Antithrombin Deficiency

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Antithrombin Deficiency
Author: Arun Rajan, MD; Chief Editor: Emmanuel C Besa, MD more... Updated: Jan 10, 2012

Background
Antithrombin III (ATIII) is currently referred to as antithrombin (AT). Antithrombin (AT) is a 58-kDa molecule belonging to the serine protease inhibitor (serpin) superfamily that plays a central role as an anticoagulant in mammalian circulation systems; its sites of action are shown in the image below.[1] In fact it is present in a wide variety of organisms ranging from thermophilic bacteria[2] to mammals. In addition to its effect as an antagonist of thrombin, it also inhibits other proteases of the coagulation cascade.[3, 4, 5, 6]

Antithrombin (AT) sites of action.

These actions are catalyzed by the interaction between antithrombin and vessel wall-associated glycosaminoglycans. Recent studies have also shown that antithrombin has anti-inflammatory actions that are independent of its effect on coagulation.[7, 8, 9, 10] The existence of antithrombin was conceptualized as long ago as 1905 by Morawitz. Olav Egeberg described the first family with thrombotic disease due to inherited antithrombin deficiency in 1965.[11] Work done in the early years of antithrombin research has been elegantly reviewed by Ulrich Abildgaard in 2007.[12] Over the last few years, there has been a growing body of data describing novel mutations in the antithrombin gene and literature helping to elucidate the molecular pathology of antithrombin deficiency.[13, 14, 15, 16, 17] For excellent patient education resources, see eMedicineHealth's patient education article Deep Vein Thrombosis.

Pathophysiology
Antithrombin belongs to the serpin family of inhibitors, which include heparin cofactor II (HCII), alpha2-antiplasmin, plasminogen activator inhibitor-1 (PAI-1), C1-inhibitor, and alpha1-antitrypsin. Antithrombin forms a 1:1 irreversible complex with its target active enzyme, and the complex is cleared by the liver with loss of enzyme activity.

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Serpins have a highly conserved structure with 3 beta-sheets and 9 alpha-helices.[18] A region known as the reactive center loop (RCL) protrudes above the core of the serpin molecule and has a sequence of amino acids that is complementary to binding sites in the active sites of the target proteases. Cleavage at the reactive center by target proteases results in the activation of a unique mechanism of inhibition.[19] Antithrombin exists in 2 forms: 90% as the alpha-form that is glycosylated at all positions and 10% as the beta form that is not glycosylated at position Asn135. Plasma antithrombin contains 432 amino acids, 6 of which are cysteine residues that form 3 intramolecular disulfide bonds. Also present are 4 glycosylation sites at Asn96, Asn135, Asn155 and Asn192, to which are attached oligosaccharide side chains.[20] The major physiologic role of the molecule, as the name implies, is the inhibition of thrombin (factor IIa). In addition, it also inhibits other serine proteinases, including activated factors X, IX, XI, and XII.[21] Antithrombin also antagonizes factor VII by accelerating the dissociation of the factor VIIa-tissue factor complex and preventing its reassociation.[6] The mechanism of inactivation of serine proteinases occurs in 2 steps, with an initial weak interaction followed by a conformational change that traps the proteinase. This mechanism is depicted in the image below.

Antithrombin (AT) neutralizes the enzyme (IIa) by forming a 1:1 stoichiometric complex (AT:IIa) between the arginine-serine sites of the 2 proteins. Binding of heparin to lysyl residues on AT results in a conformational change in AT, which makes it more available to bind thrombin (IIa), IXa, and Xa, thus markedly accelerating the rate of enzyme-inhibitor complex formation. AT also neutralizes XIa and XIIa.

