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Blood clotting functions primarily to repair and prevent bleeding from an injured vessel. However, because of the triad of inflammation, hypercoagulability, and endothelial injury, clots can form within blood vessels.1,2 Venous thrombosis accounts for more than 600,000 hospitalizations annually.1,2 If left untreated, venous thrombosis in large vessels can lead to pulmonary embolism, so that it a significant cause of morbidity and mortality.2 Although the pathophysiology of blood clotting is well understood, the treatment has varied greatly over time. In the early days, vessel ligation was a common practice, although swelling and pain in the affected extremity were frequent complications. Later, immobilization of the extremity was the standard of care, although it left the patient immobile, further increasing the risk for clot formation.3 It was many years later that anticoagulation therapy evolved as the standard of care for patients with blood clots and deep vein thrombosis (DVT). Anticoagulation was initially accomplished by administering heparin along with warfarin, a vitamin K–dependent anticoagulant.3 Although heparin and warfarin were and still are a good option for anticoagulation, ongoing monitoring of the patient’s prothrombin time (PT) and international normalized ratio (INR) is required to identify and maintain the appropriate dosage.

Within the last few years, medications belonging to another class, the new oral anticoagulants (NOACs), have emerged as safe alternatives to warfarin and do not entail the requirement for intermittent measurement of the PT and INR. It is essential that physician assistants understand the pathophysiology of clot formation and DVT, recognize the signs and symptoms of DVT in clinical practice, and be knowledgeable about the new anticoagulants and evidence-based treatments for DVT.

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History of the study of coagulation

The study of coagulation can be traced as far back as Hippocrates, the father of medicine. It was around 400 BC that he observed the blood of a wounded soldier “congealing” as it cooled.4,5 At about the same time, it was noted that placing skin over a bleeding wound halted further bleeding.4 Later, Aristotle noted that blood removed from the body “decayed,” resulting in clotting, which was thought to be due to cooling.4,5 In the 1600s, Mercurialis observed clots forming in blood vessels at normal body temperature.4,5 It was not until the early 1900s that Paul Marowitz organized coagulation factors into a scheme, or coagulation pathway, hypothesizing that multiple clotting factors act together to form a fibrin plug.4 Over the next 100 years, additional proteins involved in the coagulation process were discovered. These proteins all play an integral role in clotting and fibrinolysis.4 Coagulation is a vital process that prevents excessive bleeding when a blood vessel is injured. Multiple coagulation factors, together with platelets, function together to form a clot, preventing further bleeding. Although clotting is essential to prevent bleeding, clots can form within the lining of a vein with or without obvious injuries.1,2,4-6

The first documented case of DVT 

The first well-documented case of DVT was reported during the middle ages.3 In 1271, unilateral swelling and edema developed in the leg and ankle of Raoul, a 20-year-old Norman cobbler.3 When a leg ulcer subsequently formed, Raoul was advised to visit the tomb of King Louis IX of France to seek his healing power. (King Louis had died in 1270 and was canonized in 1297 as a Roman Catholic saint.) There, Raoul rubbed dust from the stone covering the king’s tomb into the wound. Miraculously, the wound healed, and Raoul lived for 11 more years; his recovery was thought to be a result of applying the dust.3 After this report, the identification and documentation of cases of DVT began to increase. They were primarily noted in pregnant and postpartum women.3 The clots were believed to be a consequence of the retention of “evil humors” during pregnancy.2,3 It was also thought that postpartum DVT was due to the presence of unconsumed breast milk within the legs.3 In the 17th century, the humoral theory was gradually abandoned, and in 1676, Wiseman hypothesized that blood clots were due to abnormalities within the blood.3 Later, in 1793, Hunter proposed that DVT was a venous occlusion caused by clots.3 After his discovery, Hunter performed many venous ligations above the thrombosis, thus preventing fatal pulmonary thromboembolism (PTE).3 Although vena cava ligation was controversial, this technique became more widely used at the end of the 19th century.3 The ligation could be placed at the level of the femoral vein, common iliac vein, or inferior vena cava.3 Along with ligation, the mainstay of DVT treatment was strict bed rest.3 This was often prescribed because of fear of migration of the thrombus. The patient’s limbs were often splinted to preclude clot movement. Other treatments for DVT included bloodletting, the administration of anti-inflammatory agents, the application of warm compresses, and elevation of the extremity to promote venous return.3

Pathophysiology of DVT and blood clot formation

As the diagnosis of blood clots became more common, clinicians began to realize that DVT formation was actually a complex process involving the interaction of multiple genetic and environmental factors.1-3,6,7 In the 1930s, a consensus was reached that three factors contribute to thrombosis: venous stasis, vessel wall damage, and hypercoagulability.1-3,6,7 These factors comprise the Virchow triad: hypercoagulability, hemodynamic change, and endothelial injury. Multiple other risk factors are known to increase the incidence of DVT (Table 1)6-9; however, it should be noted that many times DVT develop with no known cause.1,2

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Signs and symptoms of DVT

The presentation of DVT can vary but typically consists of pain and swelling in a lower extremity.1,2,6-9 This is often described as a feeling of fullness or dullness that worsens with walking.1,2,7,9

In many cases, mild redness and tenderness of the calf on palpation may be noted, which are due to thrombophlebitis caused by the clot. DVT may also be associated with pain in the calf elicited by passive dorsiflexion of the foot (the Homans sign).1,7,9 However, the sensitivity and specificity of this test are low.1,2 Often, the diameter of each tibia tubercle is measured and the two measurements are compared. A difference of 2 cm or more at 10 cm below the tibia tubercle increases the likelihood of DVT by a factor of 2.1,2 A proximal DVT can lead to complete venous obstruction and increased compartmental pressures.1 Typically, the presentation consists of a swollen, painful limb, which can be dusky or blue in color. A proximal DVT in a pale or white painful limb is known as phlegmasia alba dolens, and a proximal DVT in a dusky or blue limb is known as phlegmasia cerulea dolens.1,2 Either can cause limb loss and warrants aggressive therapy, including thrombolysis or catheter-guided thrombectomy.1

Which of the following tests do you most frequently recommend when you suspect a patient may have DVT?

In clinical practice, pretest scoring systems may be used to assist clinicians in diagnosing DVT. One scoring system in frequent use, the Wells criteria, looks at multiple risk factors and assigns a risk score accordingly.1,7,8 The calculation is then used before testing to determine the probability of DVT. The score should be used to guide subsequent diagnostic testing and workup. Because many patients may fall into the moderate- or intermediate-risk category, clinical judgment continues to be an important factor in diagnosing DVT.8-10

Diagnostic studies

A physical examination is of little help in diagnosing DVT, nor should it be used to rule out DVT. Contrast venography remains the gold standard in diagnosing DVT; however, it has been largely replaced by ultrasonography in most institutions.1,2,7-10 Contrast venography has a sensitivity and specificity of nearly 100% and can detect DVT in the calf, iliac vessels, and inferior vena cava that ultrasonography may miss.2 Ultrasonography is the most accurate noninvasive tool for diagnosing DVT of the lower extremity, with a sensitivity of 93% to 100% and a specificity of 97% to 100% in detecting proximal DVT.1,2,8-10 However, it should be noted that ultrasonography has several limitations. It is somewhat limited in the detection of calf and pelvic DVT, and its accuracy can be subjective and depend on the skill of the operator. Another drawback is that it cannot differentiate between an old and a new clot.10

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A D-dimer test is often ordered as well to check for breakdown products resulting from fibrin degradation by plasmin.10 Several laboratory techniques are used to check the D-dimer level; however, the enzyme-linked immunoassay (ELISA) is the most accurate. The quality of the blood specimen affects the D-dimer assay. Lipemia and hemolysis can interfere with a photo-optical assay. Hemolysis also implies the ex vivo activation of platelets and coagulation factors, rendering laboratory results invalid. The combination of ELISA and ultrasonography has a negative predictive value for DVT of nearly 100%.1,2 In a recent study, patients with a Wells score of less than 2 and a negative D-dimer test were less likely than those with a negative ultrasonography examination to have DVT on follow-up.7,8-10