Deep vein thrombosis

Blood has a natural propensity to clot when blood vessels are damaged (hemostasis) to minimize blood loss.[19] Clotting is activated by the coagulation cascade and the clearing of clots that are no longer needed is accomplished by the fibrinolytic system or fibrinolysis.[19] Reductions in fibrinolysis or increases in coagulation can increase the risk of DVT.[19]

The most common cause of death associated with DVT is when a blood clot (or multiple clots) detach from the veins (embolize), travel through the right side of the heart, and become stuck in pulmonary arteries that supply deoxygenated blood to the lungs for oxygenation. This blockage of blood flow to the lungs is called pulmonary embolism (PE). PE is most common in larger DVTs that occur in the thigh or pelvis. Both DVT and PE are considered as part of the same overall disease process, venous thromboembolism (VTE), which can occur as DVT or PE with or without DVT.[3] VTE is the third most common cause of death from cardiovascular disease, with the top two causes being coronary heart disease and ischemic stroke.[20] In addition to PE, another life-threatening concern with DVT, albeit rare, is when severe cases completely block the venous outflow of a region of the body. This can cause increased pressure leading to compartment syndrome and decreased oxygenation leading to gangrene.

Signs and symptoms of DVT, while highly variable, include pain or tenderness, swelling, warmth, dilation of surface veins, redness or discoloration, and cyanosis with fever.[5] However, some with DVT have no symptoms.[18] Signs and symptoms alone are not sufficiently sensitive or specific to make a diagnosis, but when considered in conjunction with pre-test probability, can help determine the likelihood of DVT.[18] In most suspected cases, DVT is ruled out after evaluation,[21] and symptoms are more often due to other causes, such as ruptured Baker's cyst, cellulitis, hematoma, lymphedema, and chronic venous insufficiency.[1] Other differential diagnoses include tumors, venous or arterial aneurysms, and connective tissue disorders.[22]

Depiction of a deep vein thrombosis

The three factors of Virchow's triad—venous stasis, hypercoagulability, and changes in the endothelial blood vessel lining—contribute to VTE and are used to explain its formation.[23] Venous stasis is the most consequential of these three factors.[9] Other related causes include activation of immune system components, the state of microparticles in the blood, the concentration of oxygen, and possible platelet activation.[24] Various risk factors contribute to VTE, including genetic and environmental factors, though many with multiple risk factors never develop it.[25][12]

Acquired risk factors include the strong risk factor of older age,[5] which alters blood composition to favor clotting.[26] Previous VTE, particularly unprovoked VTE, is a strong risk factor.[27] Major surgery and trauma increase risk because of tissue factor from outside the vascular system entering the blood.[28] Minor injuries,[29] lower limb amputation,[30] hip fracture, and long bone fractures are also risks.[8] In orthopedic surgery, venous stasis can be temporarily provoked by a cessation of blood flow as part of the procedure.[24] Inactivity and immobilization contribute to venous stasis, as with orthopedic casts,[31] paralysis, sitting, long-haul travel, bed rest, hospitalization,[28] and in survivors of acute stroke.[32] Conditions that involve compromised blood flow in the veins are May–Thurner syndrome, where a vein of the pelvis is compressed, and venous thoracic outlet syndrome, which includes Paget–Schroetter syndrome, where compression occurs near the base of the neck.[33][34][35]

Cancer can grow in and around veins, causing venous stasis, and can also stimulate increased levels of tissue factor.[36] Cancers of the bone, ovary, brain, pancreas, and lymphomas are especially associated with increased VTE risk.[30] Chemotherapy treatment also increases risk.[37] Obesity increases the potential of blood to clot, as does pregnancy. In the postpartum, placental tearing releases substances that favor clotting. Oral contraceptives[lower-alpha 2] and hormonal replacement therapy increase the risk through a variety of mechanisms, including altered blood coagulation protein levels and reduced fibrinolysis.[24]

The coagulation system, often described as a "cascade", consists of a group of proteins that interact to form a blood clot. DVT risk is increased by abnormalities in the cascade. The regulators, antithrombin (ᾳTHR) and activated protein C (APC) are shown in green above the blood's clotting factors they affect.

