Guideline Development Group

Summary of Evidence

Anticoagulants are the primary defense used to prevent and treat a LE DVT and consequent PE and/or PTS. Contrary to popular belief, anticoagulants do not actively dissolve a blood clot, but instead prevent new clots from forming. Although anticoagulants are often referred to as blood thinners, they do not actually thin the blood. This class of drugs works by altering certain chemicals in the blood necessary for clotting to occur. Consequently, blood clots are less likely to form in the veins or arteries, and yet continue to form where needed. While anticoagulants do not break down clots that have already formed, they do allow the body's natural clot lysis mechanisms to work normally to break down clots that have formed.

Once a LE DVT is diagnosed, anticoagulant therapy is initiated, most commonly with a low molecular weight Heparin (LMWH). Anticoagulant therapy will help to stop an existing clot from getting larger as well as prevent any new clots from forming. In addition, LMWHs have been shown to stabilize an existing clot and resolve symptoms through the drug’s anti-inflammatory properties, making a clot less likely to migrate as an embolus.

A patient diagnosed with a LE DVT is at risk of developing a PE; therefore mobility is contraindicated until intervention is initiated to reduce the chance of emboli traveling to the lungs.^74-78 According to the American College of Chest Physician (ACCP) guidelines on antithrombotic therapy, anticoagulation is the main intervention and should be initiated as soon as possible (Level I, strong evidence).^{25, 42, 59, 69} If the patient is at a high risk for bleeding, the primary contraindication to anticoagulation, then medications may not be prescribed. Therefore, prior to initiating mobility out of bed, a physical therapist should review all medications the patient has been prescribed and verify that the patient is taking an anticoagulant. The physical therapist should next consult with the medical team regarding appropriateness of mobility. Although physical therapists do not play a role in recommending the anticoagulant of choice, they should identify which anticoagulant the patient has been prescribed as well as date and time of the first dose. This will assist the physical therapist in determining when the patient has reached a therapeutic dose, and consequently, when mobility may be initiated safely.

The current options for anticoagulation include unfractionated heparin (UFH), low molecular weight heparin (LMWH), Coumadin (warfarin), Fondaparinux, and oral thrombin or Xa inhibitors (See Table 9). Most patients with a confirmed diagnosis of LE DVT or PE are prescribed a form of LMWH or Fondaparinux (both given with subcutaneous injections).^{30, 59, 69} LMWH is principally used to treat any LE DVT below the knee, at thigh level, and more proximal thrombi.³⁰ It is the anticoagulant of choice for pregnancy and for active cancer as well as the primary choice of physicians for treatment of VTE in the outpatient or home setting due to ease of use and low incidence of side effects. ^{30, 42, 59} LMWH is used in most cases except when a patient has renal dysfunction or a creatinine clearance less than 30 ml/min. Concomitant Coumadin use may be started and provided for three days with subsequent International Normalized Ratio (INR) values being determined. Most individuals will continue with their initial anticoagulant (LMWH or Fondaparinux) for three to six months for the first episode of diagnosed thrombosis. If Coumadin is given concomitantly, they will likely be removed from the initial anticoagulant and continued on Coumadin for 3-6 months.^{69, 79}

Anti-Xa levels can be used to monitor LMWH. However, evidence does not support the use of anti-Xa assay levels for predicting thrombosis and bleeding risk.⁸⁰ Pharmacokinetic studies on LMWH report maximum anti-factor Xa and anti-thrombin IIa activities occur three to five hours after subcutaneous injection of LMWH.⁸¹ The optimal therapeutic anti-Xa levels for treatment are .5-1.0 units/ml. Due to the fact LMWH is excreted primarily by kidneys, increased bleeding complications have been reported when LMWH is used in patients with renal insufficiency and other populations. Therefore, precautions for bruising and bleeding with physical therapy interventions should be taken when LMWH is used in patients with kidney injury or dysfunction, patients in extreme weight ranges, patients who are pregnant, and in neonates and infants.⁶⁰

Unfractionated heparin is indicated for individuals with high bleeding risk (Refer to Table 9) and/or renal disease. Patients with established or severe renal impairment are defined as those with an estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73m^2. . UFH is often prescribed and dosed to achieve therapeutic levels quickly. Lower speed of infusion is usually given in acute coronary syndromes whereas higher speeds of infusion are given with VTE. Several institutions have transitioned from monitoring heparin with anti-factor Xa levels instead of aPTT due to influencing factors that can alter aPTT levels.⁸² One study has shown anti-Xa detects therapeutic levels faster than aPTT (UFH patients achieved therapeutic anticoagulation in approximately 24 hours compared to patients monitored with aPTT which averaged 48 hours).⁸² Patients with a documented PE, including those hemodynamically unstable, are often prescribed UFH and similar aPTT monitoring should be reviewed by the physical therapist seeing the patient.⁶⁹

Coumadin is usually not the first medication choice for anticoagulation due to the length of time to achieve peak therapeutic levels. Coumadin is typically introduced day one during administration of another anticoagulation, usually with LMWH or UFH.⁵⁹ The loading anticoagulant (LMWH or UFH) is continued for at least 5 days until an INR greater than 2 is achieved for at least 24 hours, prior to discontinuing the loading anticoagulant, and first episodes of VTE should be treated with a target INR range of 2.5.⁷⁹ UFH or LMWH is often discontinued when the INR is greater than2.0.⁵⁹

Fondaparinux (arixtra) is similar to LMWH, is monitored using anti –Xa assays, and is often used when individuals need treatment or prophylaxis for VTE but have a history of Heparin-induced thrombocytopenia (HIT).⁴² The maximal therapeutic dosage is reached in approximately 2 -3 hours^{42, 78} Fondaparinux is also used for thrombo-prophylaxis in medical and surgical patients as is LMWH.⁶⁰

Both UFH and LMWH are associated with HIT, defined as an immune mediated reaction to heparins. HIT can occur in 2%-3% of patients treated with UFH and approximately 1% of patients treated with LMWH.⁴² HIT will result in a paradoxical increased risk for venous and arterial thrombosis and this risk lasts approximately for 100 days following initial reaction. Therefore, patients with a history of HIT should not receive either LMWH or UFH with subsequent VTE.^{42, 83} Treatment for anticoagulation in individuals with HIT involves using Fondaparinux or other thrombin specific inhibitors such as Lepirudin or Argatroban (Refer to Table 10 for more information on HIT).

Mobility decisions with an individual receiving Coumadin are based upon the initial anticoagulant and not Coumadin. Concern regarding exercise and out of bed activity should be raised for elevated INRs greater than 4 when patients are taking warfarin.⁸⁴ If the INR is between 4.0 and 5.0, resistive exercises should be avoided, with participation in light exercise only (e.g. Ratings of Perceived Exertion or RPE equal to or less than 11) due to increased risk of bleeding.⁸⁴ Ambulation should be restricted if gait is unsteady to prevent falls.⁸⁴ The likelihood of bleeding rises steeply as INR increases above 5.0.^85-87 If INR is greater than 5.0, discussion should be held with the referring physician regarding patient safety. When the INR is greater than 6.0, the medical team should consider bed rest until the INR is corrected.^{84, 85} In most cases, INRs can be corrected within 2 days.⁸⁴ When reversal of anticoagulation is needed for surgery and the patient is taking Coumadin, fresh frozen plasma is the choice to replace the anticoagulation.⁸⁵

New oral anticoagulant drugs (direct thrombin inhibitors and direct factor Xa inhibitors) are growing in popularity due to their ease of use (no laboratory monitoring, no adverse dietary or other drug interactions) and their rapid time to peak therapeutic levels. In addition, there appears to be less risk of cerebral hemorrhage as occurs in vitamin K antagonists.⁸⁵ Rivaroxaban (Xarelto), dabigitran (Pradaxa) and apixaban (Eliquis) are the three new oral anticoagulant drugs in use at this time (Refer to Table 9 for dosage, method of delivery and peak therapeutic level time frames). The new oral anticoagulant drugs are recommended by the American Association of Orthopedic Surgeons (AAOS) for hip and knee arthroplasty, but have not been tested or recommended for individuals who have cancer, are undergoing treatment for cancer, or who are pregnant.⁸⁸ There are concerns regarding reversal of anticoagulation with these medications. However, reconstructed recombinant factor Xa or activated charcoal have both been proposed as antidotes.^{88, 89} The time for reversal is the amount of time to eliminate the drug from the body which is based on their half- life, usually within 12-24 hours. With all anticoagulants there is a risk of bleeding. Therefore, in addition to the risk of venous thromboembolism, physical therapists should be aware of and assess for risk of bleeding in all patients (Refer to Table 11 for factors associated with high risk of bleeding).