Treatment options for DVT


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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.1,11 Hirudin 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.

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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.

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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.