism with pulmonary hypertension, and with the concurrent performance of surgical
pulmonary embolectomy or pulmonary thromboendarterectomy. (See "Placement of inferior vena cava
filters and their complications".)
● Oral anticoagulation with a vitamin K antagonist should prolong the INR to a target of 2.5 (range: 2.0 to
3.0). If the use of a vitamin K antagonist is contraindicated or inconvenient, long-term therapy can be
undertaken with either adjusted-dose unfractionated heparin, low molecular weight heparin, fondaparinux,
or rivaroxaban. (See "Therapeutic use of heparin and low molecular weight heparin", section on 'Use of
LMW heparin'.)
● Use of the newer oral anticoagulants (eg, dabigatran, rivaroxaban, apixaban) for the initial and/or continued
treatment of DVT is discussed separately. (See "Treatment of lower extremity deep vein thrombosis",
section on 'Factor Xa and direct thrombin inhibitors'.)
Duration of treatment — The duration of anticoagulation therapy varies with the clinical setting as well as with
patient values and preferences.
● Patients with a first thromboembolic event in the context of a reversible or time-limited risk factor (eg,
trauma, surgery) should be treated for three months.
● Patients with a first idiopathic thromboembolic event should be treated for a minimum of three months.
Following this, all patients should be evaluated for the risk/benefit ratio of long-term therapy.
● Indefinite therapy is preferred in patients with a first unprovoked episode of proximal DVT who have a
greater concern about recurrent VTE and a relatively lower concern about the burdens of long-term
anticoagulant therapy.
● In patients with a first isolated unprovoked or provoked episode of distal DVT, three months of
anticoagulant therapy, rather than indefinite therapy, appears to be sufficient.
● Most patients with advanced malignancy should be treated indefinitely or until the cancer resolves. (See
"Treatment of venous thromboembolism in patients with malignancy".)
This issue is discussed in greater detail separately. (See "Treatment of lower extremity deep vein thrombosis",
section on 'Length of treatment'.)
General medical management — The general medical management of acute DVT is individualized. Once
patients are anticoagulated, and symptoms are under control (eg, leg pain and swelling), ambulation should be
encouraged as soon as is feasible. Elastic graduated compression stockings (GCS) have mixed benefit for the
prevention of post thrombotic (post phlebitic) syndrome (PTS) but are not associated with harm. This is
discussed in more detail separately. (See "Treatment of lower extremity deep vein thrombosis", section on
'Ambulation and compression stockings'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and
“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
“patient info” and the keyword(s) of interest.)
● Basics topics (see "Patient information: Deep vein thrombosis (blood clots in the legs) (The Basics)")
● Beyond the Basics topics (see "Patient information: Deep vein thrombosis (DVT) (Beyond the Basics)"
and "Patient information: Warfarin (Coumadin) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS — Only a minority of patients suspected to have deep vein thrombosis
(DVT) actually have the disease and will require anticoagulation. This illustrates the importance of using
validated algorithms to evaluate patients with suspected DVT, along with objective testing to establish the
diagnosis.
Suspecting the diagnosis — The diagnosis of DVT is suspected in a patient with a palpable cord (reflecting a
thrombosed vein), calf pain, ipsilateral edema or swelling with a difference in calf diameters, warmth,
tenderness, erythema, and/or superficial venous dilation in one or both lower extremities. (See 'Initial approach'
above and 'Diagnosis of DVT' above.)
Pretest probability — The pretest probability of DVT can be determined by using the Wells score
(calculator 1). (See 'Pretest probability' above.)
● Patients with a low probability Wells score and a negative D-dimer are unlikely to have DVT and do not
need further testing.
● Patients with a moderate or high probability Wells score should have noninvasive testing for DVT.
Compression ultrasonography is the noninvasive approach of choice for the diagnosis of patients with a
first episode of suspected DVT.
Confirming the diagnosis — A positive noninvasive study in patients with a first episode of DVT usually
establishes the diagnosis. If the initial study is negative and the clinical suspicion of DVT is high, a repeat study
should be obtained on day 5 to 7. (See "Diagnosis of suspected deep vein thrombosis of the lower extremity".)
Screening for hypercoagulable conditions — Screening for a hypercoagulable state is not generally
recommended unless the results are likely to change subsequent therapy for the patient or family members.
(See "Evaluation of the patient with established venous thrombosis", section on 'Screening for inherited
thrombophilia'.)
Treatment — Anticoagulant therapy is indicated for patients with symptomatic proximal DVT, since pulmonary
embolism will occur in approximately 50 percent of untreated individuals, most often within days or weeks of the
event. (See 'Initial therapy' above and "Treatment of lower extremity deep vein thrombosis".)
● Initial treatment should be started acutely. Available approved choices include unfractionated heparin, low
molecular weight heparin, fondaparinux, or rivaroxaban. If a heparin preparation or fondaparinux is chosen,
treatment should be continued for at least five days and oral anticoagulation with a vitamin K antagonist
overlapped with one of these agents for at least four to five days. No such overlap is required if rivaroxaban
is chosen. The preferred choice of anticoagulation is discussed in depth separately. (See "Treatment of
lower extremity deep vein thrombosis", section on 'Initial anticoagulation regimen'.)
● Use of thrombolytic agents or thrombectomy is individualized. Patients with hemodynamically unstable

