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Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e

Chapter 237: Chapter 237: Acquired Hemolytic AnemiaAcquired Hemolytic Anemia Laurie Ann Dixon; Robin R. Hemphill

INTRODUCTIONINTRODUCTION

Acquired hemolytic anemias are a group of disorders characterized by hemolysis of red blood cells (RBCs)not due to congenital or inherited disorders of hemoglobin synthesis or of the RBC membrane. Hemolysis ofRBCs can take place within the intravascular space or in the extravascular spaces of the spleen and liver andcan produce a spectrum of disease from mild, asymptomatic illness to severe hemodynamic compromiseleading to critical ED encounters.

Presenting symptoms and signs of hemolytic anemia include those common to anemia in general: weakness,fatigue, dizziness, shortness of breath, dyspnea on exertion, tachycardia, palpitations, chest pain, new oraccentuated cardiac murmur, and pallor. RBC destruction generates free hemoglobin that is then brokendown into bilirubin. When bilirubin production exceeds the liver's ability to conjugate it for biliary and fecalexcretion, jaundice and darkened urine may develop. Splenic enlargement may promote the storage andextravascular breakdown of RBCs.

The laboratory findings characteristic of acquired hemolytic anemia demonstrate hemolysis of RBCs,hemoglobin breakdown, and compensatory RBC production (Table 237-1Table 237-1). The peripheral blood smeardisplays abnormal RBC morphology consistent with hemolysis: schistocytes generated by intravascularshearing of RBCs and spherocytes produced by extravascular phagocytosis of RBCs within the liver andspleen.

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Abbreviation: RBC = red blood cell.

TABLE 237-1

Basic Tests and Findings in the Evaluation of Hemolytic AnemiaBasic Tests and Findings in the Evaluation of Hemolytic Anemia

PurposePurpose TestTest FindingFinding

Confirm anemia/blood

loss

Hemoglobin

Hematocrit

Decreased

Decreased

Confirm compensatory

RBC production

Reticulocyte count Increased

Confirm hemolysis Peripheral smear Schistocytes—intravascular hemolysis, RBCs

fragmented by shear mechanism

Spherocytes—extravascular hemolysis, RBC

phagocytosis by macrophages

Confirm hemolysis Lactate

dehydrogenase

Potassium

Increased, released by RBCs

Increased, released by RBCs

Confirm hemolysis Haptoglobin

Free hemoglobin

Hemoglobinuria

Decreased, indicative of intravascular hemolysis

Increased, indicative of intravascular hemolysis

Present

Confirm hemoglobin

breakdown

Total bilirubin

Indirect

(unconjugated)

bilirubin

Urinary urobilinogen

Increased

Increased (hepatic conjugation of bilirubin

overwhelmed)

Increased

Intravascular hemolysis of RBCs releases hemoglobin into the bloodstream that then binds to haptoglobinand other serum proteins. The hemoglobin–haptoglobin complex travels to the liver for processing, thusdecreasing the amount of free haptoglobin in the serum—an important laboratory finding of intravascularhemolysis. Breakdown of RBCs releases lactate dehydrogenase and potassium, leading to elevation of bothin serum. With excessive hemoglobin breakdown comes increased bilirubin production that cannot beconjugated by the liver for biliary and fecal excretion. Laboratory findings associated with excess bilirubinproduction include elevated total bilirubin; elevated indirect or unconjugated bilirubin; and increasedurinary urobilinogen, a by-product of bilirubin breakdown formed by the intestine and passed into the urine.

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Excess free hemoglobin may escape binding by serum haptoglobin as well as reabsorption by the renaltubules, creating hemoglobinuria and darkened urine.

IMMUNE-MEDIATED ACQUIRED HEMOLYTIC ANEMIAIMMUNE-MEDIATED ACQUIRED HEMOLYTIC ANEMIA

Immune-mediated acquired hemolytic anemia encompasses three main categories: autoimmune,alloimmune, and drug induced.

AUTOIMMUNE HEMOLYTIC ANEMIAAUTOIMMUNE HEMOLYTIC ANEMIA

Individuals with autoimmune hemolytic anemia make antibodies against their own RBCs.1 Diagnosisrequires evidence of an antibody on the patient's RBCs, usually accompanied by an autoantibody in theplasma. The direct antigen test, also known as the direct Coombs testdirect Coombs test, is performed by combining thepatient's anticoagulated, washed RBCs with anti–immunoglobulin G and anti-C3d (complement) antibodiesto detect the presence of immunoglobulin G and/or complement on the RBC surface. A positive directantigen test consists of the detection of either immunoglobulin G or complement on the RBC surface; it does

not require the detection of both.2 A positive direct antigen test is not specific for a diagnosis of autoimmunehemolytic anemia (Table 237-2Table 237-2), nor does the presence of immunoglobulin G and/or complement on apatient's RBCs indicate the severity of disease; the direct antigen test is, however, a critical confirmatoryscreen. The indirect Coombs testindirect Coombs test looks for the presence of autoantibodies in the patient's serum, testingagainst a panel of RBCs bearing specific surface antigens. Hemolysis can take place within the vascular spaceor extravascularly within the liver or spleen.