Genetic factors account for approximately 50 to 60% of the variability in VTE rates.[4] Family history of VTE is a risk factor for a first VTE.[39] Genetic factors that increase the risk of VTE include deficiencies of three proteins that normally prevent blood from clotting—protein C, protein S, and antithrombin. Deficiencies in antithrombin, protein C, and protein S[lower-alpha 3] are rare but strong, or moderately strong, risk factors.[28][24] These three deficiencies increase the risk of VTE by about 10 times.[40] Factor V Leiden, which makes factor V resistant to inactivation by activated protein C,[39] mildly increases VTE risk by about three times.[10][39] Having a non-O blood type roughly doubles VTE risk.[24] Non-O blood type is common globally, making it an important risk factor.[41] Individuals without O blood type have higher blood levels of von Willebrand factor and factor VIII than those with O blood type, increasing the likelihood of clotting.[41] Those homozygous for the common fibrinogen gamma gene variant rs2066865 have about a 1.6 times higher risk of VTE.[42] The genetic variant prothrombin G20210A, which increases prothrombin levels,[28] increases risk by about 2.5 times.[10] Additionally, approximately 5% of people have been identified with a background genetic risk comparable to the factor V Leiden and prothrombin G20210A mutations.[10]

Blood alterations including dysfibrinogenemia,[31] low free protein S,[12] activated protein C resistance,[12] homocystinuria,[43] hyperhomocysteinemia,[28] high fibrinogen levels,[28] high factor IX levels,[28] and high factor XI levels[28] are associated with increased risk. Infection, including that of COVID-19, increases risk.[44][45] Inflammatory diseases[24][46] such as Behçet's syndrome,[47] and some autoimmune diseases,[48] such as primary antiphospholipid syndrome[49] and systemic lupus erythematosus (SLE),[50] increase risk. SLE itself is frequently associated with secondary antiphospholipid syndrome.[51] Other associated conditions include heparin-induced thrombocytopenia,[52] thrombotic storm,[53] catastrophic antiphospholipid syndrome,[54] paroxysmal nocturnal hemoglobinuria,[55] nephrotic syndrome,[12] chronic kidney disease,[56] HIV,[57] polycythemia vera,[31] intravenous drug use,[58] and smoking.[lower-alpha 4]

Some risk factors influence the location of DVT within the body. In isolated distal DVT, the profile of risk factors appears distinct from proximal DVT. Transient factors, such as surgery and immobilization, appear to dominate, whereas thrombophilias[lower-alpha 5] and age do not seem to increase risk.[61] Common risk factors for having an upper extremity DVT include having an existing foreign body (such as a central venous catheter, a pacemaker, or a triple-lumen PICC line), cancer, and recent surgery.[11]

The iliac veins (in the pelvis) include the external iliac vein, the internal iliac vein, and the common iliac vein. The common femoral vein is visible below the external iliac vein. (It is labeled simply "femoral" here.)

Provoked DVTs occur in association with acquired risk factors, such as surgery, oral contraceptives, trauma, immobility, obesity, or cancer; cases without acquired states are called unprovoked or idiopathic.[62] Acute DVT is characterized by pain and swelling[63] and is usually occlusive,[64] which means that it obstructs blood flow, whereas non-occlusive DVT is less symptomatic.[65] The label "chronic" has been applied to symptomatic DVT that persists longer than 10 to 14 days.[66] DVT that has no symptoms, but is found only by screening, is labeled asymptomatic or incidental.[67][68] An initial episode of DVT is called incident and any subsequent DVT is termed recurrent.[69][70] Bilateral DVT refers to clots in both legs while unilateral means that only a single leg is affected.[71]

DVT in the legs is proximal when above the knee and distal (or calf) when below the knee.[72][73] DVT below the popliteal vein, a proximal vein behind the knee, is classified as distal[64] and has limited clinical significance compared to proximal DVT.[74] Iliofemoral DVT has been described as involving either the iliac or common femoral vein;[75] elsewhere, it has been defined as involving at a minimum the common iliac vein, which is near the top of the pelvis.[18] Upper extremity DVT occurs in the arms or the base of the neck. A rare and massive DVT that causes significant obstruction is phlegmasia cerulea dolens, so named because of observed cases with a blue or purplish discoloration.[76][77][lower-alpha 6] It is a particularly severe form of acute, proximal, and occlusive DVT. It is life-threatening, limb-threatening, and carries a risk of venous gangrene.[78] It can occur in the arm but more commonly affects the leg.[65][79]

