Deep Venous Thrombosis & Pulmonary Embolism

Department of Medicine, University of Georgia

MD4110E: Internal Medicine I
Dr. Guram Rtskhiladze
Juma Awar
04/05/2022

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Introduction

Deep vein thrombosis (DVT), a subset of venous thromboembolism (VTE), is a major preventable cause

of morbidity and mortality worldwide. The incidence of VTE is estimated to be 1 per 1,000 people

annually, with DVT accounting for approximately two-thirds of these events. Pulmonary embolism (PE),

a dreaded complication of DVT, occurs in up to one-third of cases and is the primary contributor to

mortality. Much of the morbidity of DVT results from the development of post-thrombotic syndrome,

which occurs in up to 50% of patients within 2 years of DVT and encompasses a number of symptoms

including leg pain, swelling, and in severe cases, venous ulcers. Anticoagulation is the mainstay of

therapy for DVT, with the goal of preventing progression to PE and recurrence of thrombosis. (Stone et

al., 2017)

Pulmonary embolism (PE) occurs when there is a disruption to the flow of blood in the pulmonary artery

or its branches by a thrombus that originated somewhere else. In deep vein thrombosis (DVT), a

thrombus develops within the deep veins, most commonly in the lower extremities. PE usually occurs

when a part of this thrombus breaks off and enters the pulmonary circulation. Very rarely, PE can occur

from the embolization of other materials into the pulmonary circulation such as air, fat, or tumor cells.

(Vyas & Goyal, 2021)

Pathogenesis

There are three main predisposing factors (Virchow’s triad) which can lead to a DVT:

 Slow movement of the blood in the circulation – commonly caused by immobility, especially

after abdominal or lower limb surgery or plaster cast for a leg injury. Being overweight and

taking long-haul flights (more than 4 hours with leg cramping) can also lead to sluggish blood

flow.

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  Thicker blood – some individuals have an inherited tendency to form blood clots, termed

thrombophilia (‘liking to thrombosis’). Thrombophilia can develop in adult life due to conditions

like antiphospholipid syndrome, and nephrotic syndrome or in the setting of severe

dehydration. Pregnancy and oral contraceptives/hormone replacement treatments can also

thicken the blood.

 Damage to the lining of the vein – with trauma or insertion of long intravenous catheters.

Chemotherapy and vasculitis (vessel inflammation) can also damage veins. Damage from

previous DVT is probably the commonest reason for a second DVT. (Thachil, 2014)

Deep venous thrombosis usually begins in venous valve cusps. Thrombi consist of thrombin, fibrin, and

red blood cells with relatively few platelets (red thrombi); without treatment, thrombi may propagate

proximally or travel to the lungs (pulmonary embolism). Incase there is an atrial septal defect the

thrombi can move through it and gets in the systemic circulation and cause a stroke.

Clinical Presentation

The classic clinical presentation of DVT includes swelling, pain, warmth, and redness in the involved

extremity. Alternatively, DVT can occur asymptomatically. Individual symptoms are neither sensitive nor

specific for DVT. Trauma, infection, peripheral artery disease, and other venous diseases can present

with clinical features similar to DVT. Furthermore, DVT can coexist with any of these processes.

The most common symptoms and signs of pulmonary embolism include dyspnea, chest pain, tachypnea,

syncope, and cough. Less common symptoms and signs include fever, hemoptysis, cyanosis,

hypotension, and shock. In addition, many patients have concomitant symptoms and signs of DVT. In

patients with preexisting dyspnea (caused by heart failure, chronic obstructive pulmonary disease, or

another process), worsening of dyspnea may be the only symptom indicative of pulmonary embolism.

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Because of right heart strain, certain changes on electrocardiography may occur in patients with

pulmonary embolism, including T-wave inversion on precordial leads, right bundle branch block, and the

well-known but uncommon S1Q3T3 pattern. Such changes are neither sensitive nor specific for

pulmonary embolism. The most common chest radiography findings associated with pulmonary

embolism, such as platelike atelectasis, pleural effusion, and elevation of a hemidiaphragm, are likewise

nonspecific. Hypoxemia is common, but up to 20 percent of patients with pulmonary embolism have

normal oxygenation.

The initial evaluation of patients with suspected pulmonary embolism includes chest radiography,

electrocardiography, pulse oximetry, and blood gases. None of these tests, alone or in combination, are

sensitive or specific enough to exclude or diagnose pulmonary embolism. However, they are necessary

to evaluate for other causes of the presenting symptoms and may assist in raising or lowering the

pretest probability of pulmonary embolism. (Wilbur & Shian, 2012)

Diagnosis for DVT

As per the NICE guidelines following investigations are done:

 D-dimers (very sensitive but not very specific) 

 Coagulation profile

 Proximal leg vein ultrasound, which when positive, indicates that the patient should be treated

as having a DVT

Deciding how to investigate is determined by the risk of DVT. The first step is to assess the clinical

probability of a DVT using the Wells scoring system.

