American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.

Abstract

HomeCirculationVol. 107, No. 12American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBAmerican Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy Jack Hirsh, MD, FRCP(C), FRACP, FRSC, DSc, Valentin Fuster, MD, PhD, Jack Ansell, MD and Jonathan L. Halperin, MD Jack HirshJack Hirsh Search for more papers by this author , Valentin FusterValentin Fuster Search for more papers by this author , Jack AnsellJack Ansell Search for more papers by this author and Jonathan L. HalperinJonathan L. Halperin Search for more papers by this author Originally published1 Apr 2003https://doi.org/10.1161/01.CIR.0000063575.17904.4ECirculation. 2003;107:1692–1711Pharmacology of WarfarinMechanism of Action of Coumarin Anticoagulant DrugsWarfarin, a coumarin derivative, produces an anticoagulant effect by interfering with the cyclic interconversion of vitamin K and its 2,3 epoxide (vitamin K epoxide). Vitamin K is a cofactor for the carboxylation of glutamate residues to γ-carboxyglutamates (Gla) on the N-terminal regions of vitamin K–dependent proteins (Figure 1).1–6 These proteins, which include the coagulation factors II, VII, IX, and X, require γ-carboxylation by vitamin K for biological activity. By inhibiting the vitamin K conversion cycle, warfarin induces hepatic production of partially decarboxylated proteins with reduced coagulant activity.7,8Download figureDownload PowerPointFigure 1. The vitamin K cycle and its link to carboxylation of glutamic acid residues on vitamin K–dependent coagulation proteins. Vitamin K1 obtained from food sources is reduced to vitamin KH2 by a warfarin-resistant vitamin K reductase. Vitamin KH2 is then oxidized to vitamin K epoxide (Vit KO) in a reaction that is coupled to carboxylation of glutamic acid residues on coagulation factors. This carboxylation step renders the coagulation factors II, VII, IX, and X and the anticoagulant factors protein C and protein S functionally active. Vit KO is then reduced to Vit K1 in a reaction catalyzed by vitamin KO reductase. By inhibiting vitamin KO reductase, warfarin blocks the formation of vitamin K1 and vitamin KH2, thereby removing the substrate (vitamin KH2) for the carboxylation of glutamic acids. Vitamin K1, either given therapeutically or derived from food sources, can overcome the effect of warfarin by bypassing the warfarin-sensitive vitamin KO reductase step in the formation of vitamin KH2.Carboxylation promotes binding of the vitamin K–dependent coagulation factors to phospholipid surfaces, thereby accelerating blood coagulation.9–11 γ-Carboxylation requires the reduced form of vitamin K (vitamin KH2). Coumarins block the formation of vitamin KH2 by inhibiting the enzyme vitamin K epoxide reductase, thereby limiting the γ-carboxylation of the vitamin K–dependent coagulant proteins. In addition, the vitamin K antagonists inhibit carboxylation of the regulatory anticoagulant proteins C and S. The anticoagulant effect of coumarins can be overcome by low doses of vitamin K1 (phytonadione) because vitamin K1 bypasses vitamin K epoxide reductase (Figure 1). Patients treated with large doses of vitamin K1 (usually >5 mg) can become resistant to warfarin for up to a week because vitamin K1 accumulating in the liver is available to bypass vitamin K epoxide reductase.Warfarin also interferes with the carboxylation of Gla proteins synthesized in bone.12–15 Although these effects contribute to fetal bone abnormalities when mothers are treated with warfarin during pregnancy, 16,17 there is no evidence that warfarin directly affects bone metabolism when administered to children or adults.Pharmacokinetics and Pharmacodynamics of WarfarinWarfarin is a racemic mixture of 2 optically active isomers, the R and S forms, in roughly equal proportion. It is rapidly absorbed from the gastrointestinal tract, has high bioavailability,18,19 and reaches maximal blood concentrations in healthy volunteers 90 minutes after oral administration.18,20 Racemic warfarin has a half-life of 36 to 42 hours,21 circulates bound to plasma proteins (mainly albumin), and accumulates in the liver, where the 2 isomers are metabolically transformed by different pathways.21 The relationship between the dose of warfarin and the response is influenced by genetic and environmental factors, including common mutations in the gene coding for cytochrome P450, the hepatic enzyme responsible for oxidative metabolism of the warfarin S-isomer.18,19 Several genetic polymorphisms in this enzyme have been described that are associated with lower dose requirements and higher bleeding complication rates compared with the wild-type enzyme CYP2C9*.22–24In addition to known and unknown genetic factors, drugs, diet, and various disease states can interfere with the response to warfarin.The anticoagulant response to warfarin is influenced both by pharmacokinetic factors, including drug