DVT often develops in the calf veins and "grows" in the direction of venous flow, towards the heart.[80] When DVT does not grow, it can be cleared naturally and dissolved into the blood (fibrinolysis).[81] Veins in the leg or pelvis are most commonly affected,[8] including the popliteal vein (behind the knee), femoral vein (of the thigh), and iliac veins of the pelvis. Extensive lower-extremity DVT can even reach into the inferior vena cava (in the abdomen).[82] Upper extremity DVT most commonly affects the subclavian, axillary, and jugular veins.[11]

Upper extremity DVTs can occur in the subclavian, axillary, brachial, ulnar, and radial veins (pictured) and the jugular and brachiocephalic veins (not pictured). The cephalic and basilic veins, however, are superficial veins.[11]

The causes of arterial thrombosis, such as with heart attacks, are more clearly understood than those of venous thrombosis.[83] With arterial thrombosis, blood vessel wall damage is required, as it initiates coagulation,[83] but clotting in the veins mostly occurs without any such damage.[28] The beginning of venous thrombosis is thought to be caused by tissue factor, which leads to conversion of prothrombin to thrombin, followed by fibrin deposition.[37] Red blood cells and fibrin are the main components of venous thrombi,[28] and the fibrin appears to attach to the blood vessel wall lining (endothelium), a surface that normally acts to prevent clotting.[83] Platelets and white blood cells are also components. Platelets are not as prominent in venous clots as they are in arterial ones, but they can play a role.[24] Inflammation is associated with VTE,[lower-alpha 7] and white blood cells play a role in the formation and resolution of venous clots.[81]

D-dimer production

Often, DVT begins in the valves of veins.[81] The blood flow pattern in the valves can cause low oxygen concentrations in the blood (hypoxemia) of a valve sinus. Hypoxemia, which is worsened by venous stasis, activates pathways—ones that include hypoxia-inducible factor-1 and early-growth-response protein 1. Hypoxemia also results in the production of reactive oxygen species, which can activate these pathways, as well as nuclear factor-κB, which regulates hypoxia-inducible factor-1 transcription.[37] Hypoxia-inducible factor-1 and early-growth-response protein 1 contribute to monocyte association with endothelial proteins, such as P-selectin, prompting monocytes to release tissue factor-filled microvesicles, which presumably begin clotting after binding to the endothelial surface.[37]

D-dimers are a fibrin degradation product, a natural byproduct of fibrinolysis that is typically found in the blood. An elevated level[lower-alpha 8] can result from plasmin dissolving a clot—or other conditions.[84] Hospitalized patients often have elevated levels for multiple reasons.[21] Anticoagulation, the standard treatment for DVT, prevents further clot growth and PE, but does not act directly on existing clots.[85]

Swelling in the leg from fluid (edema) can result in "pitting" after pressure is applied

A clinical probability assessment using the Wells score (see dedicated column in the table below) to determine if a potential DVT is "likely" or "unlikely" is typically the first step of the diagnostic process. The score is used in suspected first lower extremity DVT (without any PE symptoms) in primary care and outpatient settings, including the emergency department.[1][5] The numerical result (possible score −2 to 9) is most commonly grouped into either "unlikely" or "likely" categories.[1][5] A Wells score of two or more means DVT is considered "likely" (about a 28% chance), while those with a lower score are considered "unlikely" to have DVT (about a 6% chance).[21] In those unlikely to have DVT, a diagnosis is excluded by a negative D-dimer blood test.[1] In people with likely DVT, ultrasound is the standard imaging used to confirm or exclude a diagnosis.[5] Imaging is also needed for hospital inpatients with suspected DVT and those initially categorized as unlikely to have DVT but who have a positive D-dimer test.[1]

