Venous Thromboembolism

Edited & presented by:

Haneen Omar Abuhani

• VTE is a potentially fatal disorder and significant health problem in our aging society

• VTE results from clot formation within the venous circulation and is manifested as deep vein thrombosis (DVT) and/or pulmonary embolism (PE)

• DVT is rarely fatal, but PE can result in death within minutes of symptom onset, before effective treatment can be given.

• Beyond the symptoms produced by the acute event, VTE complications, such as the postthrombotic syndrome and chronic thromboembolic pulmonary hypertension (CTPH), also cause substantial disability and suffering.

EPIDEMIOLOGY • The incidence rate of symptomatic first VTE is estimated at 132 per 100,000

patient-years

• The relative incidence of DVT:PE is approximately 2 : 1.

• Mortality 30 days after DVT is approximately 10%, compared to 15% for PE

• Women (55.6%)> men.

• Asians<whites<blacks

• Recurrent VTE rates are highest in the 180 days following the initial event and decline slowly over the next 4 to 10 years.

• In the absence of secondary prophylaxis, the 10-year cumulative recurrent VTE risk is approximately 25.0%.

ETIOLOGY

• A number of identifiable factors increase VTE risk.

• Many risk factors fall into categories constituting what is known as Virchow's triad:

1. blood stasis,

2. vascular injury,

3. Hypercoagulability

• Approximately a third of

VTEs are provoked by

identifiable risk factors.

• Hemostasis is the process responsible for maintaining circulatory system integrity following blood vessel damage

• Hemostatic clots remain localized to the vessel wall and do not greatly impair blood flow.

• Pathologic clots like those causing VTE result in blood flow impairment and often cause complete vessel occlusion

PATHOPHYSIOLOGY

• Normal circumstances:

• Endothelial cells separate collagen and TF from circulating platelets and clotting factors

• Vessel injury platelet activation and TF-mediated clotting factor cascade thrombin formation fibrin clot, which seals the breach

• Pathologic VTE:

• Often occurs without gross vessel wall damage and may be triggered by TF brought to the growing thrombus by circulating microparticles.

• Venous clots are mainly composed of fibrin, platelets, and trapped red blood cells and often occur in areas of disturbed blood flow, like deep leg vein valve cusps

• Vessel damage platelets bind to adhesion proteins like von Willebrand factor and collagen activated platelets additional platelets recruitment activated platelets;

1. change shape and release components critical for sustaining further thrombus formation into the environment surrounding the developing clot.

2. express P-selectin, an adhesion molecule that facilitates capture of blood-borne TF bearing microparticles resulting in fibrin clot formation via the coagulation cascade

3. Provide phospholipid-rich surfaces necessary for coagulation cascade reactions

• Although VTE can form in any part of the venous circulation, most begin in the leg(s).

• Thrombus isolated in calf veins is unlikely to break loose (embolize),

• Thrombus involving the popliteal and larger veins above it are more likely to embolize and travel through the right side of the heart and cause PE by lodging in the pulmonary artery or one of its branches, occluding blood flow to the lung, and impairing gas exchange.

• Without treatment, the affected portion of the lung becomes necrotic and oxygen delivery to other vital organs decreases, potentially resulting in fatal circulatory collapse

• 1. Clinical presentation may be subtle or nonspecific and objective tests are required to confirm or exclude the diagnosis. Some may have asymptomatic disease.

• 2. Classic findings (all have very low sensitivity and specificity):

a. Lower-extremity pain, warmth and swelling (worse with dependency/walking, better with elevation/rest), more likely to be unilateral.

b. Homans sign (calf pain on ankle dorsiflexion)

c. Palpable cord

d. Fever

CLINICAL PRESENTATION

1. D-dimer testing:

• Serum concentration of D-dimer, a by-product of fibrin degradation, is nearly always elevated.

• D-dimer values <500 ng/mL (mcg/L) combined with clinical decision rules are useful in ruling out the diagnosis of DVT.

• Has a very high sensitivity (95%), but low specificity (50%).

Diagnostic tests

2. Compression ultrasound : (Duplex ultrasound )

• It is the most commonly used test to diagnose DVT.

• Initial test for DVT; noninvasive, but highly operator dependent

• High sensitivity and specificity for detecting proximal thrombi (popliteal and femoral), not so for distal (calf vein) thrombi.

• “Duplex” refers to the two parts of the process:

I. Part One of the Duplex Ultrasound Process: In the first part of the process, brightness modulation ultrasound (also known as B-mode ultrasound) is used to obtain an image or picture.

II. Part Two of the Duplex Ultrasound Process: In the second part of the duplex ultrasound process, Doppler ultrasound is used to detect abnormalities of blood flow.

Absence of blood flow confirms the diagnosis of DVT.

3. Venography is the gold standard for the diagnosis of DVT.

• Most accurate test for diagnosis of DVT of calf veins .

• Invasive and infrequently used that involves injection of radiopaque contrast dye (usually an iodine dye) into a foot vein. It is expensive and can cause anaphylaxis and nephrotoxicity.

• Allows visualization of the deep and superficial venous systems, and allows assessment of patency and valvular competence

4. Impedance plethysmography

• A noninvasive alternative to Doppler ultrasound

• Blood conducts electricity better than soft tissue, so electrical impedance decreases as blood volume increases

• High sensitivity for proximal DVT, but not for distal DVT (calf veins)

• Poor specificity because there is a high rate of false positives

• As accurate as Doppler, but less operator dependent

• Clinical assessment significantly improves the diagnostic accuracy of noninvasive tests such as compression ultrasound (CUS), computed tomography pulmonary angiography (CTPA), and D-dimer.

