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Fluids & Electrolytes
Mr. J, 77, WAS ADMITTED to the ED after he slipped and fell over his living room throw rug, hitting his head on the coffee table. He was alert and oriented and denied any loss of consciousness, but he complained of a frontal headache. His home medications included warfarin, which was prescribed for a history of atrial fibrillation (AF).
He's now difficult to arouse. A stat computed tomography (CT) scan of the head without contrast reveals a large subdural hematoma.
This scenario is all too familiar to nurses who care for older adults in an acute care setting. Patients like Mr. J who are taking the anticoagulant warfarin to prevent AF-associated thrombus formation are at particular risk for traumatic intracranial hemorrhage/hematoma (TICH) following even seemingly minor trauma. TICH is a medical emergency requiring immediate reversal of anticoagulation.1 This article will review coagulation and provide important information about several commonly used anticoagulants and their reversal agents.
The major function of the coagulation system is to achieve and maintain hemostasis after an injury. One stage is blood coagulation to create a clot and stop bleeding. (See Five steps to hemostasis.)
Anticoagulants oppose coagulation by interfering with the coagulation cascade at various points, depending on the drug. (See How drugs interruptthe coagulation cascade.) Anticoagulant drugs don't lyse clots that already exist, but they can prevent thrombus formation and prevent or slow the extension of an existing clot.2
Drugs categorized as anticoagulants include indirect parenteral anticoagulants, such as heparin and low-molecular-weight heparin (LMWH), and orally administered vitamin K antagonists (VKAs) such as warfarin.3 They're prescribed to help prevent deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, and myocardial infarction (MI). The most serious adverse reaction associated with all anticoagulants is hemorrhage, which can be fatal.
Heparin is a rapid-acting anticoagulant that can be divided into two classes: unfractionated heparin (UFH) and fractionated or LMWH. Both types are used to treat DVT and PE, to prevent DVT, and to prevent complications of an MI.
Because heparin isn't absorbed via the gastrointestinal (GI) tract, it must be administered parenterally, preferably by continuous I.V. infusion or subcutaneous injection. Neither UFH nor LMWH crosses the placenta and several studies suggest that therapy with these drugs is safe for the fetus.3
UFH binds to antithrombin (AT) and inactivates thrombin (factor IIa) and factors Xa, IXa, XIa, and XIIa.3 Dosing is based on the patient's weight in kilograms (kg).
When given in therapeutic doses, heparin's anticoagulant effect is usually monitored with serial serum activated partial thromboplastin times (aPTTs). For patients receiving higher heparin doses (for example, those undergoing percutaneous coronary intervention), current guidelines recommend monitoring activated clotting time.3
Heparin-induced thrombocytopenia (HIT) is a potential complication in patients prescribed UFH. HIT is an antibody-mediated adverse reaction of heparin, associated with the presence of heparin-dependent antibodies, thrombocytopenia, and venous and arterial thrombosis.3 To assess for HIT, monitor platelet counts throughout therapy.
Derived from UFH, LMWHs are administered subcutaneously. Examples include enoxaparin, dalteparin, and tinzaparin. Advantages of LMWH over UFH include a longer half-life, allowing once- or twice-a-day administration, and a more predictable anticoagulant response, which makes coagulation monitoring unnecessary in most patients. Because of these benefits, LMWHs can be used by patients in outpatient settings. Coagulation monitoring may be indicated in patients with an unpredictable anticoagulation response, such as those with decreased renal function and obesity.4
LMWH hasn't been shown to increase bleeding risk when given in prophylactic doses and is associated with a reduced incidence of HIT.3 However, if a patient has a history of HIT associated with UFH, LMWH should be used with extreme caution, and only if expected benefits outweigh the risks. LMWHs are contraindicated in patients with a history of hypersensitivity to UFH.4
Like UFH, LMWHs produce their major anticoagulant effect by activating AT.3 Most LMWHs don't inactivate thrombin but promote factor Xa inactivation by AT. If you suspect that a patient on an LMWH is overly anticoagulated, obtain a serum anti-Xa level.5 LMWH dosing varies according to drug, indication, and the patient's weight.