 For patients with a score of 0 to 1, the clinical probability is low, but for those with 2 or above,

the clinical probability is high.

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  If a patient scores 2 or above, either a proximal leg vein ultrasound scan should be done within 4

hours, and if the result is negative, a D-dimer test should be done. If imaging is not possible

within 4 hours, a D-dimer test should be undertaken, and an interim 24-hour dose of a

parenteral anticoagulant should be given. A proximal leg vein ultrasound scan should be carried

out within 24 hours of being requested.

 In the case of a positive D-dimer test and a negative proximal leg vein ultrasound scan, the

proximal leg vein ultrasound scan should be repeated 6 to 8 days later for all patients.

 If the patient does not score 2 on the DVT Wells score, but the D-dimer test is positive, the

patient should have a proximal leg vein ultrasound scan within 4 hours, or if this is not possible,

the patient should receive an interim 24-hour dose of a parenteral anticoagulant. A proximal

leg vein ultrasound scan should then be carried out within 24 hours of being requested.

 In all patients diagnosed with DVT, treat as if there is a positive, proximal leg vein ultrasound

scan (Waheed et al., 2021)

Diagnosis for PE

Wells criteria is a scoring system most commonly used to estimate the pretest probability of having a PE.

This allows the classification of patients with suspected PE into categories of clinical or pretest

probability, based on which the diagnostic tests are chosen and interpreted.

Arterial Blood Gas (ABG) Analysis

Unexplained hypoxemia with a normal chest radiograph should raise the clinical suspicion for pulmonary

embolism (PE). Widened alveolar-arterial gradient for oxygen, respiratory alkalosis, and hypocapnia are

commonly seen findings on ABG, as a pathophysiological response to pulmonary embolism.

Brain Natriuretic Peptide (BNP)

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Elevated BNP has limited diagnostic importance in patients suspected of having PE. Right ventricle

pressure overload because of acute PE is associated with more myocardial stretch, which then releases

B-type natriuretic peptide (BNP) and N-terminal (NT)-proBNP. Thus, the levels of natriuretic peptides in

blood reflect the severity of RV dysfunction in acute PE.

D-dimer 

The quantitative enzyme-linked immunosorbent assay (ELISA) has a diagnostic sensitivity of at least 95%.

It can be used to exclude the diagnosis of PE in patients with either low or intermediate pretest

probability. A negative ELISA D-dimer, along with low clinical probability, can exclude PE without further

testing in approximately 30% of suspected patients.

Electrocardiography (ECG)

ECG abnormalities, in patients with suspected PE, are nonspecific. The most common ECG findings in PE

are tachycardia and nonspecific ST-segment and T-wave changes, S1Q3T3 pattern, right ventricular

strain, and new incomplete right bundle branch block are uncommon.

Computed Tomographic Pulmonary Angiography (CTPA)

Multidetector CTPA is the diagnostic modality of choice for patients with suspected PE. It allows

appropriate visualization of the pulmonary arteries down to the subsegmental level. CTPA can detect RV

enlargement and other indicators of RV dysfunction. The present data suggest that a negative CTPA

result is adequate for the exclusion of PE in patients who have a low or intermediate clinical probability.

CTPA may be relatively contraindicated in moderate to severe iodinated contrast allergy or renal

insufficiency.

Lung Scintigraphy

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The planar ventilation/perfusion scan (V/Q scan) is an established diagnostic test for suspected PE. V/Q

scanning is mostly performed for patients in whom CTPA is contraindicated or inconclusive, or when

additional testing is needed. A normal chest radiograph is usually required before V/Q scanning. Scans

performed on patients with abnormal chest radiographs are most likely to be false positives because the

images do not appear normal or low probability of PE in such patients. For those with a normal chest

radiograph, V/Q scanning remains the test of choice for the diagnosis of PE in pregnancy.

Pulmonary Angiography

In pulmonary angiography, contrast is injected via a catheter introduced into the right heart under

fluoroscopy, which was the gold standard in the past for the diagnosis of PE. The diagnosis of acute PE is

made on the evidence of a thrombus either as amputation of a pulmonary arterial branch or filling

defect. With the widespread emergence of CTPA, pulmonary angiography is infrequently used and

reserved for rare circumstances for patients with a high clinical probability of PE, in whom CTPA or V/Q

scanning is nondiagnostic.

Magnetic Resonance Angiography

Magnetic resonance angiography (MRA) has been assessed for several years regarding suspected PE.

However, the results of large-scale studies show that this technique, although promising, is not

recommended as a first-line test for the diagnosis of PE due to its low sensitivity, low availability in most

emergency settings, and the high proportion of inconclusive MRA scans. But it may be an imaging option

for diagnosis of PE in patients in whom neither CTPA nor V/Q scan can be performed.

