Monitoring Antithrombotic Therapies



Monitoring Antithrombotic Therapies


George A. Fritsma



Objectives


After completion of this chapter, the reader will be able to:


1. Describe the purpose of antithrombotic administration and distinguish between anticoagulants and antiplatelet therapy.


2. Describe the indications for, dosage of, and management of warfarin therapy, including how to treat warfarin overdose.


3. Monitor warfarin therapy using the prothrombin time and international normalized ratio, and compare these tests with the chromogenic X assay.


4. Perform and interpret prothrombin times using point-of-care instruments.


5. Describe the indications for, dosage of, and management of unfractionated heparin therapy, including how to establish the unfractionated heparin therapeutic partial thromboplastin time range.


6. Describe the indications, dosage, and management of low-molecular-weight heparin therapy and fondaparinux therapy.


7. Perform and interpret the results of the partial thromboplastin time and activated clotting time assays for the monitoring of unfractionated heparin therapy, and compare these tests with the chromogenic anti-Xa heparin assay.


8. Perform and interpret the results of the chromogenic anti-Xa assay for the monitoring of unfractionated heparin therapy, low-molecular-weight heparin therapy, and fondaparinux therapy.


9. Select appropriate laboratory tests for the monitoring of antithrombotic therapy, recognize appropriate testing frequency, follow appropriate timing for test administration, and interpret test results as indicating adequate, inadequate, or excessive drug dosage.


10. Describe how rivaroxaban exerts its direct anti-Xa effect; discuss methods for monitoring rivaroxaban therapy.


11. Monitor therapy with direct thrombin inhibitors, including dabigatran, using the partial thromboplastin time and the ecarin clotting time.


12. Describe the therapeutic function of the intravenous platelet glycoprotein IIb/IIIa inhibitors and describe how their effects are monitored.


13. Describe the therapeutic function of the oral platelet inhibitors aspirin, clopidogrel, ticlopidine, and prasugrel and describe how their effects are monitored.



Venous or arterial thrombotic disease is managed by antithrombotic therapy, which includes anticoagulant and antiplatelet therapy. Venous thromboembolic disease (venous thromboembolism, or VTE) includes superficial and deep vein thrombosis (DVT) and pulmonary embolism (PE) and is treated using the anticoagulants warfarin (Coumadin), standard unfractionated heparin (UFH), low-molecular-weight heparin (LMWH, enoxaparin), and synthetic pentasaccharide (fondaparinux). The direct thrombin inhibitors (DTIs) argatroban, lepirudin, and bivalirudin are additional anticoagulants substituted for heparin in patients who have developed heparin-induced thrombocytopenia (HIT) subsequent to UFH therapy (see Chapter 42). All of these anticoagulant drugs are administered intravenously except warfarin, which is an oral anticoagulant. Unfractionated heparin therapy began in the late 1930s, and warfarin therapy was first used in 1952. As of July 2010, warfarin remained the only oral anticoagulant, although at least two new oral anticoagulants, rivaroxaban and dabigatran, may be cleared by the U.S. Food and Drug Administration (FDA) in 2011 or 2012.


Arterial thrombosis includes acute myocardial infarction (AMI), ischemic cerebrovascular accident (stroke), transient ischemic attack, and peripheral arterial occlusion and is managed with the heparins, the DTIs, and the antiplatelet drugs aspirin, ticlopidine, and clopidogrel. Aspirin is particularly effective in reducing mortality when taken within 6 hours of the onset of symptoms. The platelet glycoprotein IIb/IIIa inhibitor drugs eptifibatide, abciximab, and tirofiban are used to prevent thrombosis during cardiac catheterization procedures.


Thrombolytic therapy helps resolve DVT, PE, peripheral artery occlusions, AMI, and stroke, particularly when used shortly after the onset of symptoms. Most thrombolytic therapy uses the recombinant forms of tissue plasminogen activator, reteplase and alteplase. Thrombolytic therapy raises the risk of hemorrhage, particularly intracranial hemorrhage. Thrombolytic therapy is not monitored by laboratory tests.


