Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE)

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Inherited
Acquired

Inherited VE

Inherited thrombophilia

Factor V Leiden mutation
Prothrombin gene mutation
Protein S deficiency
Protein C deficiency
Antithrombin (AT) deficiency
Rare disorders

Dysfibrinogenemia

Acquired VE

Malignancy
Presence of a central venous catheter
Surgery, especially orthopedic
Trauma
Pregnancy
Oral contraceptives
Hormone replacement therapy
Tamoxifen, Bevacizumab, Thalidomide, Lenalidomide
Immobilization
Congestive failure
Antiphospholipid antibody syndrome
Myeloproliferative disorders

Polycythemia vera
Essential thrombocythemia
Paroxysmal nocturnal hemoglobinuria

Inflammatory bowel disease
Nephrotic syndrome
Hyperviscosity
Waldenstrom's macroglobulinemia
Multiple myeloma
Marked leukocytosis in acute leukemia
Sickle cell anemia
HIV/AIDS

VIRCHOW'S TRIAD — proposes that VTE occurs as a result of:

Alterations in blood flow (i.e., stasis)
Vascular endothelial injury
Alterations in the constituents of the blood (i.e., inherited or acquired hypercoagulable state)

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.

Classic symptoms of DVT include swelling, pain, and discoloration in the involved extremity.

NOTE:

There is no 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.

Many patients are asymptomatic; however, the history may include the following:

Edema, principally unilateral, is the most specific symptom.
Massive edema with cyanosis and ischemia (phlegmasia cerulea dolens) is rare.
Leg pain occurs in 50% of patients, but this is entirely nonspecific.

Homan’s sign

Pain/discomfort in the calf muscles on forced dorsiflexion of the foot with the knee straight has been a time-honored sign of DVT. However, this sign is present in less than one third of patients with confirmed DVT.
The Homan’s sign is found in more than 50% of patients without DVT and, therefore, is nonspecific.

Superficial thrombophlebitis is characterized by the finding of a palpable, indurated, cordlike, tender, subcutaneous venous segment.
Forty percent of patients with superficial thrombophlebitis without coexisting varicose veins and with no other obvious etiology (e.g., intravenous catheters, intravenous drug abuse, soft tissue injury) have an associated DVT.

Lymphangitis or lymph obstruction
Baker's cyst
Cellulitis
Muscle strain, tear, or twisting injury to the leg
Leg swelling in a paralyzed limb
Knee abnormality

Wells Score

The Wells clinical prediction guide quantifies the pretest probability of DVT.
The model enables providers to reliably stratify their patients into high-, moderate-, or low-risk categories.
The Wells clinical prediction guide incorporates risk factors, clinical signs, and the presence or absence of alternative diagnoses.
Paralysis, paresis, or recent orthopedic casting of a lower extremity (1 point)
Recently bedridden for longer than three days or major surgery within the past four weeks (1 point)
Localized tenderness in the deep vein system (1 point)
Swelling of an entire leg (1 point)
Calf swelling 3cm greater than the other leg, measured 10cm below the tibial tuberosity (1 point)
Pitting edema greater in the symptomatic leg (1 point)
Collateral non-varicose superficial veins (1 point)
Active cancer or cancer treated within six months (1 point)
Alternative diagnosis more likely than DVT (e.g., Baker's cyst, cellulitis, muscle damage, post-phlebitic syndrome, inguinal lymphadenopathy, external venous compression) (-2 points)

Wells Score
Clinical Parameter	Score
Active cancer (treatment ongoing, or within 6 mo or palliative)	+1
Paralysis or recent plaster immobilization of the lower extremities	+1
Recently bedridden for >3 d or major surgery <4 wk	+1
Localized tenderness along the distribution of the deep venous system	+1
Entire leg swelling	+1
Calf swelling >3 cm compared with the asymptomatic leg	+1
Pitting edema (greater in the symptomatic leg)	+1
Previous DVT documented	+1
Collateral superficial veins (nonvaricose)	+1
Alternative diagnosis (as likely or greater than that of DVT)	-2
Total of Above Score: High probability: >3 Moderate probability: 1 or 2 Low probability: <0

DVT D-dimer

D-dimer fibrin fragments are present in fresh fibrin clot and in fibrin degradation products of cross-linked fibrin.
Monoclonal antibodies specific for the D-dimer fragment are used to differentiate fibrin-specific clot from non–cross-linked fibrin and from fibrinogen.
D-dimer level may be elevated in any medical condition where clots form.
D-dimer level is elevated in trauma, recent surgery, hemorrhage, cancer, and sepsis.
Many of these conditions are associated with higher risk for DVT.

Medical Conditions Associated With an Elevated D-dimer

Arterial thromboembolic disease

Myocardial infarction
Stroke
Acute limb ischemia
Atrial fibrillation
Intracardiac thrombus

Venous thromboembolic disease

Deep vein thrombosis
Pulmonary embolism
Disseminated intravascular coagulation
Preeclampsia and eclampsia
Abnormal fibrinolysis; use of thrombolytic agents

D-dimer results should be used as follows:

A negative D-dimer assay result rules out DVT in patients with low-to-moderate risk and a Wells DVT score less than 2.
All patients with a positive D-dimer assay result and all patients with a moderate-to-high risk of DVT (Wells DVT score >2) require a diagnostic study (duplex ultrasonography).

A D-dimer level less than 200 to 500 ng/mL by ELISA or a negative SimpliRED assay in conjunction with a low clinical probability of DVT appears to be useful and cost-effective in excluding DVT without the need for an ultrasound examination.

Compression Ultrasonography

In most circumstances, compression ultrasonography is the noninvasive approach of choice for the diagnosis of patients with suspected DVT.
If unavailable, impedance plethysmography with serial studies is an acceptable alternative.
One exception noted above is that impedance plethysmography is preferred for possible recurrent DVT since it normalizes more quickly after a previous episode than compression ultrasonography.

The diagnosis of venous thrombosis using compression ultrasonography is made by the findings such as:

Abnormal compressibility of the vein
Abnormal Doppler color flow
The presence of an echogenic band
Abnormal change in diameter during the Valsalva maneuver

MRI

MRI is the diagnostic test of choice for suspected iliac vein or inferior vena caval thrombosis when CT venography is contraindicated or technically inadequate.
In the second and third trimester of pregnancy, MRI is more accurate than duplex ultrasonography because the gravid uterus alters Doppler venous flow characteristics.
Expense, lack of general availability, and technical issues limit its use.

The primary objectives of Rx of DVT are to prevent and/or treat:

further clot extension
acute pulmonary embolism
the risk of recurrent thrombosis
the development of late complications, such as the postphlebitic syndrome, chronic venous insufficiency, and chronic thromboembolic pulmonary HPTN.

Anticoagulant therapy is indicated for patients with symptomatic proximal DVT, since pulmonary embolism will occur in about 50 percent of untreated individuals, most often within days or weeks of the event.

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 and who are also at low risk to bleed, are the most appropriate candidates for such treatment.

Inferior vena caval filter placement is recommended when there is a contraindication to, or a failure of, anticoagulant therapy. It is also recommended in patients with recurrent thromboembolism despite adequate anticoagulation.

Oral anticoagulation with warfarin should prolong the INR to a target of 2.5 (range: 2.0 to 3.0).

If oral anticoagulants are contraindicated or inconvenient, long-term therapy can be undertaken with either adjusted-dose unfractionated heparin, low molecular weight heparin, or fondaparinux.

Once anticoagulation has been started and the patient's symptoms (i.e., pain, swelling) are under control, early ambulation is advised.

During initial ambulation, and for the first two years following an episode of VTE, use of an elastic compression stocking has been recommended to prevent the postphlebitic syndrome.

Acute vs. chronic
Massive vs. submassive

A saddle PE is a PE that lodges at the bifurcation of the main pulmonary artery into the right and left pulmonary arteries.
Most saddle PE are submassive.
In a retrospective study of 546 consecutive patients with PE, 14 (2.6 percent) had a saddle PE.
Only two of the patients with saddle PE had hypotension.

Poor Prognosis:

Elevated Brain Natriuretic Peptide (BNP)
Right Ventricular dysfunction
Hypotension
RV thrombus
Elevated Troponin I

Most PE arise from thrombi in the deep venous system of the lower extremities. However, they may also originate in the right heart or the pelvic, renal, or upper extremity veins.
Iliofemoral veins are the source of most clinically recognized PE.
It is estimated that 50 to 80 percent of iliac, femoral, and popliteal vein thrombi (proximal vein thrombi) originate below the popliteal vein (calf vein thrombi) and propagate proximally.
The remainder arise within the proximal veins.
Fortunately, most calf vein thrombi resolve spontaneously and only 20 to 30 percent extend into the proximal veins if untreated.
After traveling to the lung, large thrombi may lodge at the bifurcation of the main pulmonary artery or the lobar branches and cause hemodynamic compromise.
Smaller thrombi continue traveling distally and are more likely to produce pleuritic chest pain, presumably by initiating an inflammatory response adjacent to the parietal pleura.
Only about 10 percent of emboli cause pulmonary infarction, usually in patients with preexisting cardiopulmonary disease.
Most pulmonary emboli are multiple, with the lower lobes being involved in the majority of cases.

PE is a common complication of deep vein thrombosis (DVT), occurring in more than 50 percent of cases with phlebographically confirmed DVT.
This suggests that factors that promote the development of DVT also increase the risk for PE.

PE Additional Risks Factors in Women

Obesity (BMI ≥29 kg/m2)
Heavy cigarette smoking (>25 cigarettes per day)
Hypertension

PE Labs

Routine laboratory findings are nonspecific.

Leukocytosis
An increased erythrocyte sedimentation rate (ESR)
Elevated serum LDH or AST (SGOT)
Normal serum bilirubin.

PE Arterial Blood Gases (ABG’s)

Arterial blood gas (ABG) measurements and pulse oximetry have a limited role in diagnosing PE.
ABG’s usually reveal hypoxemia, hypocapnia, and respiratory alkalosis.

Venous Ultrasound

Lower extremity venous ultrasound is sometimes performed during the diagnostic evaluation of PE.
The rationale is that venous thrombosis detected by ultrasound is treated similar to confirmed PE.

D-dimer Sensitivity

D-dimer levels are abnormal in approximately 95 percent of all patients with PE when measured by ELISA, quantitative rapid ELISA, or semi-quantitative rapid ELISA.

CXR

Normal
Atelectasis and/or pulmonary parenchymal abnormality
Pleural Effusion
Cardiomegally

ECG Changes

“S1 Q3 T3”
S wave in lead I
Q wave in lead III
Flipped T in lead III
Possible RBBB
Signs of cor pulmonale
Classic, but uncommon

VQ scan

Started in 1960s
Correlated well with angiogram and autopsy
“High probability” scans: 41% sensitive, 97% specific
Adequate for diagnosis in a minority of patients

Spiral CT

Spiral (helical) CT scanning with intravenous contrast (i.e., CT pulmonary angiography or CT-PA) is being used increasingly as a diagnostic modality for patients with suspected PE.
One of the most commonly cited benefits of CT-PA is the ability to detect alternative pulmonary abnormalities that may explain the patient's clinical presentation.

CT Chest

Spiral CT chest introduced in early 1990s
Sensitivity 86-100%, specificity 92-96% for central PE
63% sensitive for subsegmental PE

Pulmonary Angiography

Started in 1950s
47% positive studies had no signs on CXR
1st confirmatory test other than autopsy

ECHO for PE

RV dilates and LV is smaller in most patients
Unreliable in pts with prior cardiac dysfunction
TEE reported to be >90% sensitive and specific
Right heart dysfunction resolves after thrombolytic therapy

PE are usually multiple and preferentially in the lower lobes.
As clot burden increases, hypoxia increases. Hypercapnia and acidosis are rare.
With increased pulmonary vascular resistance secondary to obstruction, hypotension can develop.
This in turn obstructs right ventricular outflow which then causes right ventricular dilation (often with flattening and even bulging of the septum into the left ventricle).
Reduced flow from the right ventricle in turn decreases cardiac output from the left ventricle, all of which results in hypotension then cardiac arrest and death.

Respiratory Support: Oxygen, intubation
Hemodynamic Support: IVF, vasopressors
Anticoagulation
Thrombolysis
IVC Filter

Anticoagulation

Start during resuscitation phase itself
If suspicion high, start empiric anticoagulation
Evaluate patient for absolute contraindication (i.e.: active bleeding)
HEPARIN:

Lovenox: if hemodynamically stable, no renal function impairment

1mg/kg BID OR 1.5mg/kg QDay

Heparin gtt: if hypotension, renal failure

80units/kg bolus then 18units/kg infusion

Goal PTT 1.5 to 2.5 times the upper limit of normal

COUMADIN:

Start once acute anticoagulation achieved
Start with 5mg PO qday OR 10mg PO q day
If start with 10mg then achieve therapeutic INR 1.4 days sooner
Complications and morbidity no different in 5mg or 10mg start - Goal INR 2 to 3

Duration of Anticoagulation for DVT or PE*
Event	Duration	Strength of Recommendation
First Time event of Reversible cause (surgery/trauma)	At least 3 mos	A
First episode of idiopathic VTE	At least 6 mos	A
Recurrent idiopathic VTE or continuing risk factor (e.g., thrombophilia, cancer)	At least 12 mos	B
Symptomatic isolated calf-vein thrombosis	6 to 12 weeks	A
*From American College of Chest Physicians

Thrombolysis

Considered once P.E. diagnosed
If chosen, hold anticoagulation during thrombolysis infusion, then resumed
Associated with higher incidence of major hemorrhage
Indications: persistent hypotension, severe hypoxemia, large perfusion defects, right ventricular dysfunction, free-floating right ventricular thrombus, patent foramen ovale
Activase or streptokinase