Chapter 237: Acquired Hemolytic Anemia

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 of RBCs can take place within the intravascular space or in the extravascular spaces of the spleen and liver and can produce a spectrum of disease from mild, asymptomatic illness to severe hemodynamic compromise leading 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 or accentuated cardiac murmur, and pallor. RBC destruction generates free hemoglobin that is then broken down into bilirubin. When bilirubin production exceeds the liver's ability to conjugate it for biliary and fecal excretion, jaundice and darkened urine may develop. Splenic enlargement may promote the storage and extravascular breakdown of RBCs.

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

Intravascular hemolysis of RBCs releases hemoglobin into the bloodstream that then binds to haptoglobin and other serum proteins. The hemoglobin–haptoglobin complex travels to the liver for processing, thus decreasing the amount of free haptoglobin in the serum—an important laboratory finding of intravascular hemolysis. Breakdown of RBCs releases lactate dehydrogenase and potassium, leading to elevation of both in serum. With excessive hemoglobin breakdown comes increased bilirubin production that cannot be conjugated by the liver for biliary and fecal excretion. Laboratory findings associated with excess bilirubin production include elevated total bilirubin; elevated indirect or unconjugated bilirubin; and increased urinary urobilinogen, a by-product of bilirubin breakdown formed by the intestine and passed into the urine. Excess free hemoglobin may escape binding by serum haptoglobin as well as reabsorption by the renal tubules, creating hemoglobinuria and darkened urine.

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

AUTOIMMUNE HEMOLYTIC ANEMIA

Individuals with autoimmune hemolytic anemia make antibodies against their own RBCs.¹ Diagnosis requires evidence of an antibody on the patient's RBCs, usually accompanied by an autoantibody in the plasma. The direct antigen test, also known as the direct Coombs test, is performed by combining the patient's anticoagulated, washed RBCs with anti–immunoglobulin G and anti-C3d (complement) antibodies to detect the presence of immunoglobulin G and/or complement on the RBC surface. A positive direct antigen 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 autoimmune hemolytic anemia (Table 237-2), nor does the presence of immunoglobulin G and/or complement on a patient's RBCs indicate the severity of disease; the direct antigen test is, however, a critical confirmatory screen. The indirect Coombs test looks for the presence of autoantibodies in the patient's serum, testing against a panel of RBCs bearing specific surface antigens. Hemolysis can take place within the vascular space or extravascularly within the liver or spleen.

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 and fifth decades. Many cases initially designated as primary are later found to be associated with lymphoproliferative, autoimmune, or infectious diseases. In children, the disorder is commonly associated with viral or respiratory infections and can cause acute, fulminant hemolysis. Pregnancy can increase the risk of autoantibody development fivefold, but significant RBC destruction is not common. Autoimmune hemolytic anemia is further divided into autoantibody type: warm type, cold type, and mixed type (Table 237-3).¹

Warm Antibody Autoimmune Hemolytic Anemia

Warm autoantibody–mediated hemolysis is predominantly extravascular, with antibody-coated RBCs consumed mostly by splenic macrophages and, to a lesser degree, by hepatic macrophages known as Kupffer cells. Partial phagocytosis of the original RBC membrane structure leads to the formation of the more rigid, fragmentation-prone spherocyte. Increased spherocytosis found on peripheral blood smear correlates positively with severity of extravascular hemolysis.

Autoimmune hemolytic anemia is initially treated with high-dose corticosteroids, typically oral at 1 to 2 milligrams/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, mycophenolate mofetil, 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 in IgG-mediated disease and a major site of general autoantibody production. Splenectomy shows clinical benefit in up to 60% of patients, with potential for long-term remission or a complete cure. A serious complication of splenectomy is overwhelming postsplenectomy infection due to sepsis with encapsulated bacteria.⁵ Such patients should receive regular pneumococcal and meningococcal vaccinations and may benefit from daily penicillin prophylaxis.

Severe hemolysis in cases of warm antibody autoimmune hemolytic anemia may be treated with plasma exchange as a transient stabilizing measure while waiting for steroids or immunosuppressive agents to take effect. IV immunoglobulin has been used as an adjunctive treatment in children who cannot tolerate the side effects of chronic high-dose steroids or immunosuppressive agents.⁶

For a patient with life-threatening anemia, the goal is to transfuse allogeneic RBCs without producing potentially harmful transfusion reactions. Laboratory personnel must determine whether the patient's blood contains alloantibodies against RBC antigens, but first, autoantibodies—usually directed against more commonly occurring or higher prevalence RBC antigens, and thus typically panreactive against RBC panels—must be identified and sifted 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 or longer. Once completed, however, antigen-free, compatible RBC units can then be selected in hopes of providing safe and effective transfusion for the patient. If emergently needed, transfusion of the least incompatible units may be administered slowly and in the smallest amounts necessary with close monitoring.⁸

Cold 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 and triggering of the complement cascade. Hemolysis occurs in both the extravascular and intravascular spaces. Instead of splenic macrophages, the hepatic macrophages known as Kupffer cells are responsible for most of the extravascular RBC destruction. The two major cold antibody disorders are cold agglutinin disease and paroxysmal cold hemoglobinuria. Fifty percent of secondary cold antibody cases are associated with lymphoproliferative disorders, with underlying infection as the next leading cause.

