Etiology

The coagulation system in blood is complex and highly regulated. Slight perturbations in the systems that regulate coagulation can lead to bleeding or thrombosis.[12] The three factors that, individually or together, lead to most DVT are vessel injury, venous stasis, and activation of the clotting system (known as Virchow's triad).[13]

  • Vessel injury: endothelial cell damage promotes thrombus formation, usually at the venous valves, which can result in DVT, which subsequently embolizes to form pulmonary embolism (PE). Damage to the vessel wall can occur after several insults including trauma, previous DVT, surgery, venous harvest, and central venous catheterization.[14]

  • Venous stasis: poor blood flow and stasis promote the formation of thrombi. Venous stasis and congestion result in valvular damage, further promoting thrombus formation. Increased venous stasis is associated with age >40 years, immobility, obesity, general anesthesia, paralysis, spinal cord injury, myocardial infarction, prior stroke, varicose veins, advanced congestive heart failure, and advanced COPD.

  • Activation of the clotting system: several other conditions (both inherited and acquired) increase the risk of PE. These include cancer, high-estrogen states (oral contraceptives, hormone replacement, obesity, pregnancy), inflammatory bowel disease, nephrotic syndrome, sepsis, blood transfusion, and inherited thrombophilia (factor V Leiden mutation, prothrombin gene mutation, protein C and S deficiency, antithrombin deficiency, and antiphospholipid antibody syndrome).

Thus, patients who develop DVT typically experience a trigger that leads to blood coagulation (e.g., surgery or trauma that activates the coagulation system), prolonged immobility that leads to stasis, or drugs or illnesses (e.g., cancers, antiphospholipid syndrome) that can stimulate clotting. Susceptibility to thrombosis is genetically mediated. Several genetic variants in the coagulation system itself (e.g., the factor V Leiden mutation) as well as outside the coagulation system (e.g., non-O blood type) increase the risk of thrombosis. All of these factors may interact, further increasing the risk of DVT.

There is a clear association between DVT and the following:

  • Active malignancy[15]

  • Recent major surgery (especially major orthopedic procedures)

  • Recent hospitalization

  • Recent trauma

  • Medical illness (especially diseases associated with inflammation, such as acute infection)

  • Hormone replacement and oral contraceptive estrogen therapy

  • Pregnancy and the post-partum

The presence or absence and timing of risk factors relative to the diagnosis of DVT has a major impact on determining the duration of anticoagulant therapy.[16] The International Society on Thrombosis and Haemostasis has published a 4-category system of classification (presented in order of increasing risk of recurrent venous thromboembolism after an initial episode), which is consistent with American College of Chest Physicians and National Institute for Health and Clinical Excellence (UK) guidance:[17][18]​​​[19]

  • Major transient risk factors (e.g., surgery lasting >60 minutes), occurring within 3 months prior to thrombosis

  • Minor transient risk factors (e.g., oral contraceptives, medical hospitalization), occurring within 2 months prior to thrombosis

  • Unprovoked (no identifiable risk factor)

  • Provoked by a persistent risk factor (e.g., active cancer).

The American Society of Hematology and the European Society of Cardiology guidelines employ a similar framework, with some differences in terminology.[20][21][22]

Pathophysiology

Most blood clots that develop in the deep venous system of the leg begin to form just above and behind a venous valve.[23][24]

Small clots often resolve spontaneously. When propagation of the thrombus does occur, it expands and grows proximally and across the lumen of the vein. A clot might occlude the entire lumen, but it is more commonly located on one peripheral aspect of the lumen. Even when the entire lumen appears to be occluded, a small amount of flow may continue on the extreme periphery of the clot. Many DVTs arise in the calf veins and propagate proximally. However, in some instances, such as during pregnancy or following total hip arthroplasty, the clot might form initially in the groin or iliac vein region.[24] These DVTs may propagate into the more distal veins. DVTs may arise in more than one separated venous segment at the same time.

