Williams Hematology



Vitamin K Antagonists

Chemistry and Mode of Action





Complications of Therapy


Surgical Management


Novel Vitamin K Antagonists
Other Oral Anticoagulants


Inhibitors of Coagulation Factor XA

Inhibitors of Thrombin
Chapter References

The original and principal oral anticoagulants—the vitamin K antagonists—have well-known chemistry and pharmacokinetics. The standardized calibration system for monitoring treatment with vitamin K antagonists, the international normalized ratio (INR), is widely accepted. Its use increases the reliability of comparisons of treatment intensity between laboratories and improves interpretation of results obtained in clinical trials. Portable instruments for measurement of the prothrombin time permit self-management in selected cases. Computerized decision support of drug dosing contributes to improved efficacy and safety. The large number of interactions of vitamin K antagonists with other drugs is a major problem during treatment and is often the cause of bleeding complications. Predictors for hemorrhage have been related to characteristics of the patient and underlying disease as well as treatment and hemostatic variables. The detection of mutations and polymorphisms has provided some explanations for resistance or hypersensitivity to vitamin K antagonists. Among the nonhemorrhagic complications are skin necrosis, purple toe syndrome, allergic dermatologic manifestations, hepatic dysfunction, possibly reduced bone mineral density, and teratogenicity. During the perioperative state, treatment with vitamin K antagonists is managed in various ways, depending on the nature of the surgical procedure and the condition that necessitates anticoagulation. For the main indications of treatment—artificial heart valves, nonvalvular atrial fibrillation, myocardial infarction, and venous thromboembolism—large clinical trials have documented the optimum intensity of treatment. For venous thromboembolism, the duration of treatment should be tailored individually according to characteristics of the thrombotic event and presence of prothrombotic risk factors. Minidose warfarin (1 mg/day) is effective in the prophylaxis against thrombosis in central venous catheters, major gynecologic surgery, and metastatic breast cancer. A number of new oral anticoagulants, such as glycosaminoglycans or direct and selective inhibitors of factor Xa or thrombin, are under development and may prove to be safer than vitamin K antagonists due to fewer interactions with other drugs.

Acronyms and abbreviations that appear in this chapter include: INR, international normalized ratio; ISI, international sensitivity index; LMWH, low-molecular-weight heparin; P&P, prothrombin and proconvertin; PT, prothrombin time; rTF, recombinant tissue factor; TURP, transurethral resection of the prostate.

A hemorrhagic disease in cattle caused by moldy sweet clover hay was described in 1922.1 The absence or delay of blood clotting was correlated to a greatly diminished quantity of prothrombin. Isolation and purification of the “hemorrhagic agent” confirmed that the substance was dicumarol, 3,3-methylene-bis-[4-hydroxycoumarin],2 which was promptly made available for clinical studies. The first experiences of the prophylactic and therapeutic effects of the drug in deep vein thrombosis, as well as its hemorrhagic complications, were published in 1942.3,4 and 5 Warfarin, an acronym for the Wisconsin Alumni Research Foundation, in recognition of its synthesis at the University of Wisconsin in 1948, or 3-(1-phenyl-3-oxobutyl)4-hydroxycoumarin, is now the most commonly used coumarin derivative worldwide. The available compounds in different countries are either coumarin derivatives or indanedione derivatives. Some of the substances are also used as rodenticides.
These drugs have traditionally been termed oral anticoagulants, but are referred to as vitamin K antagonists in this chapter to highlight their specific effect and to distinguish them from new oral anticoagulants that have other mechanisms of action.
The coumarin derivatives have in common a 4-hydroxy–coumarin nucleus with a substituent in the 3 position (Fig. 132-1). All the 4-hydroxy–coumarin compounds have an asymmetric carbon atom, and the clinically available warfarin preparations consist of a racemic mixture of the S and R enantiomers. (S)-warfarin is four to five times more potent than (R)-warfarin as an anticoagulant and is more susceptible to interactions with other drugs.6 The formulation of warfarin for oral administration is in a crystalline form. However, amorphous warfarin sodium, which was temporarily produced, did not turn out to be bioequivalent,7 and this may also be the case for some of the generic warfarin formulations.8

FIGURE 132-1 Structure of warfarin sodium and phenindione. Common structures for coumarin and indanedione derivatives appear in boldface.

The vitamin K–dependent coagulation factors II, VII, IX, and X undergo posttranslational g-carboxylation of approximately 10 glutamic acid residues in the N-terminal Gla domain9,10 and 11 (see Chap. 112). This modification is required for the ability of the coagulation factors to bind calcium and to localize the enzymatic processes in which they participate to a phospholipid surface, such as activated platelet membranes. A reduction of the g-carboxylated sites by 1 to 6 residues will progressively impair the coagulation activity from 70 percent of normal to no activity at all. With therapeutic doses of warfarin, approximately 3 of 10 glutamic acid residues in prothrombin are not carboxylated.12,13 and 14
Simultaneously with g-carboxylation, vitamin KH2 is converted to vitamin K epoxide, which is converted back to KH2 by the sequential actions of vitamin K epoxide reductase and vitamin K reductase. These two enzymes are inhibited by the coumarin derivatives, thereby precluding further g-carboxylation.15,16 The coagulation inhibitors protein C and protein S, as well as osteocalcin, also undergo posttranslational g-carboxylation, and vitamin K antagonists cause the synthesis of their hypo- and acarboxylated forms. Some of the drug-related adverse effects can be explained by the reduced activity of these proteins (see “Skin Necrosis” and “Teratogenicity” under “Complications of Therapy”).
Warfarin is highly water soluble and is absorbed rapidly and completely from the stomach and upper gastrointestinal tract, reaching peak concentrations in plasma 60 to 90 min after oral ingestion. Impaired absorption has been described in a case with resistance to warfarin and dicumarol but not to an indanedione derivative.17 In the circulation, 98 to 99 percent of warfarin is bound to proteins, primarily to albumin, and therefore only a small fraction of the drug is biologically active. The binding to albumin occurs at site I, which is shared with phenylbutazone and azapropazone.18 Displacement of warfarin from albumin increases its anticoagulant activity, but at the same time the rate of elimination of the drug increases. Warfarin accumulates rapidly in the liver, mainly in the microsomes.19
Metabolism of warfarin is different for the two enantiomers. The biologically more potent (S)-warfarin is hydroxylated by cytochrome P450 2C9 (CYP2C9) to 7-hydroxywarfarin. Mutations in the CYP2C9 gene result in three allelic variants, and a patient with very high sensitivity to warfarin was demonstrated to be homozygous for CYP2C9*3.20 (R)-warfarin is metabolized by CYP1A2 to 6- and 8-hydroxywarfarin. The hydroxycoumarins are excreted by the kidneys. The elimination half-life of warfarin is 35 to 45 h, and the pharmacokinetics appear to be dose dependent.21 Warfarin may also be administered intravenously, and inadvertent percutaneous absorption of a warfarin-type rat poison has been reported to cause bleeding complications.22
The other vitamin K antagonists have similar pharmacokinetic characteristics, except for differences in elimination.23 Dicumarol has a lower degree of absorption from the gastrointestinal tract, and up to 36 percent of the drug can be retrieved inert in the stool.24
The variability in warfarin dose requirements to achieve a given extent of anticoagulation is wide, ranging from about 1 to 20 mg/day. This may be due to differences in clearance of the drug by the liver and in target-organ sensitivity. There is a significant negative correlation between age at start of therapy and dosage, with a reduction of requirements of approximately 20 percent over a 15-year period.25 The explanation for this finding is at least partly the decline in hepatic mass with age.26 In children, there is an even more pronounced reduction of warfarin requirements with age, with mean doses of 0.32 and 0.09 mg/kg/day in those under 1 year of age and 11 to 18 years of age, respectively.27 A number of algorithms and nomograms have been constructed to aid the physician in predicting the maintenance dose. They are usually based on the level of anticoagulation achieved after 2 to 4 days on a repeated loading dose.28,29
In rare cases, exceptionally high doses are required to achieve anticoagulation. The first hereditary form of resistance to coumarin, as well as to phenindione, with an autosomal dominant pattern was described in 1964.30 Mechanisms of warfarin resistance include impaired absorption,17 high clearance of (S)-warfarin,31 or decreased affinity of warfarin for the receptor,32 presumably associated with a decreased sensitivity of epoxide reductase.33 However, poor compliance, interactions with food or drugs, laboratory errors, or pharmacokinetic changes always have to be excluded.
Vitamin K antagonists should be started concomitantly with heparin treatment34 since it takes several days for the vitamin K antagonists to achieve an antithrombotic effect.35 Factor VII concentration drops rapidly, reaching levels that produce a prolonged prothrombin time within 24 h, but the other vitamin K–dependent coagulation factors have longer half-lives, and an antithrombotic effect is not achieved until after 72 to 96 h.36 Initiation of warfarin therapy within 3 days compared to after 7 days,37 or on day 1 compared to day 5,38 provides the same benefit with equal safety, and thus the current recommendation is to start warfarin on day 1.
The “loading” doses of warfarin that were used in the past frequently caused hemorrhage and have been abandoned.39 The plasma levels of inhibitor protein C decrease much faster than the levels of factor X when warfarin is initiated at a dose of 8 mg twice a day for 2 to 3 days instead of 6 mg daily for 3 days, and it has been speculated that the higher dose produces a transient hypercoagulable state.40 However, in a study comparing initiation of 15 mg warfarin on day 1 and 7.5 mg on days 2 and 3 with a regimen of 15 mg/day until the INR reached 1.87, both regimens were found to be safe and effective, and heparin treatment could be discontinued after 6 and 5 days, respectively.41
In patients with inherited deficiency of protein C or protein S, the initiation of treatment with vitamin K antagonists should be done with small doses and prolonged overlap with heparin to avoid skin necrosis (see “Skin Necrosis,” “Complications of Therapy”). For patients with protein C deficiency, treatment with warfarin and protein C concentrate42 or fresh-frozen plasma might be considered.
The optimal mode of cessation has likewise been a subject of debate. Indeed, there is a transient elevation of thrombin-antithrombin complexes and prothrombin fragment F1+2 after discontinuation of warfarin treatment for venous thromboembolism, with more pronounced changes after abrupt than after gradual discontinuation.43 It has, however, been difficult to prove the clinical disadvantage of abrupt cessation in patients with venous thromboembolism. In patients treated with warfarin after thrombolysis for myocardial infarction, abrupt cessation of warfarin created a gap between the rapidly rising levels of factors VII and IX and a slow normalization of protein C and S levels, mirrored by a hypercoagulable state associated with some thromboembolic events and increased levels of fibrinopeptide A.44
Anticoagulant treatment is monitored by a one-stage prothrombin time (PT) test, the Quick thromboplastin time,45 or a modification thereof, the prothrombin and proconvertin (P&P) method.46 A thromboplastin extract of a tissue, providing both tissue factor and phospholipids, is added to citrated plasma, and then the plasma is recalcified to initiate the reaction. The coagulation time reflects the activity of the extrinsic and common pathway of the coagulation cascade. In the P&P method, adsorbed ox plasma as a source of factor V and fibrinogen is also added, and thus the plasma level of these factors will not have any influence on the result.
Due to wide variations in the sensitivities of the thromboplastins used and in the recommendations for therapeutic ranges, patients in different countries or even at different centers within a single country received substantially different intensities of anticoagulation.47 As a result, multicenter trials and comparisons of treatment effects were impossible to perform or to interpret. For these reasons, recommendations were issued in 1985 to standardize the reporting of the PT by using the INR.48 This is a calibration system based on a linear relationship between the logarithm of PT ratios obtained with the reference and test thromboplastins. For an individual test, the INR is calculated according to the formula INR = (PTPatient / PTControl)ISI, where the international sensitivity index (ISI) is a correction factor for the responsiveness of the thromboplastin to the reductions in the vitamin K–dependent coagulation factors. The precision of the INR increases with lower ISI values,49 and hence it is important that the latter are as low as possible or, more specifically, close to 1.0, which is the ISI value of the World Health Organization international reference preparation. However, the type of instrument used will also affect the ISI value,50 and indeed, each local reagent-instrument combination needs calibration for the achievement of reliable INR values.51 The citrate concentration in the test tubes also affects the INR, and a single concentration should therefore be used.52 Since pooled plasma from patients stabilized on warfarin is used for the INR model, it could be presumed that INR values obtained during the induction phase are unreliable, but in a series of 43 patients tested during the initial 5 days with five different thromboplastins, the INR system showed less variance than did the PT ratios.53 The system is widely accepted in Europe and the United States.
Due to the risk of viral contamination with tissue factor extracted from animal tissues, recombinant human tissue factor (rTF)54,55 is the preferred reagent for monitoring treatment with vitamin K antagonists.56,57 The presence of heparin in the patient’s sample may influence the INR values, but some reagents, including the one based on rTF, are unaffected by heparin concentrations up to 1 IU/ml.58 Similarly, the presence of a lupus anticoagulant may have a pronounced effect on the test result, leading to falsely high INR values, but this is also to some extent dependent on the sensitivity of the thromboplastin.59,60
Although other assays to monitor treatment have shown promising results,61,62 and 63 none has replaced thromboplastin reagents. Assays of prothrombin fragment 1+2 and thrombin-antithrombin complexes have also been proposed for monitoring, but have not demonstrated improved ability to predict treatment failure or hemorrhagic risk.64,65
Portable instruments suitable for home use produce assay values that correlate well with results produced by laboratory instruments.66 Training patients in capillary blood sampling and warfarin dose adjustments can permit self-management with vitamin K antagonists.67,68 This method may also be advantageous for families with children requiring anticoagulant treatment.69
Anticoagulant therapy is often suboptimal in routine practice, with a high percentage of test results outside the targeted range.70 A computerized decision support system used by physicians and nurses can improve the quality of treatment.71,72 By collection of data via the computer system, quality control of the safety and efficacy of the anticoagulation is also facilitated. In a randomized study, computer-based control resulted in a significantly lower number of altered doses.73
The Netherlands has a nationwide organization for control of treatment with vitamin K antagonists and has documented that 80 percent of the PT of patients on long-term treatment were within the target range.74 Centralization of patients to specialized anticoagulation clinics is likely to offer an improvement of the anticoagulant management, with a reduction of thromboembolic events, major hemorrhages, and costs of hospitalizations, as demonstrated by an overview,75 a study of two consecutive cohorts,76 and a small randomized trial.77
Unstable INRs may be due to problems with reagents, instruments, or staff. Inexperienced monitors may not wait long enough for the development of a new steady state after dose adjustments and then overshoot the desired INR. Even minor matters may affect the results. Thus, the hour of the day when the blood sample is obtained may be important, since there is a diurnal variation of the INR in patients treated with vitamin K antagonists, with the peak between 4:00 A.M. and 8:00 A.M. and the nadir between 6:00 P.M. and midnight.78 The main uncertainty is, however, caused by the numerous interactions with vitamin K antagonists, described in the following section. It is therefore not surprising that the instability of anticoagulation increases with the number of concomitant drugs taken, irrespective of known specific interactions.79
Vitamin K1 (phylloquinone) is the predominant form of vitamin K present in the diet. Intake of vitamin K may cause a competition with the effect of the 4-hydroxycoumarins. Lists of foods and their vitamin K content are available from some of the manufacturers of vitamin K antagonists, but there is probably little benefit in supplying them to patients without a detailed explanation, especially since some patients may respond by omitting all vegetables from their diet. In fact, relatively few interactions between vitamin K antagonists and foods are clinically relevant, although the warfarin antagonism produced by large amounts of avocado80 or broccoli81 is highly probable. In the case of avocado, the vitamin K content is not high, but avocado oils seem to interfere with warfarin in some other way. Balanced advice to patients is the following82,83