Many lives have been saved through judicious use of antithrombotic therapy, and countless more healthy individuals have been spared thrombotic disease through long-term antithrombotic prophylaxis. However, antithrombotics are dangerous because their effective dosage ranges are narrow.1 Overdose is critical and leads to emergency department visits for uncontrolled bleeding; inadequate dosages lead to secondary (repeat), often fatal, thrombotic events. Dosages and half-lives differ among the antithrombotics and thrombolytics because of variations in formulation and metabolism.2,3


Because of these risks, laboratory monitoring of antithrombotic therapy, the earliest form of therapeutic drug monitoring, is essential. Coagulation laboratory scientists perform countless prothrombin time (PT) assays, partial thromboplastin time (PTT, activated partial thromboplastin time [APTT]) assays, and chromogenic anti–factor Xa heparin assays to monitor anticoagulant therapy, and this accounts for most of their workload. Antiplatelet therapy monitoring generates a smaller, but rapidly growing workload. Although antithrombotic therapy monitoring may seem routine, vigilance is essential to provide consistently valid results in a dangerous therapeutic world.4



Warfarin Therapy and the Prothrombin Time


Warfarin: Vitamin K Antagonist


As detailed in Chapter 40, coagulation factors II (prothrombin), VII, IX, and X depend on vitamin K for normal production, as do coagulation control proteins C, S, and Z. Vitamin K is responsible for γ-carboxylation of a series of 12 to 18 N-terminus glutamic acids, a posttranslational modification that enables these coagulation factors and control proteins to bind ionic calcium (Ca2+) and cell membrane phospholipids, especially phosphatidylserine (see Figure 40-8). Vitamin K is concentrated in green leafy vegetables and is produced by gut flora; its absence results in the production of nonfunctional des-γ carboxyl, forms of factors II, VII, IX, and X and proteins C, S, and Z.


Warfarin sodium (4-hydroxycoumarin, Coumadin) is a member of the coumarin drug family and is the formulation of coumarin most often used in North America.5 Another coumarin is dicumarol (3,3′-methylenebis-[4-hydroxycoumarin]), the original anticoagulant extracted from moldy sweet clover by Link in 1940.6 Warfarin is a vitamin K antagonist that suppresses γ-carboxylation of glutamic acid by slowing the activity of the enzyme vitamin K epoxide reductase (see Figure 40-8). During warfarin therapy, the activities of factors II, VII, IX, and X and proteins C, S, and Z become reduced as the nonfunctional des-carboxyl proteins are produced. These are called proteins induced by vitamin K antagonists (PIVKAs); they bind few calcium ions, do not assemble on phospholipid surfaces with their substrates, and therefore do not participate in coagulation. Despite several developmental efforts, in 2010 coumarins remained the only oral anticoagulants in the United States, so warfarin therapy is often called oral anticoagulant therapy. Two new oral anticoagulant drugs, rivaroxaban and dabigatran, became available in 2009 outside the United States and may be cleared by the FDA in 2011 or 2012.



Warfarin Prophylaxis and Therapy


Warfarin is prescribed prophylactically to prevent strokes in patients with atrial fibrillation and to prevent VTE after trauma, orthopedic surgery, or general surgery, and in a number of chronic medical conditions. Therapeutic warfarin inhibits the recurrence of DVT or PE. Warfarin is also used therapeutically after AMI if the event is complicated by congestive heart failure or coronary insufficiency. Warfarin is among the top 20 most commonly prescribed drugs in North America.


The standard warfarin regimen begins with a 5-mg daily oral dose. The starting dosage for people older than 70 years and people who are debilitated, malnourished, or have congestive heart failure is 2 mg/day. For people simultaneously taking drugs that are known to raise warfarin sensitivity, the starting dosage is 2 mg/day, and 2 mg/day is also the dosage used for those with inherited warfarin sensitivity. There is no loading dose, and subsequent dosing is based on patient response as measured by the PT (see the next section). The activity of each of the vitamin K–dependent coagulation factors begins to decline immediately but at different rates (Figure 46-1) for each factor, and it takes about 5 days for all the factors to reach therapeutic levels. Table 46-1 lists the plasma half-life, plasma concentration, and minimum effective plasma percentage of normal factor activity for the coagulation factors.



image
Figure 46-1 Factor VII activity decreases to 50% of normal 6 hours after warfarin therapy is begun, prolonging the factor VIIa–sensitive prothrombin time to near the therapeutic range. The half-lives of factors II (prothrombin), IX, and X are longer than that of VII; factor II activity requires at least 3 days to decline by 50%. The patient gains full anticoagulation effects approximately 5 days after the start of warfarin therapy.

