Update in Hematology

Updates from the Annual Session2 January 2001Update in HematologyFREEGeraldine P. Schechter, MD, Harish P.G. Dave, MD, and Barbara M. Alving, MDGeraldine P. Schechter, MDFrom Veterans Affairs Medical Center and George Washington University, Washington, D.C.; and National Institutes of Health, Bethesda, Maryland.Search for more papers by this author, Harish P.G. Dave, MDFrom Veterans Affairs Medical Center and George Washington University, Washington, D.C.; and National Institutes of Health, Bethesda, Maryland.Search for more papers by this author, and Barbara M. Alving, MDFrom Veterans Affairs Medical Center and George Washington University, Washington, D.C.; and National Institutes of Health, Bethesda, Maryland.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-134-1-200101020-00012 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail In selecting the articles for this Update, we found that the topics that generated the most attention in the past year were the newer concepts in anticoagulation, thrombosis, hemostasis, transfusion therapy, hemochromatosis, and novel therapies for hematologic malignancy. In each of these areas, new findings have provided better ways to treat patients.AnticoagulationClinical research in anticoagulant therapy has left many questions unanswered. The articles we have chosen suggest answers to such questions as, What is the correct daily dose of warfarin? How long should a patient continue to receive anticoagulants? Which patients should undergo prophylactic anticoagulation? The answers help to make the practice of hematology more effective and predictable.Warfarin Dose Requirement Is Influenced by the Genes Aithal GP, Day CP, Kesteven PJ, et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999; 353:717-9. [PMID: 0010073515]Variations in the rate of response to a given dose of warfarin have been problematic. Effective daily doses can range from as low as 0.5 mg to higher than 60 mg. In an effort to make sense of the puzzle, Aithal and colleagues conducted a case–control study to determine whether genetic differences in the cytochrome P450 system influence the individual variability in dose requirements for warfarin. An asymmetric carbon in warfarin (C9) produces the enantiomers R-warfarin and S-warfarin, which are metabolized by different enzymes. S-warfarin, which is three times more potent than R-warfarin, is metabolized by the cytochrome P450 CYP2C9. The authors used polymerase chain reaction to evaluate the two allelic forms of CYP2C9 that have only 5% and 12% of the activity of the wild-type enzyme in patients with low-dose warfarin requirements (≤ 1.5 mg/d; n = 36), those with normal dose requirements who were being treated in an anticoagulation clinic (clinic controls; n = 52), and normal persons (n = 100).The odds ratio for having one or more of the two variant alleles in the low-dose warfarin group compared with the normal population was 6.21. Twenty percent of patients in the low-dose group and 2% of clinic controls had two variant alleles.For the low-dose group compared with clinic controls, the odds ratio for excessive international normalized ratios at initiation of warfarin treatment was 5.97. The low-dose group was also at increased risk for bleeding complications (rate ratio, 3.68) compared with clinic controls. On the basis of these results, the researchers surmised that heterozygosity or homozygosity for the two allelic forms of CYP2C9 are associated with lower warfarin dose requirements.From our point of view, this study provides strong evidence for the role of genetic variation in the cytochrome P450 system in influencing this variability. The genetic variability may also accentuate the response to drugs that are known to induce increased sensitivity to warfarin. This study further supports the initiation of warfarin therapy at a daily dose of 5 mg, as shown in an earlier article (1).Thromboprophylaxis with Low-Molecular-Weight Heparin Was Evaluated in Hospitalized, Acutely Ill Medical Patients Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med. 1999; 341:793-800. [PMID: 0010477777]Venous thromboembolism is commonly found at autopsy of patients who have died during hospitalization. Although evidence supports routine thromboprophylaxis for surgical patients, its value for other hospitalized medical patients is not as clear. To provide that type of information, Samama and colleagues conducted a randomized, double-blind controlled trial that compared routine enoxaparin with placebo for thromboprophylaxis. Patients were randomly assigned to receive enoxaparin subcutaneously at either 40 mg/d (n = 291) or20 mg/d (n = 287) or to receive placebo (n = 288). Treatment was administered for 6 to 14 days, and patients were followed for a total of 30 days. All patients were screened for deep venous thrombosis between days 6 and 14, or earlier if thrombosis was suspected clinically. The inclusion criteria were highly selective; the investigators excluded patients with a history of stroke or major surgery in the past 3 months, those who were at increased risk for bleeding, and those who had underlying thrombophilia. Sponsored by Rhône-Poulenc Rorer, the study was conducted at 60 centers in nine countries (none in the United States) between 1996 and 1998 and enrolled 1102 patients.The incidence of venous thromboembolism (detected by bilateral venography or duplex ultrasonography for thrombosis in the lower extremities and by lung scanning, pulmonary angiography, or helical computed tomography for pulmonary emboli) was 5.5% in the group receiving 40 mg of enoxaparin daily compared with 15% in the 20-mg/d group and 14.9% in the placebo group.The authors observed that 40 mg of enoxaparin per day reduced the risk for venous thromboembolism by 63% in medical patients at moderate risk for this complication; without prophylaxis, venous thromboembolism would be assumed to occur in 9% to 26% of the patients. We were disappointed that the study did not compare enoxaparin with unfractionated heparin, and found that because the study was highly selective in its inclusion and exclusion criteria, the results may not be generalizable.After a First Episode of Idiopathic Venous Thromboembolism, Patients Should Receive Anticoagulation for More Than 3 Months 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. 1999; 340:901-7. [PMID: 0010089183]Kearon and colleagues conducted a double-blind prospective study to compare the effects of anticoagulation extended beyond 3 months on rates of symptomatic venous thromboembolism and bleeding in patients with a first episode of venous thromboembolism occurring spontaneously. All patients received 3 months of anticoagulation with warfarin and were then randomly assigned to receive continued warfarin (n = 79) or placebo (n = 83) for another 24 months. The investigators excluded patients who had transient risk factors, had known underlying hypercoagulable states (history of cancer within 5 years or inherited disorders), or required long-term treatment with drugs likely to promote a bleeding diathesis. Suspected recurrent thromboembolism was documented by comparing compression ultrasonography and impedance plethysmography findings with results of baseline studies and, if necessary, venography. Patients were also screened for factor V Leiden mutation, G20210A prothrombin mutation, anticardiolipin antibodies, and lupus anticoagulants.After patients had been followed for an average of 10 months, the study was terminated because the rate of recurrence of venous thromboembolism was 27.4% per patient-year in the placebo group compared with 1.3% per patient-year in patients who continued to receive anticoagulation (P < 0.001), a 95% reduction in recurrence. The authors found no significantly greater risk for major bleeding in the group receiving extended warfarin compared with placebo recipients (P = 0.09).The authors concluded that patients with a first episode of idiopathic venous thromboembolism should receive anticoagulation for more than 3 months, although the duration of the extension is still not defined and requires consideration of the risk for bleeding in a given patient. They also noted that only patients with a lupus anticoagulant or anticardiolipin antibody were identified as a subgroup at higher risk for recurrence after 3 months of warfarin treatment.From the internist's perspective, additional studies are needed to define the optimal duration and intensity of anticoagulant therapy that should be recommended after a first episode of thrombosis. Clinical trials should include patients with well-defined underlying hypercoagulable states associated with factor V Leiden mutation; the prothrombin gene mutation; and deficiencies of protein C, protein S, and antithrombin III.Heparin-Induced ThrombocytopeniaAlthough thromboembolic complications of heparin-induced thrombocytopenia mandate the cessation of heparin therapy, many patients with this syndrome require continued anticoagulation for their primary underlying disease. Several other drugs have been used with varying degrees of success; the most reliable of these are the thrombin-specific inhibitors argatroban and recombinant hirudin (r-hirudin).Treatment of Heparin-Induced Thrombocytopenia with Recombinant Hirudin Results in Recovery of Platelet Count and Clinical Benefit Greinacher A, Völpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation. 1999;99:73-80. [PMID: 0009884382]Greinacher and colleagues evaluated the efficacy of the thrombin-specific inhibitor recombinant hirudin [r-hirudin] for the treatment of heparin-induced thrombocytopenia in a multicenter prospective phase II study that included four groups of patients: 1) patients with heparin-induced thrombocytopenia who had thrombosis [n = 51; bolus dose, 0.4 mg/kg of body weight; subsequent dosage, 0.15 mg/kg per hour]; 2) patients with heparin-induced thrombocytopenia who did not have thrombosis [n = 18; dosage, 0.1 mg/kg per hour]; 3) patients with heparin-induced thrombocytopenia who had thrombosis and were receiving thrombolysis [n = 5]; and 4) patients with heparin-induced thrombocytopenia undergoing cardiopulmonary bypass surgery (n = 8). Different dosing regimens were used for each group. The degree of anticoagulation was measured by using the activated partial thromboplastin time, except in the bypass patients, for whom the ecarin clotting time was used. Efficacy in 71 hirudin-treated patients was compared with that in 120 historical controls.Platelet counts increased rapidly in 89% of the patients. The incidence of the combined end point of death, amputation, and new thromboembolic events was significantly reduced in patients treated with r-hirudin compared with historical controls (hazard ratio, 0.508 [95% CI, 0.290 to 0.892]; P = 0.014).Of the patients receiving r-hirudin, 30% experienced at least one bleeding event; in 13%, a major bleeding event developed. Bleeding complications were not correlated with plasma hirudin levels, and the incidence was similar to that seen in the historical controls.The authors concluded that treatment of heparin-induced thrombocytopenia with r-hirudin results in prompt recovery of platelets and clinical benefit. This first prospective study of clinical experience with r-hirudin indicates that the drug is an effective and safe alternative anticoagulant for this life- and limb-threatening disorder. The authors did not describe the outcomes of patients undergoing bypass surgery who received r-hirudin; this area requires further exploration.It should be recognized, however, that r-hirudin and argatroban also prolong the prothrombin time, thus making initiation of warfarin therapy more complex. In addition, renal function should be carefully established in patients who are to receive r-hirudin treatment because more than 90% of the drug is eliminated through the kidneys and appropriate dose adjustments must be made for renal insufficiency. Argatroban is not excreted by the kidneys but rather by the liver. Therefore, dose adjustments are not required for argatroban in patients with renal insufficiency. Argatroban and r-hirudin have no known antidote and must be used with caution in patients at risk for bleeding. The internist will want to balance this fact with the realization that patients with heparin-induced thrombocytopenia are at high risk for life-threatening thrombosis.Thrombotic Thrombocytopenic PurpuraWidespread platelet thrombi in the microcirculation characterize thrombotic thrombocytopenic purpura (TTP). Therapeutic advances have greatly improved the prognosis for this once uniformly fatal disorder. However, relapse after initial successful treatment is common. Recent studies indicate that TTP is an autoimmune disorder. This new understanding of pathophysiology may well prompt improved treatment to prevent relapse.Antibodies to von Willebrand Factor–Cleaving Protease May Explain the Clinical Presentation of TTP Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998; 339:1585-94. [PMID: 0009828246]Tsai and colleagues explored the hypothesis that the predisposition to platelet thrombi in patients with TTP is caused by a deficiency of the plasma protease that cleaves the large multimers of von Willebrand factor. Plasma von Willebrand factor–cleaving protease activity was measured in 37 patients with TTP by incubating the plasma samples with purified von Willebrand factor and assaying the von Willebrand factor dimers generated on sodium dodecylsulfate gels. Inhibitors to the protease activity were measured by incubating patient plasma or purified IgG with normal plasma and then assaying these samples for protease activity.All 37 patients had essentially no plasma protease activity in the acute phase but demonstrated normal activity in the remission period. Mean protease activity was approximately 100% in 74 plasma samples from normal study participants and from patients with other disorders, such as hemolytic anemia, thrombocytopenia, thrombosis, and heparin-induced thrombocytopenia. The researchers found that 67% of the patients with TTP had inhibitory activity against the plasma protease, which appeared to be due to IgG antibodies.The authors concluded that antibodies to von Willebrand factor–cleaving protease found in the plasma of patients with TTP play a role in the formation of platelet thrombi. In the presence of high levels of intravascular shear stress, von Willebrand factor has increased platelet-binding sites; under normal circumstances, these would be reduced through degradation of the multimers by plasma protease. The authors postulate that because the protease activity is absent in patients with TTP, platelet thrombi may be formed more easily in the circulation.The finding in this study of an IgG antibody to the enzyme suggests that TTP is an autoimmune disorder that may respond to corticosteroids in addition to plasma exchange for the acute phase. Perhaps recurrences, which occur in approximately 30% of adults, could be prevented or treated with immune suppression.Nonfamilial TTP May Have an Immune-Mediated Basis Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998; 339:1578-84. [PMID: 0009828245]The prognosis and treatment of patients with TTP or the hemolytic uremic syndrome may be influenced by the severity and cause of the von Willebrand factor–cleaving protease deficiency. Furlan and colleagues conducted a multicenter study to determine the prevalence of von Willebrand factor–cleaving protease deficiency in familial and nonfamilial TTP and the hemolytic uremic syndrome. Plasma samples were obtained from patients classified on a clinical basis by their physicians as having familial or nonfamilial TTP or the hemolytic uremic syndrome; protease activity was measured by quantitating the extent of von Willebrand factor degradation that occurred after incubation of purified von Willebrand factor with patient plasma.The results suggested that the patients with nonfamilial TTP (n = 24) had a moderate or severe decrease in protease activity during an acute event, which appeared to be due to an inhibitor (identified in a subgroup as IgG). Patients with familial TTP (n = 6) also had no protease activity, but no antibody was detected. Patients with nonfamilial (n = 13) or familial (n = 10) hemolytic uremic syndrome had normal or slightly decreased protease activity.In light of these data, together with those reported by Tsai and Lian, the authors provide strong evidence for an immune basis for nonfamilial acute TTP. They conclude that familial TTP is associated with a deficiency of von Willebrand factor–cleaving protease that is not immune mediated and that the pathogenesis of clinically defined hemolytic uremic syndrome does not appear to be related to the von Willebrand factor–cleaving protease.In our view, these two studies on TTP provide a very solid basis with which to understand the pathophysiology of TTP and on which to develop treatment strategies that go beyond plasma exchange for the acute phase. von Willebrand factor–cleaving protease is present in normal concentrations in fresh frozen plasma, probably accounting for the clinical responses to plasma infusion, and is not inactivated by solvent-detergent treatment of plasma. An important point for clinicians is that measurement of protease activity may be a way to differentiate the diagnosis of TTP from that of the hemolytic uremic syndrome. Additional prospective studies are needed to confirm the very clear distinction between these two disorders that was reported by Furlan and colleagues. The role of these assays (when they become commercially available) in guiding treatment remains to be determined.Transfusion TherapyWhen patients receive a transfusion, the intended result is improvement of oxygen delivery to the tissue. The questions that have arisen are, Does the transfusion really benefit the patient? Are we actually harming the patient?A Conservative Policy of Red-Cell Transfusion Is Equal or Superior to a Liberal Transfusion Policy Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999; 340:409-17. [PMID: 0009971864]Hebert and colleagues conducted a randomized, controlled clinical trial to compare the effect of a restricted transfusion strategy with that of a liberal strategy on mortality and severity of organ dysfunction in anemic critically ill patients. Normovolemic, anemic patients in an intensive care unit were randomly assigned to be maintained at a hemoglobin level of 70 to 90 g/L or 100 to 120 g/L. Of 2039 eligible patients, 838 consented to participate. The study was terminated before the intended recruitment goal of 1620 was met because of a slow rate of accrual. At baseline, the Acute Physiology and Chronic Health Evaluation (APACHE) II score, multiple-organ dysfunction score, primary diagnoses, number of patients receiving mechanical ventilation, and hemoglobin levels at randomization did not significantly differ between the two groups.The average daily hemoglobin level was 85 g/L in the restricted-strategy group and 107 g/L in the liberal-strategy group. In the restricted-strategy group, the number of red cell units transfused was decreased by 54% and the number of patients who were transfused was reduced by 33%. The primary outcome measure—all-cause