While the Wells score is the predominant and most studied clinical prediction rule for DVT,[21][86] it does have drawbacks. The Wells score requires a subjective assessment regarding the likelihood of an alternate diagnosis and performs less well in the elderly and those with a prior DVT. The Dutch Primary Care Rule has also been validated for use. It contains only objective criteria but requires obtaining a D-dimer value.[87] With this prediction rule, three points or less means a person is at low risk for DVT. A result of four or more points indicates an ultrasound is needed.[87] Instead of using a prediction rule, experienced physicians can make a pre-test DVT probability assessment using clinical assessment and gestalt, but prediction rules are more reliable.[1]

Compression ultrasonography for suspected deep vein thrombosis is the standard diagnostic method, and it is highly sensitive for detecting an initial DVT.[13] A compression ultrasound is considered positive when the vein walls of normally compressible veins do not collapse under gentle pressure.[21] Clot visualization is sometimes possible, but is not required.[88] Three compression ultrasound scanning techniques can be used, with two of the three methods requiring a second ultrasound some days later to rule out the diagnosis.[13] Whole-leg ultrasound is the option that does not require a repeat ultrasound,[13] but proximal compression ultrasound is frequently used because distal DVT is only rarely clinically significant.[9] Ultrasound methods including duplex and color flow Doppler can be used to further characterize the clot[9] and Doppler ultrasound is especially helpful in the non-compressible iliac veins.[88]

CT scan venography, MRI venography, or a non-contrast MRI are also diagnostic possibilities.[89] The gold standard for judging imaging methods is contrast venography, which involves injecting a peripheral vein of the affected limb with a contrast agent and taking X-rays, to reveal whether the venous supply has been obstructed. Because of its cost, invasiveness, availability, and other limitations, this test is rarely performed.[21]

• 
  An ultrasound with a blood clot visible in the left common femoral vein. (The common femoral vein is distal to the external iliac vein.)
• 
  Doppler ultrasonography showing absence of flow and hyperechogenic content in a clotted femoral vein (labeled subsartorial[lower-alpha 10]) distal to the branching point of the deep femoral vein. When compared to this clot, clots that instead obstruct the common femoral vein cause more severe effects due to impacting a significantly larger portion of the leg.[91]
• 
  An abdominal CT scan demonstrating an iliofemoral DVT, with the clot in the right common iliac vein of the pelvis

Treatment for DVT is warranted when the clots are either proximal, distal and symptomatic, or upper extremity and symptomatic.[2] Providing anticoagulation, or blood-thinning medicine, is the typical treatment after patients are checked to make sure they are not subject to bleeding.[2][lower-alpha 11] However, treatment varies depending upon the location of DVT. For example, in cases of isolated distal DVT, ultrasound surveillance (a second ultrasound after 2 weeks to check for proximal clots), might be used instead of anticoagulation.[5][93] Although, those with isolated distal DVT at a high-risk of VTE recurrence are typically anticoagulated as if they had proximal DVT. Those at a low-risk for recurrence might receive a four to six week course of anticoagulation, lower doses, or no anticoagulation at all.[5] In contrast, those with proximal DVT should receive at least 3 months of anticoagulation.[5]

Some anticoagulants can be taken by mouth, and these oral medicines include warfarin (a vitamin K antagonist), rivaroxaban (a factor Xa inhibitor), apixaban (a factor Xa inhibitor), dabigatran (a direct thrombin inhibitor), and edoxaban (a factor Xa inhibitor).[2] Other anticoagulants cannot be taken by mouth. These parenteral (non-oral) medicines include low-molecular-weight heparin, fondaparinux, and unfractionated heparin. Some oral medicines are sufficient when taken alone, while others require the use of an additional parenteral blood thinner. Rivaroxaban and apixaban are the typical first-line medicines, and they are sufficient when taken orally.[18] Rivaroxaban is taken once daily, and apixaban is taken twice daily.[5] Warfarin, dabigatran, and edoxaban require the use of a parenteral anticoagulant to initiate oral anticoagulant therapy.[18][94] When warfarin is initiated for VTE treatment, a 5-day minimum of a parenteral anticoagulant[lower-alpha 12] together with warfarin is given, which is followed by warfarin only therapy.[16][17] Warfarin is taken to maintain an international normalized ratio (INR) of 2.0–3.0, with 2.5 as the target.[96] The benefit of taking warfarin declines as the duration of treatment extends,[97] and the risk of bleeding increases with age.[98] Periodic INR monitoring is not necessary when first-line direct oral anticoagulants are used. Overall, anticoagulation therapy is complex and many circumstances can affect how these therapies are managed.[99]