interactions that affect its absorption or metabolic clearance, and by pharmacodynamic factors, which alter the hemostatic response to given concentrations of the drug. Variability in anticoagulant response also results from inaccuracies in laboratory testing, patient noncompliance, and miscommunication between the patient and physician. Other drugs may influence the pharmacokinetics of warfarin by reducing gastrointestinal absorption or disrupting metabolic clearance. For example, the anticoagulant effect of warfarin is reduced by cholestyramine, which impairs its absorption, and is potentiated by drugs that inhibit warfarin clearance through stereoselective or nonselective pathways.25,26 Stereoselective interactions may affect oxidative metabolism of either the S- or R-isomer of warfarin.25,26 Inhibition of S-warfarin metabolism is more important clinically because this isomer is 5 times more potent than the R-isomer as a vitamin K antagonist.25,26 Phenylbutazone,27 sulfinpyrazone,28 metronidazole,29 and trimethoprim-sulfamethoxazole30 inhibit clearance of S-warfarin, and each potentiates the effect of warfarin on the prothrombin time (PT). In contrast, drugs such as cimetidine and omeprazole, which inhibit clearance of the R-isomer, potentiate the PT only modestly in patients treated with warfarin.26,29,31 Amiodarone inhibits the metabolic clearance of both the S- and R-isomers and potentiates warfarin anticoagulation.32 The anticoagulant effect is inhibited by drugs like barbiturates, rifampicin, and carbamazepine, which increase hepatic clearance.31 Chronic alcohol consumption has a similar potential to increase the clearance of warfarin, but ingestion of even relatively large amounts of wine has little influence on PT in subjects treated with warfarin.33 For a more thorough discussion of the effect of enzyme induction on warfarin therapy, the reader is referred to a recent critical review.34Warfarin pharmacodynamics are subject to genetic and environmental variability as well. Hereditary resistance to warfarin occurs in rats as well as in human beings,35–37 and patients with genetic warfarin resistance require doses 5- to 20-fold higher than average to achieve an anticoagulant effect. This disorder is attributed to reduced affinity of warfarin for its hepatic receptor.A mutation in the factor IX propeptide that causes bleeding without excessive prolongation of PT also has been described.38 The mutation occurs in <1.5% of the population. Patients with this mutation experience a marked decrease in factor IX during treatment with coumarin drugs, and levels of other vitamin K–dependent coagulation factors decrease to 30% to 40%. The coagulopathy is not reflected in the PT, and therefore, patients with this mutation are at risk of bleeding during warfarin therapy.38–40 An exaggerated response to warfarin among the elderly may reflect its reduced clearance with age.41–43Subjects receiving long-term warfarin therapy are sensitive to fluctuating levels of dietary vitamin K,44,45 which is derived predominantly from phylloquinones in plant material.45 The phylloquinone content of a wide range of foodstuffs has been listed by Sadowski and associates.46 Phylloquinones counteract the anticoagulant effect of warfarin because they are reduced to vitamin KH2 through the warfarin-insensitive pathway.47 Important fluctuations in vitamin K intake occur in both healthy and sick subjects.48 Increased intake of dietary vitamin K sufficient to reduce the anticoagulant response to warfarin44 occurs in patients consuming green vegetables or vitamin K–containing supplements while following weight-reduction diets and in patients treated with intravenous vitamin K supplements. Reduced dietary vitamin K1 intake potentiates the effect of warfarin in sick patients treated with antibiotics and intravenous fluids without vitamin K supplementation and in states of fat malabsorption. Hepatic dysfunction potentiates the response to warfarin through impaired synthesis of coagulation factors. Hypermetabolic states produced by fever or hyperthyroidism increase warfarin responsiveness, probably by increasing the catabolism of vitamin K–dependent coagulation factors.49,50 Drugs may influence the pharmacodynamics of warfarin by inhibiting synthesis or increasing clearance of vitamin K–dependent coagulation factors or by interfering with other pathways of hemostasis. The anticoagulant effect of warfarin is augmented by the second- and third-generation cephalosporins, which inhibit the cyclic interconversion of vitamin K51,52; by thyroxine, which increases the metabolism of coagulation factors50; and by clofibrate, through an unknown mechanism.53 Doses of salicylates >1.5 g per day54 and acetaminophen55 also augment the anticoagulant effect of warfarin, possibly because these drugs have warfarin-like activity.56 Heparin potentiates the anticoagulant effect of warfarin but in therapeutic doses produces