Venous Thromboembolism

Hypercoagulability

Many hereditary and acquired disorders are associated with hypercoagulability. Hereditary disorders that are potent risk factors for VTE include deficiencies of natural anticoagulants such as antithrombin, protein C, and protein S (discussed in Chapters 125 and 138 ). With reduced levels of these endogenous anticoagulants, there is increased thrombin generation and the potential for clot formation. Moderate genetic risk factors for VTE include factor (F) V Leiden and the prothrombin gene mutation. FV Leiden, an FV variant that is resistant to inactivation by activated protein C, is found in about 5% of individuals of European descent. The prothrombin gene mutation, which is found in about 3% of those of European descent, is a single nucleotide polymorphism in the 3′ untranslated region that increases prothrombin synthesis. Delayed inactivation of FVa Leiden and elevated prothrombin levels lead to increased thrombin generation. Although these inherited thrombophilic disorders increase the risk of the first episode of VTE, their impact on the risk of recurrence is unclear. Consequently, routine thrombophilia testing is not recommended in patients with VTE because such tests rarely influence long-term management (see Chapter 138 ).

Up to 50% patients with the first episode of VTE have no identifiable major risk factors and are described as having unprovoked VTE. The remainder develops VTE secondary to risk factors and these episodes are considered provoked. Acquired risk factors for VTE can be divided into those that are transient or persistent and major or minor. Examples of major transient risk factors are surgery, trauma and hospitalization for COVID-19, whereas minor transient risk factors include immobilization, long-distance travel, pregnancy, and estrogen therapy. Common examples of major persistent risk factors are cancer and antiphospholipid syndrome, whereas minor persistent risk factors include advanced age, obesity, renal impairment, and chronic inflammatory disorders such as inflammatory bowel disease and rheumatoid arthritis. Patients with both hereditary and acquired risk factors are at particularly high risk of VTE because risks tend to be multiplicative rather than additive. Local factors explain why DVT usually starts in the calf.

Stasis, Hypoxia, and Endothelial Dysfunction

Most venous thrombi originate in the valve pockets of the calf veins where there is stasis and hypoxia. Consistent with slow blood flow, contrast dye lingers in the valve pockets after venography. Hypoxia occurs because the valve leaflets are avascular and the oxygen tension in the valve pockets rapidly decreases when blood flow stops because of immobility. Endothelial cells lining the valve pockets express antithrombotic proteins such as thrombomodulin and endothelial protein C receptor on their surface (see Chapter 125 ). Expression is downregulated by local hypoxia or inflammation and by reduced expression of the oscillatory shear-dependent transcription factors that endow perivalvular venous endothelial cells with an antithrombotic phenotype (see Chapters 121 and 122 ). In addition, stasis and hypoxia induce a pro-inflammatory and prothrombotic endothelial phenotype by the upregulation of adhesion molecules such as P- and E-selectin, intercellular adhesion molecule 1 (ICAM-1), and von Willebrand factor. Therefore, stasis and hypoxia in the valve pockets of the veins in the lower extremities promote a hypercoagulable microenvironment, which explains why DVT starts in this site. In contrast, upper extremity DVT is often triggered by central venous catheters or by extrinsic compression of the arm veins (e.g., Paget-Schroetter syndrome). Indwelling catheters or extrinsic compression retard blood flow, whereas delivery of chemotherapy, or antibiotics via the catheters, induces local activation of the endothelium. Regardless of whether DVT occurs in the upper or lower extremities, however, the initiators of coagulation are likely to be similar.

Initiators of Coagulation in Venous Thromboembolism

Tissue factor initiates coagulation in patients with VTE, but the source of the tissue factor remains elusive. Overt damage to the vessel wall is rarely seen with DVT. However, hypoxia and inflammatory cytokines upregulate tissue factor expression by endothelial cells and circulating monocytes and induce endothelial cell expression of adhesion molecules such as P-selectin. The importance of endothelial cell tissue factor is uncertain, but P-selectin tethers tissue, factor-bearing monocytes, and microparticles onto their surface via interaction with P-selectin glycoprotein ligand. By preventing such binding, P-selectin inhibitors attenuate venous thrombosis in animal models. Statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors attenuate tissue factor expression by monocytes, which may explain why they reduce the risk of recurrent VTE. Therefore, adhesion of tissue factor expressing leukocytes and microparticles to the activated endothelium appears to be an important driver of DVT.