mortality rate at 30 days—did not significantly differ between groups (18.7% in the restricted-strategy group vs. 23.3% in the liberal-strategy group; difference, 4.6 percentage points [CI, −0.84 to 10.2 percentage points]; P = 0.11). No difference was seen between the two groups with respect to the secondary outcome measures of mortality during the entire intensive care unit stay and mortality at 60 days. However, the mortality rate during hospitalization, another secondary outcome measure, was lower in the restricted-strategy group than in the liberal-strategy group (22.2% vs. 28.1%; P = 0.05). Kaplan–Meier survival curves were significantly improved by restricted-strategy compared with the liberal-strategy in the subgroup that was than years of (P = and in the subgroup that had severe (P = the subgroup included patients with a of or in the II system indicate more severe were a In addition, events pulmonary occurred in the restricted-strategy group than in the liberal-strategy group during the stay in the intensive care unit (P < No difference was noted in other complications between the two groups.The authors concluded that a restricted transfusion was at least to if not to a liberal transfusion for critically ill patients. We the to the lower hemoglobin level for most patients, except for those with The authors noted a difference in the percentage of patients with who were enrolled in the study compared with those not because of a of by physicians for the this difference may the of the results to patients with severe disease. The for a of benefit from a liberal transfusion are but and effects of transfusion have been as have the of realization that is and that the that can occur in this disorder is has in The three articles chosen describe research in this for of Is S, et al. A study of the clinical of the N Engl J Med. 1999; [PMID: and colleagues to the prevalence and clinical of the gene in a population of They samples obtained in from of a in which were then in 1998 for levels, and for the by at by polymerase chain Patients with greater than were also for the by mutation, which is in the All for the and patients with or levels was in 1998 were evaluated for evidence of study participants and were identified as of the had had an level and a normal The sensitivity and value of a value greater than to persons with were greater than for an had clinical of and samples from participants demonstrated levels, but only samples or had no in their and maintained normal levels the period. In 6 of levels persons with had significantly higher than The prevalence of clinically in persons who were not was in authors found that in this study in participants were for the of the of the participants were and 6 who had not received a diagnosis of a in percent of the participants maintained normal levels a is the most genetic disorder in persons of This study that clinical may be in but that most of the persons identified as for the of the gene will have increased The authors recommended measurement of and level as the initial for with the goal of patients before results in or The fact that one of the participants in this study would not have been identified if only the had been measured this should that the of the in patients who appear to have in other can be In for only of patients with clinical findings of have the with and Suspected May for et al. in patients with and other Med. 1999; [PMID: and colleagues conducted a study to determine the prevalence of in patients with a clinical diagnosis of and in patients with disease. The prevalence of and was in patients: 1) patients identified as having by criteria per year or to a and 2) patients with with suspected and documented of found in this study is shown in the of to Clinical Presentation All of the patients had increased levels, although 15% had levels than the per year used for the clinical diagnosis of The authors found that patients with and suspected have a of being for In of two of their that the patient to have or was 40 years of and that of 10 had increased authors the shown in the for of a patient with a for the of in a with a = = = The of genetic for hemochromatosis, however, is The on this article were using before of whether patients are likely to benefit from diagnosis and treatment they not the defined criteria for They that genetic and of persons with a genetic are not is not clear to which patients are likely to develop complications if they are left Should To and before et al. A of patients with and response to J Med. 1999; [PMID: and colleagues conducted an international of patients with to determine the type and of in patients with before diagnosis and The was through the of patient and the for and and many Of the received a diagnosis because of

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