Structural representations of the backbone of heparins (left), which vary in the size of their chain, and the synthetic pentasaccaride (five-sugar) fondaparinux (right)

The duration of anticoagulation therapy (whether it will last 4 to 6 weeks,[5] 6 to 12 weeks, 3 to 6 months,[18] or indefinitely) is a key factor in clinical decision making.[100] When proximal DVT is provoked by surgery or trauma a 3-month course of anticoagulation is standard.[18] When a first VTE is proximal DVT that is either unprovoked or associated with transient non-surgical risk factor, low-dose anticoagulation beyond 3 to 6 months might be used.[18] In those with an annual risk of VTE in excess of 9%, as after an unprovoked episode, extended anticoagulation is a possibility.[101] Those who finish warfarin treatment after idiopathic VTE with an elevated D-dimer level show an increased risk of recurrent VTE (about 9% vs about 4% for normal results), and this result might be used in clinical decision making.[102] Thrombophilia test results rarely play a role in the length of treatment.[49]

Treatment for acute leg DVT can continue at home instead of one being hospitalized. This applies as long as individuals feel ready for it, and those with severe leg symptoms or comorbidities would not qualify. An appropriate home environment is expected: one that can provide a quick return to the hospital if necessary, support from family or friends, and phone access.[103] Walking is suggested for those without severe pain or edema.[104] Graduated compression stockings—which apply higher pressure at the ankles and a lower pressure around the knees[95] can be trialed for symptomatic management of acute DVT symptoms, but they are not recommended for reducing the risk of post-thrombotic syndrome,[94] as the potential benefit of using them for this goal "may be uncertain".[5] Nor are compression stockings likely to reduce VTE recurrence.[105] They are, however, recommended in those with isolated distal DVT.[5]

Interventions

Thrombolysis is the injection of an enzyme into the veins to dissolve blood clots, and while this treatment has been proven effective against the life-threatening emergency clots of stroke and heart attacks, randomized controlled trials[107][108][109] have not established a net benefit in those with acute proximal DVT.[5][110] Drawbacks of catheter-directed thrombolysis (the preferred method of administering the clot-busting enzyme[5]) include a risk of bleeding, complexity,[lower-alpha 13] and the cost of the procedure.[94] Thus, anticoagulation is the preferred treatment for DVT.[94] However, this preference does not apply to those with DVT so severe that there is "impending venous gangrene".[94] As of 2016, those thought to be the best candidates for catheter-directed thrombosis have iliofemoral DVT, symptoms for less than 14 days, good functional status (ability to perform one's activities of daily living), life expectancy of at least 1 year, and a low risk of bleeding.[111][94] Of note, however, is that a variety of contraindications to thrombolysis exist.[94] Catheter-directed thrombolysis against iliofemoral DVT has been associated with a reduction in the severity of post-thrombotic syndrome at an estimated cost-effectiveness ratio of about $138,000[lower-alpha 14] per gained QALY.[112][113] Phlegmasia cerulea dolens (bottom left image) might be treated with catheter-directed thrombolysis.[18] If found in the setting of acute compartment syndrome, an urgent fasciotomy is warranted.[114]

• 
  A case of phlegmasia cerulea dolens in the left leg
• 
  A venogram before catheter-directed thrombolysis against Paget–Schroetter syndrome, a rare and severe arm DVT shown here in a judo practitioner, with highly restricted blood flow shown in the vein
• 
  After treatment with catheter-directed thrombolysis, blood flow in the axillary and subclavian vein were significantly improved. Afterwards, a first rib resection provided thoracic outlet decompression to reduce the risk of recurrent DVT and the risk of sequelae from thoracic outlet compression.[115]

An IVC filter

The placement of an inferior vena cava filter (IVC filter) is a potential treatment option when either the standard treatment for acute DVT, anticoagulation, is absolutely contraindicated (not possible), or if someone develops a PE despite being anticoagulated.[106] However, a 2020 NICE review found "little good evidence" for their use.[106] A 2018 study associated IVC filter placement with a 50% reduction in PE, a 70% increase in DVT, and an 18% increase in 30 day mortality when compared to no IVC placement.[1][116] As such, if someone develops a PE despite being anticoagulated, care should be given to optimize anticoagulation treatment and address other related concerns before considering the placement of a IVC filter.[106]

A mechanical thrombectomy device can remove venous clots, although the ACCP considers it an option only when the following conditions apply: "iliofemoral DVT, symptoms for < 7 days (criterion used in the single randomized trial), good functional status, life expectancy of ≥ 1 year, and both resources and expertise are available."[95] Anticoagulation alone is suggested over thrombectomy.[117]

For the prevention of blood clots in the general population, incorporating leg exercises and walking when sitting for hours at a time, having an active lifestyle, and maintaining a healthy body weight are recommended.[6] Walking increases blood flow through the leg veins.[118] Excess body weight is modifiable unlike most risk factors, and interventions or lifestyle modifications that help someone who is overweight or obese lose weight reduce DVT risk.[39] Statins have been investigated for primary prevention, and the JUPITER trial, which used rosuvastatin, has provided some tentative evidence of effectiveness.[10][119] Out of all the statins that have been studied, rosuvastatin appears to be the only one with the potential to reduce VTE risk.[120] However, the number needed to treat to prevent one initial VTE is about 2000, limiting its applicability.[121]

Hospital (non-surgical) patients

Low-molecular-weight heparin is usually given by subcutaneous injections with a needle under the skin of these colored areas

Acutely ill hospitalized patients are suggested to receive a parenteral anticoagulant, although the potential net benefit is uncertain.[29] Critically ill hospitalized patients are recommended to either receive unfractionated heparin or low-molecular weight heparin instead of foregoing these medicines.[29]

After surgery

The incision for a completed knee replacement surgery, a procedure that can precipitate DVT formation

Major orthopedic surgery—total hip replacement, total knee replacement, or hip fracture surgery—has a high risk of causing VTE.[125] If prophylaxis is not used after these surgeries, symptomatic VTE has about a 4% chance of developing within 35 days.[126] Following major orthopedic surgery, a blood thinner or aspirin is typically paired with intermittent pneumatic compression, which is the preferred mechanical prophylaxis over graduated compression stockings.[7]

Options for VTE prevention in people following non-orthopedic surgery include early walking, mechanical prophylaxis, and blood thinners (low-molecular-weight heparin and low-dose-unfractionated heparin) depending upon the risk of VTE, risk of major bleeding, and person's preferences.[127] After low-risk surgeries, early and frequent walking is the best preventive measure.[7]

Travelers

An example of a compression stocking

Suggestions for at-risk long-haul travelers[lower-alpha 15] include calf exercises, frequent walking, and aisle seating in airplanes to ease walking.[133][134] Graduated compression stockings have sharply reduced the levels of asymptomatic DVT in airline passengers, but the effect on symptomatic DVT, PE, or mortality is unknown, as none of the individuals studied developed these outcomes.[135] However, graduated compression stockings are not suggested for long-haul travelers (>4 hours) without risk factors for VTE. Likewise, neither aspirin nor anticoagulants are suggested in the general population undertaking long-haul travel.[29] Those with significant VTE risk factors[lower-alpha 16] undertaking long-haul travel are suggested to use either graduated compression stockings or LMWH for VTE prevention. If neither of these two methods are feasible, then aspirin is suggested.[29]

DVT is most frequently a disease of older age that occurs in the context of nursing homes, hospitals, and active cancer.[3] It is associated with a 30-day mortality rate of about 6%, with PE being the cause of most of these deaths.[1] Proximal DVT is frequently associated with PE, unlike distal DVT, which is rarely if ever associated with PE.[21] Around 56% of those with proximal DVT also have PE, although a chest CT is not needed simply because of the presence of DVT.[1] If proximal DVT is left untreated, in the following 3 months approximately half of people will experience symptomatic PE.[8]