Avoid major changes in the diet. If a change is indispensable, consult the physician and increase the frequency of monitoring temporarily.

Avoid avocado, kale, and parsley, except as a garnish or minor ingredient, as well as the Japanese dish natto.

Choose up to one serving (100 g) per day from the following: broccoli, brussels sprouts, spinach, turnip greens, or other greens.

Discuss with the physician any substantial increase or decrease in the intake of lentils, garbanzo beans, soybeans, soybean oil, liver, or other sources rich in vitamin K.

Alcohol intake, other than the occasional drink, should be discouraged.

Supplements of vitamin E seem to cause interference with vitamin K and should be avoided. Supplements with vitamin A and C have occasionally caused an increase or decrease, respectively, of the PT, and doses higher than the recommended daily allowances should be avoided.82
For poorly controlled anticoagulated patients, where no drug interaction or other obvious reason can be identified, a diet with a constant vitamin K1 content may be beneficial.84,85
Poor absorption of the vitamin K antagonists may occur in patients during periods with diarrhea, with use of liquid paraffin laxatives,86 and in patients with malabsorption syndrome.
There is an ever-growing list of drug interactions with vitamin K antagonists (Table 132-1 and Table 132-2). The vast majority of those have been reported in patients treated with warfarin, but in many cases they have been described also with at least one of the other vitamin K antagonists. At high doses, the nonsteroidal anti-inflammatory agents, as well as acetylsalicylic acid, may cause hypoprothrombinemia through inhibition of hepatic metabolism via CYP450 2C9 (phenylbutazone and analogs) or protein-binding displacement.87 Furthermore, these drugs increase the risk of bleeding by inhibiting platelet function. Finally, the risk of upper gastrointestinal hemorrhage is increased by the ulcerogenic effect of these agents.88



A number of different mechanisms of drug interactions with vitamin K antagonists have been described (Table 132-3). In most cases, metabolism of warfarin is inhibited, which in turn can be stereoselective for either the R- or S-enantiomer.83


Amitriptyline causes an unusual type of interaction with phenprocoumon during which great fluctuations of the PT have been observed.89 Chinese herbs and traditional medicines have been reported to exert an inhibiting effect on the metabolism of warfarin, sometimes resulting in pronounced hyperanticoagulation.90,91 and 92
An accentuated effect of vitamin K antagonists during the summer has been reported as a result of exposure to insecticides, such as ivermectin or metidation.93,94
Incidence Vitamin K antagonists cause more fatal side effects than any other drug in absolute numbers.95 Virtually all fatalities are related to bleeding complications. The incidence of this complication varies from one study to another due to differences in intensity of anticoagulation and patient populations. In a survey of seven trials in venous thromboembolism, only one fatal hemorrhage among 1283 patients anticoagulated for 3 months was identified,96 which illustrates the low risk observed in studies with a selected patient population. Table 132-4 compares the incidence of fatal hemorrhage in other large studies.


The definitions of major hemorrhages vary among studies. Some have specifically defined “life-threatening” hemorrhages, which had an incidence of 0.89 per 100 patient-years in a cohort study97 and 0.83 in a combined cross-sectional and prospective cohort study,98 with 7500 combined patient-years of observation. Major hemorrhages may include those with a certain drop in hemoglobin but without hospitalization, and the incidence per 100 patient-years ranged between 1.7 and 2.1 in four studies of patients with atrial fibrillation, between 0.8 and 4.1 in four trials on patients with prosthetic heart valves,96 and between 2.2 and 7.8 in three trials on patients with venous thromboembolism, with at least 100 patient-years of follow-up.99,100 and 101 In cohort studies, the incidence of major hemorrhages ranges from 1.2102 to 7.097 per 100 patient-years.
Locations The gastrointestinal tract is the most common site for major hemorrhages (66%),98 and the site of bleeding, usually a peptic ulcer, can be precisely identified in 83 percent of cases.103 However, large-bowel malignancy is another common organic lesion found in these cases, which emphasizes the importance of performing a thorough investigation to locate the source of bleeding.104 Acute abdomen requiring laparotomy in anticoagulated patients is typically caused by intramural intestinal hematoma.105
Intracranial bleeding was the most common cause of fatal hemorrhage,106 with a mortality rate of 77 percent in a prospective study of patients admitted to a department of neurosurgery.107 A majority of these patients had intracerebral hemorrhage, whereas a minority had subdural hematoma; the latter was associated with a better prognosis.107,108 Predictors for a poor prognosis of intracranial hemorrhage are age over 60 years, hematoma in the midline or ventricles, coma, arterial hypertension, and hyperanticoagulation at the time of bleeding.109 The risk of developing an intracranial hematoma after an apparently minor head injury has been estimated to be 10 times higher in patients treated with warfarin.110
Femoral neuropathy after retroperitoneal hemorrhage,111 radial nerve compression neuropathy after routine venipuncture,112 and acute carpal tunnel syndrome due to intraneural hemorrhage in the median nerve113 are rare but serious complications. Unusual sites of hemorrhage include spermatic cord hematoma,114 spontaneous spinal epidural hematoma after a coughing spell,115 and choroidal hemorrhage in age-related macular degeneration.116
Predictors Several predictors for major hemorrhage during treatment with vitamin K antagonists have been identified (Table 132-5). Among these predictors, the influence of age has been controversial. For intracranial hemorrhage, previous ischemic cerebral events, old age, hypertension, and high intensity of anticoagulation were identified as predictors.107,117


