Biotech Values

[DewDiligence]

An Overview of Traditional Anticoagulants

[This material, developed for a course in pharmacology, is a reasonable, though somewhat dated, backgrounder on the mechanisms of coagulation and the clinical characteristics of the older drugs (warfarin, heparin, and LMWH’s) used to prevent and treat thrombosis. Please chase the link below for references and ancillary materials. I’ve omitted the section on danaparoid (Orgaran) because this drug was withdrawn from the US market in 2002. The graphics in #msg-24393520 and #msg-23010615 and the articles in #msg-25160571 and #msg-18759853 are helpful companions to the discussion below.]

http://www.uspharmacist.com/index.asp?page=ce/105181/default.htm

>>
February 1, 2006
Charles H. Brown, RPh, MS Pharm, CACP
Associate Professor of Clinical Pharmacy
Purdue University
West Lafayette, Indiana

Approximately two million people in the United States are affected by venous thromboembolism (VTE) each year, resulting in 600,000 hospitalized individuals and 60,000 deaths.1 VTE is manifested as deep venous thrombosis (DVT) and pulmonary embolism (PE). Death from PE can occur within minutes after its onset unless effective medical management and antithrombotic therapy can be obtained. Although VTE can occur at almost any age, it most frequently occurs in patients who suffer from trauma, undergo major surgery, are immobilized for lengthy periods of time, or have a hypercoagulable disorder. Because VTE can be a debilitating and potentially fatal thromboembolic disorder, it is important to treat it quickly and aggressively.2-4 The purpose of this article is to provide pharmacists with an overview of factors that influence hemostasis, the pathophysiology of thrombus formation and the coagulation process, and a discussion of the traditional antithrombotic agents (i.e., warfarin, heparin compounds, and heparinoid) used for acute and chronic VTE.

PATHOPHYSIOLOGY OF COAGULATION

Maintaining hemostasis, or normal blood circulation, requires blood to freely circulate in the body through large and small blood vessels that transport oxygen, electrolytes, nutrients, plasma proteins, and waste products. To accomplish this task, a delicate balance must be maintained between the coagulation system that generates thrombin and promotes fibrin formation, and natural anticoagulant mechanisms that function to down-regulate procoagulant activity. However, blood must have the capability to form clots (i.e., thrombi) to prevent excessive blood loss when trauma occurs. Hemostasis is maintained by a number of mechanisms including the production of AT III and proteins C and S, which assist in maintaining a balance of coagulation and anticoagulation states.

Virchow’s Triad

In the mid-1850s, German pathologist Dr. Rudolf Virchow described the role of blood vessels, circulating elements in the blood, and the velocity of blood flow in the regulation of clot formation.5 Three major risk categories for VTE, known as Virchow’s triad, include, but may not be limited to:3,6-10

1. Venous stasis or abnormalities in blood flow (e.g., heart disease, atrial fibrillation, heart failure, arrhythmias, prolonged bed rest, immobility).

2. Trauma or abnormalities of surfaces in contact with circulating blood (e.g., vascular wall injury, fractures of bones, joint replacement surgery, heart valve disease and/or replacement).

3. Hypercoaguability or abnormalities in clotting components (e.g., estrogen replacement, oral contraceptives, pregnancy, malignancy, antithrombin [AT] III or AT3 deficiency, protein C or protein S deficiencies, activated protein C resistance [i.e., factor V Leiden mutation], antiphospholipid antibodies).

Alterations in any of these risk factor categories may lead to pathologic clot formation.

Platelet Function

Platelets freely circulate in the blood in an inactive state, and when needed, they assist with blood clotting by initiating the first step in thrombus formation—platelet activation. Normal endothelial cells in the tunica intima portion of blood vessels maintain blood flow by producing a number of compounds that prevent platelet adherence, inhibit activation of the coagulation cascade, and facilitate fibrinolysis.11-13 When blood vessel trauma occurs, the subendothelium can be exposed, causing the vessel to go into spasm (i.e., vasoconstriction), which decreases blood flow and limits blood loss. In response to vascular injury, the von Willebrand factor promotes platelet adhesion to the subendothelium of damaged blood vessels by interacting with glycoprotein Ib (GP Ib) receptors located on platelet surfaces. Platelets become activated and release adenosine diphosphate, which is converted to thromboxane A2. Platelet glycoprotein IIb-IIIa (GP IIb-IIIa) receptors become exposed and allow other platelets to adhere to each other and the injured site. A platelet plug forms to help prevent further blood loss and damaged vascular tissue releases tissue factor or tissue thromboplastin, which activates the coagulation cascade. If the coagulation cascade is allowed to progress, a thrombus will form.