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TABLE 237-2

Di�erential Diagnosis of Positive Direct Antigen (Direct Coombs) TestDi�erential Diagnosis of Positive Direct Antigen (Direct Coombs) Test

Autoimmune hemolytic anemia

Hemolytic transfusion reaction, acute or delayed

Hemolytic disease of newborn

Transplantation

Drug-related hemolytic anemia

IV immunoglobulin therapy

Rh(D) immunoglobulin therapy

Antilymphocyte globulin therapy

Antithymocyte globulin therapy

Sickle cell disease

β-Thalassemia

Renal disease

Multiple myeloma

Hodgkin's disease

Systemic lupus erythematosus

Human immunodeficiency virus/acquired immunodeficiency syndrome

Autoimmune hemolytic anemia can be divided into primary and secondary disease; primary, or idiopathic,disease occurs without a known underlying etiology, whereas secondary disease is associated with an

underlying disorder.1 Primary disease is more common in women, with peak incidence during the fourth andfi�h decades. Many cases initially designated as primary are later found to be associated withlymphoproliferative, autoimmune, or infectious diseases. In children, the disorder is commonly associatedwith viral or respiratory infections and can cause acute, fulminant hemolysis. Pregnancy can increase the riskof autoantibody development fivefold, but significant RBC destruction is not common. Autoimmunehemolytic anemia is further divided into autoantibody type: warm type, cold type, and mixed type (TableTable

237-3237-3).1

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Abbreviation: RBC = red blood cell.

TABLE 237-3

Categories of Autoimmune Hemolytic Anemia (AIHA)Categories of Autoimmune Hemolytic Anemia (AIHA)

Warm antibody AIHA: Autoantibodies adhere most

strongly to RBCs at 37°C (98.6°F).

70%–80% of AIHA cases

2:1 female predominance

50% primary (idiopathic) disease

50% secondary disease: lymphoproliferative,

autoimmune disease, postinfection (transient)

Usually immunoglobulin G (IgG) autoantibody

against Rh(D) antigen

Hemolysis usually extravascular

Steroid responsive: 70%–80%

Cold antibody AIHA: Autoantibodies adhere most

strongly to RBCs at 0–4°C (32–39.2°F).

Cold agglutinin disease: IgM autoantibody against ICold agglutinin disease: IgM autoantibody against I

antigenantigen

Primary disease: older females

Secondary disease: lymphoproliferative disorders,

postinfection (transient)

Raynaud's phenomenon, livedo reticularis,

vascular occlusion

Attacks precipitated by cold exposure

Rarely intravascular hemolysis

Not steroid responsive

Paroxysmal cold hemoglobinuria: IgGParoxysmal cold hemoglobinuria: IgG

autoantibody against P antigenautoantibody against P antigen

Primary disease: rare, in adults

Secondary disease: usually in children a�er upper

respiratory infection

Intravascular hemolysis during cold weather

Usually not steroid responsive

Mixed-type antibody AIHA: Autoantibodies have

variable temperature-dependent RBC adherence.

Primary disease: more common in older females

Secondary disease: lymphoproliferative and

autoimmune disorders

Usually chronic course with severe exacerbations

Usually steroid responsive

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Warm Antibody Autoimmune Hemolytic AnemiaWarm Antibody Autoimmune Hemolytic Anemia

Warm autoantibody–mediated hemolysis is predominantly extravascular, with antibody-coated RBCsconsumed mostly by splenic macrophages and, to a lesser degree, by hepatic macrophages known asKup�er cells. Partial phagocytosis of the original RBC membrane structure leads to the formation of the morerigid, fragmentation-prone spherocyte. Increased spherocytosis found on peripheral blood smear correlatespositively with severity of extravascular hemolysis.

Autoimmune hemolytic anemia is initially treated with high-dose corticosteroids, typically oral at 1 to 2milligrams/kg per day for 3 to 4 weeks, with improvement expected in 80% to 85% of patients but complete

remission in only up to 30% of patients.3

Monoclonal antibodies (e.g., rituximab), immunosuppressive agents (e.g., azathioprine, mycophenolatemofetil, cyclosporine, cyclophosphamide), or semisynthetic androgens (e.g., danazol) can be used to

decrease autoantibody production.3,4 Splenectomy removes both the main site of extravascular hemolysis inIgG-mediated disease and a major site of general autoantibody production. Splenectomy shows clinicalbenefit in up to 60% of patients, with potential for long-term remission or a complete cure. A seriouscomplication of splenectomy is overwhelming postsplenectomy infection due to sepsis with encapsulated

bacteria.5 Such patients should receive regular pneumococcal and meningococcal vaccinationspatients should receive regular pneumococcal and meningococcal vaccinations and maybenefit from daily penicillin prophylaxis.