Increased plasma levels of tissue plasminogen activator, its inhibitor, von Willebrand factor, and soluble thrombomodulin, all measured by immunochemical methods, have been found to correlate with the risk of hemorrhage.118,119 These could all be markers of endothelial dysfunction and vascular disease.
Two groups have reported the interesting finding of increased bleeding in patients with missense mutations in Ala10 in the propeptide of factor IX.120,121 The mutated protein (Ala10Val in two patients and Ala10Thr in another two) exerted a reduced affinity of the g-glutamylcarboxylase enzyme for the propeptide. This had no effect on plasma factor IX levels in the absence of vitamin K antagonists, but it significantly increased the patients’ sensitivity to warfarin treatment, with factor IX levels dropping to less than 1 to 3 percent of normal, compared to 30 to 40 percent in patients with the wild-type factor IX. Furthermore, polymorphisms in the gene coding for cytochrome P450 CYP2C9, the principal catalytic enzyme for (S)-warfarin, give rise to decreased warfarin requirement and confer an increased risk of major bleeding.122
Treatment In patients with a major hemorrhage, rapid reversal of the anticoagulant effect is essential. It is frequently difficult to give sufficient amounts of fresh-frozen plasma, due to volume restrictions, and some experts recommend infusion of prothrombin-complex concentrates.123 However, these concentrates may increase the risk of thrombosis since they contain activated coagulation factors.
Minor bleeding complications have not received much attention in the literature, but a study on epistaxis during warfarin treatment showed that the medication could be continued safely, provided that the INR was within the therapeutic range and that local hemostatic measures were taken.124
Reversal of Overdose without Hemorrhage In the absence of hemorrhage, hyperanticoagulation is preferably reversed by either discontinuation and careful observation or by vitamin K1 (phytonadione) administration. An intravenous dose of 0.5 mg vitamin K1 seems sufficient to achieve an INR in the therapeutic range in most patients within 24 h.125 However, this route of administration should be avoided if possible, since anaphylactic reactions have been described.126 For subcutaneous administration, an average dose of 4.9 mg vitamin K1 was reported as necessary,127 whereas by the oral route, between 1 and 2.5 mg were found effective and safe, reaching a therapeutic level after 16 h.128,129 and 130 Doses of vitamin K1 of 10 mg or more should be avoided, since they lead to warfarin resistance for up to a week.
Skin Necrosis Initially described in 1943,131 skin necrosis occurs with a frequency of about 1 in 5000 patients treated with vitamin K antagonists,132 although there have been occasional reports of a much higher frequency133 (see Chap. 121). It affects predominantly women (85%) and may be related to the distribution of subcutaneous fat. Areas typically involved are breasts, thighs, and buttocks. The onset is usually within 3 to 10 days from initiation of anticoagulation, but a delay of up to 15 years has been reported.133 Skin necrosis does not necessarily reappear with reinstitution of vitamin K antagonists.
Initial symptoms and signs are localized pain with a maculopapular rash, which within 24 to 48 h progresses to hemorrhagic lesions, hemorrhagic bullae, and necrosis, leaving an eschar that heals slowly. Plastic surgery is frequently required,134 and when the breast is affected, mastectomy may be necessary.
It is generally believed that the pathogenic mechanism is a hypercoagulable state caused by an imbalance between severely depressed levels of protein C and protein S and only a mild reduction of coagulation factors II, IX, and X.132,133 Preexisting deficiency of protein C or protein S, or use of large loading doses of warfarin may accentuate this imbalance. A deficiency of antithrombin may also contribute to the pathogenesis.135 Histologically, fibrin deposits are seen in small veins and venules in the dermis and subcutaneous fat, surrounded by hemorrhage and diffuse necrosis.
Prompt administration of vitamin K has been reported to halt the progression to skin necrosis.136 Treatment with vitamin K antagonists should be discontinued immediately in any event and reversed with plasma or, in the case of protein C deficiency, with a concentrate of protein C if available. Anticoagulation is continued with heparin until the lesions have healed, whereafter warfarin may be resumed, starting a low dose of 1 to 2 mg/day and gradually increasing it over 10 to 12 days.133,137
Purple Toe Syndrome Since the first report of six patients with this complication,138 only a few additional cases have been described (see Chap. 121). The syndrome develops 3 to 8 weeks after initiation of anticoagulation,138 usually with bilateral burning pain and dark blue discoloration of the toes and sides of the feet, with blanching of the skin on pressure.133 Occasionally, the hands are involved. Most of the patients have underlying cardiac disorders, diabetes mellitus, or peripheral vascular disease. It is presumed that the mechanism is cholesterol embolization from atherosclerotic plaques. Warfarin may make the plaque more friable by decreasing fibrin deposition or by hemorrhage into the plaque.133 The burning pain, but not the discoloration, disappears on discontinuation of warfarin.133 The safety of restoring warfarin in patients who have developed this complication is unclear.
Other Nonhemorrhagic Side Effects Other dermatologic side effects of warfarin are maculopapular,139 vesicular, or urticarial rashes,140 often very itchy, occurring weeks to months after beginning anticoagulation132 but occasionally after the first dose.140 Eosinophilic pleurisy141 and vasculitis142 have been described in connection with warfarin therapy. Phenindione has also been reported to cause severe hypersensitivity.23
There are a few reports of toxic hepatitis induced by different vitamin K antagonists143,144 and descriptions of intrahepatic jaundice.145,146
Finally, there are contradictory reports regarding the effect of warfarin on bone mineral density. Although osteocalcin is reproducibly reduced during warfarin treatment,147,148 and 149 in combination with increased loss of calcium in urine,147 the literature is inconsistent with regard to the effect of warfarin on reduced bone mineral density148,149,150,151 and 152 and the incidence of fractures.151
The teratogenic effects of vitamin K antagonists consist of midface and nasal hypoplasia, stippled epiphyses, hypoplasia of the digits, optic atrophy, and mental impairment.153 This is summarized as the warfarin embryopathy syndrome, but it can also be induced by other vitamin K antagonists given between weeks 6 and 12 of gestation. Previous estimates of the frequency of the syndrome after exposure to warfarin during weeks 6 to 12 range from 5.4 to 28.6 percent.154,155 In more recent retrospective and prospective studies, 0 of 46156 and 1 of 11157 first-trimester exposures respectively resulted in embryopathy, whereas in a retrospective study of Chinese patients, 16 of 29 children had features of embryopathy, which in almost all of them was restricted to nasal hypoplasia.158
A similar syndrome, with nasal hypoplasia, punctate calcifications, and abnormalities of the spine, has been described in children of mothers with vitamin K deficiency due to malabsorption, in patients with epoxide reductase deficiency,159 and in homozygotes for a point mutation in the g-glutamylcarboxylase gene associated with a deficiency of all vitamin K–dependent coagulation factors and inhibitors.160 With the addition of distal phalangeal hypoplasia, a similar constellation is found in X-linked, recessive chondrodysplasia punctata, where the mutations result in a deficiency of a heat-labile arylsulphatase.161
Vitamin K antagonist therapy during any trimester can cause central nervous system hemorrhage in approximately 1 percent of fetuses or central nervous system malformation without apparent hemorrhage in about 4 to 5 percent.154
Artificial Heart Valves and Pregnancy There are numerous reports of artificial heart valve thrombosis during pregnancy, the majority of which occurred during anticoagulation with heparin, and some with fatal outcome.156,157,162 It has therefore been considered advisable to use a vitamin K antagonist for these patients during the second and early phase of the third trimester after providing mothers with information about the risks and benefits in comparison with heparin.154
Warfarin is not contraindicated during breastfeeding, since the concentration in breast milk is less than 25 ng/ml and warfarin is not detectable in the plasma of the breastfed infants.163
One of the frequent questions regarding treatment with vitamin K antagonists concerns the management during surgery or other invasive procedures. The possibilities range from uninterrupted anticoagulation to reversal of the vitamin K antagonism.
There is no need to reduce or discontinue anticoagulant treatment for cutaneous surgery164,165 or for soft-tissue aspirations or injections.166,167 Pacemaker surgery is also safe, provided that proper surgical technique is used.168 For oral surgery, randomized, placebo-controlled studies have shown that unchanged anticoagulation is safe, provided that it is combined with local irrigation or a mouth rinse with a 5% solution of tranexamic acid in connection with surgery and then repeated four times daily for a week.169,170 and 171 However, it has also been demonstrated that discontinuation of treatment with vitamin K antagonists for 2 days prior to the tooth extraction to achieve an INR of 1.5 or less may be as safe, even in patients with artificial heart valves.172 Local anesthesia of the lower jaw with a posterior nerve block should probably be avoided.
Treatment of benign prostate hyperplasia with neodymium:YAG laser ablation has been performed without interruption of the anticoagulation, but there is a risk of major hemorrhage of approximately 15 percent.173,174
For cardiac surgery, treatment with vitamin K antagonists can be continued, maintaining an INR of about 2.4.175 In comparison with a reduced dose of warfarin, this regimen led to a lower heparin requirement to prolong the activated coagulation time and diminished blood loss.175 For vascular surgery, surgeons must use meticulous hemostatic technique to allow uninterrrupted anticoagulation for prevention of occlusion of graft or operated blood vessel.
For other types of surgery, a modification of the treatment is necessary. Thus, it is useful to know the rate by which the INR decreases after discontinuation of warfarin. The results of a kinetic study in 22 patients are presented in Table 132-6. The exponential decay of INR does not start until 29 h after the last dose.176 In case of anticoagulation after venous thromboembolism, the likelihood of a perioperative thromboembolic event during a few days is smaller than the risk of postoperative hemorrhage, and thus, brief discontinuation of warfarin is safe close to the time of planned surgery.177 However, if thrombosis occurred close to the time of planned surgery, it is preferable to postpone surgery or to follow one of the regimens suggested for patients with artificial heart valves. In the latter patients, the risk of thrombus formation on the valve may be perceived as low during a few days of interrupted anticoagulation, since the annual risk without any antithrombotic treatment averages about 10 percent.178 This does not take into account the increased perioperative risk due to activation of coagulation and of the fibrinolytic activity. Thus, in one study, 2 of 10 patients with mitral or combined mechanical valves had fatal strokes when anticoagulation was interrupted 3 to 5 days before surgery.179


A regimen that has been used for elective surgery in 197 anticoagulated patients180 is shown in Fig. 132-2. Of 84 patients with artificial heart valves, major hemorrhage occurred in 3 who had transurethral resection of the prostate (TURP) and in 8 of 99 with major surgery, whereas 2 of the 197 patients developed ischemic stroke.180 TURP is a procedure with a high hemorrhagic risk, and in another study, a similar regimen, but with complete interruption of heparin 4 h before and throughout surgery, was attempted.181 Still, 1 of 12 patients had hemorrhage requiring transfusion, and 3 were readmitted for late bleeding. In general, the hemorrhagic complications have required transfusion or reoperation, whereas the ischemic strokes have resulted in chronic sequelae.

FIGURE 132-2 Example of a perioperative regimen for patients on anticoagulant therapy with a high risk of thromboembolism. The infusion rate of heparin is increased to 210 U/h when the patient returns to the ward. Heparin is discontinued when the INR is in the therapeutic range for 2 consecutive days. (Adapted from S Vigano’D’Angelo et al.180).

The risk of thromboembolism depends on the type and position of the prosthesis and, to some extent, on patient-related factors. In a randomized study, the risk was lower with Björk-Shiley valves than with Edwards-Duro-Medics or Medtronic-Hall valves.182 In a meta-analysis, the risk of thromboembolism was highest with a caged-ball valve (Starr-Edwards), 30 percent lower with a tilting disk valve (Björk-Shiley, Sorin, Medtronic-Hall, and Omnicarbon), and 50 percent lower with a bileaflet valve (St. Jude, DuroMedics, and CarboMedics).178 In a cohort study, the risks with these different valves per 100 patient-years were 2.5, 0.7, and 0.5, respectively.183 The risk is twice as high with a mitral prosthesis as with an aortic prosthesis.178 Other factors that may increase the risk of thromboembolism are age,183 hypertension, and smoking,184 whereas the effects of left atrial enlargement and atrial fibrillation have been controversial.184,185
A retrospective cohort study of 1608 unselected patients with mechanical heart valves showed that the optimal antithrombotic effect was achieved at an INR of 2.5 to 4.9, and thus a target of 3.0 to 4.0 was recommended.183 In one study, a target INR of 2.0 to 3.0 was as effective as an INR of 3.0 to 4.5, but there were significantly fewer minor hemorrhages in the former group.186 The risks of thromboembolism were, however, 2.4 and 2.1 per 100 patient-years, respectively, compared to 0.71 in the cohort study; thus, whether the intensity can be lowered is controversial.
Several studies have been performed with the St. Jude Medical prosthesis with low-intensity warfarin prophylaxis (INR £ 2.5) in combination with dipyridamole and sometimes also acetylsalicylic acid. The incidence of thromboembolism ranged from 0.5 to 1.3 per 100 patient-years.187,188,189 and 190 In a meta-analysis of five randomized trials where antiplatelet therapy or placebo was added to the prophylaxis with vitamin K antagonists, the combined regimen reduced thromboembolism by 67 percent, but at a cost of a 65 percent increase in hemorrhage and 250 percent increase in major gastrointestinal hemorrhage.191 In a review of 16 studies with warfarin and acetylsalicylic acid compared with monotherapy with either agent, it was concluded that the combination should be reserved for patients with a high risk of thromboembolism and possibly also for those with ischemic heart disease, and that the daily dose of acetylsalicylic acid should not exceed 100 mg.192
Bioprosthetic heart valves also confer a risk of thromboembolism, accentuated during the first 3 months after surgery. During this period, it is recommended to use vitamin K antagonists, aiming at an INR 2.0 to 3.0, and to continue warfarin indefinitely in cases with atrial fibrillation, atrial thrombosis detected at echocardiography, or after a systemic embolic episode.193
To reduce the incidence of ischemic stroke of 4.5 percent per year in chronic nonvalvular (nonrheumatic) atrial fibrillation,194 prophylaxis is considered increasingly important. Five major placebo-controlled trials have been performed to evaluate warfarin in the primary prevention of thromboembolism (Table 132-7). A meta-analysis of these trials, including 3706 patients, showed a reduction of relative risk of ischemic stroke of 68 percent with warfarin, valid for all age groups except in those younger than 65 years of age.195 The annual incidence of fatal bleeding ranged from 0.0 to 0.8 percent, while the annual incidence of major hemorrhages ranged from 0.2 to 2.0 percent. The recommended target INR is 2.0 to 3.0.194 At this level, warfarin reduces the levels of prothrombin fragment 1+2, b-thromboglobulin, and fibrin D-dimer, which are elevated before treatment. Minidose warfarin does not affect these parameters196,197 and was not shown to be clinically effective.198