only slight prolongation of the PT.Drugs such as aspirin,57 nonsteroidal antiinflammatory drugs,58 penicillins (in high doses),59,60 and moxolactam52 increase the risk of warfarin-associated bleeding by inhibiting platelet function. Of these, aspirin is the most important because of its widespread use and prolonged effect.61 Aspirin and nonsteroidal antiinflammatory drugs also can produce gastric erosions that increase the risk of upper gastrointestinal bleeding. The risk of clinically important bleeding is heightened when high doses of aspirin are taken during high-intensity warfarin therapy (international normalized ratio [INR] 3.0 to 4.5).57,62 In 2 studies, one involving patients with prosthetic heart valves63 and the other involving asymptomatic individuals at high risk of coronary artery disease,64 low doses of aspirin (100 mg and 75 mg daily, combined with moderate- and low-intensity warfarin anticoagulation, respectively) also were associated with increased rates of minor bleeding.The mechanisms by which erythromycin65 and some anabolic steroids66 potentiate the anticoagulant effect of warfarin are unknown. Sulfonamides and several broad-spectrum antibiotic compounds may augment the anticoagulant effect of warfarin in patients consuming diets deficient in vitamin K by eliminating bacterial flora and aggravating vitamin K deficiency.67Wells et al68 critically analyzed reports of possible interactions between drugs or foods and warfarin. Interactions were categorized as highly probable, probable, possible, or doubtful. There was strong evidence of interaction in 39 of the 81 different drugs and foods appraised; 17 potentiate warfarin effect and 10 inhibit it, but 12 produce no effect. Many other drugs have been reported to either interact with oral anticoagulants or alter the PT response to warfarin.69,70 A recent review highlighted the importance of postmarketing surveillance with newer drugs, such as celecoxib, a drug that showed no interactions in Phase 2 studies but was subsequently suspected of potentiating the effect of warfarin in several case reports.71 This review also drew attention to potential interactions with less well-regulated herbal medicines. For these reasons, the INR should be measured more frequently when virtually any drug or herbal medicine is added or withdrawn from the regimen of a patient treated with warfarin.The Antithrombotic Effect of WarfarinThe antithrombotic effect of warfarin conventionally has been attributed to its anticoagulant effect, which in turn is mediated by the reduction of 4 vitamin K–dependent coagulation factors. More recent evidence, however, suggests that the anticoagulant and antithrombotic effects can be dissociated and that reduction of prothrombin and possibly factor X are more important than reduction of factors VII and IX for the antithrombotic effect. This evidence is indirect and derived from the following observations: First, the experiments of Wessler and Gitel72 more than 40 years ago, which used a stasis model of thrombosis in rabbits, showed that the antithrombotic effect of warfarin requires 6 days of treatment, whereas an anticoagulant effect develops in 2. The antithrombotic effect of warfarin requires reduction of prothrombin (factor II), which has a relatively long half-life of ≈60 to 72 hours, compared with 6 to 24 hours for other K-dependent factors responsible for the more rapid anticoagulant effect. Second, in a rabbit model of tissue factor–induced intravascular coagulation, the protective effect of warfarin is mainly a result of lowering prothrombin levels.73 Third, Patel and associates74 demonstrated that clots formed from umbilical cord plasma (containing about half the prothrombin concentration of adult control plasma) generated significantly less fibrinopeptide A, reflecting less thrombin activity, than clots formed from maternal plasma. The view that warfarin exerts its antithrombotic effect by reducing prothrombin levels is consistent with observations that clot-bound thrombin is an important mediator of clot growth75 and that reduction in prothrombin levels decreases the amount of thrombin generated and bound to fibrin, reducing thrombogenicity.74The suggestion that the antithrombotic effect of warfarin is reflected in lower levels of prothrombin forms the basis for overlapping heparin with warfarin until the PT (INR) is prolonged into the therapeutic range during treatment of patients with thrombosis. Because the half-life of prothrombin is ≈60 to 72 hours, ≥4 days’ overlap is necessary. Furthermore, the levels of native prothrombin antigen during warfarin therapy more closely reflect antithrombotic activity than the PT.76 These considerations support administering a maintenance dose of warfarin (≈5 mg daily) rather than a loading dose when initiating therapy. The rate of lowering prothrombin levels was similar with either a 5- or a 10-mg initial warfarin dose,77 but the anticoagulant protein C was reduced more rapidly and more patients were excessively anticoagulated (INR >3.0) with a 10-mg loading dose.Management of Oral Anticoagulant TherapyMonitoring Anticoagulation IntensityThe PT is the most common test used to monitor oral anticoagulant therapy.78 The PT responds to reduction of 3 of the 4 vitamin K–dependent procoagulant clotting factors (II, VII, and X) that are reduced by warfarin at a rate proportionate to their respective half-lives. Thus, during the first few days of warfarin therapy, the PT reflects mainly reduction of factor VII, the half-life of which is ≈6 hours. Subsequently, reduction of factors X and II contributes to prolongation of the PT. The PT assay is performed by adding calcium and thromboplastin to citrated plasma. The traditional term “thromboplastin” refers to a phospholipid-protein extract of tissue (usually lung, brain, or placenta) that contains both the tissue factor and phospholipid necessary to promote activation of factor X by factor VII. Thromboplastins vary in responsiveness to the anticoagulant effects of warfarin according to their source, phospholipid content, and preparation.79–81 The responsiveness of a given thromboplastin to warfarin-induced changes in clotting factors reflects the intensity of activation of factor X by the factor VIIa/tissue factor complex. An unresponsive thromboplastin produces less prolongation of the PT for a given reduction in vitamin K–dependent clotting factors than a responsive one. The responsiveness of a thromboplastin can be measured by assessing its International Sensitivity Index (ISI) (see below).PT monitoring of warfarin treatment is very imprecise when expressed as a PT ratio (calculated as a simple ratio of the patient’s plasma value over that of normal control plasma) because thromboplastins can vary markedly in their responsiveness to warfarin. Differences in thromboplastin responsiveness contributed to clinically important differences in oral anticoagulant dosing among countries82 and were responsible for excessive and erratic anticoagulation in North America, where less responsive as well as responsive thromboplastins were in common use. Recognition of these shortcomings in PT monitoring stimulated the development of the INR standard for monitoring oral anticoagulant therapy, and the adoption of this standard improved the safety of oral anticoagulant therapy and its ease of monitoring.The history of standardization of the PT has been reviewed by Poller80 and by Kirkwood.83 In 1992, the ISI of thromboplastins used in the United States varied between 1.4 and 2.8.84 Subsequently, more responsive thromboplastins with lower ISI values have come into clinical use in the United States and Canada. For example, the recombinant human preparations consisting of relipidated synthetic tissue factor have ISI values of 0.9 to 1.0.85 The INR calibration model, adopted in 1982, is now used to standardize reporting by converting the PT ratio measured with the local thromboplastin into an INR, calculated as follows: INR = (patient PT/mean normal PT)ISIor log INR = ISI (log observed PT ratio),where ISI denotes the International Sensitivity Index of the thromboplastin used at the local laboratory to perform the PT measurement. The ISI reflects the responsiveness of a given thromboplastin to reduction of the vitamin K–dependent coagulation factors. The more responsive the reagent, the lower the ISI value.80,83,86Most commercial manufacturers provide ISI values for thromboplastin reagents, and the INR standard has been widely adopted by hospitals in North America. Thromboplastins with recombinant tissue factor have been introduced with ISI values close to 1.0, yielding PT ratios virtually equivalent to the INR. According to the College of American Pathologists Comprehensive Coagulation Survey, implementation of the INR standard in the United States increased from 21% to 97% between 1991 and 1997.82 As the INR standard of reporting was widely adopted, however, several problems surfaced. These are reviewed briefly below.As noted above, the INR is based on ISI values derived from plasma of patients on stable anticoagulant doses for ≥6 weeks.87 As a result, the INR is less reliable early in the course of warfarin therapy, particularly when results are obtained from different laboratories. Even under these conditions, however, the INR is more reliable than the unconverted PT ratio88 and is thus recommended during both initiation and maintenance of warfarin treatment. There is also evidence that the INR is a reliable measure of impaired blood coagulation in patients with liver disease.89Theoretically, the INR could be made more precise by using reagents with low ISI values, but laboratory proficiency studies indicate that this produces only modest improvement,90–93 whereas reagents with higher ISI values result in higher coefficients of variation.94,95 Variability of ISI determination is reduced by calibrating the instrument with lyophilized plasma depleted of vitamin K–dependent clotting factors.95–97 Because the INR is based on a mathematical relationship using a manual method for clot detection, the accuracy of the INR measurement can be influenced by the automated clot detectors now used in most laboratories.98–103 In general, the College of American Pathologists has recommended that laboratories use responsive thromboplastin reagents (ISI <1.7) and reagent/instrument combinations for which the ISI has been established.104ISI values provided by manufacturers of thromboplastin reagents are not invariably correct,105–107 and this adversely affects the reliability of measurements. Local calibrations can be performed by using plasma samples with certified PT values to determine the instrument-specific ISI. The mean normal plasma PT is determined from fresh plasma samples from ≥20 healthy individuals and is not interchangeable with a laboratory control PT.108 Because the distribution of PT values is not normal, log-transformation and calculation of a geometric mean are recommended. The mean normal PT should be determined with each new batch of thromboplastin with the same instrument used to assay the PT.108The concentration of citrate used to anticoagulate plasma affects the INR.109,110 In general, higher citrate concentrations (≥3.8%) lead to higher INR values,109 and underfilling the blood collection tube spuriously prolongs the PT because excess citrate is present. Using collection tubes containing 3.2% citrate for blood coagulation studies can reduce this problem.The lupus anticoagulants prolong the activated partial thromboplastin time but usually cause only slight prolongation of the PT, according to the reagents used.111,112 The prothrombin and proconvertin tests113,114 and measurements of prothrombin activity or native prothrombin concentration have been proposed as alternatives,76,114–116 but the optimum method for monitoring anticoagulation in patients with lupus anticoagulants is uncertain.Practical Warfarin Dosing and MonitoringWarfarin dosing may be separated into initial and maintenance phases. After treatment is started, the INR response is monitored frequently until a stable dose-response relationship is obtained; thereafter, the frequency of INR testing is reduced.An anticoagulant effect is observed within 2 to 7 days after beginning oral warfarin, according to the dose administered. When a rapid effect is required, heparin should be given concurrently with warfarin for ≥4 days. The common practice of administering a loading dose of warfarin is generally unnecessary, and there are theoretical reasons for beginning treatment with the average maintenance dose of ≈5 mg daily, which usually results in an INR of ≥2.0 after 4 or 5 days. Heparin usually can be stopped once the INR has been in the therapeutic range for 2 days. When anticoagulation is not urgent (eg, chronic atrial fibrillation), treatment can be commenced out of hospital with a dose of 4 to 5 mg/d, which usually produces a satisfactory anticoagulant effect within 6 days.77 Starting doses <4 to 5 mg/d should be used in patients sensitive to warfarin, including the elderly,40,117 and in those at increased risk of bleeding.The INR is usually checked daily until the therapeutic range has been reached and sustained for 2 consecutive days, then 2 or 3 times weekly for 1 to 2 weeks, then less often, according to the stability of the results. Once the INR becomes stable, the frequency of testing can be reduced to intervals as long as 4 weeks. When dose adjustments are required, frequent monitoring is resumed. Some patients on long-term warfarin therapy experience unexpected fluctuations in dose-response due to changes in diet, concurrent medication changes, poor compliance, or alcohol consumption.The safety and effectiveness of warfarin therapy depends critically on maintaining the INR within the therapeutic range. On-treatment analysis of the primary prevention trials in atrial fibrillation found that a disproportionate number of thromboembolic and bleeding events occurred when the PT ratio was outside the therapeutic range.118 Subgroup analyses of other cohort studies also have shown a sharp increase in the risk of bleeding when the INR is higher than the upper limit of the therapeutic range,116,119–122 and the risk of thromboembolism increased when the INR fell to <2.0.123,124Point-of-Care Patient Self-TestingPoint-of-care (POC) PT measurements offer the potential for simplifying oral anticoagulation management in both the physician’s office and the patient’s home. POC monitors measure a thromboplastin-mediated clotting time that is converted to plasma PT equivalent by a microprocessor and expressed as either the PT or the INR. The original methodology was incorporated into the Biotrack instrument (Coumatrak; Biotrack, Inc) evaluated by Lucas et al125 in 1987. These investigators