pulmonary embolus (PE) or massive iliofemoral thrombosis and a low bleeding risk are the most
appropriate candidates. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower
extremity deep vein thrombosis", section on 'Lower extremity deep vein thrombosis'.)
● Inferior vena caval filter placement is recommended when there is a contraindication to, or a complication
of, anticoagulant therapy in an individual with, or at high risk for, proximal vein thrombosis or PE. (See
"Placement of inferior vena cava filters and their complications".)
Treatment duration — The duration of anticoagulation therapy varies with the clinical setting as well as with
patient values and preferences. (See "Treatment of lower extremity deep vein thrombosis", section on 'Length of
treatment' and "Treatment of lower extremity deep vein thrombosis", section on 'Distal (calf vein) thrombosis'.)
● Patients with a first proximal DVT due to a reversible or time-limited risk factor (eg, trauma, surgery) and
those with a first unprovoked or provoked episode of distal DVT should be treated for three months.
● Indefinite therapy might be preferred in patients with a first unprovoked episode of proximal DVT or
pulmonary embolism who have a greater concern about recurrent VTE and a relatively lower concern
about the risks and burdens of long-term anticoagulant therapy.
● Most patients with advanced malignancy should be treated indefinitely or until the cancer resolves. (See
"Treatment of venous thromboembolism in patients with malignancy".)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Goodacre S. In the clinic. Deep venous thrombosis. Ann Intern Med 2008; 149:ITC3.
2. Lechner D, Wiener C, Weltermann A, et al. Comparison between idiopathic deep vein thrombosis of the
upper and lower extremity regarding risk factors and recurrence. J Thromb Haemost 2008; 6:1269.
3. Cushman M, Tsai AW, White RH, et al. Deep vein thrombosis and pulmonary embolism in two cohorts:
the longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117:19.
4. Alikhan R, Cohen AT, Combe S, et al. Risk factors for venous thromboembolism in hospitalized patients
with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164:963.
5. Bezemer ID, van der Meer FJ, Eikenboom JC, et al. The value of family history as a risk indicator for
venous thrombosis. Arch Intern Med 2009; 169:610.
6. Zöller B, Li X, Sundquist J, Sundquist K. Age- and gender-specific familial risks for venous
thromboembolism: a nationwide epidemiological study based on hospitalizations in Sweden. Circulation
2011; 124:1012.
7. Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: The value of clinical assessment in the diagnosis of
deep venous thrombosis. Ann Intern Med 2005; 143:129.
8. Qaseem A, Snow V, Barry P, et al. Current diagnosis of venous thromboembolism in primary care: a
clinical practice guideline from the American Academy of Family Physicians and the American College of
Physicians. Ann Intern Med 2007; 146:454.
9. Birdwell BG, Raskob GE, Whitsett TL, et al. The clinical validity of normal compression ultrasonography
in outpatients suspected of having deep venous thrombosis. Ann Intern Med 1998; 128:1.
10. Huisman MV, Büller HR, ten Cate JW, Vreeken J. Serial impedance plethysmography for suspected deep
venous thrombosis in outpatients. The Amsterdam General Practitioner Study. N Engl J Med 1986;
314:823.
11. Hull R, Hirsh J, Sackett DL, et al. Clinical validity of a negative venogram in patients with clinically
suspected venous thrombosis. Circulation 1981; 64:622.
12. Gorman WP, Davis KR, Donnelly R. ABC of arterial and venous disease. Swollen lower limb-1: general
http://www.uptodate.com/contents/approach-to-the-diagnosis-and-therapy-of-lower-extremity-deep-vein-thrombosis?topicKey=PULM%2F1322&elapsedTi… 10/20
assessment and deep vein thrombosis. BMJ 2000; 320:1453.

13. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein
thrombosis in clinical management. Lancet 1997; 350:1795.
14. Subramaniam RM, Chou T, Heath R, Allen R. Importance of pretest probability score and D-dimer assay
before sonography for lower limb deep venous thrombosis. AJR Am J Roentgenol 2006; 186:206.
15. van der Velde EF, Toll DB, Ten Cate-Hoek AJ, et al. Comparing the diagnostic performance of 2 clinical
decision rules to rule out deep vein thrombosis in primary care patients. Ann Fam Med 2011; 9:31.
16. Tamariz LJ, Eng J, Segal JB, et al. Usefulness of clinical prediction rules for the diagnosis of venous
thromboembolism: a systematic review. Am J Med 2004; 117:676.
17. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest
2008; 133:454S.
18. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest 2012; 141:e419S.
Topic 1322 Version 30.0
GRAPHICS
Risk factors (causes) for the development of venous thrombosis
Inherited thrombophilia
Factor V Leiden mutation
Prothrombin gene mutation
Protein S deficiency
Protein C deficiency
Antithrombin (AT) deficiency
Rare disorders
Dysfibrinogenemia
Acquired disorders
Malignancy
Presence of a central venous catheter
Surgery, especially orthopedic
Trauma
Pregnancy
Oral contraceptives
Hormone replacement therapy
Tamoxifen, Thalidomide, Lenalidomide
Immobilization
Congestive failure
Antiphospholipid antibody syndrome
Myeloproliferative disorders
Polycythemia vera
Essential thrombocythemia
Paroxysmal nocturnal hemoglobinuria
Inflammatory bowel disease
Nephrotic syndrome
Graphic 59759 Version 6.0
Skin changes of chronic venous insufficiency
Longstanding edema in this patient with chronic venous insufficiency

led to moderately advanced pigment changes on the medial and
lateral ankles, which extend onto the dorsum of the foot. The left
medial ankle displays a healed venous ulcer below the malleolus; the
right lateral ankle has a small, active, venous ulcer (arrow).
Courtesy of Patrick C Alguire, MD.
Diagnostic algorithm in patients with suspected deep

vein thrombosis
Adapted from Wells, PS, Anderson, DR, Bormanis, J, et al, Lancet 1997;
350:1795.
Pretest probability of deep vein thrombosis (Wells score)
Clinical feature Score
Active cancer (treatment ongoing or within the previous 6 months or palliative) 1
Paralysis, paresis, or recent plaster immobilization of the lower extremities 1
Recently bedridden for more than 3 days or major surgery, within 4 weeks 1
Localized tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
Calf swelling by more than 3 cm when compared to the asymptomatic leg 1

(measured below tibial tuberosity)
Pitting edema (greater in the symptomatic leg) 1
Collateral superficial veins (nonvaricose) 1
Alternative diagnosis as likely or more likely than that of deep venous -2

thrombosis
Score
High probability 3 or
greater
Moderate probability 1 or 2
Low probability 0 or less
Modification:
This clinical model has been modified to take one other clinical feature into account: a
previously documented deep vein thrombosis (DVT) is given the score of 1. Using this
modified scoring system, DVT is either likely or unlikely, as follows:
DVT likely 2 or
greater
DVT unlikely 1 or less
Adapted from Wells, PS, Anderson, DR, Bormanis, J, et al, Lancet 1997; 350:1795 and Wells, PS,
Anderson, DR, Rodger, M, et al. N Engl J Med 2003; 349:1227.
Risk of venous thromboembolism associated with use of oral

contraceptives, factor V leiden, and/or prothrombin gene mutation
OC Use* Factor V Leiden Factor II G20210A Odds ratio•
- - - 1.0
+ - - 2.3
- - + 3.2
- + - 5.9
+ - + 7.1
+ + - 10.2
- + + 14.7
+ + + 17.0
* Oral contraceptives; factor II is prothrombin.

• Crude odds ratio for risk of venous thromboembolism given the combination of risks (-: risk not
present; +: risk present).
Adapted from Emmerich, J, et al. Thromb Haemost 2001; 86:809.
Clinical settings which may interfere with testing for thrombophilia
Confounding Factors
Hypercoagulable disorder
for testing Acute Heparin
Warfarin therapy
thrombosis therapy
Antithrombin (deficiency) Can be Lowered NC; Rarely

lowered* increased
Antiphospholipid antibodies NC NC NC
Factor V Leiden NC NC NC
Factor VIII level Acute phase reactant. Do not test while inflammation
is still present.
Lupus anticoagulant NC Cannot False positives