Serial transesophageal echocardiography in 14 patients with atrial fibrillation demonstrated that during 4 weeks of anticoagulation with warfarin 16 of 18 atrial thrombi resolved completely and no new thrombi were formed.199 This is in line with the experience that the use of warfarin for 3 to 4 weeks before cardioversion reduces the 1 to 3 percent incidence of procedure-related thromboembolism by 90 percent.200 There is a potential for thrombus formation in the atria during the weeks after successful cardioversion due to stunning of mechanical function and decreased left atrial appendage emptying velocity.201 Anticoagulation should therefore be provided for 3 weeks prior to and 4 weeks after cardioversion at an intensity of INR 2.0 to 3.0 or, alternatively, with heparin.202,203
In a randomized trial in patients with cerebral ischemia of presumed arterial, noncardiac origin, secondary prophylaxis with warfarin targeted at an INR of 3.0 to 4.5 was not safe and resulted in 3.0 fatal and 4.8 intracranial hemorrhages per 100 patient-years. Moreover, this regimen was not more effective than acetylsalicylic acid, 30 mg/day.204 In a small, nonrandomized study, patients with systemic embolization and mobile aortic atheroma had a reduced risk of stroke if they received warfarin.205 In patients with nonvalvular atrial fibrillation, secondary stroke prevention with warfarin (target INR 2.5 to 4.0) reduced the risk of stroke from 12 to 4 percent per year without causing any intracranial bleeding event, whereas acetylsalicylic acid, 300 mg/day, was not more effective than placebo.206 In comparison with indobufen 100 or 200 mg b.i.d., warfarin targeted at an INR of 2.0 to 3.5 was equally effective in preventing vascular complications.207
Primary prevention of thrombosis in patients at high risk of ischemic heart disease is effective using the combination of a low dose of warfarin and acetylsalicylic acid.208 Thus, warfarin targeted at an INR of 1.3 to 1.8 reduced the risk of myocardial ischemic events, and addition of low-dose acetylsalicylic acid conferred an additional benefit, although the risk of bleeding increased.208
In patients with unstable angina, the addition of warfarin, targeted at an INR of 2.0 to 2.5, to acetylsalicylic acid 150 mg/day reduces the risk of progression of the culprit lesion.209 However, after aortocoronary bypass surgery, warfarin, targeted at an INR of 2.8 to 4.8, did not reduce the risk of vein graft occlusion in comparison with acetylsalicylic acid 50 mg/day.210 Angiographic follow-up of the patency of vein grafts did not reveal any positive effect of warfarin on the progression of atherosclerosis.211
Patients with myocardial infarction have a 10 percent risk of suffering a reinfarction during the first year, followed by an annual risk of 5 percent.212 Secondary prophylaxis is therefore essential; however, of the many randomized studies performed, only a few were sufficiently large to allow for firm conclusions (Table 132-8). These studies, as well as a meta-analysis,213 demonstrated a reduction of mortality and major cardiovascular events by administration of warfarin. Although there was a significant increase in the risk of major hemorrhage, there was an overall benefit from anticoagulation.213 Data from the largest of these trials (ASPECT) was used to estimate the optimum intensity of anticoagulation, which was between INR 2.0 and 4.0.214 Warfarin targeted at INR 2.0 to 2.5 was not superior to acetylsalicylic acid 150 mg in the AFTER study,215 conceivably since this intensity was insufficient. With even lower intensity of anticoagulation, using 1 or 3 mg/day of warfarin, no benefit over acetylsalicylic acid 160 mg could be detected in the CARS trial.216


In a retrospective cohort analysis the use of warfarin resulted in a reduced risk of death, primarily those due to cardiac events, and of hospital admission for heart failure.217 Since other studies have shown a relatively low incidence of systemic embolization in chronic heart failure, it has been suggested that the use of warfarin be limited to patients with atrial fibrillation or previous embolic events.218
Several studies have demonstrated a benefit of long-term therapy with vitamin K antagonists after bypass surgery in the lower limb with regard to graft function, limb salvage, and patient survival.219,220 and 221 Antiplatelet agents may, however, be at least as effective with less severe side effects for this indication.222,223
Orthopedic surgery confers a particularly high risk of venous thromboembolism, with a frequency of deep vein thrombosis as high as 70 percent. Minidose warfarin (1 mg daily), which has a negligible effect on the INR, does not provide effective prophylaxis in this situation.224 Low-dose warfarin, which prolongs the PT about 1.2 to 1.5 times the control value, is associated with a low rate of symptomatic pulmonary embolism (0.3–0.7%) after total joint arthroplasty,225,226 and 227 but in a randomized trial it was not more effective than acetylsalicylic acid.225 Full-dose warfarin targeted at an INR of 2.0 to 3.0 has been compared with low-molecular-weight heparin (LMWH) in several randomized trials and the efficacy, measured as thrombosis on screening after about 7 to 9 days, was usually superior with LMWH.228,229,230,231 and 232 In some of the studies, warfarin caused less hemorrhage than LMWH,228,231,232 and a meta-analysis of 22 trials with combinations of warfarin, LMWH, or unfractionated heparin reiterated the relative safety of warfarin.233 Several analyses of cost-effectiveness have, however, yielded results in favor of LMWH for arthroplasty of the hip as well as of the knee.234,235,236 and 237
A “two-step” warfarin regimen, beginning with a lower dose 10 to 14 days before arthroplasty and postoperative adjustment to reach an INR of 2.2, did not provide any advantage compared with initiation of therapy the night before surgery.238
Prophylaxis with warfarin after surgery for acetabular or pelvic fractures resulted in an incidence of symptomatic deep vein thrombosis and pulmonary embolism of 3 and 1 percent respectively, with minimal bleeding complications.239
The risk of venous thromboembolism after orthopedic surgery is not eliminated by 7 to 10 days of postoperative prophylaxis, and several studies have investigated the benefit of prolonged prophylaxis at home. In a study of 96 patients after orthopedic surgery, a fixed low dose of warfarin (2 mg/day) was compared with an adjusted higher dose given for 1 month. The regimens appeared equally effective and safe, and the fixed low dose virtually eliminated the need for monitoring.240
For major gynecological surgery, fixed minidose warfarin (1 mg/day) started an average of 20 days before surgery was as effective as, but safer than, warfarin targeted at an INR of 1.5 to 2.5.241
A randomized trial demonstrated that minidose warfarin reduced the risk of venous thrombosis associated with chronic central venous catheters from 38 to 10 percent during 90 days.242 In a retrospective study of patients with central venous catheters for long-term total parenteral nutrition, minidose warfarin was not less effective than a low-dose regimen with PT prolonged to 1.2 to 1.5 times that of control subjects.243 However, for those patients with thrombosis on minidose warfarin, a switch to the higher dose significantly reduced the risk of recurrent thrombosis.243
Although it is more difficult to maintain a stable therapeutic INR (2.0–3.0) in patients with cancer than in patients without cancer,244 the risk of warfarin-induced hemorrhage is similar.245 For patients with metastatic breast cancer receiving chemotherapy, minidose warfarin for 6 weeks, followed by adjusted low-dose warfarin targeted at an INR of 1.3 to 1.9 (mean dose 2.6 mg/day), was effective in reducing the risk of venous thromboembolism (0.7 versus 4.4% with placebo) without increasing the risk of hemorrhage.246
In patients with membranous nephropathy, prophylaxis against thromboembolism with vitamin K antagonists appears to provide benefits that outweigh the risks.247
Established Venous Thromboembolism Treatment with vitamin K antagonists is started concomitantly with heparin in acute venous thromboembolism (see “Initiation of Therapy,” under “Dosing”). In a randomized trial, a target INR of 2.0 to 2.5 was associated with a significant reduction of hemorrhage without any increase of thromboembolic endpoints when compared to an INR of 3.0 to 4.5.248 A slightly wider range, of INR 2.0 to 3.0, is more convenient and often used,101,249,250 and the incidence of major hemorrhage is 4.7 to 8.8 per 100 patient-years. With a slightly modified range of INR 2.0 to 2.85, this incidence drops to 2.4 per 100 patient-years.99,251 This intensity is also sufficient for patients with inherited thrombophilia or venous thromboembolism in combination with antiphospholipid antibodies.252 In patients with systemic lupus erythematosus, antiphospholipid antibodies, and venous thromboembolism, a higher intensity is, however, required253,254 (see Chap. 128).
Multicenter trials with sufficiently large numbers of patients have shown that, if the duration of secondary prophylaxis is prolonged from 4 weeks to 3 months, the risk of recurrence during 1 year is reduced from 7.8 to 4 percent101; and when it is prolonged from 6 weeks to 6 months, the risk during 2 years is reduced from 18.1 to 9.5 percent.251 These patients were included after the first event of venous thromboembolism, and the prolonged treatment did not cause any increase of major hemorrhages.101,251 In another trial, patients with a second episode of venous thromboembolism were randomized between 6 months and indefinite duration of anticoagulation.99 The risk of recurrence over 4 years was reduced from 20.7 to 2.6 percent, but at the cost of a trend toward more major hemorrhages: 2.7 versus 8.6 percent. After discontinuation of the secondary prophylaxis, there was a recurrence rate of 4 to 5 percent per year for several years.99,251
Risk factors for an increased risk of recurrence include proximal deep vein thrombosis255; pulmonary embolism255; idiopathic thromboembolism or a permanent triggering factor255; hereditary deficiency of antithrombin, protein C, or protein S256; hyperhomocysteinemia257; and antiphospholipid antibodies.252 The latter are also a predictor of an increased risk of cardiovascular death, which justifies long-term secondary prophylaxis.
In pulmonary hypertension, either primary or induced by the anorectic drug aminorex, warfarin has a positive effect on survival.258
A few case reports have described a dramatic positive effect of warfarin on migraine259 and improvement by low doses of warfarin on calcinosis in systemic sclerosis.260 Vitamin K antagonists have been reported to improve survival in small-cell carcinoma of the lung261,262 and to reduce the cancer incidence and mortality in patients with heart disease.263
Alcohol and ester analogs of (R) -(+)(S)-warfarin have reduced protein binding, which can be utilized for the development of alternative agents with a lower risk of interactions with other drugs.264
The oral bioavailability of unfractionated heparin can be increased to 8 percent by addition of delivery agents that improve the gastrointestinal absorption.265 LMWH are of a size that should make oral administration feasible. Sulodexide is composed of 80 percent iduronylglycosaminoglycan sulfate and 20 percent dermatan sulfate, and has almost complete bioavailability after oral administration and an equivalent antithrombotic effect compared with heparin.266,267 Heparan sulfate has been given orally in a study of patients after myocardial infarction.268
Direct and selective factor Xa inhibitors for oral use in humans are currently under development and have shown a potent antithrombotic effect with minimal or no influence on the bleeding time in animal models.269,270
Several low-molecular-weight active-site inhibitors of thrombin are selective and have a high degree of bioavailablity.271,272,273 and 274 A small active-site–directed thrombin inhibitor is not only a potent antithrombotic agent,275 but by being easily incorporated into newly formed thrombi, it enhances the susceptibility of the clot to spontaneous lysis.272 Some of these agents are currently in early-phase clinical trials. A rapid onset of activity, favorable dose-response relationships, renal excretion rather than metabolism by hepatic enzymes, and decreased potential for drug interactions via enzyme competition or protein binding could make these oral agents good candidates for replacement of both heparin and vitamin K antagonists in the prophylaxis and treatment of thrombotic disorders.

Schofield FW: A brief account of a disease in cattle simulating hemorrhagic septicaemia due to feeding sweet clover. Can Vet Rec 3:74, 1922.

Overman RS, Stahmann MA, Sullivan WR, et al: Studies on the haemorrhagic sweet clover disease: IV. The isolation and crystallization of the haemorrhagic agent. J Biol Chem 141:941, 1941.

Allen EV, Barker NW, Waugh JM: A preparation from spoiled sweet clover (3,3′-methylene-bis-(4-hydroxycoumarin)) which prolongs coagulation and prothrombin time of the blood: A clinical study. JAMA 120:1009, 1942.

Butsch WC, Stewart JD: Clinical experience with dicoumarin, 3,3′-methylene-bis-(4-hydroxycoumarin). JAMA 120:10256, 1942.

Lehmann J: Hypoprothrombinaemia produced by methylene-bis-(hydroxycoumarin): Its use in thrombosis. Lancet 1:318, 1942.

O’Reilly RA, Aggeler PM: Determinants of the response to oral anticoagulant drugs in man. Pharmacol Rev 22:35, 1970.

Richton-Hewett S, Foster E, Apstein CS: Medical and economic consequences of a blinded oral anticoagulant brand change at a municipal hospital. Arch Intern Med 148:806, 1988.

DeCara JM, Croze S, Falk RH: Generic warfarin: A cost-effective alternative to brand-name drug or a clinical wild card? Chest 113:261, 1998.

Willingham AK, Matschiner JT: Changes in phylloquinone epoxidase activity related to prothrombin synthesis and microsomal clotting activity in the rat. Biochem J 140:435, 1974.

Stenflo J, Fernlund P, Egan W, Roepstorff P: Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci USA 71:2730, 1974.

Magnusson S, Sottrup-Jensen L, Petersen TE, Morris HR, Dell A: Primary structure of the vitamin K–dependent part of prothrombin. FEBS Lett 44:189, 1974.

Paul B, Oxley A, Brigham K, et al: Factor II, VII, IX, and X concentrations in patients receiving long term warfarin. J Clin Pathol 40:94, 1987.