Compression Ultrasonography (US)

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PE originates from a lower limb DVT in a majority of patients, and only rarely from upper-limb DVT

(mostly following venous catheterization). In one study, DVT was found in 70% of patients with proven

PE. (Vyas & Goyal, 2021)

Treatment

Prompt diagnosis and treatment of VTE with appropriate medications may prevent thrombus extension

and embolization, relieve acute symptoms, prevent cardiopulmonary collapse, and reduce the risk of

long-term complications. Empiric treatment during the evaluation period is controversial and not

evidence based. In a hemodynamically unstable patient with a high probability of VTE, intravenous

thrombolytic therapy can be considered. Similarly, if there is a delay in obtaining a definitive diagnostic

test in a hemodynamically unstable patient with a high probability of VTE, parenteral anticoagulation

should be considered until a diagnosis is confirmed.

After diagnosis, most patients with DVT can be treated as an outpatient, except in cases of limb

ischemia, significant comorbidities (e.g., end-stage renal disease), functional limitations, high bleeding

risk, or nonadherence concerns.

Anticoagulation Choices

Once VTE is diagnosed and the patient is stabilized if needed, anticoagulation should be initiated unless

contraindicated. Guideline recommendations for anticoagulation are divided into phases: initial phase

(first week after diagnosis), long-term phase (second week to three months), and extended phase

(beyond three months).

In the initial phase of anticoagulation, a decision must be made between using the vitamin K antagonist

warfarin or a direct-acting oral anticoagulant. If warfarin is selected, concomitant parenteral

anticoagulation is required for at least five days; if dabigatran or edoxaban is selected they should be

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initiated after five to 10 days of initial therapy with a parenteral anticoagulant. Guidelines recommend

low-molecular-weight over unfractionated heparin, which is supported by multiple therapeutic trials

showing greater effectiveness and safety and lower mortality. However, unfractionated heparin is

preferred in patients with severe renal insufficiency, high bleeding risk, hemodynamic instability, or

morbid obesity. Apixaban (Eliquis) and rivaroxaban (Xarelto) do not require concomitant use of heparin

at initiation.

If warfarin is used, patients require careful education on food and drug interactions and the importance

of regular office visits to check international normalized ratio until a steady state is achieved.

Direct-Acting Oral Anticoagulants

In 2012, rivaroxaban became the first direct-acting oral anticoagulant approved by the U.S. Food and

Drug Administration for treatment of DVT and PE. Several others followed. These agents belong to two

classes: direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (apixaban, edoxaban, and

rivaroxaban).

There are logistic benefits of direct-acting anticoagulants compared with warfarin—primarily that no

regular monitoring is required because of their predictable pharmacokinetics.

Thrombolysis

Because of the high risk of bleeding, thrombolysis is restricted to specific circumstances. Expert

consensus guidelines support thrombolytic therapy in patients with persistent hypotension or shock

secondary to acute PE. Also, when patients with acute PE who are on anticoagulation deteriorate but

are not yet hypotensive, systemic thrombolysis is recommended as long as the risk of bleeding is

low. There is better evidence for systemic thrombolysis than for catheter-directed thrombolysis.

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Massive proximal lower extremity thrombosis or ilio-femoral thrombosis associated with severe

symptoms or limb-threatening ischemia for less than 14 days is the only widely accepted indication for

thrombolytic therapy in patients with DVT.

Inferior Vena Cava Filters

An inferior vena cava filter is rarely indicated, and evidence for safety and effectiveness is lacking. If

there is an absolute contraindication to therapeutic anticoagulation, complications from

anticoagulation, or failure of anticoagulation in a patient with acute proximal DVT, an inferior vena cava

filter may be indicated. Its use for other reasons is controversial. (Wilbur & Shian, 2017)

Catheter-based and surgical embolectomy are other options available to providers for patients with

hemodynamically significant PE.

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References

 Stone, J., Hangge, P., Albadawi, H., Wallace, A., Shamoun, F., Knuttien, M. G., Naidu,

S., & Oklu, R. (2017). Deep vein thrombosis: pathogenesis, diagnosis, and medical

management. Cardiovascular diagnosis and therapy, 7(Suppl 3), S276–S284.

https://doi.org/10.21037/cdt.2017.09.01

 Thachil J. (2014). Deep vein thrombosis. Hematology (Amsterdam, Netherlands), 19(5),

309–310. https://doi.org/10.1179/1024533214Z.000000000284

 Vyas V, Goyal A. Acute Pulmonary Embolism. [Updated 2021 Aug 11]. In: StatPearls

[Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

https://www.ncbi.nlm.nih.gov/books/NBK560551/

 Waheed SM, Kudaravalli P, Hotwagner DT. Deep Vein Thrombosis. [Updated 2021 Aug

11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022

Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507708/

 Wilbur, J., & Shian, B. (2012). Diagnosis of deep venous thrombosis and pulmonary

embolism. American family physician, 86(10), 913–919.

https://www.aafp.org/afp/2012/1115/p913.html

 Wilbur, J., & Shian, B. (2017). Deep Venous Thrombosis and Pulmonary Embolism:

Current Therapy. American family physician, 95(5), 295–302.

https://www.aafp.org/afp/2017/0301/p295.html

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