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 f irst

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 iscomplementary 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 I Ia). In addition, it also inhibits other serine proteinases, including activated factors X, IX, XI, andXII.

[21]Antithrombin also antagonizes factor VIIby 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 the2 proteins. Binding of heparin to lysyl residues on AT results in a conformational change in AT, which makes it more available to bindthrombin (I Ia), IXa, and Xa, thus markedly accelerating the rate of enzyme-inhibitor complex formation. AT also neutralizes XIa andXIIa.

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 byheparin and related glycosaminoglycans. Under optimal conditions, the interaction between thrombin and antithrombin

could be accelerated by as much as 2000 times. I t should be noted that the catalytic effect of heparin is achievedwhen 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 bloodcomponents 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 thrombinformed 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 inameliorating disseminated intravascular coagulation [DIC]).

HCII is another physiologic inhibitor of hemostasis that appears to contribute about 20-30% of plasma (AT) heparin-cofactor 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 culturedmonocytes 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 s tudies 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 tosuggest 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 def iciency) have a variableincidence of thrombotic disease, whereas most homozygous individuals have a 100% frequency of thromboticdisease, which may be fatal at an early age.

Inherited or acquired antithrombin deficiencies (AT defic iencies) predispose affected individuals to serious venous

and arterial thrombotic disease. Although it is well recognized that inherited antithrombin deficiency (AT deficiency) is amore serious disorder than inherited deficiencies of proteins Cor S, there is much variability in thrombotic

manifestations in patients with inherited antithrombin def iciency. A population-based case control study found a 5-fold

increased risk of thrombosis when antithrombin def iciency (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 antithrombindeficiency (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 def iciency (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% ofindividuals 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 lowerextremity 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 forantithrombin, 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 def iciency); 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 andheparin-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 def iciency states in which heterozygous mutations lead to a complete loss of the mutantantithrombin 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 thesecases. 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 def iciency (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% ofadult 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 levelsand 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. Extracorporealmembrane 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 normalpregnancy, 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 morelikely 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 alsoreduce 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 liverplays 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 asignificantly 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 syndromelose antithrombin in the urine, resulting in reduced plasma

levels, and they are at higher risk for thrombotic events. Conversely, patients with inherited antithrombindeficiency (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 andmortality.

Sepsis: Interest in the role of antithrombin deficiency (AT deficiency) in the setting of sepsis and the critically illpatient 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 clinicalcondition 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 ofantithrombin 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 def iciency (AT deficiency) in the

setting of sepsis, as well as its treatment.Consumptive coagulopathies such as DIC, thrombotic microangiopathy, and acute hemolytic transfusion

reactionsare 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 def iciency (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 I I antithrombin deficiency is at least

twice as common as type I antithrombin def iciency 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 I I heparin binding site antithrombin def iciency 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 ofantithrombin deficiency (AT deficiency). In hereditary type I antithrombin deficiency, the lifetime risk is between 50%

and 85%. In patients with type II antithrombin def iciency, 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 def iciency (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 orinadequately treated, they may die f rom 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 venousthrombosis (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 ofdevelopmental abnormalities.

Race

Although no overt racial predilection for antithrombin deficiency (AT def iciency) 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 def iciency) 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 def iciency) 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 notautomatically imply an inherited deficiency. Serial follow-up may be necessary in families with inherited antithrombin

deficiency (AT deficiency) to prove an inherited defic iency of antithrombin. If the genetic mutation in the family is

known, the diagnosis is much simplified by the presence or absence of the specif ic 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, orsevere 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 DisclosuresAuthorArun 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 Associationand 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


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 ClinicalOncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis


Specialty Editor BoardDavid 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


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, AmericanCollege 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 EditorEmmanuel 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, AmericanSociety of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences


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