Malhotra OP: Dicumarol-induced prothrombins containing 6,7 and 8 g-carboxyglutamic acid residues: Isolation and characterization. Biochem Cell Biol 67:411, 1989.

Esnouf MP, Prowse CV: The gamma-carboxy glutamic content of human and bovine prothrombin following warfarin treatment. Biochim Biophys Acta 490:471, 1977.

Whitlon DS, Sadowski JA, Suttie JW: Mechanisms of coumarin action: Significance of vitamin K epoxide reductase inhibition. Biochemistry 17:1371, 1978.

Fasco MJ, Hildebrandt EF, Suttie JW: Evidence that warfarin anticoagulant action involves two distinct reductase activities. J Biol Chem 257:11210, 1982.

Talstad I, Gamst ON: Warfarin resistance due to malabsorption. J Intern Med 236:465, 1994.

Rajaian H, Symonds HW, Bowmer CJ: Drug binding sites on chicken albumin: A comparison to human albumin. J Vet Pharmacol Ther 20:421, 1997.

Sutcliffe FA, MacNicoll AD, Gibson GG: Aspects of anticoaglant action: A review of the pharmacology, metabolism and toxicology of warfarin and congeners. Rev Drug Metabol Interact 5:225, 1987.

Steward DJ, Haining RL, Henne KR, et al: Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 7:361, 1997.

King SY, Joslin MA, Raudibaugh K, Pieniaszek HJ Jr, Benedek IH: Dose-dependent pharmacokinetics of warfarin in healthy volunteers. Pharm Res 12:1874, 1995.

Abell TL, Merigian KS, Lee JM, Holbert JM, McCall JW: Cutaneous exposure to warfarin-like anticoagulant causing an intracerebral hemorrhage: A case report. J Toxicol Clin Toxicol 32:69, 1994.

Shetty HG, Woods F, Routledge PA: The pharmacology of oral anticoagulants: Implications for therapy. J Heart Valve Dis 2:53, 1993.

Weiner M, Shapiro S, Axelrod J, et al: The physical disposition of dicumarol in man. J Pharmacol Exp Ther 99:409, 1950.

Wynne HA, Kamali F, Edwards C, Long A, Kelly P: Effect of ageing upon warfarin dose requirements: A longitudinal study. Age Ageing 25:429, 1996.

Wynne H, Cope L, Kelly P, Whittingham T, Edwards C, Kamali F: The influence of age, liver size and enantiomer concentrations on warfarin requirements. Br J Clin Pharmacol 40:203, 1995.

Andrew M, Marzinotto V, Brooker LA, et al: Oral anticoagulation therapy in pediatric patients: A prospective study. Thromb Haemost 71:265, 1994.

Routledge PA, Davies DM, Bell SM, Cavanagh JS, Rawlins MD: Predicting patients’ warfarin requirements. Lancet 2:854, 1977.

Cazaux V, Gauthier B, Elias A, et al: Predicting daily maintenance dose of fluindione, an oral anticoagulant drug. Thromb Haemost 75:731, 1996.

O’Reilly RA, Aggeler PM, Hoag MS, et al: Hereditary transmission of exceptional resistance to coumarin anticoagulant drugs. N Engl J Med 271:809, 1964.

Hallak HO, Wedlund PJ, Modi MW, et al: High clearance of (S)-warfarin in a warfarin-resistant subject. Br J Clin Pharmacol 35:327, 1993.

Alving BM, Strickler MP, Knight RD, Barr CF, Berenberg JL, Peck CC: Hereditary warfarin resistance: Investigation of a rare phenomenon. Arch Intern Med 145:499, 1985.

Cain D, Hutson SM, Wallin R: Warfarin resistance is associated with a protein component of the vitamin K 2,3-epoxide reductase enzyme complex in the rat liver. Thromb Haemost 80:128, 1998.

Richards RL: Venous thrombosis. Br Med J 2:217, 1966.

Deykin D, Wessler S, Reimer SM: Evidence for an antithrombotic effect of dicumarol. Am J Physiol 199:1161, 1960.

Hellemans J, Vorlat M, Verstraete M: Survival time of prothrombin and factors VII, IX and X after complete synthesis blocking doses of coumarin derivatives. Br J Haematol 9:506, 1963.

Gallus A, Jackaman J, Tillettt J: Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 2:1293, 1986.

Hull RD, Raskob GE, Rosenbloom D, et al: Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 322:1260, 1990.

O’Reilly R, Aggeler PM: Studies on coumarin anticoagulant drugs: Initiation of warfarin therapy without a loading dose. Circulation 38:169, 1968.

Iguchi A, Sato K: Protein C response to induction of warfarin treatment after coronary bypass operation. Thorac Cardiovasc Surg 42:222, 1994.

Schulman S, Lockner D, Bergstörm K, Blombäck M: Intensive initial oral anticoagulation and shorter heparin treatment in deep vein thrombosis. Thromb Haemost 52:276, 1984.

De Stefano V, Mastrangelo S, Schwarz HP, et al: Replacement therapy with a purified protein C concentrate during initiation of oral anticoagulation in severe protein C congenital deficiency. Thromb Haemost 70:247, 1993.

Palareti G, Legnani C, Guazzaloca G, et al: Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants: A prospective study. Thromb Haemost 72:222, 1994.

Grip L, Blombäck M, Schulman S: Hypercoagulable state and thromboembolism following warfarin withdrawal in post–myocardial-infarction patients. Eur Heart J 12:1225, 1991.

Quick AJ: On constitution of prothrombin. Am J Physiol 140:212, 1943.

Owren PA, Aas K: The control of dicumarol therapy and the quantitative determination of prothrombin and proconvertin. Scand J Clin Lab Invest 3:201, 1951.

Lam-Po-Tang PR, Poller L: Oral anticoagulant therapy and its control: An international survey. Thromb Diath Haemorrh 34:419, 1975.

Loeliger EA, van den Besselaar AM, Lewis SM: Reliability and clinical impact of the normalization of the prothrombin times in oral anticoagulant control. Thromb Haemost 53:148, 1985.

Taberner DA, Poller L, Thomson JM, Darby KV: Effect of international sensitivity index (ISI) of thromboplastins on precision of international normalised ratios (INR). J Clin Pathol 42:92, 1989.

Poggio M, van den Besselaar AMHP, van der Velde EA, Bertina RM: The effect of some instruments for prothrombin time testing on the international sensitivity index (ISI) of two rabbit tissue thromboplastin reagents. Thromb Haemost 62:868, 1989.

Poller L, Thomson JM, Taberner DA: Effect of automation on prothrombin time test in NEQUAS surveys. J Clin Pathol 42:97, 1989.

Danielson CF, Davis K, Jones G, Benson J, Arney K, Martin J: Effect of citrate concentration in specimen collection tubes on the international normalized ratio. Arch Pathol Lab Med 121:956, 1997.

Johnston M, Harrison L, Moffat K, Willan A, Hirsh J: Reliability of the international normalized ratio for monitoring the induction phase of warfarin: Comparison with the prothrombin time ratio. J Lab Clin Med 128:214, 1996.

Paborski LR, Tate KM, Harris RJ, et al: Purification of recombinant human tissue factor. Biochemistry 28:8072, 1989.

Rehemtulla A, Pepe M, Edgington TS: High level expression of recombinant human tissue factor in Chinese hamster ovary cells as a human thromboplastin. Thromb Haemost 65:521, 1991.

Finazzi G, Falanga A, Galli M, Cortelazzo S, Remuzzi A, Barbui T: Recombinant versus high-sensitivity conventional thromboplastin: A randomized clinical study in patients on oral anticoagulation. Thromb Haemost 72:804, 1994.

Barcellona D, Biondi G, Vannini ML, Marongiu VF: Comparison between recombinant and rabbit thromboplastin in the management of patients on oral anticoagulant therapy. Thromb Haemost 75:488, 1996.

Solomon HM, Randall JR, Simmons VL: Heparin-induced increase in the international normalized ratio: Responses of 10 commercial thromboplastin reagents. Am J Clin Pathol 103:735, 1995.

Della Valle P, Crippa L, Safa O, et al: Potential failure of the international normalized ratio (INR) system in the monitoring of oral anticoagulation in patients with lupus anticoagulants. Ann Med Interne 147:10, 1996.

Moll S, Ortel TL: Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 127:177, 1997.

Dati F, Barthels M, Conard J, et al: Multicenter evaluation of a chromogenic substrate method for photometric detection of prothrombin time. Thromb Haemost 58:856, 1987.

Kornberg A, Francis CW, Pellegrini VD Jr, Gabriel KR, Marder VJ: Comparison of native prothrombin antigen with the prothrombin time for monitoring oral anticoagulant prophylaxis. Circulation 88:454, 1993.

Smith KJ, Singaraju C, Smith LF: Factor IX metal ion-dependent antigen assays for measurement of warfarin effect. Am J Clin Pathol 87:370, 1987.

Haushofer A, Halbmayer WM, Dittel M, Prachar H, Mlczoch J, Fischer M: Course of thrombin activation markers in patients implanted with Palmaz-Schatz stents: First experiences with a post-interventional anticoagulation regimen. Blood Coagul Fibrinol 5:697, 1994.

Tripodi A, Cattaneo M, Molteni A, Cesana BM, Mannucci PM: Changes of prothrombin fragment 1+2 (F 1+2) as a function of increasing intensity of oral anticoagulation: Considerations on the suitability of F 1+2 to monitor oral anticoagulant treatment. Thromb Haemost 79:571, 1998.

Anderson DR, Harrison L, Hirsh J: Evaluation of a portable prothrombin time monitor for home use by patients who require long-term oral anticoagulant therapy. Arch Intern Med 153:1441, 1993.

Ansell JE, Patel N, Ostrovsky D, Nozzolillo E, Peterson AM, Fish L: Long-term patient self-management of oral anticoagulation. Arch Intern Med 155:2185, 1995.

Hasenkam JM, Kimose HH, Knudsen L, et al: Self management of oral anticoagulant therapy after heart valve replacement. Eur J Cardiothorac Surg 11:935, 1997.

Massicotte P, Marzinotto V, Vegh P, Adams M, Andrew M: Home monitoring of warfarin therapy in children with a whole blood prothrombin time monitor. J Pediatr 127:389, 1995.

Pell JP, McIver B, Stuart P, Malone DN, Alcock J: Comparison of anticoagulant control among patients attending general practice and a hospital anticoagulant clinic. Br J Gen Pract 43:152, 1993.

Vadher BD, Patterson DL, Leaning M: Comparison of oral anticoagulant control by a nurse-practitioner using a computer decision-support system with that by clinicians. Clin Lab Haematol 19:203, 1997.

Vadher B, Patterson DL, Leaning M: Evaluation of a decision support system for initiation and control of oral anticoagulation in a randomised trial. Br Med J 314:1252, 1997.

Ageno W, Turpie AGG: A randomized comparison of a computer-based dosing program with a manual system to monitor oral anticoagulant therapy. Thromb Res 91:237, 1998.

van den Besselaar AM, van der Meer FJ, Gerrits-Drabbe CW: Therapeutic control of oral anticoagulant treatment in The Netherlands. Am J Clin Pathol 90:685, 1988.

Ansell JE, Hughes R: Evolving models of warfarin management: Anticoagulation clinics, patient self-monitoring, and patient self-management. Am Heart J 132:1095, 1996.

Chiquette E, Amato MG, Bussey HI: Comparison of an anticoagulation clinic with usual medical care. Arch Intern Med 158:1641, 1998.

Lee YP, Schommer JC: Effect of a pharmacist-managed anticoagulation clinic on warfarin-related hospital readmissions. Am J Health Syst Pharm 53:1580, 1996.

Bleske BE, Welage LS, Warren EW, Brown MB, Shea MJ: Variations in prothrombin time and international normalized ratio over 24 hours in warfarin-treated patients. Pharmacotherapy 15:709, 1995.

Williams JRB, Griffin JP, Parkins A: Effect of concomitantly administered drugs on the control of long-term anticoagulant therapy. Q J Med 45:63, 1976.

Blickstein D, Shaklai M, Inbal A: Warfarin antagonism by avocado. Lancet 337:914, 1991.

Kempin SJ: Warfarin resistance caused by broccoli. N Engl J Med 308:1229, 1983.