reported a correlation coefficient (r) of 0.96 between reference plasma PT and capillary whole blood PT, findings that were confirmed in other studies.126By early 2000, the US Food and Drug Administration (FDA) had approved 3 monitors for patient self-testing at home,127 but each instrument has limitations. Instruments currently marketed for this purpose are listed in Table 1. In a study128 in which a derivative of the Biotrack monitor (Biotrack 512; Ciba-Corning) was used, the POC instrument compared poorly with the Thrombotest, the former underestimating the INR by a mean of 0.76. Another Biotrack derivative (Coumatrak; DuPont) was accurate in an INR range of 2.0 to 3.0 but gave discrepant results at higher INR values.129 In another study, the Ciba-Corning monitor underestimated the results when the INR was >4.0, but the error was overcome by using a revised ISI value to calculate the INR.130 Several investigators131–133 reported excellent correlations with reference plasma PT values when a second category of monitor (CoaguChek; Roche Diagnostics, Inc) was used. The ISI calibration with this system, based on an international reference preparation, was extremely close to indices adopted by the manufacturer for both whole blood and plasma.134 Both classes of monitors (Biotrack and Coagu-Chek) compared favorably with traditionally obtained PT measurements at 4 laboratories and with the standard manual tilt-tube technique established by the World Health Organization using an international reference thromboplastin.135 Laboratories using a more sensitive thromboplastin showed close agreement with the standard, whereas agreement was poor when insensitive thromboplastins were used; INR determinations with the Coumatrak and CoaguChek monitors were only slightly less accurate than the conventional method used in the best clinical laboratories. TABLE 1. Capillary Whole Blood (Point-of-Care) PT InstrumentsInstrumentClot Detection MethodologyType of SampleHome Use ApprovalWB indicates whole blood.*All instruments in this category are based on the original Biotrack model (Protime Monitor 1000) and licensed under different names. The latest version available is the CoaguChek Pro and Pro/DM (as models evolved, they acquired added capabilities); earlier models are no longer available.†CoaguChek not actively marketed for home use at the time of this writing. Thrombolytic Assessment System not available for home use.‡Hemochron Jr and GEM PCL are simplified versions of the ProTIME Monitor.§Avosure instruments removed from market when manufacturer (Avocet, Inc) ceased operations (2001). Technology has since been purchased by Beckman Coulter.∥INRange system manufactured by Hemosense, Inc, is currently in development.Protime Monitor 1000Clot initiation: ThromboplastinCapillary WBNoCoumatrak*Clot detection: Cessation of blood flow through capillary channelVenous WBCiba Corning 512 Coagulation Monitor*CoaguChek Plus*CoaguChek Pro*CoaguChek Pro/DM*CoaguChekClot initiation: ThromboplastinCapillary WBYes†CoaguChek SClot detection: Cessation of movement of iron particlesVenous WB Plasma(CoaguChek only)Thrombolytic Assessment SystemRapidpoint CoagProTIME MonitorClot initiation: ThromboplastinCapillary WBYesHemochron Jr‡Clot detection: Cessation of blood flow through capillary channelVenous WBGEM PCL‡Avosure Pro+§Clot initiation: ThromboplastinCapillary WBYesAvosure Pro§Clot detection: Thrombin generations detected by fluorescent thrombin probeVenous WB PlasmaAvosure PT§HarmonyClot initiation: ThromboplastinCapillary WBYesClot detection: Cessation of blood flow through capillary channelVenous WBINRatio∥Clot initiation: ThromboplastinCapillary WBYesClot detection: Change in impedance in sampleVenous WBA third category of POC capillary whole blood PT instruments (ProTIME Monitor; International Technidyne Corporation) differs from the other 2 types of instruments in that it performs a PT in triplicate (3 capillary channels) and simultaneously performs level 1 and level 2 controls (2 additional capillary channels). In a multiinstitutional trial, 136 the instrument INR correlated well with reference laboratory tests and those performed by a healthcare provider (venous sample, r=0.93; capillary sample, r=0.93; patient fingerstick, r=0.91). In a separate report involving 76 warfarin-treated children and 9 healthy control subjects, the coefficient of correlation between venous and capillary samples was 0.89. Compared with venous blood tested in a reference laboratory (ISI=1.0), correlation coefficients were 0.90 and 0.92, respectively.137 Published results with a fourth type of PT monitor (Avocet PT 1000) in 160 subjects demonstrate good correlation when compared with reference laboratory INR values with capillary blood, citrated venous whole blood, and citrated venous plasma (r=0.97, 0.97, and 0.96, respectively).138The feasibility and accuracy of patient self-testing at home initially was evaluated