How Venous Thrombosis Occurs

Causes of VTE

Venous thrombolembolism (VTE) is often associated with cancer, trauma, and surgery. In some cases, described as idiopathic, a patient has no clear exposing risk factor (ie, no triggering event).²⁵ Current approaches to prevention and treatment of VTE are based on recognition of identifiable risk factors and an understanding of the pathological processes that lead to thrombosis.

Virchow's triad

Over 150 years ago, the German pathologist Rudolph Virchow postulated that thrombus formation and propagation resulted from abnormalities of (1) blood flow, (2) the vessel wall, and (3) blood components. These three factors are known as Virchow’s triad.²⁶

Since Virchow first published his observations, the features of this triad have been further refined^{27, 28}:

Blood flow — abnormalities of haemorheology and turbulence at vessel bifurcations and stenotic regions
Vessel walls — abnormalities in the endothelium, such as atherosclerosis and associated vascular inflammation
Blood components — abnormalities in coagulation and fibrinolytic pathways

Virchow's Triad

Advances in laboratory techniques now enable clinicians to quantify some of these thrombosis-related factors that, when abnormal, confer a “prothrombotic” or “hypercoagulable” state.²⁸ This state is associated with an increased risk of VTE and other cardiovascular diseases, including atrial fibrillation, coronary heart disease, and heart failure.

Who is at risk?

Many identifiable factors contribute to an increased risk of VTE. These can be divided into predisposing risk factors (ie, patient characteristics) and exposing or situational factors (ie, acute medical conditions, acute trauma, and surgery).

Major orthopaedic surgery is an example of an exposing risk factor. These surgical procedures are associated with about twice the rate of VTE as general surgery. Consistent with Virchow’s triad, the increased risk of VTE in major orthopaedic surgery may be linked to^{3, 26}:

Damage to the vessel wall during the procedure
Increased procoagulant activity, such as increased thrombin generation
Venous stasis from postoperative immobility

The need for primary prevention

The American College of Chest Physicians (ACCP) has reviewed the results of several randomised controlled clinical trials of VTE in patients undergoing major orthopaedic surgery without thromboprophylaxis.³ The rates of total DVT, assessed 7 to 14 days after surgery, are 40% to 80% following hip or knee arthroplasty or hip fracture surgery. Because of this high risk, the ACCP recommends primary prevention of VTE for all patients undergoing major orthopaedic surgery of the lower limb.

Important exposing risk factors for VTE include:

Surgery and trauma^{3, 29}

Hip and knee arthroplasty
Hip and other lower extremity fracture
Multiple trauma
Major surgery for malignancy
Arthroscopic repair of cruciate ligament and meniscectomy
Other surgical procedures, duration >30 minutes
Plaster cast immobilisation of lower limb

Nonsurgical conditions and factors³

Stroke with paralysis
Acute decompensated COPD
Acute heart failure, NYHA III or IV
Sepsis
Acute infection with immobilisation
Active malignancy
Acute inflammatory disease with immobilisation
Central venous catheters

Important predisposing risk factors for VTE include^{29, 30, 31}:

Thrombophilia
History of VTE
History of malignancy
Pregnancy and the postpartum period
Age >60 years
Obesity (BMI >30)
Oestrogen therapy
Chronic heart failure
Varicose veins

Imbalances in the coagulation system and thrombosis

The function of the coagulation system depends on a delicate balance between natural coagulant and anticoagulant factors, as well as on the balance between the coagulation and fibrinolytic systems. Thrombosis can result when there is an imbalance in these systems.