Severe hemolysis in cases of warm antibody autoimmune hemolytic anemia may be treated with plasmaexchange as a transient stabilizing measure while waiting for steroids or immunosuppressive agents to takee�ect. IV immunoglobulin has been used as an adjunctive treatment in children who cannot tolerate the side

e�ects of chronic high-dose steroids or immunosuppressive agents.6

For a patient with life-threatening anemia, the goal is to transfuse allogeneic RBCs without producingpotentially harmful transfusion reactions. Laboratory personnel must determine whether the patient's bloodcontains alloantibodies against RBC antigens, but first, autoantibodies—usually directed against morecommonly occurring or higher prevalence RBC antigens, and thus typically panreactive against RBC panels—must be identified and si�ed out because the presence of autoantibodies can hide the existence of

alloantibodies.7 The testing process can be both labor and time intensive, sometimes requiring 6 hours orlonger. Once completed, however, antigen-free, compatible RBC units can then be selected in hopes ofproviding safe and e�ective transfusion for the patient. If emergently needed, transfusion of the leastincompatible units may be administered slowly and in the smallest amounts necessary with close

monitoring.8

Cold Antibody Autoimmune Hemolytic AnemiaCold Antibody Autoimmune Hemolytic Anemia

Cold autoantibodies lead to clumping or agglutination of RBCs on peripheral smear at cooler temperatures.Cold antibody autoimmune hemolytic anemia is associated with complement fixation on the RBC surface

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and triggering of the complement cascade. Hemolysis occurs in both the extravascular and intravascularspaces. Instead of splenic macrophages, the hepatic macrophages known as Kup�er cells are responsible formost of the extravascular RBC destruction. The two major cold antibody disorders are cold agglutinin diseasecold agglutinin diseaseand paroxysmal cold hemoglobinuriaparoxysmal cold hemoglobinuria. Fi�y percent of secondary cold antibody cases are associated withlymphoproliferative disorders, with underlying infection as the next leading cause.

Cold agglutinin diseaseCold agglutinin disease is exacerbated by the cold, so more episodes of acute hemolysis are seen during

winter.9 Because the peripheral circulation is typically cooler than the central circulation, secondaryRaynaud's phenomenon and vascular occlusion can complicate cold agglutinin disease, leading toacrocyanosis and tissue necrosis/gangrene. Painful discoloration and mottling of the skin consistent with

livedo reticularis may be seen.10 Less commonly, cold urticaria and hemorrhagic vesicles may develop.11

Primary cold agglutinin disease causes chronic, recurrent hemolysis in older adults, particularly females,with a peak incidence at age 70 years old. As with all of the idiopathic autoimmune hemolytic anemias, anassociated underlying disease process may be discovered well a�er initial presentation of cold agglutinindisease; in particular, an occult lymphoproliferative disorder may be the source of the aberrant coldautoantibodies.

Secondary cold agglutinin disease may present a�er infection with Mycoplasma pneumoniae, Epstein-Barrvirus, or infectious mononucleosis, adenovirus, cytomegalovirus, influenza, varicella-zoster virus, humanimmunodeficiency virus, Escherichia coli, Listeria monocytogenes, or Treponema pallidum. Hemolysistypically begins 2 to 3 weeks a�er the onset of illness, corresponding with peak antibody developmentagainst the infectious agent, and resolves about 2 to 3 weeks a�er resolution of the infectious illness. Manypatients with Mycoplasma pneumonia and infectious mononucleosis will have measurable cold agglutinintiters, but far fewer will develop symptoms and signs of hemolytic anemia. Conversely, cold agglutinindisease associated with lymphoproliferative diseases such as chronic lymphocytic leukemia and lymphomaproduces high autoantibody levels with the potential for significant hemolysis.

Agglutination of RBCs can confound an automated CBC device; the mean corpuscular volume may be falselyelevated, whereas the hemoglobin registers spuriously low. Holding the blood tube in warm hands maydecrease RBC clumping for more reliable CBC results. A CBC with confusing or bizarre results should undergoperipheral smear examination. Peripheral smear findings of cold agglutinin disease include spherocytosis,

anisocytosis, poikilocytosis, polychromasia, and agglutination.12 The direct antigen test demonstratesadherence of complement to patient RBCs, but cold autoantibodies are typically washed o� the RBCs duringthe elution process and thus are not identified. Other laboratory findings correspond with those routinelyseen in cases of hemolytic anemia, including findings consistent with intravascular hemolysis in some coldagglutinin disease cases (Table 237-1).

An important principle in treating cold agglutinin disease is keeping the extremities and appendages,particularly the nose and ears, warm in cold weather. Patients should take a daily folate supplement forhealthy RBC production. Cold agglutinin disease is less likely to respond to steroids, with response rates as

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low as 35%.9 Splenectomy is less e�ective in treating cold agglutinin disease because splenic macrophagesplay a lesser role in IgM-mediated cold antibody disease. Severe hemolysis has been treated successfullywith immunosuppressive agents such as chlorambucil, cyclophosphamide, interferon-α, fludarabine, or

rituximab.9 Because immunoglobulin M autoantibodies have an intravascular distribution, plasmapheresismay assist by removing autoantibodies from the circulation when combined with immunosuppressiveagents.