Control protein activities also become reduced, especially the activity of protein C, which has a 6-hour half-life, so for the first 2 or 3 days of warfarin therapy the patient actually risks a thrombotic event. For this reason, warfarin therapy is “covered” by UFH, LMWH, or pentasaccharide therapy for at least 5 days. Failure to provide anticoagulant therapy during this period may result in warfarin skin necrosis, a severe reaction requiring débridement of dead tissue.7



Monitoring Warfarin Therapy Using the Prothrombin Time Assay


The PT effectively monitors warfarin therapy because it is sensitive to reductions of factors II, VII, and X (Figure 46-2). The PT reagent consists of tissue factor, phospholipid, and ionic calcium, so it triggers the coagulation pathway at the level of factor VII. Owing to the 6-hour half-life of factor VII, the PT begins to prolong within 6 to 8 hours; however, anticoagulation becomes therapeutic only when the activities of factors II and X decrease to less than 50% of normal, in approximately 5 days.


image
Figure 46-2 The prothrombin time (PT) reagent activates the extrinsic coagulation pathway beginning with factor VII. The PT is prolonged by deficiencies of factors VII, X, V, II (prothrombin), and fibrinogen when the fibrinogen concentration is less than 100 mg/dL. The PT is prolonged in warfarin therapy, because it responds to the reduced VII, X, and prothrombin activity. The partial thromboplastin time (PTT) reagent activates the intrinsic coagulation pathway through factor XII, assisted by prekallikrein (pre-K) and high-molecular-weight kininogen (HMWK). The PTT is prolonged by deficiencies of pre-K; HMWK; factors XII, XI, IX, VIII, and X; prothrombin; and fibrinogen when the fibrinogen concentration is less than 100 mg/dL. The PTT is prolonged in unfractionated heparin (UFH) therapy because UFH activates the plasma control protein antithrombin, which neutralizes the serine proteases XIIa, XIa, Xa, IXa, and IIa (thrombin [Thr]). TF, Tissue factor.

The first PT is assayed 24 hours after therapy is initiated; subsequent PTs are performed daily until two consecutive results are within the target therapeutic range. Monitoring continues every 4 weeks until the completion of therapy, which often lasts for 6 months following a thrombotic event. Warfarin therapy for atrial fibrillation is of indefinite length, possibly lifelong. Close monitoring is essential for successful warfarin therapy, because the therapeutic range is narrow. Underanticoagulation signals the danger of thrombosis or secondary thrombosis (rethrombosis); overdose carries the danger of hemorrhage.



Reporting Prothrombin Time Results and the International Normalized Ratio


The medical laboratory scientist reports PT results to the nearest tenth of a second and provides the PT reference interval for comparison. In view of the inherent variations among thromboplastin reagents, and to accomplish interlaboratory normalization, all laboratories report the international normalized ratio (INR) for patients with a stable response to anticoagulant therapy using the following formula8:


INR=(PTpatient/PTnormal)ISI


image

where PTpatient is the PT of the patient in seconds, PTnormal is the geometric mean of the PT reference interval in seconds, and ISI is the international sensitivity index applied as an exponent in the formula.


Thromboplastin producers generate the ISI by performing an orthogonal regression analysis comparing the results of their PT reagents for 50 or more anticoagulated specimens and 10 or more normal specimens with the published results of the international reference thromboplastin (World Health Organization human brain thromboplastin).9 Most manufacturers provide ISIs for a variety of coagulation instruments, because each may respond differently to their thromboplastins; for instance, some coagulometers rely on photometric changes, whereas others use an electromechanical system (see Chapter 47). Most thromboplastin reagents have ISIs near 1, which is the ISI of the World Health Organization’s thromboplastin. Automated coagulation timers request the reagent ISI from the operator or obtain it directly from a reagent vial bar code and compute the INR for each assay result. Although INRs are meant to be computed only for patients taking anticoagulants in whom the response to therapy has stabilized, they typically are reported for all patients, even those who are not taking warfarin. During the first 5 days of warfarin therapy, the astute physician and medical laboratory scientist ignore the INR as unreliable and interpret the PT results in seconds, comparing it with the reference interval.





Effect of Diet and Drugs on Warfarin Therapy


Dietary vitamin K decreases warfarin’s effect and reduces the INR. Green vegetables are an important source of vitamin K, but vitamin K also is concentrated in liver, avocados, parenteral nutrition formulations, multivitamins, red wine, over-the-counter nutrition drinks, and over-the-counter dietary supplements. A patient who is taking warfarin is counseled to maintain a regular balanced diet and to follow up dietary or dietary supplement changes with additional PT assays and dosage adjustments if necessary.


Warfarin is metabolized in the mitochondrial cytochrome P-450 (CYP 2C9) pathway of hepatocytes, the “disposal system” for at least 80 drugs. Theoretically, use of any drug metabolized through the CYP 2C9 pathway may unpredictably suppress or enhance the effects of warfarin. Amiodarone, metronidazole, and cimetidine typically double or triple the INR. Any change in drug therapy, like a change in diet, must be followed up with additional PT assays and dosage adjustments.


Warfarin is contraindicated during pregnancy, because it causes birth defects. When anticoagulation is desired during pregnancy—for instance, in women who possess a thrombosis risk factor—LMWH or fondaparinux is prescribed.



Effect of Polymorphisms on Warfarin Therapy


Two polymorphisms generate variations in enzymes of the cytochrome P-450 pathway. These are CYP2C9*2 and CYP2C9*3, which reduce pathway activity and slow the metabolic breakdown of warfarin. Likewise, there is a polymorphism that affects the key enzyme of vitamin K metabolism, vitamin K epoxide reductase. This polymorphism, named VKORC1, slows vitamin K reduction, which makes the patient more sensitive to warfarin. In patients possessing one, two, or all three of these polymorphisms, warfarin therapy should begin at 2 mg/day and should be adjusted and monitored daily until the INR remains consistently in the therapeutic range. The standard 5 mg/day regimen risks hemorrhage in these patients. In 2007, the FDA required that drug manufacturers add a statement on all vials of warfarin recommending that physicians screen patients for dosage-affecting polymorphisms. Although the FDA recommendation does not carry the weight of a black box warning, numerous molecular diagnostics manufacturers have developed short turn-around assays for these three polymorphisms. Screening for these polymorphisms is the first and most public example of pharmacogenomic laboratory testing, although as of 2010 it had not been universally endorsed.10


Conversely, warfarin receptor insufficiency may render the patient resistant to warfarin therapy. Some patients require dosages of 20 mg/day or higher to achieve a therapeutic INR. The search is on for polymorphisms responsible for such “warfarin resistance,“ and by 2012 or 2013, at least one such assay may become available from reference laboratories.11




Reversal of Warfarin Overdose


Table 46-2 provides recommendations for the reversal of a warfarin overdose based on INR and clinical evidence of bleeding. The concerns surrounding warfarin therapy will recede in importance as new oral anticoagulants are cleared for distribution in the United States (see the sections on rivaroxaban and dabigatran).




Prothrombin Time Point-of-Care Testing


The following instruments have been cleared by the FDA for point-of-care PT measurement using a venous whole-blood specimen or capillary specimen, or both:



Most of these instruments are portable and are hand-held.13


Point-of-care instruments permit near-patient PT testing at anticoagulation clinics, bedside testing, self-testing, and testing of infants. The operator or patient performs a capillary puncture and captures the free-flowing capillary blood in a cartridge that is transferred to the instrument. Alternatively, a drop of anticoagulated venous whole blood may be transferred to the test cartridge. No point-of-care instrument measures PTT, although several report activated clotting time (ACT).


Each instrument uses individual patented technology to generate a PT with an INR, and each produces reference intervals and target therapeutic ranges in INR units and seconds that may diverge slightly from plasma-based central laboratory results. In many cases, the manufacturer programs in a linear electronic conversion factor so that the readout more closely matches plasma results. The manufacturer also provides internal electronic calibration and whole-blood controls. Before point-of-care instruments are placed in service, laboratory scientists validate the units’ measurements using a plasma-based PT assay as the reference method, comparing the results obtained by each method through linear regression and a test of means such as the Student t-test. Owing to inherent variation, laboratory scientists advise that each point-of-care analyzer’s test results be compared with its own reference interval and target therapeutic range.


The pharmacists and nurse practitioners who typically manage anticoagulation clinics appreciate point-of-care instruments for their instantaneous turnaround. Patient waiting time is eliminated, and dosage adjustment can be made at the time of the patient’s visit. Clinics so equipped capitalize on the convenience factor to attract patients and maximize the time their anticoagulation is within the therapeutic range.

Related posts:

Introduction to Leukocyte Neoplasms Bone Marrow Failure Coagulation Instrumentation Cytochemistry Hematopoiesis Platelet Production, Structure, and Function

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Jun 12, 2016 | Posted by in HEMATOLOGY | Comments Off on Monitoring Antithrombotic Therapies

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