Deep Vein Thrombosis: History and Evolution of Treatment

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.1,2If 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.

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.4Later, 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.3In 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

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

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.2Ultrasonography 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

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

Treatment options for DVT

Heparin

The first anticoagulants can be traced back to the 1800s. In 1884, a scientist named Haycraft extracted a pure anticoagulant, known at the time as hirudin, from the saliva of leeches.1,11Hirudin could not be used as a potent anticoagulant until 1986, when it was produced by genetic engineering.1,3,11 In 1916, a medical student named McLean, while studying the procoagulant activity of crude ether and alcohol extracts of the brain, liver, and heart, noticed the anticoagulant activity of heparphosphatide.1,12 McLean observed that as heparphosphatide was exposed to air, it began to act like an anticoagulant.1,12 After McLean’s discovery, his mentor, Howell, worked further with heparphosphatide and after mixing it with phospholipids named it heparin.12 In 1933, Charles Scott produced the first purified heparin, and it was used in humans in 1935.12,13

The first clinical use of heparin was for chemoprophylaxis in surgical patients. In 1937, Murray and Crafoord published data evaluating surgical patients who received prophylaxis for DVT.14 Despite the lack of randomized, placebo-controlled clinical trials, the effectiveness of heparin was obvious. Therefore, in the 1940s, heparin began to be used to treat and prevent venous thrombosis.14 

Today, heparin and its low-molecular-weight derivatives are still effective medications for the prevention and treatment of DVT and PTE. Heparin is a sulfated polysaccharide that works primarily by inactivating thrombin and activated factor X.15,16 This occurs through an antithrombin-dependent mechanism. The binding of heparin to antithrombin III (ATIII) causes a conformational change that results in the activation of ATIII when the loop at the reactive site becomes more flexible.15 The activated molecule binds to thrombin, factor X, and other proteases involved in clotting, thus inhibiting clot formation.15,16 Optimal amounts of heparin have been known to accelerate these reactions up to 2000-fold.16 Unfractionated heparin may be injected intravenously or subcutaneously and is rapidly effective.

Low-molecular-weight heparins (LMWHs) are manufactured derivatives of unfractionated heparin in which the molecules are much smaller. Less protein and cellular binding result in pharmacokinetics that are much more predictable than those of unfractionated heparin. LMWHs are given subcutaneously and often used in the initial treatment of DVT, as well as in DVT prophylaxis. Peak activity is achieved approximately 4 hours after administration.15,16 LMWHs have mostly anti-Xa activity, so they are generally monitored with an anti-Xa assay. LMWHs are cleared by the kidneys; therefore, monitoring is required in patients with renal disease, obese patients, young children, and pregnant women.15,16 The multiple anticoagulants within this class, which vary in molecular weight, include enoxaparin, parnaparin, dalteparin, and many others.17 See Table 2 for dosing.

 

Vitamin K–dependent anticoagulants, warfarin

The vitamin K–dependent coagulation factors were first discovered in the prairies of North Dakota and Alberta, Canada. Here, at the beginning of the 20th century, cattle were dying in large numbers of “hemorrhagic disease” or “sweet clover disease.”3,18,19 In 1924, a Canadian veterinary pathologist named Schofield discovered that the disease was caused by a moldy type of sweet clover. Although he determined that Aspergillus organisms were the cause of the mold, they were not the cause of the prolonged bleeding times occurring in the cattle.3,18,19 The bleeding issues were easily treated by removing the clover from the diet of the cattle and transfusing the animals with bovine blood.1,18,19 Paul Link and his colleagues later discovered that a nontoxic substance, coumarin, was oxidized to dicoumarol in moldy hay. It was this substance that caused the bleeding in the cattle.18 These investigators also demonstrated that the effects of dicoumarol could be reversed with vitamin K. After 2 years, vitamin K was used to treat DVT.14,20 Later, Link and his colleagues discovered the existence of a more potent analogue of dicoumarol. This chemical analogue, named warfarin, was used later, in 1948, as a pesticide in rodents.3,18,20 In 1950, Link recommended that warfarin be used in clinical medicine.3,18,20 After some hesitation on the part of clinicians about using in humans a substance that was designed to exterminate rats, warfarin began to gain acceptance within the medical community, and in 1954 it was approved by the Food and Drug Administration (FDA) for human use.3 Although the anticoagulant effect of warfarin begins within 24 hours, the peak effect takes 72 to 96 hours. Therefore, unfractionated heparin or LMWH is used in conjunction with warfarin until a therapeutic INR of 2.5 to 3.0 can be achieved. The INR is used to evaluate the extrinsic pathway of coagulation, indicating how fast a patient’s blood clots. Warfarin is known to prolong the PT and INR by inhibiting the synthesis of vitamin K–dependent clotting factors. These include factors II, VII, IX, and X, as well as the anticoagulant proteins C and S.