Infection-related cold antibody disease does not require immunosuppressive therapy because the hemolyticanemia is usually self-limited. RBC transfusion can be performed for patients at risk for significant cardiac orcerebrovascular ischemia, but transfused blood should be infused at 37°C (98.6°F) using a blood warmer.Transfusions should be limited as they may worsen ongoing hemolysis because most cold antibodies actagainst the I/i group antigens that are found on most donor RBCs. Donor complement in the transfusedproduct also may exacerbate ongoing hemolysis.

Paroxysmal cold hemoglobinuriaParoxysmal cold hemoglobinuria is caused by a biphasic hemolysin immunoglobulin G autoantibody called

the Donath-Landsteiner (D-L) antibody that is directed against the P antigen system found on most RBCs.13

This potent autoantibody binds to RBCs and fixes early complement cascade proteins at low temperatures,whereas terminal complement components adhere and produce intravascular lysis of RBCs at warmer,physiologic temperatures.

Bursts of cold weather–induced intravascular hemolysis lead to bouts of dark urine or hemoglobinuria forwhich the disease is named. Other presenting symptoms include attacks of high fever, chills, headache,abdominal cramps, nausea and vomiting, diarrhea, and leg and back pain, all exacerbated by cold weather.Cold urticaria may develop as well as extremity paresthesias and Raynaud's phenomenon.

Primary paroxysmal cold hemoglobinuria is a rare, idiopathic, chronic condition occurring in adults,characterized by cold-induced episodes of massive hemolysis. Secondary disease occurs predominantly inchildren, usually seen a�er a preceding upper respiratory infection. Most pediatric cases are self-limited andnonrecurring, but severe cases may take weeks to resolve. With severe hemolysis, hemoglobinuria iscommon, and methemoglobinemia may be seen. Acute renal failure may develop as a complication.Pediatric paroxysmal cold hemoglobinuria may occur a�er infections with measles, mumps, Epstein-Barrvirus, cytomegalovirus, varicella, adenovirus, influenza A, M. pneumoniae, Haemophilus influenzae, and E.coli. Adult patients with chronic, relapsing disease should be tested for syphilis, because cold-provokedhemolysis has been associated with tertiary or late syphilis as well as with congenital syphilis.

During an attack of paroxysmal cold hemoglobinuria, acutely low hemoglobin may be seen on CBC due tosudden, severe hemolysis. The peripheral smear may demonstrate erythrophagocytosis, the engulfment of

RBCs by neutrophils.12 Presence of the biphasic D-L immunoglobulin G antibody on laboratory testing ispathognomonic. Patient serum is added to two tubes containing human type O RBCs. The first tube, thecontrol, is incubated at 37°C (98.6°F) or physiologic temperature, whereas the second tube is incubated firstat 0°C (32°F) and then at 37°C (98.6°F). The D-L test is positive if hemolysis is present in the second tube,

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indicating presence of the biphasic D-L antibody, while absent in the control tube.14 The direct antigen test isusually positive for complement just before or a�er a paroxysm but o�en negative in between paroxysms inpatients with chronic, relapsing disease.

Patients with paroxysmal cold hemoglobinuria should be kept warm. Steroids can be considered in childrenwith severe hemolytic anemia, but because infection-related disease tends to be self-limited, benefit isuncertain. Disease secondary to syphilis responds to e�ective antibiotic treatment. Splenectomy is nothelpful, and plasmapheresis should be used only as a temporizing measure in life-threatening cases. RBCtransfusion using a blood warmer should be limited to cases of severe hemolysis because most donor unitsare P antigen positive and may stimulate further production of antibodies. Rituximab can successfully treat

primary paroxysmal cold hemoglobinuria in adults.15

Mixed-Type Autoimmune Hemolytic AnemiaMixed-Type Autoimmune Hemolytic Anemia

Mixed-type autoimmune hemolytic anemia, with both warm and cold autoantibodies to RBCs, presents asprimary or secondary disease, most commonly associated with lymphoproliferative and autoimmune

diseases, particularly systemic lupus.1 The course of illness is usually chronic with severe exacerbations. Likethe warm antibody disorder, the mixed type is usually steroid responsive, can be treated with splenectomy,and responds to immunosuppressive therapy.

ALLOIMMUNE HEMOLYTIC ANEMIAALLOIMMUNE HEMOLYTIC ANEMIA

Alloimmune hemolytic anemiaAlloimmune hemolytic anemia requires exposure to allogeneic RBCs with subsequent alloantibodyformation. In the laboratory, alloantibodies react specifically with the allogeneic RBCs that triggered theirproduction; these antibodies do not react against a patient's own RBCs. A well-known example of this iswhen the Rh(D)-negative maternal immune system develops immunoglobulin G alloantibodies on exposureto Rh(D)-positive fetal RBCs. The maternal alloantibodies can then cross the placenta, leading to fetal RBC

destruction in a condition known as hemolytic disease of the newborn.16 Anemia can range from mild topotentially fatal, producing intrauterine fetal death. The term hydrops fetalis has been used to describe theanasarca seen in severe cases. Transplacental or fetomaternal hemorrhage, the inciting stimulus formaternal alloantibody formation, may occur during amniocentesis, chorionic villus sampling, delivery, orabortion (threatened or otherwise) or even during external cephalic version. Administration of anti-Dimmunoglobulin G with any fetomaternal hemorrhage event and soon a�er delivery will suppress maternalalloantibody formation and prevent hemolytic disease of the newborn. Treatment of established hemolyticdisease of the newborn employs intrauterine and intravascular fetal transfusion and may include plasmaexchange and/or IV immunoglobulin therapy.

Most adults who develop alloimmune hemolytic anemia have a history of RBC transfusion, which sensitizespatients to allogeneic RBC antigens. A subsequent transfusion can result in immediate alloantibodyproduction, resulting in the fever, chest and flank pain, tachypnea, tachycardia, hypotension,hemoglobinuria, and oliguria seen in the hemolytic transfusion reaction (see chapter 238, "Transfusion

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Therapy"). In patients with high alloantibody titers, the hemolytic reaction can be immediate. Delayedalloantibody-mediated hemolysis is possible, with hemolytic transfusion reaction symptoms presenting 3 to7 days a�er transfusion (see chapter 238).

DRUG-INDUCED HEMOLYTIC ANEMIADRUG-INDUCED HEMOLYTIC ANEMIA

Drug-induced hemolytic anemia is rare, estimated at 1 in 1,000,000 patients, where drug exposure induces

antibody formation leading to the destruction of RBCs.17 More than 100 drugs are known to induce

autoantibody production against patient RBCs (Table 237-4Table 237-4).18 Drug-induced hemolytic anemia can result ineither a positive or negative direct antigen test and can be di�icult to distinguish from autoimmunehemolytic anemia, so a careful review of current medications is important in patients with a new hemolyticanemia.

TABLE 237-4

Most O�en Cited Drugs Inducing Hemolytic AnemiaMost O�en Cited Drugs Inducing Hemolytic Anemia

Cephalosporins Cefotetan

Ce�riaxone

Cephalothin

Chemotherapeutic agents Fludarabine

Interferon

Oxaliplatin

Nonsteroidal anti-inflammatory drugs Diclofenac

Mefenamic acid

Phenacetin

Tolmetin

Penicillins Penicillin G

Piperacillin

Miscellaneous Catechin (antidiarrheal)

Levodopa (antiparkinsonian)

Methyldopa (antihypertensive)

Nomifensine (antidepressant)

Quinidine (antiarrhythmic)

Rifampin (antibiotic)

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Patients with severe hemolysis and anemia require hospitalization and further evaluation. In all cases, stopthe o�ending drug immediately. In the event that medications are required for treatment of patients in theED who have evidence of ongoing hemolysis, refrain if possible from using listed agents (Table 237-4).Steroids can be used in cases of drug-related severe hemolysis.

MICROANGIOPATHIC SYNDROMESMICROANGIOPATHIC SYNDROMES

The two classic syndromes associated with microangiopathic hemolytic anemia are thrombotic

thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS).19,20 Both syndromes involveplatelet aggregation in the microvascular circulation via mediation of von Willebrand factor.Microangiopathic hemolytic anemia or schistocyte-forming hemolysis occurs from fragmentation of RBCsduring travel through these partially occluded arterioles and capillaries. Although TTP and HUS are clinicalsyndromes with characteristic features, overlap does occur, sometimes making di�erentiation di�icult. TTPis more common in adults, whereas HUS is more common in children. TTP typically induces more prominentneurologic e�ects, with deposition of platelet aggregates in a broader distribution, whereas HUS morespecifically a�ects the renal system.

THROMBOTIC THROMBOCYTOPENIC PURPURATHROMBOTIC THROMBOCYTOPENIC PURPURA

The classic pentad for TTP includes CNS abnormalities, renal pathology, fever, microangiopathic hemolyticanemia, and thrombocytopenia. Untreated TTP carries a high mortality rate, but plasma exchange therapy

can achieve remission of disease in >80% of patients.20,21,22 Groups at higher risk for TTP include women,patients age 30 to 50 years old, individuals of African descent, and Hispanics.

PathophysiologyPathophysiology

The pathophysiology of TTP is connected to a specific metalloprotease ADAMTS-13 (a disintegrin andmetalloproteinase with a thrombospondin type 1 motif, member 13, also known as von Willebrand factor–cleaving protease). ADAMTS-13 is made by hepatic stellate cells, glomerular podocytes, and vascularendothelial cells. Its function is to cleave von Willebrand factor that has been unfolded by shear stress withinthe microvasculature of arterioles and capillaries. Without this cleavage function, unfolded von Willebrandfactor monomers can form large multimers that lead to formation of intravascular microthrombi. TTP has

been associated with ADAMTS-13 activity at levels <10% of normal.23 Severely deficient ADAMTS-13 activityalone does not reliably trigger TTP; o�en other precipitating or contributing factors are important, includingpregnancy, infection, inflammation, and medication use.

ADAMTS-13 activity levels typically decrease by up to 30% during pregnancy, although not usually to the

severely low levels associated with TTP.23 It is hypothesized that the hypercoagulable state of pregnancycombined with the decreased ADAMTS-13 activity level may set the stage for TTP in pregnancy. TTP is rareduring pregnancy, seen in <1 per 100,000. Published literature o�ers conflicting opinions as to when TTPmost commonly occurs during pregnancy—either during the second trimester or early in the third

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trimester,24,25,26 or at term or postpartum.27 TTP shares many clinical and laboratory features with pre-eclampsia–eclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count), and acute

fatty liver of pregnancy.20 Still, symptoms of severe pre-eclampsia or HELLP before 24 weeks of gestationshould raise suspicion for TTP.

Human immunodeficiency virus infection, particularly with progression to acquired immunodeficiencysyndrome, is associated with the microangiopathic anemia and thrombocytopenia that characterize TTP. Ontesting, some human immunodeficiency virus patients with TTP-like illness have severely deficient ADAMTS-13 activity levels and thus may benefit from plasma exchange therapy. However, others withmicroangiopathic hemolytic anemia and thrombocytopenia in the setting of human immunodeficiencyvirus/acquired immunodeficiency syndrome have normal ADAMTS-13 activity levels, questioning whether

the TTP label and plasma exchange therapy should be applied.28,29

Influenza vaccination has been implicated as a TTP trigger, leading to production of autoantibody against

ADAMTS-13.30 Acute pancreatitis, capable of inducing a systemic inflammatory response, has also beenassociated with TTP, although moderately rather than severely low ADAMTS-13 activity levels lead to

uncertainty about a TTP diagnosis versus some other thrombotic microangiopathic process.31,32

Drugs associated with TTP include ciprofloxacin, ofloxacin, levofloxacin, quinine, sirolimus when used withcalcineurin inhibitors such as cyclosporine, risperidone, clopidogrel, lansoprazole, valacyclovir, mitomycin,

infliximab, and ticlopidine.20 Ticlopidine in particular is thought to induce autoantibody formation againstADAMTS-13 as well as microvascular endothelial cell injury in genetically susceptible individuals within 2 to12 weeks of starting the medication. Clopidogrel use can also incite microvascular endothelial cell injurywithin 2 weeks of use. Ticlopidine has been associated with more severe thrombocytopenia andmicroangiopathic hemolysis than clopidogrel, whereas clopidogrel has produced more significant renal

insu�iciency not readily responsive to plasma exchange therapy.33 Days to weeks may be required to achieveremission in ticlopidine/clopidogrel-associated TTP cases.

Clinical FeaturesClinical Features

Shearing of RBCs across these microthrombi produces the microangiopathic hemolytic anemia. Plateletaggregation in TTP leads to systemic platelet depletion or thrombocytopenia. When these microthrombi areconcentrated in the CNS and renal arterioles and capillaries (though notably not found in venules), theypromote tissue ischemia and necrosis, with resultant end-organ damage such as seizure, stroke, other focalneurologic deficits, coma, and acute renal injury.

Along with findings of severe anemia and thrombocytopenia of <20,000/mm3 (<20 × 109/L), serum and urinetests may corroborate ongoing intravascular hemolysis (Table 237-1) with renal injury or failure. Because TTPthrombi do not incorporate fibrin, TTP can be distinguished from disseminated intravascular coagulation bynormal coagulation studies.

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TreatmentTreatment

Plasma exchange therapy is very e�ective in TTP with the goal to achieve a normal platelet count.20,21 Dailyplasmapheresis (plasma exchange) of 40 mL/kg or up to 1.0 to 1.5 times a patient's plasma volume isperformed and then either weaned in frequency or stopped once normal counts are reached for 2 to 3consecutive days. Infusion of plasma replaces defective or insu�icient ADAMTS-13, and removal of plasmarids the body of defective ADAMTS-13, autoantibodies against the metalloprotease, and large von Willebrandfactor multimers.

If plasmapheresis cannot be performed immediately, fresh frozen plasma infusion can be initiated, with

pheresis occurring later.20 Infusion with factor VIII concentrate containing ADAMTS-13 activity can beconsidered for patients with plasma allergy a�er specialist consultation and review.

Severe TTP may require additional interventions such as RBC transfusion, anticonvulsants,antihypertensives, and hemodialysis. Avoid platelet transfusionsAvoid platelet transfusions, except in life-threatening bleeding orintracranial hemorrhage, because acutely worsened thrombosis can lead to renal failure and, potentially,death. AspirinAspirin can exacerbate hemorrhagic complications in the setting of severe thrombocytopenia but canstill be used for cerebrovascular and cardiovascular indications in patients with adequate platelet counts.Heparin is not beneficial in TTP. Corticosteroids, rituximab, and cyclosporine may play a role in the treatment

of autoimmune TTP.20,21 Discontinue the inciting drug in all cases of drug-associated TTP.