“Thrombophilia” refers to an inherited or acquired imbalance in the coagulation system that leads to an increased risk of thrombosis. (In a converse sense, “haemophilia” is an inherited or acquired imbalance that predisposes to excessive bleeding.) Clinicians should suspect thrombophilia in patients with recurrent VTE or a family history of VTE, in patients who develop VTE with no apparent exposing risk factors, and in women who experience multiple spontaneous abortions or stillbirths.³²

Approximately one in three patients with VTE has an inherited thrombophilia.²⁶ Genetic mutations affecting Factor V (known as Factor V Leiden) and Factor II are common forms of thrombophilia. Rare causes include deficiencies of the natural anticoagulants protein C, protein S, and antithrombin.³² Patients with thrombophilia may require special attention for prophylaxis and longer-term anticoagulant therapy following an episode of VTE, depending on the type of thrombophilia and their risk of VTE recurrence.³²

Patients with a hypercoagulability state are also prone to thrombosis. Hypercoagulability occurs when there is pathological activation of the coagulation system. Surgery and significant trauma, both of which breach the integrity of the vascular system, are associated with hypercoagulability. Malignancy and serious infection also can disrupt the balance of the coagulation system, leading to thrombosis.²⁶

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Article references

25 - Turpie AG, Chin BS, Lip GY. Venous thromboembolism: pathophysiology, clinical features, and prevention. BMJ. 2002;325(7369):887-890.
26 - Merli GJ. Pathophysiology of venous thrombosis, thrombophilia, and the diagnosis of deep vein thrombosis-pulmonary embolism in the elderly. Clin Geriatr Med. 2006;22(1):75-92, viii-ix.
27 - Jerjes-Sanchez C. Venous and arterial thrombosis: a continuous spectrum of the same disease? Eur Heart J. 2005; 26(1):3-4.
28 - Lip GY, Blann AD. Thrombogenesis and fibrinolysis in acute coronary syndromes. Important facets of a prothrombotic or hypercoagulable state? J Am Coll Cardiol. 2000;36(7):2044-2046.
3 - 1. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6)(suppl):381S-453S.
29 - 1. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften. S3-Leitlinie. Prophylaxe der venösen Thromboembolie (VTE) Version vom 18. März 2009.
30 - Alikhan R, Cohen AT, Combe S, et al; MEDENOX Study. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med. 2004;164(9):963-968.
31 - Kucher N, Koo S, Quiroz R, et al. Electronic alerts to prevent venous thromboembolism among hospitalized patients. N Engl J Med. 2005;352(10):969-977.
32 - Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344(16):1222-1231.

Venous thromboembolism: A condition in which a blood clot (thrombus) forms in a vein, which in some cases then breaks free and enters the circulation as an embolus, finally lodging in and completely obstructing a blood vessel, e.g., in lungs causing a PE. The term encompasses both DVT and PE.
Procoagulant: A substance that promotes the coagulation of blood.
Thrombin: Also called Factor IIa, thrombin performs two functions in the coagulation cascade: activating platelets, and catalysing the conversion of soluble fibrinogen into insoluble fibrin. It is formed from prothrombin by a reaction that is catalysed by Factor Xa.
American College of Chest Physicians: Multidisciplinary international medical society based in Northbrook, Illinois, USA, that focuses on the treatment and prevention of all diseases of the chest. It has over 16,000 active members with physicians representing all chest medicine disciplines. Publishes the journal Chest.
Thromboprophylaxis: The use of medication or medical devices to prevent the formation of blood clots.
Venous catheter: A tube inserted into a vein to deliver medication (such as chemotherapy) to a patient.
Antithrombin: Antithrombin, also known as antithrombin III, is the most important member of a larger family of antithrombins. It is a small protein molecule (a glycoprotein) produced in the liver that binds to a specific pentasaccharide sequence on heparin. This binding to heparin leads to an anticoagulant effect through two different mechanisms: It causes a conformational change in antithrombin that allows antithrombin to bind to and thereby inhibit Factor Xa, which leads to a subsequent decrease in thrombin levels It causes a direct increase of thrombin inhibition as a result of antithrombin binding to the heparin pentasaccharide sequence and thrombin binding to an adjacent segment of heparin at the same time.
Prophylaxis: The prevention of a disease or pathological condition.
Hypercoagulability: A potentially dangerous state of an increased tendency for blood to coagulate, even within blood vessels. Hypercoagulability can be an inherited condition (e.g., Factor V Leiden mutation) or acquired through circumstance (e.g., cancer).