Coagulation Cascade [see diagram in #msg-23010615

The coagulation cascade is divided into three distinct segments: the intrinsic, extrinsic, and common pathways.11,13,14 The cascade involves a series of serine protease enzymes known as zymogens (e.g., factors XII, XI, X, IX, VII, and II [prothrombin]) and protein cofactors. Activation of factors V and VIII results in an exaggerated amount of thrombin production and the formation of a fibrin mesh. Normally, all clotting factors are inactive and freely circulate in the blood. When required, stimuli convert an inactive zymogen precursor into the active form, which consequently converts the next precursor in the sequence. Activation of zymogen precursors occurs on platelets and the vessel wall with the aid of phospholipid and calcium.13 The coagulation cascade terminates in the conversion of prothrombin to thrombin and of fibrinogen to fibrin, an insoluble protein. Thrombin is responsible for the conversion of factors V and VIII, which creates a positive feedback loop that greatly accelerates the production of more thrombin. [This feedback loop passes through FXa.] In addition, thrombin and other platelet activation stimulators promote further platelet aggregation through their interactions with the GP IIb-IIIa receptor.

Thrombin generation occurs through the extrinsic and intrinsic pathways of the coagulation cascade.14,15 The extrinsic pathway is the major physiologic pathway for the initiation of fibrin formation and is activated in response to vessel injury and/or exposure of the procoagulant, tissue factor.16 Tissue factor forms a complex with factor VIIa. The factor VIIa–tissue factor complex activates factor X in the common pathway and factor IX in the intrinsic pathway.15 The intrinsic pathway, which is considered important for fibrin maintenance and propagation, can be activated when blood vessels are damaged by some trauma.16 When this occurs, negatively charged blood vessel surfaces that are in contact with the blood activate factor XII. Additionally, activated platelets can activate factor XI.

Both the intrinsic and extrinsic pathways intersect at the common or final pathway with the activation of factor X.11,13,14 Along with phospholipid and calcium, factors Va and Xa convert prothrombin (factor II) to thrombin (factor IIa), which then cleaves fibrinogen to form fibrin monomers. Finally, when fibrin monomers achieve a critical concentration, they begin to precipitate and polymerize to form fibrin strands. Factor XIIIa covalently bonds these strands to one another to form a rigid mesh. Any interference with factor Xa activity directly affects the amount of fibrin formed in the terminal portion of the clotting cascade.

Endogenous Anticoagulant Mechanisms

Endogenous anticoagulant mechanisms operate at the level of the coagulation cascade to control the production of thrombin and resultant fibrin formation.17-19 These mechanisms include the regulation of factors Va and VIIIa by the protein C system and the inhibition of tissue factor–factor VIIa–mediated extrinsic pathway activation by tissue factor inhibitor. Endogenous anticoagulants include heparin sulfate, protein C, protein S, and AT III. One of the most important physiologic mechanisms for the control of coagulation is based on AT and enhancement of its in vivo inhibitory activity by natural anticoagulant molecules that line the vascular endothelium and promote uninterrupted blood flow.20 AT is the most powerful endogenous inhibitor of thrombin and factor Xa activities and, to some extent, is involved in neutralizing factors IXa, XIa, and XIIa.21

Thrombomodulin propagates thrombin by converting inactive protein C to activated protein C. When combined with its cofactor, protein S, protein C enzymatically inactivates factors Va and VIIIa.11,13 Activated protein C also stimulates the release of tissue plasminogen activator (t-PA). Heparin sulfate is secreted by endothelial cells and exponentially accelerates AT activity. Heparin cofactor II also inhibits thrombin in a similar manner. Tissue factor pathway inhibitor (TFPI) plays an important role by regulating the initiation of the coagulation cascade.

If a thrombus forms, the blood automatically activates a clot-removal system to degrade the fibrin mesh into soluble end-products known as fibrin degradation products.14,16 Plasminogen, an endogenous substance in the blood and tissue, is converted to plasmin (a thrombolytic) to lyse the blood clot. As long as these endogenous anticoagulant mechanisms are intact, the formation of the fibrin clot will be limited to the site of tissue injury. Disruptions in the clot removal system (i.e., hypercoagulable states) often result in thrombosis.22,23

VTE PHARMACOTHERAPY

Antithrombotic pharmacotherapy, which is typically used to treat patients with acute VTE, often involves the use of parenterally administered drugs. Depending upon various patient and disease factors, pharmacotherapy may be initiated with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). In some instances, heparinoid therapy may be used. Chronic pharmacotherapy of VTE almost always uses warfarin, the only oral antithrombotic agent available in the U.S. [This will almost certainly change in the next few years, however.] All anticoagulant agents either directly or indirectly interfere with certain complex processes in the clotting cascade and prolong blood clotting time.