Transformation to the final complex involves formation of a highly stable bond between the Arg393 residue on antithrombin and the Ser residue on thrombin. The formation of the antithrombin-proteinase complex is catalyzed by heparin and related glycosaminoglycans. Under optimal conditions, the interaction between thrombin and antithrombin could be accelerated by as much as 2000 times. It should be noted that the catalytic effect of heparin is achieved when its concentration is far below that of antithrombin and its target proteinases. Many in vitro studies have established the relative rates of thrombin generation and neutralization, but a study by Undas et al quantified the changes in the rate of activation and inactivation of several hemostatic factors in blood serially sampled from a bleeding time cut.[22] In this in vivo test system with an active, ongoing interaction between blood components and the injured vessel wall in flowing blood, it was noted that thrombin-antithrombin (TAT) complexes started increasing within 30 seconds of the bleeding time cut and reached a maximum by 180 seconds. The pattern of increase was typical of the 2 phases of activation, which have been described in other models of thrombosis, with an initial 60- to 90-second initiation phase followed by a subsequent propagation phase, during which activation reaches its maximum level.[22] In the healthy volunteers, under basal conditions, the amount of thrombin formed exceeded TAT formation at all time points tested until bleeding stopped. TAT complexes formed following the neutralization of thrombin by antithrombin have been used as a surrogate marker for thrombin generation; serial changes in TAT levels have been used to determine alterations of the extent of hemostatic activation in the course of a disease or to assess the impact of specific therapy (eg, the effect of heparin in ameliorating disseminated intravascular coagulation [DIC]). HCII is another physiologic inhibitor of hemostasis that appears to contribute about 20-30% of plasma (AT) heparincofactor activity in the presence of large amounts of heparin; HCII does not contribute to antifactor Xa activity. Therefore, it has been suggested that, in the assessment of the true heparin cofactor activity of antithrombin, the antifactor Xa activity of antithrombin be measured within 30 seconds of incubation with factor Xa in the presence of small amounts of heparin in order to exclude the contribution of HCII to this assay. The use of low doses of heparin in the test system and the use of factor Xa rather than thrombin allows for an accurate assessment of antithrombin's heparin cofactor activity with avoidance of the contribution of HCII to this assessment. Thrombomodulin, an endothelial cell receptor for thrombin, also binds antithrombin and accelerates its anticoagulant effect. In a purified system, tissue factor pathway inhibitor (TFPI) also appeared to potentiate the ability of antithrombin

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to neutralize activated coagulation factors. Antithrombin is synthesized primarily in the liver. It is secreted into the plasma in the form of a molecule containing 432 amino acids with a molecular weight of 58,200. The normal plasma level is 150 mcg/mL and the plasma half-life is approximately 3 days. Independent of its anticoagulant properties, antithrombin also exerts anti-inflammatory and anti-proliferative effects. A number of studies have documented the ability of antithrombin to inhibit leukocyte rolling and adhesion.[23] The ability of this molecule to inhibit leukocyte-endothelial cell interaction is at least partly due to the release of prostacyclins from endothelial cells. Oelschlager et al have shown that antithrombin produces a dose-dependent reduction in both lipopolysaccharide and tumor necrosis factor (TNF)alpha activation of nuclear factor kB (NF-kB) in cultured monocytes and endothelial cells. As a result, the synthesis of proinflammatory mediators such as interleukin (IL)-6, IL-8, and TNF is decreased, leading to an anti-inflammatory effect. A number of studies have also shown that cleaved antithrombin has potent antiangiogenic and antitumor properties. Larsson and colleagues have shown that fibroblast growth factor (FGF)-induced angiogenesis in the chick embryo and angiogenesis in mouse fibrosarcoma tumors is inhibited by treatment with latent antithrombin. There is literature to suggest that latent antithrombin may also induce apoptosis of endothelial cells by disrupting cell-matrix interactions. Patients with antithrombin deficiency (AT deficiency) have prolonged circulation of activated coagulation factors, which increases the risk of thrombus formation at sites that fulfill Virchow's postulates (stasis, alteration of coagulability of the blood, and vessel wall damage). A 50% reduction in the level of antithrombin activity is sufficient to tilt the balance in favor of thrombosis; patients who are heterozygous for antithrombin deficiency (AT deficiency) have a variable incidence of thrombotic disease, whereas most homozygous individuals have a 100% frequency of thrombotic disease, which may be fatal at an early age. Inherited or acquired antithrombin deficiencies (AT deficiencies) predispose affected individuals to serious venous and arterial thrombotic disease. Although it is well recognized that inherited antithrombin deficiency (AT deficiency) is a more serious disorder than inherited deficiencies of proteins C or S, there is much variability in thrombotic manifestations in patients with inherited antithrombin deficiency. A population-based case control study found a 5-fold increased risk of thrombosis when antithrombin deficiency (AT deficiency) was associated with another genetic defect that predisposes to thrombosis.[24, 25] This risk increased to 20-fold when antithrombin deficiency was coupled with an acquired risk factor for thrombosis.[24] Variable co-inheritance of other thrombophilic mutations (eg, activated protein C [APC] resistance, factor V Leiden, protein C or S deficiency, thrombomodulin gene mutations, methylene tetrahydrofolate reductase (MTHFR) deficiency, high lipoprotein(a) levels) is the reason for discordance in thrombotic manifestations among individuals within a family with antithrombin deficiency (AT deficiency). The type of mutation also influences the phenotype. For example, the heterozygous form of a commonly inherited variant of antithrombin affecting the heparin-binding site (HBS) is not a risk factor for thrombosis. The location and type of mutation also affects the phenotype; for instance, the replacement of the normal threonine-85 (85 Thr) by a nonpolar methionine (known as antithrombin wibble) results in a mild adult-onset thrombotic disease, whereas replacement of the same85 Thr by a polar lysine (known as antithrombin wobble) results in severe and early onset of thrombosis in childhood. Interestingly, a rise in body temperature in the presence of an antithrombin wobble, as with fevers, can add additional conformational stress on the antithrombin wobble protein, tilting the balance in favor of thrombosis. A cooperative interplay of risk factors occurs in individuals, depending on their genetic and acquired thrombophilic risk factors. Thus, the presence of an additional inherited or acquired risk factor(s) in a patient with antithrombin deficiency adds to the thrombophilic burden and necessitates aggressive prophylaxis in high-risk situations. Ample evidence documents the high risk of venous thromboembolism (VTE) events in patients with antithrombin deficiency (AT deficiency), whether it is inherited or acquired. Inherited antithrombin deficiency contributes to about 1% of VTE in the affected population. Studies of families with inherited antithrombin deficiency (AT deficiency) show that an increasing proportion of affected individuals develop thrombotic complications starting in their teen years, with spontaneous thrombosis in approximately 40% of patients. In the remaining 60%, additional precipitating factors, such as oral contraceptive use, pregnancy, labor and delivery, surgery, or trauma, may precipitate a thrombotic event. By age 50 years, more than 50% of individuals with inherited antithrombin deficiency have had VTE, in contrast with only 5% of nondeficient individuals. There has been a suggestion that antipsychotic drugs may potentiate thrombosis; this requires further validation. A homozygous type of antithrombin deficiency (antithrombin III Kumamoto) has been reported to be present in a

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family with consanguinity. It was shown to be associated with arterial thrombotic disease. The patient developed cerebral arterial thrombosis at age 17 years and subsequently developed venous thrombosis. Evidence for a role of antithrombin deficiency (AT deficiency) in arterial thrombotic disease is now emerging. The most common thrombotic manifestations in patients with antithrombin deficiency (AT deficiency) include lower extremity VTE, with recurrent VTE being common. Other sites of thrombosis include the inferior vena cava, hepatic and portal veins, and renal, axillary, brachial, mesenteric, pelvic, cerebral, and retinal veins. Arterial thrombosis is strikingly less common.

Antithrombin gene
The gene for antithrombin is located on chromosome 1 band q23.1-23.9, has 7 exons and 6 introns, and is 13.5 kilobases (kb) long. The promoter region does not have a TATA or CAAT box. A control element at the 5' flanking region is apparently critical for efficient synthesis of antithrombin, with homology to an enhancer of murine and human genes. The mRNA is 1567 nucleotides long, encodes approximately 432 amino acids, codes for a signal peptide for antithrombin, and has an approximately 175 base pair (bp) 3' untranslated region. Two modes of splicing of the primary transcript are feasible at 2 sites in the first intron; the result is either a full native antithrombin molecule or a truncated product with a portion left within the cell. Mutations that lead to a loss of function result in antithrombin deficiency (AT deficiency); those that affect the Arg393 site (P1 site) near the carboxy terminal end have a major impact on antithrombin activity. However, mutations at Ser394 (P1' site) have variable effects on different enzymes, depending on the mutation. An up-to-date listing of mutations affecting the antithrombin gene is available at the Antithrombin Mutation Database.[26] A review of published mutations shows that they are distributed throughout the molecule, with reactive center defects having the biggest impact and heparin-binding defects carrying the least thrombotic risk.

Classification of antithrombin deficiency

Antithrombin deficiency (AT deficiency) states can be broadly classified into 2 types. Type I antithrombin deficiency states in which heterozygous mutations lead to a complete loss of the mutant antithrombin protein result in immunologic and functional levels that are 50% or less than normal. The genetic basis of type I mutations includes major gene deletions or point mutations, with point mutations accounting for most of these cases. The mutations appear to cause a quantitative reduction in antithrombin synthesis by various processes, including premature termination of translation, aberrant RNA processing, and production of unstable antithrombin molecules that have short plasma half lives.[20] A report described 22 novel mutations in the antithrombin gene, of which 9 missense mutations resulted in type I deficiency and led to low antithrombin activity and antigen levels. Clinically these mutations were associated with venous thrombosis occurring before the age of 32 years.[13] Homozygous type I antithrombin deficiency (AT deficiency) is almost always fatal in utero.[21] Type II antithrombin deficiency states are usually the result of single amino acid changes that result in functional deficits in a molecule that is otherwise synthesized and secreted into the plasma in a normal fashion. The variant antithrombin molecules may have abnormalities at the reactive site or the heparin binding site. Most cases of type II antithrombin deficiency are also heterozygous, although rare cases of homozygous type II deficiency have been described.[21] There also exists a third category of type II antithrombin deficiency in which multiple or "pleiotropic" abnormalities affect the reactive site, the heparin binding site, or the plasma concentration. Type II heparin binding site variants are not associated with a high risk of thrombosis unless the affected individual is a homozygote.[20]

Acquired causes of antithrombin deficiency

Neonates: Neonates are particularly vulnerable because of the reduced level of antithrombin at birth (30-50% of adult levels), even in healthy, full-term babies. However, healthy newborns do not have the thrombotic tendency noted in adults with similarly reduced values because of simultaneous reductions in their procoagulant levels and perhaps due to a protective role of alpha2-macroglobulin as a thrombin inhibitor in the neonate and in childhood. Antithrombin levels depend on the gestational age of the newborn, and they rise to approximately 60% of that of adult levels 1 month after birth. Genetic mutations also influence this level, but the superimposition of serious illnesses, which can

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further reduce antithrombin, due to increased consumption, decreased production, or both, can have significant consequences. Acute respiratory distress syndrome (ARDS): ARDS is a known secondary cause of antithrombin deficiency (AT deficiency), and this is a major cause of both morbidity and mortality in the newborn. Extracorporeal membrane oxygenation used in the treatment of respiratory failure can be associated with reduced antithrombin and thrombotic events. Other causes of acquired reductions of antithrombin in neonates include sepsis, asphyxia, liver disease, other causes of DIC, and maternal preeclampsia or eclampsia.[27, 28] Pregnancy: Although it is widely believed that no substantial reduction of antithrombin occurs during normal pregnancy, a Scandinavian study reported that antithrombin levels were lower during the third trimester of pregnancy and in the postpartum period.[29] Pregnancy-induced antithrombin deficiency (AT deficiency) is more likely to be seen in twin and triplet pregnancies.[30] Diseases associated with pregnancy, such as eclampsia, hypertension of pregnancy, hepatopathy characterized by elevations in liver enzymes, and DIC, can also reduce antithrombin levels. In these conditions, low-grade activation of coagulation with consumption of antithrombin is evident before gross deterioration of coagulation parameters occurs.[31, 27] Liver disease: Synthesis of antithrombin and other physiologically important inhibitors of hemostasis, synthesis of procoagulants, and clearance of activated coagulation factors are all regulated by the liver. Thus, the liver plays a central role in hemostasis. The severity of liver disease correlates with reductions in antithrombin antigen levels. These reductions are not only due to impaired synthesis, but also to an element of increased consumption, particularly when additional risk factors, such as sepsis, surgery, and hypotension, are present in patients with chronic liver disease. Patients with acute, massive hepatocellular injury and elevations of liver enzyme levels can often have a significantly larger component of a consumptive process than patients with slowly progressive end-stage liver disease. Because of the decreased synthesis of inhibitors as well as the decreased ability to clear activated coagulation factors, patients undergoing orthotopic liver transplantation predictably develop DIC with reduction in antithrombin levels. Kidney disease: Patients with nephrotic syndrome lose antithrombin in the urine, resulting in reduced plasma levels, and they are at higher risk for thrombotic events. Conversely, patients with inherited antithrombin deficiency (AT deficiency) may develop renal failure due to renal vein thrombosis or due to fibrin deposition in the glomeruli. The degree of compromise in renal function may be such that these patients need renal replacement therapy. Furthermore, as renal dysfunction develops, these patients would lose progressively more antithrombin in the urine and, thus, be more prone to developing thrombotic episodes.[32] Bone marrow transplantation: Veno-occlusive disease (VOD) is seen in patients who undergo bone marrow transplantation, particularly in unrelated-donor transplantations, and it is associated with the development of microthrombi in the terminal hepatic venules. This results in a rapid, marked deterioration of liver function, causing a coagulopathy with a reduction in the level of antithrombin and, consequently, significant morbidity and mortality. Sepsis: Interest in the role of antithrombin deficiency (AT deficiency) in the setting of sepsis and the critically ill patient has been growing, in which there appears to be a correlation between the severity of illness and the degree of antithrombin reduction.[21] However, to what extent the depletion of antithrombin affects the clinical condition of such patients remains to be determined. Several trials regarding the use of antithrombin as a treatment in the intensive care setting concluded overall that although there is some benefit to such therapy, large supra-physiologic doses of antithrombin are necessary. In addition, the concurrent use of any form of heparin removes whatever benefit may be derived from antithrombin treatment in this setting.[21] Also of concern until recently has been the fact that antithrombin replacement was only available as a pooled plasma-derived product, which still carries an uncertain risk of transfusion-transmitted diseases.[21] Thus, more investigation is needed regarding antithrombin deficiency (AT deficiency) in the setting of sepsis, as well as its treatment. Consumptive coagulopathies such as DIC, thrombotic microangiopathy, and acute hemolytic transfusion reactions are associated with antithrombin depletion.[21] Drug-induced reduction in antithrombin levels: Heparin given by intravenous or subcutaneous routes causes an approximately 30% reduction in antithrombin levels, presumably due to rapid clearance in vivo of heparin-antithrombin complexes. Plasma samples to determine baseline antithrombin levels must therefore not be drawn after exposure to heparin. Estrogens/oral contraceptives: A large body of literature shows that estrogens/oral contraceptives can reduce antithrombin levels, resulting in a hypercoagulable state. Acquired antithrombin deficiency (AT deficiency) has also been described with asparaginase therapy.[33]

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Epidemiology
Frequency
United States An autosomal dominant trait, inherited antithrombin deficiency (AT deficiency) has a prevalence between 0.2/1000 and 0.5/1000. In the general population, the incidence is thought to be in the range of 0.2-0.4%, with approximately 65% of biochemically affected individuals experiencing a thrombotic event. In patients who develop venous thrombosis, the prevalence of hereditary antithrombin deficiency (AT deficiency) is between 1:20 and 1:200.[21] Among the subtypes of antithrombin deficiency, type II antithrombin deficiency is at least twice as common as type I antithrombin deficiency in the general population.[34] However, in symptomatic patients, cases of type I antithrombin deficiency represent about 80% of the total cases.[35] The frequency of acquired antithrombin deficiency (AT deficiency) depends on the frequency of the associated disease process. International In a study of 4000 Scottish blood donors, the prevalence of type I antithrombin deficiency was found to be 0.2/1000 and that of type II heparin binding site antithrombin deficiency was found to be 2-3/1000.[36] Antithrombin deficiency (AT deficiency) is not restricted to any particular ethnic group and has been found in many countries.

Mortality/Morbidity
Patients who are heterozygous for type I or II antithrombin deficiency develop significant thromboembolic complications, generally involving the deep veins. The lifetime risk of developing VTE depends on the subtype of antithrombin deficiency (AT deficiency). In hereditary type I antithrombin deficiency, the lifetime risk is between 50% and 85%. In patients with type II antithrombin deficiency, the risk of developing VTE is higher in those patients who have reactive site defects as compared to heparin-binding site defects. In some subgroups of type II antithrombin deficiency patients, the lifetime risk of developing VTE is about 20%.[21] The incidence of pregnancy-related VTE in women with antithrombin deficiency (AT deficiency) could be as high as 50%.[21] Patients may develop recurrent VTE disease at an early age and, if the condition is unrecognized or inadequately treated, they may die from such events. Long-term consequences, such as chronic leg ulcerations, severe venous varicosities, and postphlebitic syndrome, are common from repeated episodes of VTE, which cause significant morbidity. The prognosis of patients with reductions in antithrombin as part of other systemic disorders depends on the underlying disorder. The frequency of arterial thrombotic complications is low, but mutations leading to arterial thromboses have been described. Pregnancy-related complications such as recurrent fetal loss, preeclampsia, and others (eg, hypertension; thrombocytopenia; DIC syndromes; hemolysis, elevated liver enzymes, and low platelet count [HELLP]) are associated with antithrombin deficiency (AT deficiency). Nephrotic syndrome has been associated with reductions in antithrombin and an increased incidence of venous thrombosis (renal vein, 60%; VTE, 40%) with only a 3% incidence of arterial thrombosis. It is now recognized that thrombophilic mutations, including those affecting antithrombin, may be the cause of spontaneous miscarriages; thrombotic complications during embryogenesis can lead to a variety of developmental abnormalities.

Race
Although no overt racial predilection for antithrombin deficiency (AT deficiency) is known, the literature, especially from the Far East, has described the presence of novel mutations in the antithrombin gene that have observed in thrombophilic patients in specific population groups.[37, 38]

Sex
Antithrombin deficiency (AT deficiency) is inherited as an autosomal dominant trait. Some mutations require

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homozygosity (2 doses of the gene [ie, autosomal recessive]) to be clinically significant. Both men and women can present with the inherited disorder.

Age
Clinical manifestations of antithrombin deficiency (AT deficiency) are evident at an early or later age, depending on the severity of the inherited genetic defect and also on the co-inheritance or presence of other thrombophilic mutations, drugs, or diseases. Neonates normally have approximately 60% of adult antithrombin levels despite the absence of a prothrombotic state. Premature infants have even lower values. Thus, a reduction in antithrombin level in these instances does not automatically imply an inherited deficiency. Serial follow-up may be necessary in families with inherited antithrombin deficiency (AT deficiency) to prove an inherited deficiency of antithrombin. If the genetic mutation in the family is known, the diagnosis is much simplified by the presence or absence of the specific mutation. The severely affected homozygous form of antithrombin deficiency may lead to spontaneous fetal loss, babies born small for their gestational age due to a small placenta secondary to thrombosed placental vessels, or severe thrombotic problems at birth. In other instances, thrombotic manifestations may start in the teenage years. Acquired antithrombin reductions are usually secondary to other illnesses or drugs.

Contributor Information and Disclosures

Author Arun Rajan, MD Clinical Fellow, Medical Oncology Branch, National Cancer Institute/National Institutes of Health Arun Rajan, MD is a member of the following medical societies: American Medical Association and American Society of Clinical Oncology Disclosure: Nothing to disclose. Coauthor(s) Sara J Grethlein, MD Senior Attending Physician, Cancer Treatment Center, Bassett Healthcare Network Sara J Grethlein, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Clinical Oncology, and American Society of Hematology Disclosure: Nothing to disclose. Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis Disclosure: Nothing to disclose. Specialty Editor Board David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of

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Medicine Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group Disclosure: No financial interests None None Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association Disclosure: Renal Ventures Ownership interest Other Chief Editor Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences Disclosure: Nothing to disclose.

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