Harris JE: Interaction of dietary factors with oral anticoagulants: Review and applications. J Am Diet Assoc 95:580, 1995.

Wells PS, Holbrook AM, Crowther NR, Hirsh J: Interactions of warfarin with drugs and food. Ann Intern Med 121:676, 1994.

Sorano GG, Biondi G, Conti M, Mameli G, Licheri D, Marongiu F: Controlled vitamin K content diet for improving the management of poorly controlled anticoagulated patients: A clinical practice proposal. Haemostasis 23:77, 1993.

Booth SL, Charnley JM, Sadowski JA, Saltzman E, Bovill EG, Cushman M: Dietary vitamin K1 and stability of oral anticoagulation: Proposal of a diet with constant vitamin K1 content. Thromb Haemost 77:504, 1997.

Reynolds JEF: Cardiovascular agents, in Martindale: The Extra Pharmacopoeia, 31st ed, p 965. London, Royal Pharmaceutical Society, 1996.

Chan TY: Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs: Mechanisms, clinical significance, and avoidance. Ann Pharmacother 29:1274, 1995.

Gabb GM: Fatal outcome of interaction between warfarin and a non-steroidal anti-inflammatory drug. Med J Aust 164:700, 1996.

Hampel H, Berger C, Muller-Spahn F: Modified oral anticoagulant potency in an amitriptyline-treated patient. Acta Haematol 96:178, 1996.

Tam LS, Chan TY, Leung WK, Critchley JA: Warfarin interactions with Chinese traditional medicines: Danshen and methyl salicylate medicated oil. Aust NZ J Med 25:258, 1995.

Yu CM, Chan JC, Sanderson JE: Chinese herbs and warfarin potentiation by “danshen.” J Intern Med 241:337, 1997.

Janetzky K, Morreale AP: Probable interaction between warfarin and ginseng. Am J Health Syst Pharm 54:692, 1997.

Homeida HMA, Bagi IA, McNicholas AM, et al: Coagulation abnormalities and ivermectin. Lancet 1:1346, 1988.

Fernández MA, Ballesteros S, Aznar J: Oral anticoagulants and insecticides. Thromb Haemost 80:724, 1998.

Anonymous: ADR reporting in Sweden in 1991. Bulletin from Swedish Adverse Drug Reaction Advisory Committee 62:1, 1993.

Levine MN, Raskob G, Landefeld S, Hirsh J: Hemorrhagic complications of anticoagulant treatment. Chest 108:276S, 1995.

Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH: The risk for and severity of bleeding complications in elderly patients treated with warfarin: The National Consortium of Anticoagulation Clinics. Ann Intern Med 124:970, 1996.

White RH, McKittrick T, Takakuwa J, Callahan C, McDonell M, Fihn S: Management and prognosis of life-threatening bleeding during warfarin therapy: National Consortium of Anticoagulation Clinics. Arch Intern Med 156:1197, 1996.

Schulman S, Granqvist S, Holmström M, et al: The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 336:393, 1997.

Schulman S, Lockner D, Juhlin-Dannfelt A: The duration of oral anticoagulation after deep vein thrombosis: A randomized study. Acta Med Scand 217:547, 1985.

Anonymous: Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism: Research Committee of the British Thoracic Society. Lancet 340:873, 1992.

McKenna CJ, Galvin J, McCann HA, Sugrue DD: Risks of long-term oral anticoagulation in a non-trial medical environment. Ir Med J 89:144, 1996.

Choudari CP, Rajgopal C, Palmer KR: Acute gastrointestinal haemorrhage in anticoagulated patients: Diagnoses and response to endoscopic treatment. Gut 35:464, 1994.

Norton SA, Armstrong CP: Lower gastrointestinal bleeding during anticoagulant therapy: A life-saving complication? Ann R Coll Surg Engl 79:38, 1997.

Euhus DM, Hiatt JR: Management of the acute abdomen complicating oral anticoagulation therapy. Am Surg 56:581, 1990.

Landefeld CS, Goldman L: Major bleeding in outpatients treated with warfarin: Incidence and prediction by factors known at the start of outpatient therapy. Am J Med 87:144, 1989.

Mathiesen T, Benediktsdottir K, Johnsson H, Lindqvist M, von Holst H: Intracranial traumatic and non-traumatic haemorrhagic complications of warfarin treatment. Acta Neurol Scand 91:208, 1995.

Hylek EM, Singer DE: Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 120:897, 1994.

Ernestus RI, Speder B, Pakos P, Hildebrandt G, Klug N: Intracerebral hemorrhage during treatment with oral anticoagulants: Risk factors, therapy and prognosis. Zentralbl Neurochir 55:24, 1994.

Saab M, Gray A, Hodgkinson D, Irfan M: Warfarin and the apparent minor head injury. J Accid Emerg Med 13:208, 1996.

Alberty-Ryöppy A, Juntunen J, Salmi T: Femoral neuropathy following anticoagulant therapy for “economy class syndrome” in a young woman. Acta Chir Scand 151:643, 1985.

Davison BL, Kosmatka PK, Ferlic RJ: Acute radial nerve compression following routine venipuncture in an anticoagulated patient. Am J Orthop 25:712, 1996.

Bindiger A, Zelnik J, Kuschner S, Gellman H: Spontaneous acute carpal tunnel syndrome in an anticoagulated patient. Bull Hosp Jt Dis 54:52, 1995.

McKenney MG, Fietsam R Jr, Glover JL, Villalba M: Spermatic cord hematoma: Case report and literature review. Am Surg 62:768, 1996.

Maingi M, Glynn MF, Scully HE, Graham AF, Floras JS: Spontaneous spinal epidural hematoma in a patient with a mechanical aortic valve taking warfarin. Can J Cardiol 11:429, 1995.

Edwards P: Massive choroidal hemorrhage in age-related macular degeneration: a complication of anticoagulant therapy. J Am Optom Assoc 67:223, 1996.

Hart RG, Boop BS, Anderson DC: Oral anticoagulants and intracranial hemorrhage: Facts and hypotheses. Stroke 26:1471, 1995.

Brännström M, Jansson JH, Boman K, Nilsson TK: Endothelial haemostatic factors may be associated with mortality in patients on long-term anticoagulant treatment. Thromb Haemost 74:612, 1995.

Jansson JH, Boman K, Brännström M, Nilsson TK: High concentration of thrombomodulin in plasma is associated with hemorrhage. Circulation 96:2938, 1997.

Chu K, Wu SM, Stanley T, Stafford DW, High KA: A mutation in the propeptide of factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 98:1619, 1996.

Oldenburg J, Quenzel EM, Harbrecht U, et al: Missense mutations at ALA-10 in the factor IX propeptide: An insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 98:240, 1997.

Aithal GP, Day CP, Kesteven PJL, Daly AK: Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353:717, 1999.

Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF: Emergency oral anticoagulant reversal: The relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 77:477, 1997.

Srinivasan V, Patel H, John DG, Worsley A: Warfarin and epistaxis: Should warfarin always be discontinued? Clin Otolaryngol 22:542, 1997.

Shetty HG, Backhouse G, Bentley DP, Routledge PA: Effective reversal of warfarin-induced excessive anticoagulation with low dose vitamin K1. Thromb Haemost 67:13, 1992.

O’Reilly RA, Kearns P: Intravenous vitamin K1 injections: Dangerous prophylaxis. Arch Intern Med 155:2127, 1995.

Fetrow CW, Overlock T, Leff L: Antagonism of warfarin-induced hypoprothrombinemia with use of low-dose subcutaneous vitamin K1. J Clin Pharmacol 37:751, 1997.

Crowther MA, Donovan D, Harrison L, McGinnis J, Ginsberg J: Low-dose oral vitamin K reliably reverses over-anticoagulation due to warfarin. Thromb Haemost 79:1116, 1998.

Pengo V, Banzato A, Garelli E, Zasso A, Biasiolo A: Reversal of excessive effect of regular anticoagulation: Low oral dose of phytonadione (vitamin K1) compared with warfarin discontinuation. Blood Coagul Fibrinol 4:739, 1993.

Weibert RT, Le DT, Kayser SR, Rapaport SI: Correction of excessive anticoagulation with low-dose oral vitamin K1. Ann Intern Med 126:959, 1997.

Flood EP, Redish MH, Bociek SJ: Case report: Thrombophlebitis migrans disseminata: Report of a case in which gangrene of a breast occurred. NY State J Med 43:1121, 1943.

Gallerani M, Manfredini R, Moratelli S: Non-haemorrhagic adverse reactions of oral anticoagulant therapy. Int J Cardiol 49:1, 1995.

Sallah S, Thomas DP, Roberts HR: Warfarin and heparin-induced skin necrosis and the purple toe syndrome: Infrequent complications of anticoagulant treatment. Thromb Haemost 78:785, 1997.

Miura Y, Ardenghy M, Ramasastry S, Kovach R, Hochberg J: Coumadin necrosis of the skin: Report of four patients. Ann Plast Surg 37:332, 1996.

Colman RW, Rao AK, Rubin RN: Warfarin skin necrosis in a 33-year-old woman. Am J Hematol 43:300, 1993.

van Amstel WJ, Boekhout-Mussert MJ, Loeliger EA: Successful prevention of skin necrosis by timely administration of vitamin K. Blut 36:89, 1978.

Jillella AP, Lutcher CL: Reinstituting warfarin in patients who develop warfarin skin necrosis. Am J Hematol 52:117, 1996.

Feder W, Auerbach R: “Purple toes”: An uncommon sequela of oral coumarin drug therapy. Ann Intern Med 55:911, 1961.

Antony SJ, Krick SK, Mehta PM: Unusual cutaneous adverse reaction to warfarin therapy. South Med J 86:1413, 1993.

Grosset AB, Allen JE, Rodgers GM: Anticoagulation with anisindione in patients who are intolerant of warfarin. Am J Hematol 46:138, 1994.

Kuwahara T, Hamada M, Inoue Y, Aono S, Hiwada K: Warfarin-induced eosinophilic pleurisy. Intern Med 34:794, 1995.

Krahn MJ, Pettigrew NM, Cuddy TE: Unusual side effects due to warfarin. Can J Cardiol 14:90, 1998.

Hautekeete M, Holvoet J, Hubens H: Cytolytic hepatitis related to the oral anticoagulant phenprocoumon. Gastroenterol Clin Biol 19:223, 1995.

Hohler T, Schnutgen M, Helmreich-Becker I, Mayet WJ, Mayer zum Buschenfelde KH: Drug-induced hepatitis: A rare complication of oral anticoagulants. J Hepatol 21:447, 1994.

Jones DB, Makepeace MC, Smith PM: Jaundice following warfarin therapy. Postgrad Med J 56:671, 1980.

Rehnqvist N: Intrahepatic jaundice due to warfarin therapy. Acta Med Scand 204:335, 1978.

Jie K-SG, Gijsbers BLMG, Knapen MHJ, Hamulák K, Frank HL, Vermeer C: Effects of vitamin K and oral anticoagulants on urinary calcium excretion. Br J Haematol 83:100, 1993.

Sato Y, Honda Y, Kunoh H, Oizumi K: Long-term oral anticoagulation reduces bone mass in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Stroke 28:2390, 1997.

Lafforgue P, Daver L, Monties JR, Chagnaud C, de Boissezon MC, Acquaviva PC: Bone mineral density in patients given oral vitamin K antagonists. Rev Rhum Engl Ed 64:249, 1997.

Philip WJ, Martin JC, Richardson JM, Reid DM, Webster J, Douglas AS: Decreased axial and peripheral bone density in patients taking long-term warfarin. Q J Med 88:635, 1995.

Jamal SA, Browner WS, Bauer DC, Cummings SR: Warfarin use and risk for osteoporosis in elderly women: Study of Osteoporotic Fractures Research Group. Ann Intern Med 128:829, 1998.

Worcester EM, Sebastian JL, Hiatt JG, Beshensky AM, Sadowski JA: The effect of warfarin on urine calcium oxalate crystal growth inhibition and urinary excretion of calcium and nephrocalcin. Calcif Tissue Int 53:242, 1993.

Stevenson RE, Burton OM, Ferlauto GJ, Taylor HA: Hazards of oral anticoagulants during pregnancy. JAMA 243:1549, 1980.

Ginsberg JS, Hirsh J, Turner DC, Levine MN, Burrows R: Risk to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost 61:197, 1989.