OutcomeOutcome

TTP relapse, defined as a new case onset >30 days a�er completion of remission-achieving plasma exchangetherapy, is seen in 20% to 50% of cases, most o�en within 2 years a�er the initial episode. Patients with

ADAMTS-13 activity levels <10% are at increased risk for relapse.23 Triggers for relapse may be the same asthose inciting original cases. Relapses may present with milder symptoms and less severe hematologicfindings. Patients with multiple relapses may experience them farther and farther apart, and total volume

and duration requirements for plasma exchange therapy are lessened in subsequent cases.34

The maternal mortality rate from TTP has been reduced significantly with the use of plasma exchangetherapy, but fetal mortality has remained high secondary to placental microvascular occlusion, ischemia,and infarction. TTP may relapse with subsequent pregnancy, so a�ected women should be counseledaccordingly. Because of this association, females of child-bearing age presenting with microangiopathichemolytic anemia and thrombocytopenia should be assessed for an unsuspected pregnancy.

HEMOLYTIC-UREMIC SYNDROMEHEMOLYTIC-UREMIC SYNDROME

HUS, a common cause of acute renal failure in childhood, consists of microangiopathic hemolytic anemia,

acute nephropathy or renal failure, and thrombocytopenia.19,20,35 HUS can be classified as typical or

atypical, with prognosis favoring typical cases.34 Typical HUS occurs in children about 1 week into a case of

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infectious diarrhea, o�en bloody and without associated fever. The causative agent of typical HUS is Shiga

toxin–producing E. coli, with serotype O157:H7 predominating in North America.35,36 Shiga toxin issometimes alternatively labeled verocytotoxin in the literature. Other less common causes of diarrhea-associated HUS include Shigella, Yersinia, Campylobacter, and Salmonella. Atypical HUS occurs in olderchildren and adults; may be di�icult to distinguish from TTP because of extrarenal involvement; is caused byother infectious organisms, such as Streptococcus pneumoniae and Epstein-Barr virus; or may have anoninfectious source, such as bone marrow transplantation or the administration of immunosuppressant or

chemotherapeutic agents.35

Store-bought refrigerated ground beef and frozen ground beef patties, frozen pepperoni pizza, bagged freshspinach, prepackaged raw cookie dough, as well as lettuce, cheddar, and ground beef found in fast food havebeen implicated in multistate E. coli O157:H7 infection outbreaks with HUS occurring as a complication of

each of the outbreaks.36 HUS has also occurred a�er drinking water from a municipal source contaminatedby E. coli O157:H7.

PathophysiologyPathophysiology

Ingested via contaminated food or water, Shiga toxin–producing E. coli O157:H7 possesses potent virulence

factors that allow invasion of intestinal epithelial cells and subsequent transmural intestinal migration.35 Theensuing colonic inflammation produces the characteristic hemorrhagic colitis associated with E. coli O157:H7and other Shiga toxin–producing bacteria. Shiga toxin, once absorbed into the systemic circulation, bindswith greatest a�inity to receptors found on the surfaces of glomerular and renal tubular epithelial andendothelial cells and, to a lesser extent, to receptors lining cerebral and colonic epithelial and endothelialcells and pancreas. Molecular mimicry may exist between human CD36, an antigen found on endothelial cellsand platelets, and Shiga toxin, so that antibody formed against the toxin may bind to CD36 and incite the

pathologic processes leading to HUS.37

Toxin-mediated microvascular injury promotes platelet aggregation (and therefore, systemic depletion,leading to thrombocytopenia) and thrombus formation at the injury site. Further upregulation of epithelialand endothelial cell receptors with high a�inity for Shiga toxin creates a vicious cycle of thrombosis, andmicroangiopathic hemolytic anemia via shearing of RBCs over microthrombi contributes to tissue ischemiaand necrosis. Microthrombi within the pancreas have been postulated to cause pancreatic β-cell death andsubsequent deficits in insulin secretion. Thus, patients with HUS may present with hyperglycemia consistentwith new-onset diabetes mellitus. Some may even go on to have chronic insulin requirements with increased

morbidity and mortality rates.38

Clinical FeaturesClinical Features

Onset of HUS is typically 2 to 14 days a�er diarrhea develops, so patients may present during the diarrhealillness phase, with abdominal cramps, with or without bloody diarrhea, and, o�en, without fever. For thepatient with nonbloody diarrhea, testing stool for fecal leukocytes can reveal occult inflammatory colitis,

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thereby prompting stool culture, specifically for E. coli O157:H7.35 For the patient with bloody diarrhea, theresults of stool testing for Shiga toxin–producing bacteria, including E. coli O157:H7, can guide medicaltreatment, alert providers that the complication of HUS should be anticipated, and aid in the cause of publichealth disease monitoring and outbreak prevention. In addition to the studies required for diagnosinghemolytic anemia, electrolyte and renal function panels should be obtained to detect nephropathy andassociated electrolyte disturbances, while urinalysis should be examined for RBCs, RBC casts, protein, and

other evidence of acute nephropathy.35

TreatmentTreatment

Typical HUS is treated with supportive care, with focus on hydration, pain control, and RBC or platelet

transfusion in cases of significant anemia or profound thrombocytopenia associated with active bleeding.39