Another frequent complication of proximal DVT, and the most frequent chronic complication, is post-thrombotic syndrome, where individuals have chronic venous symptoms.[5] Symptoms can include pain, itching, swelling, paresthesia, a sensation of heaviness, and in severe cases, leg ulcers.[5] After proximal DVT, an estimated 20–50% of people develop the syndrome, with 5–10% experiencing severe symptoms.[136] Post-thrombotic syndrome can also be a complication of distal DVT, though to a lesser extent than with proximal DVT.[137]

Recurrence of DVT is another potential consequence. In the 10 years following an initial VTE, about 30% of people will have a recurrence.[138][3] VTE recurrence in those with prior DVT is more likely to recur as DVT than PE.[139] Cancer[5] and unprovoked DVT are strong risk factors for recurrence.[27] After initial proximal unprovoked DVT with and without PE, 16–17% of people will have recurrent VTE in the 2 years after they complete their course of anticoagulants. VTE recurrence is less common in distal DVT than proximal DVT.[140] In upper extremity DVT, annual VTE recurrence is about 2–4%.[98] After surgery, a provoked proximal DVT or PE has an annual recurrence rate of only 0.7%.[27]

About 1.5 out of 1000 adults a year have a first VTE in high-income countries,[141][142] and about 5–11% of people will develop VTE in their lifetime.[12][13] VTE becomes much more common with age.[12] VTE rarely occurs in children, but when it does, it predominantly affects hospitalized children.[143] Children in North America and the Netherlands have VTE rates that range from 0.07 to 0.49 out of 10,000 children annually.[143] Meanwhile, almost 1% of those aged 85 and above experience VTE each year.[3] About 60% of all VTEs occur in those 70 years of age or older,[8] and those aged 65 and above are subject to about a 15 times higher risk than those aged 40 and below.[14] Incidence is about 18% higher in males than in females.[4] VTE occurs in association with hospitalization or nursing home residence about 60% of the time, active cancer about 20% of the time, and a central venous catheter or transvenous pacemaker about 9% of the time.[3]

During pregnancy and after childbirth, acute VTE occurs about 1.2 of 1000 deliveries. Despite it being relatively rare, it is a leading cause of maternal morbidity and mortality.[144] After surgery with preventive treatment, VTE develops in about 10 of 1000 people after total or partial knee replacement, and in about 5 of 1000 after total or partial hip replacement.[145] About 400,000 Americans develop an initial VTE each year, with 100,000 deaths or more attributable to PE.[142] In England, an estimated 25,000 a year die from hospital-related VTE.[146] Asian and Hispanic individuals have a lower VTE risk than whites or Blacks.[4]

In North American and European populations, around 4–8% of people have a thrombophilia,[40] most commonly factor V leiden and prothrombin G20210A. For populations in China, Japan, and Thailand, deficiences in protein S, protein C, and antithrombin predominate.[147] Non-O blood type is present in around 50% of the general population and varies with ethnicity, and it is present in about 70% of those with VTE.[41][148] Altogether, global data is incomplete,[149] and as of 2011, available data was dominated by North American and European populations.[15]

DVT occurs in the upper extremities in about 4–10% of cases,[11] with an incidence of 0.4–1.0 people out of 10,000 a year.[5] A minority of upper extremity DVTs are due to Paget–Schroetter syndrome, also called effort thrombosis, which occurs in 1–2 people out of 100,000 a year, usually in athletic males around 30 years of age or in those who do significant amounts of overhead manual labor.[34][115]

Serena Williams has spoken at length about a frightening encounter she had with VTE while she was hospitalized in 2017.[150]

Being on blood thinners because of DVT can be life-changing because it may prevent lifestyle activities such as contact or winter sports to prevent bleeding after potential injuries.[151] Head injuries prompting brain bleeds are of particular concern. This has caused NASCAR driver Brian Vickers to forego participation in races. Professional basketball players including NBA players Chris Bosh and hall of famer Hakeem Olajuwon have dealt with recurrent blood clots,[152] and Bosh's career was significantly hampered by DVT and PE.[153]