Iturbe-Alessio I, Del Carmen Fonseca M, Mutchinik O, Santos MA, Zajarias A, Salazar E: Risks of anticoagulant therapy in pregnant women with artificial heart valves. N Engl J Med 315:1390, 1986.

Sbarouni E, Oakley CM: Outcome of pregnancy in women with valve prostheses. Br Heart J 71:196, 1994.

Lécuru F, Desnos M, Taurelle R: Anticoagulant therapy in pregnancy: Report of 54 cases. Acta Obstet Gynecol Scand 75:217, 1996.

Wong V, Cheng CH, Chan KC: Fetal and neonatal outcome of exposure to anticoagulants during pregnancy. Am J Med Genet 45:17, 1993.

Menger H, Lin AE, Toriello HV, Bernert G, Spranger JW: Vitamin K deficiency embryopathy: A phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. Am J Med Genet 72:129, 1997.

Brenner B, Sanchez-Vega B, Wu SM, Lanir N, Stafford DW, Solera J: A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K–dependent blood coagulation factors. Blood 92:4554, 1998.

Franco B, Meroni G, Parenti G, et al: A cluster of sulfatase genes on Xp22.3: Mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell 81:15, 1995.

Salazar E, Izaguirre R, Verdejo J, Mutchinick O: Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol 27:1698, 1996.

Orme MLE, Lewis PJ, de Swiet M, et al: May mothers given warfarin breast-feed their children? Br Med J 1:1564, 1977.

Otley CC, Fewkes JL, Frank W, Olbricht SM: Complications of cutaneous surgery in patients who are taking warfarin, aspirin, or nonsteroidal anti-inflammatory drugs. Arch Dermatol 132:161, 1996.

Billingsley EM, Maloney ME: Intraoperative and postoperative bleeding problems in patients taking warfarin, aspirin, and nonsteroidal antiinflammatory agents: A prospective study. Dermatol Surg 23:381, 1997.

Raj G, Kumar R, McKinney WP: Safety of intramuscular influenza immunization among patients receiving long-term warfarin anticoagulation therapy. Arch Intern Med 155:1529, 1995.

Thumboo J, O’Duffy JD: A prospective study of the safety of joint and soft tissue aspirations and injections in patients taking warfarin sodium. Arthritis Rheum 41:736, 1998.

Goldstein DJ, Losquadro W, Spotnitz HM: Outpatient pacemaker procedures in orally anticoagulated patients. Pacing Clin Electrophysiol 21:1730, 1998.

Borea G, Montebugnoli L, Capuzzi P, Magelli C: Tranexamic-acid as a mouthwash in anticoagulant-treated patients undergoing oral surgery: An alternative method to discontinuing anticoagulant therapy. Oral Surg Oral Med Oral Pathol 75:29, 1993.

Ramström G, Sindet-Pedersen S, Hall G, Blombäck M, älander U: Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification of oral anticoagulants. J Oral Maxillofac Surg 51:1211, 1993.

Souto JC, Oliver A, Zuazu-Jausoro I, Vives A, Fontcuberta J: Oral surgery in anticoagulated patients without reducing the dose of oral anticoagulant: A prospective randomized study. J Oral Maxillofac Surg 54:27, 1996.

Saour JN, Ali HA, Mammo LA, Sieck JO: Dental procedures in patients receiving oral anticoagulation therapy. J Heart Valve Dis 3:315, 1994.

Kingston TE, Nonnenmacher AK, Crowe H, Costello AJ, Street A: Further evaluation of transurethral laser ablation of the prostate in patients treated with anticoagulant therapy. Aust NZ J Surg 65:40, 1995.

Bolton DM, Costello AJ: Management of benign prostatic hyperplasia by transurethral laser ablation in patients treated with warfarin anticoagulation. J Urol 151:79, 1994.

Dietrich W, Dilthey G, Spannagl M, Richter JA: Warfarin pretreatment does not lead to increased bleeding tendency during cardiac surgery. J Cardiothorac Vasc Anesth 9:250, 1995.

White RH, McKittrick T, Hutchinson R, Twitchell J: Temporary discontinuation of warfarin therapy: changes in the International Normalized Ratio. Ann Intern Med 122:40, 1995.

Kearon C, Hirsh J: Management of anticoagulation before and after elective surgery. N Engl J Med 336:1506, 1997.

Cannegieter SC, Rosendaal FR, Briët E: Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circlation 89:635, 1994.

Katholi RE, Nolan SP, McGuire LB: Living with prosthetic heart valves: Subsequent noncardiac operations and the risk of thromboembolism or hemorrhage. Am Heart J 92:162, 1976.

Vigano’D’Angelo S, Tsoureli E, Crippa L, Tomassini L, D’Angelo A: Prevalence of hemorrhagic and thrombotic complications in patients requiring oral anticoagulation and submitted to elective surgery: A study of 197 consecutive patients. Thromb Res 91(suppl 1):S100, 1998.

Chakravarti A, MacDermott S: Transurethral resection of the prostate in the anticoagulated patient. Br J Urol 81:520, 1998.

Kuntze CE, Ebels T, Eijgelaar A, Homan van der Heide JN: Rates of thromboembolism with three different mechanical heart valve prostheses: A randomised study. Lancet 8637:514, 1989.

Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJM, Vandenbroucke JP, Briët E: Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 333:11, 1995.

Butchart EG, Moreno de la Santa P, Rooney SJ, Lewis PA: Arterial risk factors and ischemic cerebrovascular events after aortic valve replacement. J Heart Valve Dis 4:1, 1995.

Burchfiel CM, Hammermeister KE, Krause-Steinrauf H, et al: Left atrial dimension and risk of systemic embolism in patients with a prosthetic heart valve. J Am Coll Cardiol 15:32, 1990.

Acar J, Iung B, Boissel JP, et al: AREVA: Multicenter randomized comparison of low-dose versus standard-dose anticoagulation in patients with mechanical prosthetic heart valves. Circulation 94:2107, 1996.

Scudicky D, Essop MR, Wisenbaugh T, et al: Frequency of prosthetic valve-related complications with very low level warfarin anticoagulation combined with dipyridamole after valve replacement using St. Jude Medical prosthesis. Am J Cardiol 74:1137, 1994.

Hayashi J, Nakazawa S, Oguma F, Miyamura H, Eguchi S: Combined warfarin and antiplatelet therapy after St. Jude Medical valve replacement for mitral valve disease. J Am Coll Cardiol 23:672, 1994.

Yamak B, Sener E, Kiziltepes U, et al: Low dose anticoagulation after St. Jude Medical prosthesis implantation in patients under 18 years of age. J Heart Valve Dis 4:274, 1995.

Kontozis L, Skudicky D, Hopley MJ, Sareli P: Long-term follow-up of St. Jude Medical prosthesis in a young rheumatic population using low-level warfarin anticoagulation: An analysis of the temporal distribution of causes of death. Am J Cardiol 81:736, 1998.

Cappelleri JC, Fiore LD, Brophy MT, Deykin D, Lau J: Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: A meta-analysis. Am Heart J 130:547, 1995.

Loewen P, Sunderji R, Gin K: The efficacy and safety of combination warfarin and ASA therapy: A systematic review of the literature and update of guidelines. Can J Cardiol 14:717, 1998.

Turpie AGG: Antithrombotic therapy following heart valve replacement. Thromb Haemost 77:382, 1997.

Koefoed BG, Gulløv AL, Petersen P: Prevention of thromboembolic events in atrial fibrillation. Thromb Haemost 78:377, 1997.

Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: Analysis of pooled data from five randomized controlled trials. Arch Intern Med 154:1449, 1994.

Koefoed BG, Feddersen C, Gulløv AL, Petersen P: Effect of fixed minidose warfarin, conventional dose warfarin and aspirin on INR and prothrombin fragment 1+2 in patients with atrial fibrillation. Thromb Haemost 77:845, 1997.

Lip GY, Lip PL, Zarifis J, et al: Fibrin D-dimer and beta-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation: Effects of introducing ultra-low-dose warfarin and aspirin. Circulation 94:425, 1996.

Gulløv AL, Koefoed BG, Petersen P, et al: Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 158:1513, 1998.

Collins LJ, Silverman DI, Douglas PS, Manning WJ: Cardioversion of nonrheumatic atrial fibrillation: Reduced thromboembolic complications with 4 weeks of precardioversion anticoagulation are related to atrial thrombus resolution. Circulation 92:160, 1995.

Petersen P: Thromboembolic complications in atrial fibrillation. Stroke 21:4, 1990.

Grimm RA, Stewart WJ, Maloney JD: Impact of electrical cardioversion for atrial fibrillation on left atrial appendage function and spontaneous echo contrast: Characterisation by simultaneous transoesophageal echocardiography. J Am Coll Cardiol 22:1359, 1993.

Laupacis A, Albers G, Dalen J, Dunn M, Feinberg W, Jacobsen A: Antithrombotic therapy in atrial fibrillation: 4th ACCP Consensus Conference on Antithrombotic Therapy. Chest 108:352S, 1995.

Mayet J, Wasan B, Sutton GC: Cardioversion of atrial arrhythmias: Audit of anticoagulation management. J R Coll Physicians Lond 31:313, 1997.

Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group: A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. Ann Neurol 42:857, 1997.

Dressler FA, Craig WR, Castello R, Labovitz AJ: Mobile aortic atheroma and systemic emboli: Efficacy of anticoagulation and influence of plaque morphology on recurrent stroke. J Am Coll Cardiol 31:134, 1998.

EAFT (European Atrial Fibrillation Trial) Study Group: Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 342:1255, 1993.

Morocutti C, Amabile G, Fattapposta F, et al: Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation: SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Stroke 28:1015, 1997.

Medical Research Council’s General Practice Research Framework: Thrombosis prevention trial: Randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 351:233, 1998.

Williams MJ, Morison IM, Parker JH, Stewart RA: Progression of the culprit lesion in unstable coronary artery disease with warfarin and aspirin versus aspirin alone: Preliminary study. J Am Coll Cardiol 30:364, 1997.

van der Meer J, Hillege HL, Kootstra GJ, et al: Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants, the CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands. Lancet 342:257, 1993.

Post Coronary Artery Bypass Graft Trial Investigators: The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 336:153, 1997.

Mehta RH, Eagle KA: Secondary prevention in acute myocardial infarction. Br Med J 316:838, 1998.

Yusuf S, Michaelis W, Hua A, et al: Effects of oral anticoagulants on mortality, reinfarction and stroke after myocardial infarction [abstr]. Circulation (suppl):343, 1995.

Azar AJ, Cannegieter SC, Deckers JW, et al: Optimal intensity of oral anticoagulant therapy after myocardial infarction. J Am Coll Cardiol 27:1349, 1996.

Julian DG, Chamberlain DA, Pocock SJ: A comparison of aspirin and anticoagulation following thrombolysis for myocardial infarction (the AFTER study): A multicentre unblinded randomised clinical trial. Br Med J 313:1429, 1996.

Coumadin Aspirin Reinfarction Study (CARS): Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Lancet 350:389, 1997.

Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA: Warfarin anticoagulation and survival: A cohort analysis from the Studies of Left Ventricular Dysfunction. J Am Coll Cardiol 31:749, 1998.

Cheng JW, Spinler SA: Should all patients with dilated cardiomyopathy receive chronic anticoagulation? Ann Pharmacother 28:604, 1994.

Schneider E, Brunner U, Bollinger A: Medikamentose rezidivprophylaxe nach femoropoplitealer arterienrekonstruktion. Angio 2:73, 1979.

De Smit P, van Urk H: Dutch oral anticoagulation trial. Acta Chir Austr 24:5, 1992.

Kretschmer G, Herbst F, Prager M, et al: A decade of oral anticoagulant treatment to maintain autologous vein grafts for femoropopliteal atherosclerosis. Arch Surg 127:1112, 1992.

Antiplatelet Trialist’s Collaboration: Collaborative overview of randomised trials of antiplatelet therapy: II. Maintenance of vascular graft or arterial patency by antiplatelet therapy. Br Med J 308:159, 1994.

Do DD, Mahler F: Low-dose aspirin combined with dipyridamole versus anticoagulants after femoropopliteal percutaneous transluminal angioplasty. Radiology 193:567, 1994.

Fordyce MJ, Baker AS, Staddon GE: Efficacy of fixed minidose warfarin prophylaxis in total hip replacement. Br Med J 303:219, 1991.

