EMS Providers Should Be Wary of the Implications of Anticoagulants

A 76-year-old woman slips and falls while walking through her home. She sustains a minor laceration to her forehead. Her daughter, who is with her, calls 9-1-1. At the scene, you find her alert, reporting pain only at the site of the laceration. She and her daughter report no loss of consciousness. Her medical history is significant for hypertension and atrial fibrillation. The daughter hands you the medication list, which shows Toprol XL, Pradaxa and Colace. Vital signs are unremarkable, and her Glasgow Coma Scale (GCS) score is 15. Her finger stick blood sugar is 98. An 18 g IV is placed in her right anticubital vein.

You elect to take to her to a nearby community hospital. En route, she becomes agitated and attempts to pull out her IV. After you arrive at the hospital, the staff gives her 1 mg of Ativan via IV to help with agitation. A computed tomography (CT) scan of her head shows a traumatic subarachnoid with an overlying moderately sized subdural hematoma. After the patient is out of the CT scanner, she becomes more combative, and her GCS deteriorates to an 8. She’s immediately intubated for airway protection.

The patient is given fresh frozen plasma (FFP), prothrombin complex concentrate and activated Factor-VII in an attempt to stop the bleeding. The community hospital doesn’t have neurosurgical capabilities, so the patient is transferred to a trauma center. At the trauma center, she’s taken to the operating room. Unfortunately, a post-op head CT scan shows brain herniation. She doesn’t awaken, and her family withdraws her life support two days later.

Anticoagulants have been on the market for more than 80 years. They’re used to treat a variety of disorders, including atrial fibrillation, pulmonary embolism and acute myocardial infarction. Until recently, the mainstays of treatment have been heparins and Vitamin K antagonists (e.g., warfarin).
Side effects, dietary restrictions and expensive monitoring have fueled a search for alternative agents to these traditional treatments. In the past few years, novel anticoagulants have started to enter the American market. It’s important for EMS providers to be familiar with both old and new anticoagulants and their implications for triage and treatment of the injured patient.

Patient Population
Anticoagulants have a large and increasing presence in the American healthcare system. The number of dispensed outpatient prescriptions for Warfarin increased 45%–from 21 million in 1998 to nearly 31 million in 2004.(1) As the above case illustrates, the presence of an anticoagulant on a patient’s medication list can change a minor fall into serious trauma. The patient population that takes these medications varies from a young woman on therapeutic anticoagulation for a pulmonary embolism to a nursing-home resident on subcutaneous heparin for deep venous thrombosis prophylaxis. Despite this variety, these medications are prescribed disproportionately to geriatric patients who are at the greatest risk for bleeding complications.(2)

Different classes of anticoagulants target different parts of the body’s normal coagulation pathways. Coagulation works as a cascade with earlier parts of the system activating later parts, leading to a positive reinforcement cycle.

The final common pathway for all the enzymes is the enzyme thrombin. Once activated, thrombin cleaves fibrinogen into fibrin, the main component in the fibrous mesh that makes up a clot. Warfarin and other Vitamin K antagonists block function of upstream enzymes of the clotting cascade, preventing thrombin from becoming active. Heparin activates a thrombin inhibitor, slowing fibrin formation. Newly developed agents can bind to thrombin, directly decreasing its activity. The mechanism of action has important implications for the strategies of reversal of these medications in the bleeding patient.

Implications for EMS
As the case presentation illustrates, anticoagulants can turn a low-risk injury into a life-threatening hemorrhagic event. Anticoagulation is key in the treatment of many conditions, but the focus in prehospital and emergency settings is often on reversing these drug’s effects. Understanding the mechanisms of action for these agents is important because the target of a particular anticoagulant will determine the best strategy for its reversal.
Caring for a bleeding patient who has been anticoagulated can be complicated, often requiring various blood products and reversal agents. In the case of some of the newer anticoagulants, these reversal measures may not be effective, placing increased emphasis on early and effective source control and adequate supportive measures.

It’s imperative that prehospital providers be familiar with the commonly used anticoagulants and their effects on bleeding. Some EMS systems have developed quick reference cards to assist providers in identifying drugs that cause coagulopathy (see Figure 1, p. 30). A bleeding or potentially bleeding patient who’s taking these medications should be routed to the nearest facility capable of giving large volumes of blood products, performing hemodialysis and surgically controlling a site of bleeding.

1. Wysowski D, Nourjah P, Swartz L. Bleeding complications with warfarin use: A prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167(13):1414—1419.
2. Hylek E, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115(21):2684—2686.