measure possible
Protein C (deficiency) Can be NC Cannot measure•

lowered*
Protein S (deficiency) Can be NC Cannot measure•

lowered*
Prothrombin gene mutation NC NC NC
Acquired AT deficiency:
neonatal period, pregnancy, liver disease, DIC, nephrotic syndrome, major surgery,
acute thrombosis, treatment with L-asparaginase, heparin, or estrogens
Acquired Protein C deficiency:
neonatal period, liver disease, DIC, chemotherapy (CMF), inflammation, acute

thrombosis, treatment with warfarin or L-asparaginase
Acquired Protein S deficiency:
neonatal period, pregnancy, liver disease, DIC, acute thrombosis, treatment with
warfarin, L-asparaginase, or estrogens
NC: not changed; LMW heparin: low molecular weight heparin; AT: antithrombin; DIC:
disseminated intravascular coagulation; CMF: cyclophosphamide, methotrexate, 5-fluorouracil.
* Results can be affected by acute thrombosis; it is most cost effective to avoid testing for these
deficiencies during the initial presentation. However, if plasma levels are well within the normal
range at presentation, deficiency of these proteins is essentially excluded. Common causes for
an acquired deficiency of Antithrombin (AT), Protein C, or Protein S are listed below:
• If it is important to measure for these deficiencies while the patient is still anticoagulated,
switch the treatment to full dose heparin or LMW heparin and discontinue coumadin for at least
two weeks before measurement. Comparing protein S or C levels with prothrombin antigen in
stably anticoagulated patients is not reliable, as accurate measurement of prothrombin antigen
levels is a research assay which is not generally available.
Minimal requirements for early hospital discharge or outpatient

therapy of venous thromboembolic disease
The responsible physician must ensure that all of the following

conditions apply:
The patient is ambulatory and in stable condition, with normal vital signs
There is a low a priori risk of bleeding in the patient
Severe renal insufficiency is not present
There is a practical system in place for the following:

Administration of LMW heparin and/or warfarin with appropriate monitoring, and
Surveillance and treatment of recurrent VTE and bleeding complications
VTE: venous thromboembolism; LMW heparin: low molecular weight heparin.
Adapted from Hyers, TM, Agnelli, G, Hull, RD, et al. Antithrombotic therapy for venous
thromboembolic disease. Chest 2001; 119:176S. (Sixth ACCP Consensus Conference on
Antithrombotic Therapy).
Example of a weight-based nomogram for intravenous

unfractionated heparin infusion for treatment of venous
thromboembolism and/or pulmonary embolism
Initial dose 80 units/kg bolus, then 18 units/kg per hour*
aPTT result Action Next aPTT **
aPTT <35 80 units/kg bolus, then 6 hours

seconds (<1.2 x increase infusion rate by 4
control) units/kg per hour
aPTT 35 to 45 40 units/kg bolus, then 6 hours

seconds (1.2 to increase infusion rate by 2
1.5 x control) units/kg per hour
aPTT 46 to 70 No change (therapeutic 6 hours (when two consecutive values

seconds • (1.5 to range) are within therapeutic range, then next
2.3 x control) aPTT in morning)
aPTT 71 to 90 Decrease infusion rate by 2 6 hours

seconds (2.3 to units/kg per hour
3.0 x control)
aPTT >90 Hold infusion 1 hour, then 6 hours

seconds (>3.0 x decrease infusion rate by 3
control) units/kg per hour
aPTT: activated partial thromboplastin time.

This table is provided as an example of a locally developed and validated unfractionated
heparin weight-based dose adjustment nomogram. It reflects the original aPTT ranges, bolus
sizes, and suggested changes in infusion rate that were present at the time the study was
performed. [1] The therapeutic ranges (ie, relationship between the aPTT and anti-factor Xa
activity), initial and subsequent bolus sizes, and sizes of the infusion rate changes, as well as
dosing differences depending on the disorder under treatment (eg, venous thromboembolism,
stroke, acute coronary syndrome) should be established separately for each institution.
* Use of total body weight (TBW) is suggested for calculating the initial bolus dose and infusion
rate for most obese patients. For additional information see “Management of the critically ill
obese patient”, section “Anticoagulants”.
•
Therapeutic aPTT range of 46 to 70 seconds corresponded to anti-Xa activity of 0.3 to 0.7
units/mL. The target aPTT range in a particular institution should reflect what is known about
the local reagents and equipment to perform the assay. [2]
** The first aPTT should be obtained 4 to 6 hours after the initial heparin bolus.
References:
1. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared
with a "standard care" nomogram. A randomized controlled trial. Ann Intern Med 1993; 119:874.
2. Garcia DA, Baglin TP, Weitz JI A, et al. Parenteral Anticoagulants: Antithrombotic therapy and
Prevention of Thrombosis, American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines (9th Edition). Chest 2012; 141:e24S-e43S.
Disclosures
Disclosures: Stephen A Landaw , MD, PhD Employee of UpToDate, Inc. Employee (Spouse): Mass Medical Society (New England
Journal of Medicine). Kenneth A Bauer, MD Consultant/Advisory Boards: Bayer [Anticoagulation (Rivaroxaban)];
Janssen[Anticoagulation (Rivaroxaban)]; BMS [Anticoagulation (Apixaban)]; Pfizer [Anticoagulation (Apixaban)]; Boehringer Ingelheim
[Anticoagulation (Dabigatran, Etexilate)]; Daiichi Sankyo [Anticoagulation (Edoxaban - investigational)]; Instrumentation Laboratory
[Coagulation Diagnostics (Laboratory Instruments and Reagents)]. Law rence LK Leung, MD Nothing to disclose. Jess Mandel, MD
Nothing to disclose. Geraldine Finlay, MD Employee of UpToDate, Inc.
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting
through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately
referenced content is required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