Should acute renal failure develop, hemodialysis may be required. Infection with E. coli O157:H7 should not

be treated with antimotility drugs because these agents appear to increase the risk of developing HUS.40

Antibiotics for the treatment of E. coli O157:H7 diarrhea is controversial because in vitro studies have foundthat antibiotics may increase Shiga toxin expression from the bacteria, and case-control human studies have

found that antibiotic treatment of the diarrheal illness may increase the risk of developing HUS.40,41 Atypical

HUS is treated with eculizumab.42

OutcomeOutcome

Acute renal failure occurs in 55% to 70% of patients with typical HUS, but most, up to 85%, recover kidney

function.35 Mortality in typical HUS is about 5% to 15%. Historically, patients with atypical HUS had a pooroutcome, with permanent renal failure or neurologic damage occurring in about half of patients and amorality rate approaching 25%. Aggressive treatment, including eculizumab, appears to significantly reduce

the incidence of permanent renal failure and lower the death rate in atypical HUS.42

MACROVASCULAR HEMOLYSISMACROVASCULAR HEMOLYSIS

A prosthetic heart valveprosthetic heart valve may create turbulent blood flow with high shear stress across the valve. Oldergeneration mechanical heart valves were subject to deterioration that produced subsequent hemolysis, buthemolysis associated with current prosthetic heart valve models is most o�en attributed to paravalvularleak. Such leaks may occur at the time of valve placement or develop later in the life of the prosthetic valve if

infection or calcification promotes dehiscence.43 Particularly a�er mitral valve replacement, hemolysis mayoccur at both clinically insignificant and significant levels.

Macrovascular hemolysis can also occur a�er intracardiac patch repairintracardiac patch repair or aortofemoral bypassaortofemoral bypass; in patientswith coarctation of the aorta, severe aortic valve disease, or ventricular assist devicescoarctation of the aorta, severe aortic valve disease, or ventricular assist devices; and in patientsrequiring the use of extracorporeal circulation such as during cardiopulmonary bypass, plasma exchange, or

hemodialysis.44,45,46 Although the mechanics and shear stress applied to blood through extracorporeal

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circulatory interventions may drive hemolysis, the composition or contamination of diluents and dialysates

may also contribute.45

RBCs hemolyzed in the macrocirculation bear the characteristic fragmented appearance of schistocytes seen

on peripheral smear. Increased schistocytosis correlates with more severe hemolysis.43 Other laboratoryfindings are consistent with intravascular hemolysis (Table 237-1).

Patients with ongoing mild macrovascular hemolysis should receive supplemental iron and folate to promotehealthy reticulocytosis. By reducing the heart rate, β-blocker therapy may decrease RBC shear stress in thepresence of a prosthetic valve and thereby mitigate hemolysis. Pentoxifylline, a xanthine derivative thatreduces blood viscosity and improves RBC flexibility and deformability, can reduce hemolysis associated

with prosthetic heart valves.43 Hemolysis associated with extracorporeal circulation typically begins duringthe procedure, but such patients may or may not exhibit symptoms until hours a�erward. In particular,dialysis patients treated in the outpatient setting may present to the ED for evaluation and treatment ofsymptoms caused by hemolysis. Severe macrovascular hemolysis may necessitate blood transfusion,whether during an isolated episode or repeat episodes.

ADDITIONAL CAUSES OF HEMOLYSISADDITIONAL CAUSES OF HEMOLYSIS

Infection, envenomation, chemical exposure, and trauma can also result in hemolysis (Table 237-5Table 237-5).

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Abbreviations: G6PD = glucose-6-phosphate dehydrogenase; RBC = red blood cell.

TABLE 237-5

Additional Causes of HemolysisAdditional Causes of Hemolysis

CauseCause DisorderDisorder CommentsComments

Infection

Malaria Blackwater fever or hemoglobinuria

Babesiosis Protozoan infects and damages with RBC

Clostridium

perfringens

Toxin lyses RBCs

Leptospirosis Weil's syndrome; toxin lyses RBCs

Envenomation

Hymenoptera stings Requires massive venom injection

Brown recluse

spider

Part of systemic loxoscelism

Pit viper; Crotalinae;

Elapidae; Viperinae

Intravascular RBC destruction

Chemical exposure

Arsine Hemolysis can present 24 h a�er exposure

Naphthalene Mothballs; well water contaminated by toxic dumps; can a�ect fetus in

utero and neonates; patients with G6PD deficiency at higher risk47,48

Direct impact trauma

March

hemoglobinuriaRunners, soldiers, karate, conga drummers49,50; hemoglobinuria but

usually not anemia

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1. 

2. 

3. 

4. 

5. 

6. 

7. 

8. 

9. 

10. 

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USEFUL WEB RESOURCESUSEFUL WEB RESOURCES

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American Society of Hematology Clinical Guidelines—http://www.hematology.org/Practice/Guidelines/2934.aspx

British Committee for Standards in Haematology Guidelines (subcommittee of the British Society forHaematology)—http://www.bcshguidelines.com/guidelinesMenu.asp

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