Warfarin has been used as an anticoagulant for many years. The advantages of warfarin are its relatively low cost and the fact that if needed its effects can be reversed with vitamin K and fresh frozen plasma.21 Its major disadvantages are that continual monitoring is required, certain foods interfere with its anticoagulant effects, and it may cause episodes of either gastrointestinal or intracranial bleeding.21 It should also be noted that many medications interact with warfarin, so that even closer follow-up of the patient’s INR and consult with the pharmacy are required.

For decades, vitamin K antagonists, such as warfarin, have been the mainstay of DVT treatment. NOACs, developed to optimize the management of DVT, have helped to overcome some of the limitations of traditional DVT management.21,22 Over the last 5 years, four NOACs have been approved to treat DVT.21,22 These include direct thrombin inhibitors as well as inhibitors of factor Xa.22 After extensive testing in clinical trials, rivaroxaban, dabigatran, apixaban, and edoxaban have been approved by the FDA for the treatment of DVT or venous thromboembolism (VTE). These medications have the advantage of more predictable effects, so that the need for continual monitoring is eliminated.22 The NOACs also have a shorter half-life than that of warfarin, which is an advantage if anticoagulation must be abruptly stopped.21Although more costly, the new medications have provided a safe form of anticoagulation that requires less monitoring and follow-up in comparison with other anticoagulants.

Direct thrombin inhibitors. Dabigatran (Pradaxa) is a direct, reversible, potent competitive inhibitor of thrombin. Inhibition of thrombin prevents the conversion of fibrinogen to fibrin and thus prevents clot formation.22 The primary route of elimination is via the kidneys, which clear about 85% of the drug. In the treatment of DVT with dabigatran, it is recommended that initially the drug be administered parenterally for 5 to 10 days. Peak activity occurs within 1 to 6 hours, and the drug has a half-life of 12 to 17 hours.21,22 The dose should be adjusted in patients with renal failure, defined as creatinine clearance below 30 mL/min.22 

The disadvantages of dabigatran include a higher cost compared with warfarin, the need for twice-daily dosing, and a slightly increased risk for gastrointestinal bleeding (6.1% with dabigatran vs 4% with warfarin).21,22 Initially, another disadvantage of dabigatran was the lack of a true reversal agent, although in October 2015, idarucizumab (Praxbind) was approved as a reversal agent for dabigatran. Despite the few disadvantages, dabigatran has proved to be a safer anticoagulant than warfarin.22 The RE-LY study evaluated dabigatran relative to warfarin in more than 18,000 patients over a 2-year span. The investigators found a significant reduction in the overall incidence of stroke (relative risk [RR] 0.64%, 95% confidence interval [CI] 0.51-0.81, P <0.001) and intracranial hemorrhage (RR 0.40, 95% CI 0.27-0.60, P < 0.001) when dabigatran was compared with warfarin, showing it to be a safe alternative to warfarin therapy.21,22 Two other large studies, ROCKET-AF (rivaroxaban) and ARISTOTLE (apixaban), compared these medications with warfarin. The studies showed rivaroxaban and apixaban to be superior to warfarin, with similar or lower rates of hemorrhage.23,24

Factor Xa inhibitors. Apixaban (Eliquis), rivaroxaban (Xerelto), and edoxaban (Savaysa) are all direct factor Xa inhibitors. They keep factor Xa from binding to its substrate, prothrombin, thus preventing clot formation. Multiple clearance mechanisms exist for this class of oral anticoagulants. Approximately 30% of the drug is excreted by the kidneys, with the remainder metabolized by the liver. The factor Xa inhibitors are currently used for stroke prevention and the treatment of nonvalvular atrial fibrillation as well as DVT and VTE.21,22

The major disadvantages of factor Xa inhibitors include the lack of a true reversal agent, the need for twice-daily dosing, and increased cost. Despite these few disadvantages, the NOACs have begun to replace warfarin in the treatment of DVT and VTE. NOAC dosing and treatment for DVT are summarized in Table 3.

Conclusion

DVT and thromboembolism are a significant source of morbidity and mortality. It is imperative that clinicians understand how to recognize and treat DVT. Over the years, the treatment of DVT has evolved to include a new class of medications, the NOACs. Although the use of NOACs presents some disadvantages, such as increased cost, a lack of antidotes, and a limited number of laboratory methods available to monitor their activity, there are clear advantages to prescribing NOACs to patients at risk for DVT. These medications have a wide therapeutic window and cause fewer drug-drug interactions than the older agents; in addition, because of their shorter half-life, it easier to discontinue treatment abruptly with NOACs than with warfarin. These features, along with the lack of the need for continual monitoring of the INR, make NOACs a safe and reasonable treatment option for patients with DVT.

John B. Hurt, MPAS, PA-C, is an assistant professor and director of clinical education, Department of Physician Assistant Studies, Samford University, in Birmingham, AL; Kristopher Maday, MS, PA-C, is the program director and associate professor, University of Tennessee Health Science Center, Physician Assistant Program, in Memphis; Michelle Brown, PhD, MS, MLS (ASCP), SBB, is an assistant professor and program director, Healthcare Simulation, University of Alabama Birmingham; and  Paul M. Harrelson, MPAS, PA-C, is a program director at Samford University.