Classified as a VKA, warfarin is the most commonly prescribed oral anticoagulant on the market. It acts by inhibiting the synthesis of vitamin K-dependent coagulation factors, including factors II (prothrombin), VII, IX, and X, and the anticoagulant proteins C and S.3,6 Because prothrombin has a 60-hour half-life and warfarin's peak anticoagulant effect may be delayed 72 to 96 hours, this drug can't be used in emergencies.6 Unlike heparin, warfarin can cross the placenta, so it's not safe to use during pregnancy unless the potential benefits to the mother justify potential risks to the fetus.3 Warfarin is classified in Pregnancy Category D in women with mechanical heart valves and in Pregnancy Category X in women with all other indications.4
After oral administration, warfarin is rapidly absorbed from the GI tract. Most (99%) binds to plasma proteins, mainly albumin.3 After discontinuation, warfarin's anticoagulant effects persist for 2 to 5 days because of its long half-life.5
Although widely prescribed, warfarin has some significant disadvantages, including a narrow therapeutic index and variable dose response among patients. It interacts with many drugs and foods, and lab control is difficult to standardize.3 Consequently, patients must be closely monitored to ensure safe and therapeutic use of warfarin.
Evaluate a patient's response to warfarin by monitoring the prothrombin time/international normalized ratio (INR). The optimal therapeutic range for the INR depends on various factors, such as the condition being treated and the patient's bleeding risk. However, for most indications, an INR of 2.0 to 3.0 is considered therapeutic.3
Dabigatran is a recently approved oral direct thrombin inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF.7 Research has shown that compared to warfarin, dabigatran prevents approximately five more strokes per 1,000 patients per year.8 The FDA is evaluating postmarketing reports to determine if dabigatran is causing more serious bleeding than would be expected based on data from the large clinical trial that supported the drug's approval.9
Dosing is usually 150 mg twice a day without regard to food. For patients with renal dysfunction (creatinine clearance 15 to 30 ml/minute), the dabigatran dose is 75 mg twice daily. Dabigatran isn't recommended for patients with severe renal dysfunction (creatinine clearance <15 ml/minute), because research on this patient population is insufficient.4,10
Dabigatran doesn't require routine anticoagulation monitoring, but it should be discontinued if bleeding is evident or suspected.
Reversing anticoagulation effects before an elective procedure is much different than reversal in an emergency. Before planned outpatient surgery, for example, warfarin is normally withheld for 4 to 5 days due to its long half-life. Dabigatran should be held for 1 to 2 days or 3 to 5 days before surgery, depending on the patient's renal function.7 Anticoagulants with a shorter half-life, such as UFH or an LMWH, are often started and maintained as a bridging or temporary therapy for patients with a moderate-to-high risk of thrombosis until oral anticoagulants can be safely restarted.10 UFH is discontinued on the day of surgery to prevent intraoperative bleeding.