Tennis star Serena Williams was hospitalized in 2011 for PE thought to have originated from DVT.[154] Years later, in 2017, due to her knowledge of DVT and PE, Serena accurately advocated for herself to have a PE diagnosed and treated. During this encounter with VTE, she was hospitalized after a C-section surgery and was off of blood thinners. After feeling the sudden onset of a PE symptom, shortness of breath, she told her nurse and requested a CT scan and an IV heparin drip, all while gasping for air. She started to receive an ultrasound to look for DVT in the legs, prompting her to express dissatisfaction to the medical staff that they were not looking for clots where she had symptoms (her lungs), and they were not yet treating her presumed PE. After being diagnosed with PE and not DVT, and after receiving heparin by IV, the coughing from the PE caused her C-section surgical site to open and the heparin contributed to bleeding at the site. Serena later received an IVC filter while in the hospital.[150]

Other notable people have been affected by DVT. Former US President Richard Nixon had recurrent DVT,[155] and so has former Secretary of State Hillary Clinton. She was first diagnosed while First Lady in 1998 and again in 2009.[156] Dick Cheney was diagnosed with an episode while Vice President,[157] and TV show host Regis Philbin had DVT after hip-replacement surgery.[158] DVT has also contributed to the deaths of famous people. For example, DVT and PE played a role in rapper Heavy D's death at age 44.[159] NBC journalist David Bloom died at age 39 while covering the Iraq War from a PE that was thought to have progressed from a missed DVT.[160] And actor Jimmy Stewart had DVT that progressed to a PE and triggered a fatal heart attack when he was 89.[158][161]

History

Rudolf Virchow

Warfarin, a common vitamin K antagonist, was the mainstay of pharmocological treatment for about 50 years.

The book Sushruta Samhita, an Ayurvedic text published around 600–900 BC, contains what has been cited as the first description of DVT.[165] In 1271, DVT symptoms in the leg of a 20-year-old male were described in a French manuscript, which has been cited as the first case or the first Western reference to DVT.[165][166]

In 1856, German physician and pathologist Rudolf Virchow published his analysis after the insertion of foreign bodies into the jugular veins of dogs, which migrated to the pulmonary arteries. These foreign bodies caused pulmonary emboli, and Virchow was focused on explaining their consequences.[167] He cited three factors, which are now understood as hypercoaguability, stasis, and endothelial injury.[168] It was not until 1950 that this framework was cited as Virchow's triad,[167] but the teaching of Virchow's triad has continued in light of its utility as a theoretical framework and as a recognition of the significant progress Virchow made in expanding the understanding of VTE.[167][168]

Methods to observe DVT by ultrasound were established in the 1960s.[89] Diagnoses were commonly performed by impedance plethysmography in the 1970s and 1980s,[169] but ultrasound, particularly after utility of probe compression was demonstrated in 1986, became the preferred diagnostic method.[165] Yet, in the mid 1990s, contrast venography and impedance plethysmography were still described as common.[170]

Multiple pharmacological therapies for DVT were introduced in the 20th century: oral anticoagulants in the 1940s, subcutaneous injections of LDUH in 1962 and subcutaneous injections of LMWH in 1982.[171] For around 50 years, a months-long warfarin (Coumadin) regimen was the mainstay of pharmacological treatment.[172][173] To avoid the blood monitoring required with warfarin and the injections required by heparin and heparin-like medicines, a new generation of oral anticoagulant pills that do not require blood monitoring has sought to replace these traditional anticoagulants.[173] In the late 2000s to early 2010s, direct oral anticoagulants—including rivaroxaban (Xarelto), apixaban (Eliquis), and dabigatran (Pradaxa)—came to the market, making this field of medicine fast changing.[27] The New York Times described a "furious battle" among the three makers of these drugs "for the prescription pads of doctors".[172]

A 2019 study published in Nature Genetics reported more than doubling the known genetic loci associated with VTE.[10] In their updated 2018 clinical practice guidelines, the American Society of Hematology identified 29 separate research priorities, most of which related to patients who are acutely or critically ill.[29] Inhibition of Factor XI, P-selectin, E-selectin, and a reduction in formation of neutrophil extracellular traps are potential therapies that might treat VTE without increasing bleeding risk.[179]

• Disseminated intravascular coagulation
• Superficial vein thrombosis
• Thrombotic microangiopathy
• HELLP syndrome
• Deaths from thrombosis

Cited literature

• Clinical prediction website – Wells score for deep vein thrombosis