Approach To The Diagnosis and Therapy of Lower Extremity Deep Vein Thrombosis

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Approach To The Diagnosis and Therapy of Lower Extremity Deep Vein Thrombosis

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4/27/2014 Approach to the diagnosis and therapy of lower extremity deep vein thrombosis

Official reprint from UpToDate®

Authors Section Editors Deputy Editor

EPIDEMIOLOGY — The Longitudinal Investigation of Thromboembolism Etiology (LITE), which combined

causes of venous thrombosis", section on 'Cardiovascular diseases'.)

● Presence of an acute infectious disease

● History of immobilization or prolonged hospitalization/bed rest

can induce antiphospholipid antibodies such as hydralazine, procainamide, and phenothiazines.

● Muscle strain, tear, or twisting injury to the leg — 40 percent

SCREENING FOR A HYPERCOAGULABLE STATE

A thrombophilic state leading to venous thrombosis can be inherited or acquired:

● Congenital/inherited (eg, factor V Leiden, protein C deficiency)

● Prevent further clot extension

● Use of thrombolytic agents or thrombectomy is individualized. Patients with hemodynamically unstable

Use of UpToDate is subject to the Subscription and License Agreement.

assessment and deep vein thrombosis. BMJ 2000; 320:1453.

Topic 1322 Version 30.0

Risk factors (causes) for the development of venous thrombosis

Prothrombin gene mutation

Antithrombin (AT) deficiency

Presence of a central venous catheter

Surgery, especially orthopedic

Hormone replacement therapy

Tamoxifen, Thalidomide, Lenalidomide

Antiphospholipid antibody syndrome

Paroxysmal nocturnal hemoglobinuria

Inflammatory bowel disease

Graphic 59759 Version 6.0

Skin changes of chronic venous insufficiency

Longstanding edema in this patient with chronic venous insufficiency

Courtesy of Patrick C Alguire, MD.

Graphic 56758 Version 2.0

Diagnostic algorithm in patients with suspected deep

Graphic 52720 Version 2.0

Pretest probability of deep vein thrombosis (Wells score)

Clinical feature Score

Active cancer (treatment ongoing or within the previous 6 months or palliative) 1

Paralysis, paresis, or recent plaster immobilization of the lower extremities 1

Localized tenderness along the distribution of the deep venous system 1

Entire leg swollen 1

Calf swelling by more than 3 cm when compared to the asymptomatic leg 1

Pitting edema (greater in the symptomatic leg) 1

Collateral superficial veins (nonvaricose) 1

Alternative diagnosis as likely or more likely than that of deep venous -2

Low probability 0 or less

DVT unlikely 1 or less

Graphic 75871 Version 1.0

Risk of venous thromboembolism associated with use of oral

OC Use* Factor V Leiden Factor II G20210A Odds ratio•

* Oral contraceptives; factor II is prothrombin.

Adapted from Emmerich, J, et al. Thromb Haemost 2001; 86:809.

Graphic 72836 Version 1.0

Clinical settings which may interfere with testing for thrombophilia

Antithrombin (deficiency) Can be Lowered NC; Rarely

Lupus anticoagulant NC Cannot False positives

Protein C (deficiency) Can be NC Cannot measure•

Protein S (deficiency) Can be NC Cannot measure•

Prothrombin gene mutation NC NC NC

Acquired Protein C deficiency:

neonatal period, liver disease, DIC, chemotherapy (CMF), inflammation, acute

Acquired Protein S deficiency:

Graphic 76966 Version 3.0

Minimal requirements for early hospital discharge or outpatient