Lotke PA, Palevsky H, Keenan AM, et al: Aspirin and warfarin for thromboembolic disease after total joint arthroplasty. Clin Orthop (324):251, 1996.

Lieberman JR, Sung R, Dorey F, Thomas BJ, Kilgus DJ, Finerman GA: Low-dose warfarin prophylaxis to prevent symptomatic pulmonary embolism after total knee arthroplasty. J Arthroplasty 12:180, 1997.

Vresilovic EJ Jr, Hozack WJ, Booth RE, Rothman RH: Incidence of pulmonary embolism after total knee arthroplasty with low-dose coumadin prophylaxis. Clin Orthop (286):27, 1993.

Hull R, Raskob G, Pineo G, et al: A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 329:1370, 1993.

RD Heparin Arthroplasty Group: RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. J Bone Joint Surg Am 76:1174, 1994.

Leclerc JR, Geerts WH, Desjardins L, et al: Prevention of venous thromboembolism after knee arthroplasty: A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 124:619, 1996.

Heit JA, Berkowitz SD, Bona R, et al: Efficacy and safety of low molecular weight heparin (ardeparin sodium) compared to warfarin for the prevention of venous thromboembolism after total knee replacement surgery: A double-blind, dose-ranging study, Ardeparin Arthroplasty Study Group. Thromb Haemost 77:32, 1997.

Francis CW, Pellegrini VD Jr, Totterman S, et al: Prevention of deep-vein thrombosis after total hip arthroplasty: Comparison of warfarin and dalteparin. J Bone Joint Surg Am 79:1365, 1997.

Palmer AJ, Koppenhagen K, Kirchhof B, Weber U, Bergemann R: Efficacy and safety of low molecular weight heparin, unfractionated heparin and warfarin for thrombo-embolism prophylaxis in orthopaedic surgery: A meta-analysis of randomised clinical trials. Haemostasis 27:75, 1997.

Menzin J, Colditz GA, Regan MM, Richner RE, Oster G: Cost-effectiveness of enoxaparin vs low-dose warfarin in the prevention of deep-vein thrombosis after total hip replacement surgery. Arch Intern Med 155:757, 1995.

O’Brien BJ, Anderson DR, Goeree R: Cost-effectiveness of enoxaparin versus warfarin prophylaxis against deep-vein thrombosis after total hip replacement. Can Med Ass J 150:1083, 1994.

Garcia-Zozaya I: Warfarin vs enoxaparin for deep venous thrombosis prophylaxis after total hip and total knee arthroplasty: A cost comparison. J Ky Med Assoc 96:143, 1998.

Hawkins DW, Langley PC, Krueger KP: A pharmacoeconomic assessment of enoxaparin and warfarin as prophylaxis for deep vein thrombosis in patients undergoing knee replacement surgery. Clin Ther 20:182, 1998.

Francis CW, Pellegrini VD Jr, Leibert KM, et al: Comparison of two warfarin regimens in the prevention of venous thrombosis following total knee replacement. Thromb Haemost 75:706, 1996.

Fishmann AJ, Greeno RA, Brooks LR, Matta JM: Prevention of deep vein thrombosis and pulmonary embolism in acetabular and pelvic fracture surgery. Clin Orthop 305:133, 1994.

Wilson MG, Pei LF, Malone KM, Polak JF, Creager MA, Goldhaber SZ: Fixed low-dose versus adjusted higher-dose warfarin following orthopedic surgery: A randomized prospective trial. J Arthroplasty 9:127, 1994.

Poller L, McKernan A, Thomson JM, Elstein M, Hirsch PJ, Jones JB: Fixed minidose warfarin: A new approach to prophylaxis against venous thrombosis after major surgery. Br Med J 295:1309, 1987.

Bern MM, Lokich JJ, Wallach SR, et al: Very low doses of warfarin can prevent thrombosis in central venous catheters: A randomized prospective trial. Ann Intern Med 112:423, 1990.

Veerabagu MP, Tuttle-Newhall J, Maliakkal R, Champagne C, Mascioli EA: Warfarin and reduced central venous thrombosis in home total parenteral nutrition patients. Nutrition 11:142, 1995.

Bona RD, Sivjee KY, Hickey AD, Wallace DM, Wajcs SB: The efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 74:1055, 1995.

Bona RD, Hickey AD, Wallace DM: Efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost 78:137, 1997.

Levine M, Hirsh J, Gent M, et al: Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet 343:886, 1994.

Sarasin FP, Schifferli JA: Prophylactic oral anticoagulation in nephrotic patients with idiopathic membranous nephropathy. Kidney Int 45:578, 1994.

Hull R, Hirsh J, Jay R, et al: Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 307:1676, 1982.

Hull RD, Raskob GE, Rosenbloom D, et al: Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 152:1589, 1992.

Kearon C, Gent M, Hirsh J, et al: A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 340:901, 1999.

Schulman S, Rhedin AS, Lindmarker P, et al: A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism: Duration of Anticoagulation Trial Study Group. N Engl J Med 332:1661, 1995.

Schulman S, Svenungsson E, Granqvist S, Duration of Anticoagulation Trial Study Group: The predictive value of anticardiolipin antibodies in patients with venous thromboembolism. Am J Med 104: 332, 1998.

Rosove MH, Brewer PM: Antiphospholipid thrombosis: Clinical course after the first thrombotic event in 70 patients. Ann Intern Med 117:303, 1992.

Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR: The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 332:993, 1995.

Schulman S: Optimal duration of oral anticoagulant therapy in venous thromboembolism. Thromb Haemost 78:693, 1997.

Pabinger I, Schneider B: Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency: A cooperative, retrospective study. Arterioscler Thromb Vasc Biol 16:742, 1996.

Eichinger S, Stümpflen A, Hirschl M, et al: Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 80:566, 1998.

Frank H, Mlczoch J, Huber K, Schuster E, Gurtner HP, Kneussl M: The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest 112:714, 1997.

Suresh CG, Neal D, Coupe MO: Warfarin treatment and migraine. Postgrad Med J 70:37, 1994.

Yoshida S, Torikai K: The effects of warfarin on calcinosis in a patient with systemic sclerosis. J Rheumatol 20:1233, 1993.

Zacharski LR, Henderson WG, Rickles FR, et al: Effect of warfarin on survival in small cell carcinoma of the lung. JAMA 245:831, 1980.

Maurer LH, Herndon JE, Hollis DR, et al: Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: A Cancer and Leukemia Group B study. J Clin Oncol 15:3378, 1997.

Carpi A, Sagripanti A, Poddighe R, Gherarducci G, Nicolini A: Cancer incidence and mortality in patients with heart disease: Effect of oral anticoagulant therapy. Am J Clin Oncol 18:15, 1995.

Kerr JS, Li HY, Wexler RS, et al: The characterization of potent novel warfarin analogs. Thromb Res 88:127, 1997.

Leone-Bay A, Paton DR, Freeman J, et al: Synthesis and evaluation of compound that facilitate the gastrointestinal absorption of heparin. J Medic Chem 41:1163, 1998.

Pinto A, Corrao S, Galati D, et al: Sulodexide versus calcium heparin in the medium-term treatment of deep vein thrombosis of the lower limbs. Angiology 48:805, 1997.

Harenberg J: Review of pharmacodynamics, pharmacokinetics, and therapeutic properties of sulodexide. Med Res Rev 18:1, 1998.

Zawilska K, Elikowski W, Turowiecka Z, et al: On the action of a heparan-like glycosaminoglycan (Hemovasal) on the mechanism of haemostasis and fibrinolysis. Thromb Res 78:211, 1995.

Sato K, Kawasaki T, Hisamichi N, et al: Antithrombotic effects of YM-60828 in three thrombosis models in guinea pigs. Eur J Pharmacol 350:87, 1998.

Morishima Y, Tanabe K, Terada Y, Hara T, Kunitada S: Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor: Comparison with a direct thrombin inhibitor and antithrombin III-dependent anticoagulants. Thromb Haemost 78:1366, 1997.

Lee K, Hwang SY, Hong S, et al: Structural modification of an orally active thrombin inhibitor, LB30057: Replacement of the D-pocket-binding naphthyl moiety. Bioorg Med Chem 6:869, 1998.

Mehta JL, Chen L, Nichols WW, Mattsson C, Gustafsson D, Saldeen TG: Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery. J Cardiovasc Pharmacol 31:345, 1998.

Rebello SS, Miller BV, Basler GC, Lucchesi BR: CVS-1123, a direct thrombin inhibitor, prevents occlusive arterial and venous thrombosis in a canine model of vascular injury. J Cardiovasc Pharmacol 29:240, 1997.

Bajusz S, Barabas E, Fauszt I, et al: Active site-directed thrombin inhibitors: Alpha-hydroxyacyl-prolyl-arginals, new orally active stable analogues of D-Phe-Pro-Arg-H. Semin Thromb Hemost 22:243, 1996.

Eriksson BI, Carlsson S, Halvarsson M, Risberg B, Mattsson C: Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat. Thromb Haemost 78:1404, 1997.

Lundström T, Rydén L: Haemorrhagic and thromboembolic complications in patients with atrial fibrillation on anticoagulant prophylaxis. J Intern Med 225:137, 1989.

Hurlen M, Erikssen J, Smith P, Arnesen H, Rollag A: Comparison of bleeding complications of warfarin and warfarin plus acetylsalicylic acid: A study in 3166 outpatients. J Intern Med 236:299, 1994.

Palareti G, Leali N, Coccheri S, et al: Bleeding complications of oral anticoagulant treatment: An inception-cohort, prospective collaborative study (ISCOAT), Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 348:423, 1996.

Forfar JC: A 7-year analysis of haemorrhage in patients on long-term anticoagulant treatment. Br Heart J 42:128, 1979.

Stroke Prevention in Atrial Fibrillation Investigators: Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med 156:409, 1996.

van der Meer FJ, Rosendaal FR, Vandenbroucke JP, Briet E: Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost 76:12, 1996.

Isaacs C, Paltiel O, Blake G, Beaudet M, Conochie L, Leclerc J: Age-associated risks of prophylactic anticoagulation in the setting of hip fracture. Am J Med 96:487, 1994.

Fihn SD, McDonell M, Martin D, et al: Risk factors for complications of chronic anticoagulation: A multicenter study, Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 118:511, 1993.

O’Neill PA, Crossley D, Taberner DA, Fairweather DS: Safety of anticoagulation in the elderly: Reasons for discontinuing therapy. Postgrad Med J 68:824, 1992.

Schulman S: Quality of oral anticoagulant control and treatment in Sweden. Duration of Anticoagulation (DURAC) Trial Study Group. J Intern Med 236:143, 1994.

Levine MN, Raskob G, Hirsh J: Risk of haemorrhage associated with long-term anticoagulant therapy. Drugs 30:444, 1985.

Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B: Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: The Copenhagen AFASAK study. Lancet 1:175, 1989.

Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators: The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 323:1505, 1990.

Stroke Prevention in Atrial Fibrillation Study: Final results. Circulation 84:527, 1991.

Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C: Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 18:349, 1991.

Ezekowitz MD, Bridgers SL, James KE, et al: Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation: Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 327:1406, 1992.

British Medical Research Council: An assessment of long-term anticoagulant administration after cardiac infarction. Br Med J 2:837, 1964.

Ebert RV, Borden CW, Hipp HR, Holzman D, Lyon AF, Schnaper H: Long-term anticoagulant therapy after myocardial infarction. JAMA 207:2263, 1969.

A double-blind trial to assess long-term oral anticoagulant therapy in elderly patients after myocardial infarction: Report of the Sixty Plus Reinfarction Study Research Group. Lancet 2:989, 1980.

Smith P, Arnesen H, Holme I: The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 323:147, 1990.

Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group: Effect of long-term oral anticoagulant treatment on mortality and cardiovascular morbidity after myocardial infarction: Lancet 343:499, 1994.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology


  1. […] issues Associated By using MenopauseSiedem szczęśliwych liczbSenior Care in Hillsborough, CACHAPTER 132 ORAL ANTICOAGULATIONvar base_url_sociable = […]

  2. […] Breast Cancer & Biotechnology: Bigger Than PinkUse of Alternative Therapies for Children With CancerWhen triple negative breast cancer spreads to the liver what are the chances of survivalBreast Cancer CausesAlternative Therapy for Breast Cancer: by Sheldon FeldmanCHAPTER 132 ORAL ANTICOAGULATION […]

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: