Deep Vein Thrombosis: Definition, Anatomy, and Pathophysiology

Deep vein thrombosis (DVT) develops when a blood clot (thrombus) forms in a deep vein.1 Most DVT occurs in the legs, but it can also appear in the arms, as well as the mesenteric and pelvic veins.2 Lower extremity DVT is classified as either proximal or distal.3 Proximal DVT arises in the iliac, deep femoral, or popliteal veins, whereas distal occurs in the veins of the calf, most frequently in the posterior tibial and peroneal veins, and less frequently in the anterior tibial and muscular veins.3,4 Notably, the risk of subsequent embolization in proximal DVT is double that of isolated distal DVT.3 Hence, proximal DVT has a less favorable prognosis.5 Regardless of the vein in which it forms, DVT tends to originate on the venous endothelium in regions of sluggish blood flow above and below venous valves.2,5

The pathophysiology of DVT has been attributed to 3 principle risk factors: a change in blood flow in the form of venous stasis, endothelial injury, and blood hypercoagulability – known collectively as Virchow’s triad.6 Stasis sufficient to precipitate DVT can result from prolonged immobility, due to – for example – a long plane trip or train ride, or secondary to a paralytic neurological injury.7 The significant role that venous stasis plays in the etiology of DVT is most clearly demonstrated by the finding that stroke patients with hemiparesis have a sevenfold greater risk of developing DVT in their paralyzed leg relative to their non-paralyzed leg.6 Relevant causes of endothelial injury include trauma, recent surgery, and intravenous drug use.7 Hypercoagulability can stem from inflammatory conditions such as systemic lupus erythematosus or inflammatory bowel disease, cancer, sepsis, previous thromboembolic disease, the nephrotic syndrome, or inherited or acquired thrombophilias .7-10 Additional risk factors that do not fit neatly into Virchow’s triad include pregnancy, oral contraceptive use, cardiac disease, age greater than 60 years, cytotoxic chemotherapy, and obesity.7,9 Some risk factors are more consequential than others. For instance, paralytic neurological injury is significantly more dangerous than prolonged immobility.9 Many DVT patients have multiple simultaneous risk factors. In one DVT patient cohort, 76 percent of subjects had 2 or more risk factors, and 39 percent had 3 or more.9 Moreover, these factors tend to be additive.7,9 Beyond those cases in which at least 1 risk factor is clearly present, some DVT is idiopathic.5

Venous thrombi are made of a fibrin-bound aggregate of red blood cells, white blood cells, and platelets.2 They form when tissue factor is exposed, thrombin is created, and firbrinogen is transformed into fibrin.8 Once the clots have formed, they often resolve – as least to some degree – on their own. Among one group of DVT patients, 86 percent showed some degree of venous reopening (recanalization) within 3 months of the initial clotting event.5 The smaller the size of the thrombi, the more quickly and completely recanalization occurs.5 However, recanalization is not always the positive development one might suppose, since it is when clots begin to migrate away from the veins and back toward the heart that some of the most significant DVT sequelae can arise. When they embolize, clots can find their way into the pulmonary circulation, where they can cause a pulmonary embolism (PE). They also have the potential to enter the arterial circulation by way of an atrial septal defect, or a patent foramen ovale.8

The Complications of DVT

Some of the most important sequelae of DVT include PE, the post-thrombotic syndrome (PTS), the formation of subsequent DVT, and death. PE is defined as the blockage of an artery in the lungs.2,11 PE can lead to alveolar hyperventilation, diminished gas exchange, decreased pulmonary compliance, and increased airway resistance.2,8 This cascading chain of physiological derangements can eventually cause right heart failure, ultimately leading to death in some cases.8 In PTS, incomplete recanalization after a DVT clot causes venous obstruction, which in turn results in venous hypertension. In response to this hypertension, capillaries dilate and become more permeable, which can cause localized edema, leg pain, eczema, and venous ulceration.12 One additional complication of DVT is a phenomenon called phlegmasia cerulea dolens (blue, painful leg) in which a large-sized DVT totally blocks venous blood flow away from the leg, yielding limb discoloration and ischemia, venous gangrene, and systemic hypovolemic shock.13,14

DVT results in PE in 15 to 32 percent of cases, and PTS in 56 percent of cases.15 Because it is so common for DVT and PE to co-occur, they are sometimes considered to be part of a single disease entity: venous thromboembolism.2 In addition, DVT has a recurrence rate – from time of initial diagnosis – of 10 percent at 1 year, 24 percent at 5 years, and 30 percent at 8 years.5,15 The case fatality rate among hospitalized patients with DVT is 5 percent, and 5-year mortality can be as high as 39 percent.5 Despite this, it is nonetheless important to bear in mind that in at least some cases, DVT does not result in any pathology whatsoever.16

The Medical and Economic Impact of DVT

In both human and economic terms, DVT and subsequent VTE exact substantial costs. In 2016, the worldwide incidence rate of VTE was 115 to 269 per 100 000, with a corresponding worldwide mortality rate of 9.4 to 32.3 per 100 000.17 One study found that, in high-income countries in 2014, VTE necessitating hospitalization was the second leading cause of disability-adjusted-life-years lost, which exceeds those lost to adverse drug events and nosocomial pneumonia.18 In Europe, VTE is estimated to kill 370 000 people every year – a total greater than that caused by AIDS, breast cancer, prostate cancer, and automobile accidents combined – and costs the continent roughly $3.7 billion annually.8,9,19 In the United States, there are approximately 2 million annual cases of DVT, which result in about 250 000 hospitalizations and 300 000 deaths – more than those due to myocardial infarction or stroke.5,7,8 Even more Americans are at risk for DVT. Since about one quarter of DVT is acquired in the hospital, close to 14 million hospitalized patients are at risk of acquiring it annually.8 All of this costs between $9 billion and $52 billion a year.20

DVT Treatment and Its Shortcomings

The standard of care after an initial DVT episode consists of long-term treatment for 3 months with anticoagulant medications.3,21,22 For patients who have had a second episode, or who have comorbid cancer, guidelines recommend extended anticoagulation i.e., treatment without a scheduled stopping point.21 Interestingly, although there is widespread consensus that all proximal DVT should be treated with anticoagulation, there is some controversy over whether, and when, it is indicated for isolated distal DVT.3,21-23 This treatment is intended to prevent PE and the formation of subsequent DVT.22,24 Anticoagulation should only be initiated after DVT has been diagnosed, most commonly by compressive ultrasound of the legs.3,5,25,26

Several different anticoagulants are used to treat DVT. Among these are various preparations of heparin – which works by boosting the suppression of factor Xa and thrombin by antithrombin – and vitamin K antagonists (VKAs) such as warfarin.22,25,27 Newer agents called direct oral anticoagulants (DOACs), which inhibit either thrombin or factor Xa, are also available.27 American Heart Association DVT treatment guidelines recommend initial 5 days’ anticoagulation with heparin, as well as concomitant and subsequent administration of a VKA, or a DOAC, for longer term anticoagulation.22,27 The American College of Chest Physicians suggests initiating therapy with a DOAC rather than a VKA, with or without initial anticoagulation, depending on the specific agent used.21

Unfortunately, there are significant limitations associated with the use of these medications. Most importantly, although medical anticoagulation therapy can help prevent new thrombi from forming, it is incapable of dissolving preexisting clots, regardless of which specific medication is employed.5 Hence, the potential for thrombi to propagate remains, and despite anticoagulation therapy, PTS manifests in approximately 50 percent of DVT patients within 2 years.28,29 Limitations specific to VKAs include a narrow therapeutic index, the need for routine coagulation monitoring due to patients’ genetic variability, which can result in pharmacokinetic and pharmacodynamic heterogeneity, and a large number of interactions with foods and other medications.5,27,30 Adverse effects that may also restrict their use include teratogenicity and bleeding, particularly intracranial bleeding.25,27,31 DOACs, in turn, are contraindicated in patients with severe renal failure, and may increase the chance of gastrointestinal bleeding.27 Also, DOACs pose unique therapeutic drug monitoring challenges.27 And whereas VKAs can be reversed with vitamin K and prothrombin complex concentrate, only 1 out of the 4 DOACs currently approved in the United States is reversible.27

Beyond anticoagulants, other DVT treatment modalities are available. Elastic compression stockings – which reduce the frequency of PTS – can sometimes be helpful, and the American College of Chest Physicians advises that they should be used in certain cases.21,32 However, 21.1 percent of patients treated with stockings still go on to develop PTS.32 Another treatment option is thrombolytic therapy, in which thrombolytic medications, such as tissue-type plasminogen activator, are administered intravenously, in the hope of lysing the clot, and thereby diminishing the risk of PE and PTS.33 But difficulties associated with this approach include ensuing complications such as stroke and intracerebral hemorrhage.34 It is also possible to treat DVT via pharmacomechanical thrombolysis (PT), in which thrombolytic medication is applied directly into the clot, while the clot is simultaneously excised through mechanical means.29 Nevertheless, recent evidence has demonstrated that, relative to standard anticoagulation alone, PT does not diminish the risk of PTS, even though it does heighten the chance of major hemorrhage.22

Abbreviations used:

DOAC = direct oral anticoagulant DVT = deep vein thrombosis PE = pulmonary embolism PT = pharmacomechanical thrombolysis PTS = post-thrombotic syndrome VKA = vitamin K antagonist VTE = venous thromboembolism


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