Endothelial damage appears to be less important in venous thromboembolism (VTE) than in arterial thrombosis.[25]​ Unlike platelet-rich arterial thrombi, VTE is composed mainly of fibrin and entrapped erythrocytes (red clots). Although platelet aggregation is seen, it is not evident at the site of thrombus attachment, suggesting that activation of the coagulation cascade precedes platelet activation.[25][26]​​

Acute thrombus begins to be dissolved by the body's fibrinolytic system as soon as a clot begins to form. Thus, elevated levels of breakdown products of cross-linked fibrin, particularly the fragment called D-dimer, appear in the blood soon after a clot begins to form. Therefore, testing for D-dimer is an important component of the evidence-based approach to diagnosing suspected DVT.​[27][28]

Classification

DVT: lower extremity

The following is an informal clinical classification.

(a) Superficial versus deep

  • Superficial vein thrombosis (SVT)

    • Palpable thrombi in subcutaneous veins just below the skin (e.g., in a varicose vein) are classified as SVT; also referred to as superficial thrombophlebitis.

    • Most SVT confer less risk of complications than DVT and are managed differently. However, thrombi in the proximal portion of the greater saphenous vein (especially if within a few centimeters of the sapheno-femoral junction) may pose some risk of propagation and pulmonary embolization because the greater saphenous vein joins the common femoral vein in the groin. SVT in the proximal greater saphenous vein are often managed in the same way as DVT.

  • DVT

    • Thrombi form within veins deep to the muscular tissue planes.

(b) Proximal versus distal

  • Proximal venous thrombosis

    • DVTs in the popliteal or more proximal (femoral, deep femoral, common femoral, iliac, and vena cava) deep veins are classified as proximal.

  • Distal or calf vein thrombosis

    • DVTs in the three major axial calf veins (posterior tibial, anterior tibial, peroneal) below the popliteal vein and clots in the muscular vein branches (gastrocnemius and soleus) are considered distal deep calf vein thrombi. Some people may have anatomic variation of the distal deep veins, including paired peroneal veins, or a tibial-peroneal trunk rather than an immediate trifurcation distal to the popliteal vein. Thrombi in these areas are also distal DVTs. DVT isolated to the distal veins have a lower risk of causing pulmonary embolism and post-thrombotic syndrome, and are sometimes managed differently than proximal DVT.

(c) Acute versus subacute, or chronic

  • Acute venous thrombosis confirmed by duplex ultrasound has the following characteristics: vein width at site of the thrombus is wider than the unaffected vein on the contralateral side (i.e., dilated vessel), and ultrasound echoes are not prominent (i.e., the clot is not echogenic). Acute DVT often correlates with recent onset of symptoms. Acute clots may totally or partially obstruct flow.

  • Subacute or chronic DVTs are associated with some narrowing of the vein, partial but incomplete compressibility of the vessel, and hyperechogenicity in the vein lumen. The involved vein is normal-sized or contracted. Chronic clots may totally or partially obstruct flow. Chronic DVT can occur with or without anticoagulant treatment in symptomatic or asymptomatic DVT.

  • The time over which an acute DVT takes on subacute or chronic characteristics on ultrasound has not been well validated, and likely varies between people. Distinguishing a new acute DVT from a prior DVT is best accomplished by direct comparison with prior imaging studies.

DVT: upper extremity

The following is an informal clinical classification.

(a) Superficial versus deep thrombosis

  • Thrombi in subcutaneous veins just below the skin that are palpable on the forearm or upper arm (i.e., basilic and cephalic veins) are classified as superficial.

  • Brachial, axillary, subclavian, or innominate (or brachiocephalic) veins, and the superior vena cava, are classified as deep. The internal jugular vein is also considered to be a deep vein.

(b) Proximal versus distal

  • The distinction of proximal versus distal DVT is not clearly defined for the upper extremity. Management studies of upper extremity DVT have often included cases involving the axillary and more proximal veins. The risk of embolization, and management of DVT in the brachial vein, is less certain.

(c) Acute versus subacute, or chronic

  • Criteria are similar to lower-extremity venous thrombosis. However, inability to compress the subclavian and other centrally located veins makes diagnosis and classification more difficult.

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