• Simple clinical assessment checklists such as the Wells score can be used to determine if a patient is "likely" or "unlikely" to have DVT or PE

• In general, patients with an unlikely probability of VTE should first have their D-dimer tested. If the D-dimer result is below the defined cutoff point, VTE is ruled out; if above the cutoff point, the patient should have appropriate diagnostic imaging (either CUS for

suspected DVT or CTPA for suspected PE)

Deep vein thrombosis diagnostic algorithm

GENERAL APPROACH TO TREATMENT OF VTE

• Anticoagulation is the mainstay of treatment for VTE; DVT and PE are treated similarly

• After VTE is confirmed objectively, therapy with a rapid-acting anticoagulant should be instituted as soon as possible. Anticoagulants can be administered in the outpatient setting in most patients with DVT.

• Three months is the appropriate initial duration of anticoagulation therapy for the acute first episode of VTE for all patients. This duration is also recommended when the initial thrombotic event was associated with a major transient or reversible risk factor (eg, surgery, hospitalization).

• Continuing anticoagulation is required to prevent new VTE episodes not directly related to the preceding episode. Extended therapy beyond 3 months should be considered for patients with a first unprovoked (idiopathic) VTE when feasible because of a relatively high recurrence rate.

• Several factors predict risk of recurrence following an episode of unprovoked VTE. The strongest predictors of recurrence are male sex and a positive D-dimer assay measured 1 month after stopping anticoagulant therapy. These factors are incorporated into scoring systems to predict recurrence such as the DASH score and the Vienna prediction model.

• In patients with VTE and active cancer, extended therapy is rarely stopped because of a high recurrence risk.

Decision algorithm: Acute treatment of VTE

• Patients with isolated distal DVT and a high risk of recurrence should be treated with 3 months of anticoagulation. If the risk of recurrence is low, then they can be treated with a short course (4-6 weeks) of anticoagulation (prophylactic dose or full dose) or with surveillance compression ultrasound.

• Patients with proximal DVT should receive at least 3 months of anticoagulation therapy. An extended course of anticoagulation should be determined based on a combination of venous ultrasound findings, risk/benefit balance, patient compliance with therapy, and the patient’s preference.

• Patients without cancer should be treated with direct oral anticoagulants (DOACs) or warfarin, while patients with cancer should receive low molecular weight heparin (LMWH).

• For acute DVT, initial anticoagulation should be one of the following regimens: 1) apixaban 10 mg twice a day for 7 days, then 5 mg twice a day; 2) dabigatran 150 mg twice a day after a 5- to 10-day lead-in course of LMWH; 3) edoxaban 60 mg daily (30 mg if creatinine clearance 30-50 ml/min or potent proton pump inhibitor use) after a 5- to 10-day lead-in course; 4) rivaroxaban 15 mg twice a day for 21 days, then 20 mg daily; or 5) warfarin with a goal international normalized ratio (INR) 2-3 and LMWH for 5-10 days (until INR >2).

• Various risk prediction models can be used to assess the risk of VTE recurrence. These include the Vienna model, the DASH score, and HERDOO-2.

• For extended secondary prophylaxis against recurrent DVT, patients can be treated with low-dose aspirin, apixaban 2.5 mg twice a day, or rivaroxaban 10 mg daily. In general, anticoagulation is preferred over aspirin therapy.

• For upper extremity DVT, ultrasound is the diagnostic modality of choice and treatment is similar to lower extremity DVT.

• During pregnancy, LMWH is the recommended anticoagulation for initial and long-term treatment. Anticoagulation should be continued for at least 6 weeks after delivery (for a minimum of 3 months of treatment).

• The management of DVT of the leg should also include elevation and analgesia; in limb-threatening DVT, thrombolysis may also be considered.

• Recent trial evidence suggests that use of elastic compression stockings following a DVT does not reduce the incidence of post-thrombotic syndrome.

• Patients who have had VTE and have a strong contraindication to anticoagulation and those who continue to have new pulmonary emboli despite therapeutic anticoagulation should have an inferior vena cava (IVC) filter inserted to prevent life-threatening PE.

Prophylaxis of VTE

• All patients admitted to hospital should be assessed for their risk of developing VTE and appropriate prophylactic measures should be put in place.

• Both medical and surgical patients are at increased risk.

• Early mobilisation of patients is important to prevent DVT, and those at medium or high risk require additional antithrombotic measures; these may be pharmacological or mechanical.

• There is increasing evidence in high-risk groups, such as patients who have had major lower limb orthopaedic surgery and abdominal or pelvic cancer surgery, for protracted thromboprophylaxis for as long as 30 days or so after the procedure.

• Particular care should be taken with the use of pharmacological prophylaxis in patients with a high risk of bleeding or with specific risks of haemorrhage related to the site of surgery or the use of spinal or epidural anaesthesia.

Complications

1. Pulmonary embolus (PE) can originate from the iliofemoral, pelvic, calf, ovarian, axillary, subclavian, and internal jugular veins, as well as the inferior vena cava and cavernous sinuses of the skull—see Chapter 3 for discussion on PE

2. Phlegmasia cerulea dolens(painful, blue, swollen leg)

a. Occurs in extreme cases of DVT—indicates that major venous obstruction has occurred

b. Severe leg edema compromises arterial supply to the limb, resulting in impaired sensory and motor function

c. Venous thrombectomy is indicated

3. Post thrombotic syndrome (chronic venous insufficiency [CVC])

a. It occurs in around 30% of patients who sustain a proximal lower limb DVT.

b. It occurs due to damage of venous valves by the thrombus. and results in persistent leg swelling, heaviness and discoloration. The most severe complication of this syndrome is ulceration around the medial malleolus.

b. Residual venous obstruction and valvular incompetence lead to ambulatory HTN.