WARFARIN

Pharmacotherapeutics

Warfarin is currently the only FDA-approved oral antithrombotic agent in the U.S. for the prevention and treatment of VTE and thromboembolic complications associated with atrial fibrillation, heart valve replacement, and myocardial infarction.11,24

Dosage and Administration: The initial recommended oral dose of warfarin for most patients is 5 to 7.5 mg once daily, which should be taken at the same time each day. Warfarin can be taken without regard to meals. Warfarin sodium (Coumadin/Bristol-Myers Squibb) tablets are available in nine strengths (1, 2, 2.5, 3, 4, 5, 6, 7.5, and 10 mg) that are color-coded for easy identification.24 A generic form of warfarin sodium is also available. Although rarely utilized in clinical practice, Coumadin is also available in an intravenous (IV) dosage form, 2 mg/mL. The initial oral dose of 5 mg daily is commonly utilized and is titrated daily to achieve a stable prothrombin time/international normalized ratio (PT/INR) appropriate for the patient and thromboembolic disorder (TABLE 1). To maintain patients within the appropriate therapeutic INR range, the average daily dose of warfarin is about 4 to 5 mg. However, the daily dose can range from less than 1 mg/day to more than 20 mg/day. While patient response to warfarin therapy varies considerably, many patients can achieve a stable INR in seven to 10 days. The maintenance dose of warfarin for many patients ranges from 2 to 7.5 mg/day. Age, hepatic function, underlying disease states, patient-specific metabolic characteristics (i.e., cytochrome P-450 [CYP 450] isoenzymes), and numerous drug interactions greatly influence dosing requirements.11,25,26

Loading Doses: These doses often cause erratic changes in the INR, generally provide little or no therapeutic advantage, and may be unsafe because of rapid and excessive depression of factor VII and protein C. Significant increases from baseline in the INR value during early stages of warfarin therapy can be very misleading because increased values occur primarily as a result of factor VII and protein C suppression (due to their shorter half-lives), while little change in factors II and X have occurred due to their long half-lives (TABLE 2).11,25,26

Missed Doses: Although patients should always check with their health care provider first, usually a missed dose will be taken as soon as possible. However, if it is almost time for the patient’s next dose, the skipped dose should be omitted. Patients should not double the dose or take extra amounts of warfarin.11,25,26

Pharmacokinetics

Following oral administration, warfarin is readily absorbed, reaches a peak plasma concentration in about 90 minutes, and is 99% bound to plasma proteins, primarily albumin. Warfarin undergoes oxidative CYP 450 enzyme biotransformation in the liver, specifically, CYP 1A2, 2C, 2C19, 2C18, and 3A4 enzymes. Less than 2% of the oral dose is excreted in the urine. Warfarin is commercially available as a racemic mixture of R and S isomers. The S isomer is two to five times more potent than the R isomer. Interestingly, metabolism of warfarin is isomer-specific. The CYP 2C enzyme metabolizes the S isomer, whereas the CYP 1A2 and CYP 3A4 enzymes metabolize the R isomer.11,12,24-26

Pharmacodynamics

Warfarin exerts its anticoagulant effect by inhibiting the enzymes responsible for the cyclic interconversion of vitamin K–dependent carboxylation of several coagulation factors, including prothrombin (factor II), factor VII, factor IX, factor X, and the anticoagulant proteins C and S.27 Warfarin has no direct effect on circulating clotting factors or previously formed thrombi. Warfarin’s full anticoagulant effect is often not achieved until several days after treatment initiation or change in the daily dose because depletion of the active coagulation factors depends on the elimination half-lives of clotting factors (TABLE 2). Changes in the INR during the early days of treatment indicate warfarin suppression of factor VII and protein C. With prothrombin’s long half-life (about 60 hours), approximately eight to 16 days are required to achieve full antithrombotic effect after initiation of therapy.28 During this period, there is significant underanticoagulation, and an anticoagulant with a quicker onset of action, typically an UFH or LMWH product, is often required as a “bridge.”25,29 Duration of action after discontinuation of warfarin depends upon the resynthesis of vitamin K–dependent clotting factors.

Warfarin Overdose Antidote:24 When the INR is elevated and the risk of bleeding is of major concern, the administration of low-dose vitamin K 2.5 mg orally or phytonadione (Mephyton/Merck) 0.5 to 1 mg via slow IV or subcutaneous (SC) injection begins to normalize the PT/INR within four to eight hours. Use of IV doses of vitamin K can cause anaphylactic reactions. In an emergency situation in which a patient has a very high INR and is at high risk of bleeding, fresh whole blood, fresh frozen plasma, or plasma concentrates of vitamin K–dependent clotting factors may be helpful in reversing warfarin effects.

Contraindications/Precautions24

Warfarin is contraindicated in patients who have a documented allergy to warfarin, thrombocytopenia (i.e., platelet count of less than 150,000 mm3) or uncontrollable bleeding; who are undergoing lumbar puncture, regional anesthesia, or surgery of the eye, brain, or spinal cord; and in those who are at high risk of bleeding (e.g., hemophilia, dissecting aneurysm, gastrointestinal [GI] ulcers, uncontrolled hypertension, vitamin K deficiency, liver disease, alcoholism).

As a precaution, all intramuscular (IM) injections should be avoided due to the risk of forming a hematoma. Dietary intake of foods, vitamin products, and herbal products with a high vitamin K content should be limited (TABLE 3). Elderly individuals may be at higher risk of bleeding due to major trauma (e.g., falls, surgeries).

INR Equation

INR = (Patient PT value / Mean PT time for the laboratory)ISI value

INR: international normalized ratio; PT: prothrombin.

Warfarin is listed as a “pregnancy category X” drug and is generally considered to be contraindicated in pregnant or lactating women and in women planning a pregnancy.

Adverse Effects11,13,24,29,30

Common adverse effects of warfarin include bleeding (especially when INR is greater than 2.0) with secondary bruising, hematuria, and heme-positive stools. Warfarin therapy is associated with a cumulative incidence of bleeding after 48 months, ranging from 3% in low-risk patients to 53% in highest-risk patients.

Less common adverse effects include fetal hemorrhage and teratogenesis, purple toe syndrome (may occur after three to eight weeks of therapy), skin necrosis (may occur early in therapy), alopecia (rare), urticaria, dermatitis, fever, GI disturbances (e.g., nausea, vomiting, diarrhea), and red-orange urine.24

Drug Interactions

Warfarin may be associated with more clinically significant drug–drug interactions than any other drug on the market. Careful monitoring and dosage adjustments of warfarin are recommended when a potentially interacting prescription drug, nonprescription drug, or herbal product is added or discontinued from a patient’s drug regimen. Lifestyle issues (e.g., diet, use of alcohol or tobacco) can also greatly influence patient response to warfarin.11,24,25

Agents commonly associated with increasing warfarin’s anticoagulant effects (increased INR) include alcohol (especially binge drinking), aspirin, amiodarone, cimetidine, ciprofloxacin, clarithromycin, clofibrate, erythromycin, fluconazole, fluvoxamine, lovastatin, levofloxacin, metronidazole, omeprazole, quinidine, sertraline, trimetho-prim-sulfamethoxazole, drugs that inhibit CYP enzyme metabolism (e.g., CYP 1A2, 2C9, 2C19, 2C18, 3A4), drugs that are highly protein-bound to albumin, “G” herbal products (e.g., garlic, ginger, ginkgo, ginseng), grapefruit juice, soy, and high doses of vitamin E.11,24,25

Agents commonly associated with decreasing anticoagulant effects (decreased INR) include barbiturates, carbamazepine, cholestyramine, griseofulvin, phenytoin, rifabutin, rifampin, vitamin K, drugs that induce CYP 450 enzyme metabolism (e.g., isoniazid, prednisone, thyroid products, azathioprine), herbal products (e.g., coenzyme Q10, green tea, St. John’s wort), and foods high in vitamin K (e.g., broccoli, brussels sprouts, cole slaw, spinach).11,24,25

Agents commonly associated with increased risk of bleeding include aspirin, NSAIDs, other anticoagulant drugs, platelet aggregation inhibitor agents, and prednisone.11,24,25 An alternative to using aspirin is acetaminophen, which can be used safely in most patients.

Patient Monitoring

Warfarin therapy has a narrow therapeutic window and requires frequent monitoring with clinical laboratory tests to ensure optimal outcomes and minimize bleeding complications.11,31 The PT, also known as the “protime,” has been used for decades to measure the anticoagulant effects of warfarin. The PT measures the biologic activity of factors II, VII, and X, which correlate well with warfarin’s anticoagulant effect. However, the PT test is problematic because of the wide variability in the International Sensitivity Index (ISI) of the thromboplastin reagent utilized by the lab. Addressing the need for standardization, the World Health Organization developed a reference thromboplastin reagent and recommended the use of the INR to monitor warfarin therapy.11

The INR, determined by a mathematic equation, reflects a patient’s PT value compared with the standardized PT value, helps correct for the differences in the ISI value of thromboplastin reagents (see INR EQUATION).

When warfarin therapy is initiated, the PT lab test is often performed two to three times per week until warfarin dosage changes and PT/INR test values become relatively stable. The PT lab test is then performed perhaps every two to four weeks to monitor the effectiveness of warfarin therapy. In addition to INRs, other clinical laboratory tests that are periodically needed include complete blood count (CBC) and urine and stool testing for occult blood.11,24,25

Patients receiving warfarin therapy should limit their consumption of foods that contain a high vitamin K content (TABLE 3). While warfarin therapy can usually be adjusted to accommodate regular, small amounts of these foods, large quantities or binging can cause the INR to vary greatly.

HEPARINS

Heparin is a naturally occurring substance produced by mast cells in humans and other animals. Although commercially available heparin was originally derived from beef lung, it is now mainly obtained from porcine intestine cells. Heparin is a heterogeneous mixture of low- and high-molecular-weight polysaccharides ranging from 3,000 to 30,000 daltons.11,24,25 When LMWH became available, heparin became known as standard heparin or UFH to differentiate older heparin products from newer LMWH products.

Like UFH, LMWH compounds are heterogeneous mixtures of sulfonated glycosaminoglycans with about one third of the molecular weight of UFH. Although all LMWH preparations have predominately shorter chains that contain both the pentasaccharide sequence and the thrombin-binding structures, their proportions greatly vary.11,28 Enoxaparin (Lovenox Injection/Sanofi Aventis), the first commercially available LMWH product, was introduced in the U.S. in 1993. Enoxaparin, dalteparin (Fragmin/Pfizer), and tinzaparin (Innohep/Pharmion Corp.) are currently available in the U.S. The LMWH products are derived by the chemical or enzymatic depolymerization of UFH and contain molecules that are shorter than those found in UFH. Currently, all LMWH products are administered by SC injection either once or twice daily. These products are derived from UFH by chemical or enzymatic depolymerization, yielding low-molecular-weight fragments of UFH.11,32,33

Heparin and LMWH agents combine with antithrombin to preferentially block the activation of factor X but also exert some antifactor IIa activity based on the degree to which longer chains are present in LMWH preparations [#msg-24393520]. Since LMWH products are manufactured by different methods of depolymerization, they differ in size, pharmacokinetic properties, and anticoagulant profile and are generally not considered clinically interchangeable.

Pharmacotherapeutics of Heparins

UFH has multiple indications and is available for both SC and continuous IV infusion administration.24 In clinical practice, UFH is generally the preferred anticoagulant to use during pregnancy and in situations requiring a rapid anticoagulant effect and a short duration of action when discontinued. As a continuous infusion, UFH is indicated for the treatment of pulmonary embolism, evolving stroke, and massive DVT; in patients undergoing open heart surgery and renal dialysis; for the prevention of postoperative venous thrombosis; and as adjunct therapy with a thrombolytic to treat an acute myocardial infarction. When administered subcutaneously, it is indicated for the prophylaxis of DVT. UFH can also be used as a heparin lock flush for IV catheters.5,34 With the increased popularity of LMWH products, UFH use has significantly diminished but continues in some hospitals and is preferred by some clinicians for certain thromboembolic conditions.

UFH dosing and Administration: The dosage of UFH is individualized to the patient, the thromboembolic disorder, and the severity of the disorder.24 UFH is dosed in international units (IUs), not milligrams. Continuous IV infusion is used to achieve and maintain full anticoagulation around the clock. In many patients, UFH therapy is initiated by giving an IV bolus dose followed by continuous IV heparin infusion of the drug. In hospitals, dosing of UFH is often determined by utilizing a weight-based heparin nomogram. Because there is substantial interpatient variability in anticoagulant response to UFH, frequent monitoring for therapeutic effects is needed.

LMWH products are indicated for the prevention of DVT and PE after hip or knee replacement surgery, prevention of DVT and PE after abdominal surgery, treatment of DVT with or without PE, and for unstable angina or non-Q-wave myocardial infarction.24

LMWH dosing and Administration: All LMWH products are available in fixed-dose prefilled syringes. Some products also have a multidose vial for weight-based dosing.24 LMWHs are administered by SC injection with either once- or twice-daily dosing. Dosage reduction is recommended in patients when creatinine clearance (CrCl) is less than 30 mL/min.

Patient Monitoring: Therapy with LMWH requires monitoring with baseline CBC and platelet counts. Periodically, CBC tests should be obtained and urine and stool should be checked for occult blood. Adjusting LMWH dosages and monitoring serum antifactor Xa levels should be considered in patients who have renal insufficiency (i.e., CrCl less than 30 mL/min), are morbidly obese, have low weight (i.e., less than 45 kg for women and less than 57 kg for men), are pediatric, are pregnant, or receive hemodialysis.

Pharmacokinetics of Heparins

UFH: UFH is not absorbed from the GI tract because it is readily destroyed by gastric acid. UFH must be administered by SC or IV routes.11,24 There is minimal or no biotransformation of heparin in plasma or the liver. It is a heavily sulfated compound with high negatively charged groups that promote extensive, nonspecific binding to several plasma and cellular proteins. The bioavailability of heparin is 20% to 40% with SC injection and about 70% to 80% when given intravenously. When administered by IV bolus followed by a continuous IV infusion, UFH has an immediate onset of action (up to 20 minutes) with a biological half-life of 60 to 90 minutes (dose dependent). When administered by SC injection, UFH has a slow onset of action (peak plasma levels occur in two to four hours) that allows it to be used for chronic prophylaxis of DVT. Since UFH is a heterogeneous mixture, its potency can vary greatly in commercial products. For this reason, a “heparin curve” should be determined at least yearly by the hospital’s clinical laboratory to document the relation between the therapeutic activated partial thromboplastin time (aPTT) range corresponding to heparin serum concentrations of 0.2 IU/mL to 0.4 IU/mL using protamine titration, or run antifactor Xa assay (therapeutic range 0.3 IU/mL to 0.7 IU/mL).11,24,25 Since heparin greatly binds to plasma proteins, frequent monitoring of aPTT lab tests is required. Additional UFH information is listed in TABLE 4.

LMWH:24 LMWH products generally have more predictable activities than UFH products. Due to their high degree of bioavailability (about 90%), LMWHs are well absorbed from SC injection. Peak antifactor Xa levels occur in three to five hours and persist for about 12 hours. The half-lives of products vary and are as follows: enoxaparin, 3.5 to 5.9 hours; dalteparin, 2.8 to four hours; and tinzaparin, two hours. While some degree of hepatic desulfation and depolymerization occur, much of the drug is eliminated renally. Additional LMWH information is listed in TABLE 4.

Pharmacodynamics of Heparins

UFH: UFH exerts its anticoagulant effect via AT. Heparin binds to and produces a conformational change in AT, converting it into a rapid inhibitor of factor Xa, thrombin (factor IIa), and other clotting factors. Heparin suppresses fibrin formation and limits the formation of a stable clot. Heparin-activated AT binds to the active site of thrombin but also blocks the fibrin-binding site. Thus, in a fibrin clot in which thrombin and fibrin are already bound, heparin is unable to inactivate thrombin.1,11 Low-dose SC heparin therapy (prophylactic dosing) deactivates factor Xa but has minimal effect on already produced thrombin and does not normally alter aPTT levels. Heparin has little effect on blood clots that have already formed, and it is antagonized by platelet factor 4 (PF4) released from activated platelets.1,11

Because of the size and heterogeneity of heparin preparations, approximately one third of heparin molecules in a given preparation exhibit anticoagulant activity. This activity is limited to a relatively smaller proportion of molecules (approximately 30%) whose structures include a pentasaccharide sequence.35 Studies have demonstrated that the anticoagulant effect of heparin requires a plasma cofactor, known as AT.36 Heparin exerts its anticoagulant effect by binding to AT through a unique glucosamine unit in the pentasaccharide sequence.34,37 This process inhibits the active center serine of thrombin and other coagulation enzymes by producing a conformational change at the arginine-reactive site that transforms AT from a slow progressive thrombin inhibitor to one that greatly accelerates the rate of thrombin (1,000 times) and/or factor Xa (300 times) inactivation.34

Heparin Overdose or Supratherapeutic aPTT Value: In these situations, IV heparin infusion should be placed on hold or stopped. Many hospitals have heparin protocols that instruct the clinician to “hold IV heparin infusion for one hour, then restart heparin infusion at a lower infusion rate.” With patients who are at high risk for bleeding, some clinicians will hold heparin therapy one to two hours and get an aPTT test immediately before restarting the heparin infusion. If this aPTT value is within expected limits, then the heparin infusion can be restarted at a lower infusion rate.

UFH Antidote: The drug protamine sulfate may be used to reverse a heparin overdose or a supratherapeutic aPTT value.35 Protamine sulfate is a small protein molecule with positive charges that bond with negative charges of heparin. This attraction occurs immediately and lasts for about two hours. Protamine sulfate is administered by slow IV infusion no faster than 20 mg/min or 50 mg in 10 minutes. A dose of 0.5 to 1 mg of protamine sulfate will neutralize 100 units of heparin. As a precaution, no more than 100 mg of protamine sulfate should be administered within a two-hour period.

LMWH: The anticoagulant activity of LMWH occurs by the same active pentasaccharide sequence that mediates the anticoagulant action of UFH. Since their LMWH chains are shorter than UFH, LMWHs inactivate thrombin to a lesser extent than UFH because their smaller molecular fragments cannot simultaneously bind thrombin and AT [#msg-24393520]. Therefore, LMWHs inhibit factor Xa to a greater extent than do thrombin or IIa.4 LMWHs display reduced binding to plasma and cellular proteins and have a more predictable dose response than does UFH.

LMWH Antidote: Protamine sulfate helps reverse a LMWH overdose but only reverses the anticoagulant effects by about 60% to 70%.24

Contraindications and Precautions

Heparin is contraindicated in patients with a documented case of heparin-induced thrombocytopenia (HIT) within the past four months and in patients who are hypersensitive to beef or pork products. It is also contraindicated in patients with thrombocytopenia (platelet count less than 150,000 mm3) or uncontrollable bleeding and during or immediately after eye, brain, or spinal cord surgeries, lumbar puncture, regional anesthesia, and threatening abortion.24

LMWHs are contraindicated in patients with a documented case of HIT within the past four months or in patients with current thrombocytopenia.24 Due to the risk of a hematoma formation, all IM injections should be avoided in patients with a documented case of HIT within the past four months. Adjusted dosing and monitoring of antifactor Xa levels are suggested for patients with renal insufficiency (i.e., CrCl less than 30 mL/min) or low weight (i.e., less than 45 kg for women and less than 57 kg for men), pediatric patients, and patients who are morbidly obese, pregnant, or receiving hemodialysis.24

Adverse Effects24

UFH: The most common adverse effect of UFHs is bleeding with secondary bruising, hematuria, and heme-positive emesis or stools.11,24 Other effects include thrombocytopenia, hypersensitivity reactions (nonallergic mediated), local irritation, and hematoma from SC administration. HIT, a severe drop in platelet counts (following exposure to a heparin product) as a result of the formation of heparin antibodies, is a less common adverse effect. Osteoporosis and bone fractures occur rarely with doses of 15,000 or more units/day for longer than five months.24

LMWH: The most common adverse effects of LMWHs are bleeding with secondary bruising and heme-positive urine or stools, but these are considered to be less than standard heparin. Less common adverse effects include type II HIT, which occurs much less often with LMWH than with UFH.11,24 However, LMWH cross-reacts with antibodies against UFH and should not be given as an alternative anticoagulant in patients with new-onset HIT or a history of HIT.

Drug Interactions24

UFH and LMWH can interact with other anticoagulants, especially warfarin, platelet aggregation inhibitor agents (e.g., aspirin, ibuprofen, indomethacin), or drugs that weaken host defense against hemorrhage. Concurrent use of UFH and LMWH with warfarin will increase the patient’s risk of bleeding; therefore, they should only be used upon the advice of their health care provider. IV UFH is incompatible with a number of other IV drugs and should be administered in a separate IV line.

Patient Monitoring

UFH baseline aPTT, PT/INR, and CBC values are needed. To avoid falsely elevated aPTT values, blood specimens should not be drawn from heparin locks, IV catheters, or infusion ports that were previously exposed to heparin. Although more painful for the patient, it is best to obtain specimens by venipuncture each time an aPTT specimen is drawn. Following the initiation of heparin therapy, aPTT labs should be monitored every six hours and a CBC should be obtained every other day. The dose of heparin should be titrated to achieve and maintain an aPTT value in the appropriate therapeutic range. Patients should be monitored daily for signs of external bruising and bleeding, and urine and stools should be tested for occult blood.

…CONCLUSION

Medical management of TEDs in the U.S. has changed dramatically since the introduction of orally administered warfarin in the mid-1950s. Antithrombotic therapy with warfarin for stroke prevention is a proven cost-effective therapy for patients ages 65 to 75 years with nonvalvular atrial fibrillation. A recent meta-analysis of 16 clinical trials established that the aggregate relative risk reduction of stroke was 62% in patients with atrial fibrillation who were taking warfarin and had an INR in the 2.0 to 3.0 range.39 Despite warfarin’s proven efficacy to reduce the risk of stroke, the drug is not heavily prescribed to many patients, especially the elderly population. Warfarin requires close monitoring of the patient and routine blood tests (i.e., INR and CBCs) to ensure therapeutic effectiveness and patient safety. Pharmacists and/or nurse-managed “Coumadin clinics” manage the therapy of many outpatients. Warfarin is currently the only oral agent available in the U.S. for chronic antithrombotic therapy for TED.

IV UFH therapy for the treatment and prevention of DVTs and PEs was the agent of choice for institutionalized patients during the 1970s to early 1990s. However, frequent dosage changes and close monitoring of aPTT lab tests and hospitalization costs have basically restricted the use of UFH to inpatients.

Parenteral LMWH products were introduced in the mid 1980s, and were widely accepted as the standard of care for acute TED therapy in the early 1990s. Their utilization is heavily influenced by its equal efficacy as UFH and because it can be used to treat many patients as outpatients, thus avoiding costly hospital expenses. LMWH products are very effective and require either the patient or caregiver to administer the drug parenterally.

--
Table 1
Recommended Guidelines for Patients Receiving Oral Anticoagulant Therapy

Indications: Target INR (Goal Range)
Prophylaxis of venous thrombosis (high-risk) surgery 2.5 (2.0 to 3.0)
Treatment of venous thrombosis 2.5 (2.0 to 3.0)
Treatment of PE 2.5 (2.0 to 3.0)
Prevention of systemic embolism
Tissue heart valves
Valvular heart disease
Atrial fibrillation 2.5 (2.0 to 3.0)
Bileaflet mechanical values 2.5 (2.0 to 3.0)
Mechanical prosthetic valves (high risk) 3.0 (2.5 to 3.5)
Certain patients with thrombosis and the antiphospholipid syndrome 3.0 (2.5 to 3.5)
AMI (to prevent recurrent AMI) 3.0 (2.5 to 3.5)
INR: international normalized ratio; PE: pulmonary embolism;
AMI: acute myocardial infarction.

Source: References 25, 26.


Table 2
Elimination Half-Life of Vitamin K–Dependent Coagulation Proteins

Protein Half-life (hours)
Factor VII 4–6
Factor IX 20–30
Factor X 24–40
Prothrombin (Factor II) 60–100
Protein C 8–10
Protein S 40–60
[Source: References 25-27.]


Table 4
Comparison of UFH and LMWH

Property UFH LMWH
Molecular weight: 3,000 to 30,000* 1,000 to 10,000*
Average molecular weight: 12,000 to 15,000* 4,000 to 5,000*
Anti-factor Xa to factor IIa activity ratio: 1:1 2:4. 4
Absorption: Highly protein bound Low protein binding
Bioavailability: SC ~20% SC >90%
IV 70% to 80% IV >90%
Distribution: Aqueous Aqueous
Metabolism: Some hepatic Minimal hepatic
Route of elimination: Reticular endothelial and endothelial, also renal (low) Renal (predominantly)
Dose-dependent clearance: Yes No
Onset of action: Immediately 1–2 hours
Elimination half-life: 1–1.5 hours 2–4.5 hours (high end of range with low creatine clearance [CrCl])
Capable of inactivation of platelet-bound factor Xa: No Yes
aPTT lab monitoring: Yes No
Anti–factor Xa lab monitoring: No Yes/No
Inhibition of platelet function: +4† +2
Protein binding: +4† +1
Endothelial cell binding: +3† 0
Antidote for toxicity: Protamine SO4 Protamine SO4 (~60% to 75% effective)
Risk of HIT: 2% to 5% 1% to 2% (cross-reactivity when heparin is positive for PF4)
Pregnancy category: C B

* Measured in daltons.
† A value of 4 is high and 0 is low.
<<