In addition to tissue factor, emerging data suggest that the contact system also plays a part in the initiation of coagulation in VTE. Neutrophil extracellular traps (NETs) extruded from activated neutrophils trapped within venous thrombi provide a scaffold for platelet adhesion and activate FXII, thereby initiating coagulation via the intrinsic pathway (see Chapters 121 and 125 ). Likewise, inorganic polyphosphate released from activated platelets enhances FXII activation. Thrombin feedback activation of FXI, a reaction enhanced by polyphosphate, amplifies coagulation via the intrinsic pathway. With increasing evidence that the contact system is involved in the initiation of VTE, FXI has emerged as a target for new anticoagulants that have the potential to be safer than those that inhibit FXa or thrombin (see Chapter 143 ).

There is mounting evidence that platelets play a part in the pathogenesis of VTE. Venous thrombi consist of a central core that lies adjacent to the vessel wall and is rich in fibrin and trapped red blood cells and an overlying shell composed of platelet-rich layers. There is evidence from mouse models that platelets are important in the initiation and propagation of venous thrombosis. Thus, P-selectin-dependent recruitment of platelets and leukocytes is essential for thrombus formation after incomplete ligation of the inferior vena cava because inhibition or depletion of platelets or neutrophils suppressed thrombus formation in this model. Likewise, platelet depletion abrogated spontaneous venous thrombosis induced by concomitant knockdown of antithrombin and protein C. In addition, antiplatelet agents such as aspirin or clopidogrel attenuated thrombosis in a murine venous stasis model. Findings in mice may be translatable to humans because patients with acute VTE have evidence of systemic platelet activation and increased levels of platelet-derived soluble P-selectin. Therefore, platelets likely contribute to VTE, which explains why aspirin is effective for its prevention, albeit less so than anticoagulants.

Stabilization, Embolization, and Resolution of Venous Thrombi

In patients with DVT, the risk of PE appears to be dependent on the size and the stability of the thrombus. The importance of thrombus size is highlighted by the fact that calf DVT rarely causes PE, whereas up to 50% of patients with proximal DVT have associated PE. Clot stability also influences the risk of PE. Thrombin activates FXIII, which stabilizes the clot and renders it more resistant to lysis by crosslinking the fibrin polymers and by facilitating retention of red blood cells in the thrombus. Enhanced thrombin generation and subsequent FXIII activation in patients with FV Leiden could explain the epidemiological evidence that DVT is more common than PE in such patients. This concept is supported by the results of studies in mice. Thus, treatment with dabigatran after ferric chloride-induced femoral vein thrombosis enhanced PE by suppressing thrombin-mediated FXIII activation. Conversely, FXIII supplementation reduced the risk of PE without promoting thrombus growth.

Thrombus resolution depends on fibrinolysis, which occurs when plasminogen is converted to plasmin. Degradation of thrombi by plasmin likely explains why most calf DVT resolve spontaneously. Migration of leukocytes into the thrombus promotes fibrinolysis and contributes to early thrombus resolution by releasing clot digesting enzymes. Impaired fibrinolysis has been linked to recurrent VTE and up to 50% of patients with proximal DVT have ultrasound evidence of residual vein occlusion 1 year after their index event. Reduced blood flow contributes to PTS, which is the major long-term complication of DVT.

Deep Vein Thrombosis

DVT typically causes swelling, pain, and erythema of the affected extremity. DVT in the proximal veins of the lower extremity is more likely to be symptomatic than DVT confined to the calf veins. Extensive thrombosis involving the iliac and femoral veins can cause phlegmasia cerulea dolens, an uncommon limb-threatening syndrome characterized by severe leg pain, swelling, venous gangrene, and arterial ischemia with loss of distal pulses.

The differential diagnosis of patients with suspected DVT includes musculoskeletal disorders (muscle or tendon strains or tears), lymphatic obstruction, venous insufficiency, a ruptured popliteal (Baker) cyst, cellulitis, sciatica, muscle hematoma, and post-thrombotic syndrome.

Pulmonary Embolism

The most common symptoms and signs of PE include dyspnea on exertion, chest pain which is often pleuritic in nature, tachypnea, and cough. Many patients with PE have concomitant symptoms and signs of DVT. Less common symptoms and signs include fever, hemoptysis, cyanosis, hypotension, and shock. Other non-specific symptoms include palpitations, anxiety, and lightheadedness.

Patients with severe PE often have dyspnea at rest and hypotension, and they may present with syncope because of hypoxemia and low cardiac output. Central and peripheral cyanosis can occur, and the jugular veins may be distended if right heart failure develops. The second heart sound can be widely split, and the pulmonic component may be loud because of delayed emptying of the right ventricle. A right ventricular heave may be present with severe PE because of acute pulmonary hypertension.

When patients present with chest symptoms suggestive of PE, the differential diagnosis includes pulmonary disorders, such as pneumonia, an exacerbation of chronic obstructive lung disease or asthma, pleurisy secondary to connective tissue disease, cardiac disorders such as heart failure, acute coronary syndrome, or pericarditis; and musculoskeletal disorders such as rib fracture.

Diagnostic Tests