Heparin's anticoagulant effect can last 4 to 6 hours. If a patient experiences major bleeding complications, pro tamine sulfate can rapidly reverse the anticoagulant effects after heparin is discontinued.11 Protamine sulfate is a basic protein derived from fish sperm that binds to heparin to form a stable salt.12
The protamine dosage given for reversal depends on the dosage of heparin. Administering 1 mg I.V. will reverse the effects of about 100 units of heparin.3,4,11,12 However, due to the rapid decrease in blood heparin concentrations after heparin is discontinued, the recommended pro tamine dose varies according to the length of time since the last heparin dose was administered.4
Use caution when administering protamine because some patients may experience a type I hypersensitivity reaction, including anaphylaxis. Patients at increased risk of an allergic reaction have preexisting antibodies against protamine sulfate; these include patients who've previously received protamine sulfate-containing insulin and those who are allergic to fish.11,12 Men who are infertile or who've had a vasectomy may also be at higher risk because of the presence of antiprotamine antibodies in their serum.12 Pretreat at-risk patients with corticosteroids and antihistamines if prescribed.3 Administer protamine very slowly (over 10 minutes) in doses not to exceed 50 mg to minimize the risk of severe adverse reactions.12
Although serious bleeding is less likely with LMWHs, protamine will also reverse their anticoagulant effects if bleeding occurs.9 As a rule, 1 mg of protamine reverses 1 mg of enoxaparin given within the last 8 hours. The prescriber may consider a second dose if aPTT is still prolonged 2 to 4 hours after the first protamine dose.4,11
Protamine will also reverse the effects of dalteparin and tinzaparin; 1 mg reverses the effects of every 100 anti-Xa international units of dalteparin or tinzaparin given within the last 8 hours.4,5 The prescriber may consider an additional dose of 0.5 mg for each 100 anti-Xa international units of dalteparin or tinzaparin if the aPTT is still prolonged 2 to 4 hours after the first protamine dose.4
Note that protamine never completely neutralizes antifactor Xa activity-the maximum is 60% to 75%. The main risk of excessive protamine administration is a worsening of the bleeding potential.4,13
The first step in reversing the effects of warfarin and other VKAs is to withhold the drug. Vitamin K, a naturally occurring fat-soluble vitamin necessary for hepatic production of factors II, VII, IX, and X, is typically included in first-line therapy for reversal of warfarin's effects. But if a patient taking warfarin presents with a high INR but no bleeding, it's better to simply withhold the warfarin and not treat with vitamin K if possible in order to prevent vitamin-K induced resistance to warfarin once warfarin is restarted.8
If giving vitamin K is necessary, the response to oral vitamin K is more predictable than vitamin K administered parenterally. If vitamin K must been given parenterally, the subcutaneous route is preferred. Don't give vitamin K intramuscularly because of the risk of hematoma formation.4
Vitamin K is generally given I.V. only in emergencies to treat serious bleeding. It can be given by slow I.V. infusion, along with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), or recombinant factor VIIa (rVIIa). Administer I.V. vitamin K slowly and monitor the patient for cardiac dysrhythmias or a type I hypersensitivity reaction, including anaphylaxis.
The usual dosing range for vitamin K is 2.5 to 25 mg, depending on the patient's INR value and bleeding risk. Vitamin K's onset of action is 6 to 10 hours when given orally and 1 to 2 hours when given I.V. Its peak effect occurs in 24 to 48 hours when given orally and in 12 to 14 hours when given I.V.4 Replacing clotting factors with FFP, PCC, or rVIIa will further speed the reversal of warfarin's effects.
FFP is a blood product that, if stored properly, contains all the clotting factors including the labile factors V and VIII, and fibrinogen.14 In an emergency, FFP administration may be delayed due to the need for ABO blood typing, FFP thawing, and transport time from the blood bank. Because the FFP is a larger fluid volume, it may also take longer to infuse.15
PCC contains factors I, VII, IX, and X.16 Recent research showed that after infusion, PCC had a 30-minute correction time, compared to 24 hours after I.V. vitamin K administration.17 PCC thawing time when compared to FFP is also faster, so treatment can begin sooner. Compared to FFP, it's associated with fewer complications related to fluid overload because a smaller volume is needed to reverse anticoagulation.11
No antidote for dabigatran is currently available. A patient on this drug who is bleeding may receive FFP or whole blood as prescribed.3
All patients treated with anticoagulants must be educated about the risk of excessive anticoagulation and hemorrhage. In patients on warfarin therapy, these factors increase the risk:6
* age 65 or older
* high intensity of anticoagulation (INR >4.0)
* history of variable INR values
* history of certain conditions, including GI bleeding, cerebrovascular disorders, trauma, anemia, and renal impairment
* concurrent use of other drugs that increase bleeding risk, such as antiplatelet drugs, nonsteroidal anti- inflammatory drugs (NSAIDs), and selective serotonin reuptake inhibitors
* prolonged duration of warfarin therapy.