Types of Agents

Initially discovered in naturally occurring sweet clover, warfarin and other Vitamin K antagonists inhibit the formation of Vitamin K-dependant clotting factors II, VII, IX and X. As the first effective oral anticoagulant, warfarin has gained wide use and popularity. Its narrow therapeutic window and many drug and dietary interactions make it a cumbersome medication to manage.

Bleeding is a major concern with warfarin therapy. After insulin, warfarin is the most common drug implicated in the U.S. emergency department visits for adverse drug events.1 Its ability to inhibit all aspects of the coagulation cascade can make relatively minor vascular injuries life-threatening bleeds. All bleeding patients require source control and, if necessary, replacement of blood products. Patients who bleed while they’re on vitamin K antagonists also need to take exogenous vitamin K and fresh frozen plasma (FFP) to reverse their coagulopathy.

Used commercially since the 1920s, heparin is a naturally occurring sugar polymer. Medical heparin ranges in size from 5,000 to more than 40,000 daltons. Heparin activates antithrombin III, a potent inhibitor of thrombin and other coagulation proteins. Low-molecular weight heparins (LMWHs) are purified polysaccharide chains that weigh less than 8,000 daltons. They can be given subcutaneously less frequently than traditional heparin, making them useful in bridging patients to Coumadin or for patients who can’t tolerate oral agents.2 The most common LMWHs in the U.S. are enoxaparin (Lovenox) and dalteparin (Fragmin).

Heparin can be reversed with the peptide molecule protamine sulfate. This positively charged molecule will bind to and inactivate heparin. The protamine-heparin complex is then removed from the body. Low molecular weight heparins are also typically reversed with protamine. This antidote is less effective for LMWH, however. Protamine reverses only about 60% of the anticoagulant activity of LMWH, leaving significant amounts of active agent in the body.(3)

Marketed as Pradaxa, dibigatran etexilate is the first orally available direct thrombin inhibitor in the American market. It’s been investigated for use in prevention of deep venous thrombosis (DVT) after orthopedic surgery, treatment of DVT and prevention of stroke in patient with atrial fibrillation. It has predictable pharmacokinetics that allow for twice-daily dosing without regular lab monitoring.(4)

Despite the predictable dosing, bleeding has become a major concern with this drug. Currently, no reversal agent for dibigatran exists, which raises concerns about treating severe bleeding. Such traditional reversal agents as FFP or prothrombin complex concentrates (PCC) aren’t thought to be effective at reversing this agent because they don’t have sufficient amounts of thrombin to replace the depleted stores. Dialysis has been discussed as a possibility to reverse bleeding complications. It’s estimated that up to 60% of the drug can be removed from the body using hemodialysis.(5,6) Currently, treatment of bleeding while on dibigatran focuses on stopping the drug, source control and supportive care. The drug company that makes dibigatran, Boehringer-Ingelheim, has confirmed that there were 260 fatal bleeding events worldwide between March 2008 and October 31, 2011.(7) The Food & Drug Administration is currently reviewing the safety concerns of Pradaxa in light of these data.

Future Therapies
Based on proteins isolated from leeches, rivaroxaban and apixaban inhibit factor Xa. Marketed as Xarelto and Eliquis respectively, these medications have been approved for prophylaxis of DVT in Europe. Phase III clinical trials are currently underway in the U.S. for prevention and treatment of DVT. In small studies, these agents have been show to be effectively reversed by PCCs.(8)

1. U.S. Department of Health and Human Services. (Aug. 16, 2007). FDA Approves Updated Warfarin (Coumadin) Prescribing Information Events. In U.S. Food & Drug Administration. Retrieved Feb. 2012, from www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108967.htm.
2. Lee A, Levine M, Baker R, et al. Low-molecular-weight heparin versus vs. a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 349(2):146—153.
3. Warkentin T, Crowther M. Reversing anticoagulants both old and new. Can J Anaesth. 2002;49(6):S11—S25.
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139—1151.
5. Lichtman M, Beutler E, Kaushansky K, et al. Williams Hematology, 7th Edition. McGraw-Hill, New York: 261—271, 2006.
6. Eisert WG, Hauel N, Stangier J, et al. Dabigatran: An oral novel potent reversible nonpeptide inhibitor of thrombin. Arterioscler Thromb Vasc Biol. 2010;30(10):1885—1889.
7. U.S. Department of Health and Human Services. (Dec, 7, 2011). Pradaxa (dabigatran etexilate mesylate): Drug safety communication–Safety review of post-market reports of serious bleeding events. In U.S. Food and Drug Administration. Retrieved Dec. 7, 2011, from www.fda.gov/drugs/drugsafety/ucm282724.htm.
8. Eerenberg ES, Kamphuisen P, Slipkens M, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate. Circulation. 2011;124(14):1573—1579.

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