When assessing patients who are at a higher risk of bleeding, begin with the patient's mental status and vital signs, as well as appropriate coagulation studies as indicated. Keep venipunctures to a minimum, and avoid intramuscular injections. If bleeding occurs at an injection site, apply pressure for 5 to 10 minutes or until hemostasis is obtained. Also follow these assessment guidelines:6,18
* When monitoring vital signs, watch for hypotension and tachycardia.
* When monitoring lab values, watch for anemia and thrombocytopenia.
* Regularly assess for signs and symptoms of bleeding, such as bleeding gums, ecchymoses, petechiae, epistaxis, melena, hematuria, hematemesis, menorrhagia, and headaches or mental status changes.
* Assess the skin for necrosis and hematomas.
* Perform medication reconciliation to identify drugs that may increase or decrease the prescribed drug's anticoagulant effect. Even antibiotics can affect a drug's anticoagulation effects; for example, ciprofloxacin can increase warfarin's anticoagulant effect and nafcillin can decrease its effect.6
If applicable, administer humidified oxygen to prevent drying of mucous membranes and epistaxis. Notify the healthcare provider of abnormal vital signs or lab values, or uncontrolled bleeding.
To prevent dangerous complications and ensure therapeutic benefits, educate patients about bleeding precautions, dietary considerations, and follow-up care. Make sure patients know what type of anticoagulant they're taking, why it was prescribed, and how to take it correctly. For example, stress to patients and their families that the medication should be taken at the same time every day. Medication Guides have been created for patients taking warfarin and dabigatran. Review these with patients and make sure they have a copy to take home.
Teach patients to avoid over-the-counter (OTC) products containing aspirin or other NSAIDs because these will increase their prescribed drug's anticoagulant effects.6,7 In addition, tell patients taking warfarin that many herbal supplements affect coagulation; for example, garlic and ginkgo biloba, can increase bleeding risks.18 Other herbal products and foods may decrease warfarin's effects, including St. John's wort, ginseng, and grapefruit juice.6 Instruct patients to check with the healthcare provider before using any OTC drug or herbal product, and to inform all their healthcare providers, including dentists, about all the drugs they take.
Also advise patients to avoid or curtail alcohol consumption. If a patient is likely to consume alcohol during therapy, the healthcare provider should be informed so that dosing can be adjusted if needed.
Warn active patients to avoid physical activities that may cause injuries, such as contact sports. Advise patients to use soft bristle toothbrushes and electric razors to prevent abrasions. Give older adults information on home safety and fall prevention. Make sure patients who will be using LMWH at home can return-demonstrate proper subcutaneous injection technique.
Patients taking anticoagulants must know how to recognize and report adverse reactions that require prompt medical attention, such as bleeding that doesn't stop within 15 minutes; unusually heavy menstrual bleeding; blood-tinged or bloody urine; black, tarry stools; dizziness or severe headaches; vomiting blood or material that looks like coffee grounds; unusual bruising; frequent nose bleeds; extremities that are painful, pale, or blue; and painful or dark-looking toes.
Patients taking VKAs such as warfarin should monitor their consumption of foods that are high in vitamin K, such as green leafy vegetables and broccoli. Advise patients not to change their dietary habits, but to maintain consistent intake of green leafy vegetables.6 Encourage them to discuss dietary habits with the healthcare provider so he or she can prescribe the safest dose of warfarin.
Advise all patients on anticoagulant therapy to wear a medical alert tag indicating the medication they're taking.
Keeping the previous discussion in mind, let's return to the patient we met at the beginning of this article. After successful endotracheal intubation and cervical spine immobilization, Mr. J has a critically high INR: 7.1. The physician places warfarin therapy on hold and prescribes 10 mg of vitamin K by slow I.V. infusion and four units of FFP now. A stat call is placed to a neurosurgeon and the patient is transferred to the neurologic ICU for further monitoring, evaluation, and treatment.
Caring for patients with serious bleeding who are receiving anticoagulation can be challenging. By promptly identifying the adverse effects of anticoagulants and responding appropriately, you can help prevent dangerous complications.
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