Cold 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, secondary Raynaud's phenomenon and vascular occlusion can complicate cold agglutinin disease, leading to acrocyanosis 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, an associated underlying disease process may be discovered well after initial presentation of cold agglutinin disease; in particular, an occult lymphoproliferative disorder may be the source of the aberrant cold autoantibodies.

Secondary cold agglutinin disease may present after infection with Mycoplasma pneumoniae, Epstein-Barr virus, or infectious mononucleosis, adenovirus, cytomegalovirus, influenza, varicella-zoster virus, human immunodeficiency virus, Escherichia coli, Listeria monocytogenes, or Treponema pallidum. Hemolysis typically begins 2 to 3 weeks after the onset of illness, corresponding with peak antibody development against the infectious agent, and resolves about 2 to 3 weeks after resolution of the infectious illness. Many patients with Mycoplasma pneumonia and infectious mononucleosis will have measurable cold agglutinin titers, but far fewer will develop symptoms and signs of hemolytic anemia. Conversely, cold agglutinin disease associated with lymphoproliferative diseases such as chronic lymphocytic leukemia and lymphoma produces high autoantibody levels with the potential for significant hemolysis.

Agglutination of RBCs can confound an automated CBC device; the mean corpuscular volume may be falsely elevated, whereas the hemoglobin registers spuriously low. Holding the blood tube in warm hands may decrease RBC clumping for more reliable CBC results. A CBC with confusing or bizarre results should undergo peripheral smear examination. Peripheral smear findings of cold agglutinin disease include spherocytosis, anisocytosis, poikilocytosis, polychromasia, and agglutination.¹² The direct antigen test demonstrates adherence of complement to patient RBCs, but cold autoantibodies are typically washed off the RBCs during the elution process and thus are not identified. Other laboratory findings correspond with those routinely seen in cases of hemolytic anemia, including findings consistent with intravascular hemolysis in some cold agglutinin 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 for healthy RBC production. Cold agglutinin disease is less likely to respond to steroids, with response rates as low as 35%.⁹ Splenectomy is less effective in treating cold agglutinin disease because splenic macrophages play a lesser role in IgM-mediated cold antibody disease. Severe hemolysis has been treated successfully with immunosuppressive agents such as chlorambucil, cyclophosphamide, interferon-α, fludarabine, or rituximab.⁹ Because immunoglobulin M autoantibodies have an intravascular distribution, plasmapheresis may assist by removing autoantibodies from the circulation when combined with immunosuppressive agents.

Infection-related cold antibody disease does not require immunosuppressive therapy because the hemolytic anemia is usually self-limited. RBC transfusion can be performed for patients at risk for significant cardiac or cerebrovascular 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 act against the I/i group antigens that are found on most donor RBCs. Donor complement in the transfused product also may exacerbate ongoing hemolysis.

Paroxysmal 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 for which 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 in children, usually seen after a preceding upper respiratory infection. Most pediatric cases are self-limited and nonrecurring, but severe cases may take weeks to resolve. With severe hemolysis, hemoglobinuria is common, and methemoglobinemia may be seen. Acute renal failure may develop as a complication. Pediatric paroxysmal cold hemoglobinuria may occur after infections with measles, mumps, Epstein-Barr virus, 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-provoked hemolysis 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 to sudden, 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 is pathognomonic. Patient serum is added to two tubes containing human type O RBCs. The first tube, the control, is incubated at 37°C (98.6°F) or physiologic temperature, whereas the second tube is incubated first at 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, indicating presence of the biphasic D-L antibody, while absent in the control tube.¹⁴ The direct antigen test is usually positive for complement just before or after a paroxysm but often negative in between paroxysms in patients with chronic, relapsing disease.

Patients with paroxysmal cold hemoglobinuria should be kept warm. Steroids can be considered in children with severe hemolytic anemia, but because infection-related disease tends to be self-limited, benefit is uncertain. Disease secondary to syphilis responds to effective antibiotic treatment. Splenectomy is not helpful, and plasmapheresis should be used only as a temporizing measure in life-threatening cases. RBC transfusion using a blood warmer should be limited to cases of severe hemolysis because most donor units are 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 Anemia

Mixed-type autoimmune hemolytic anemia, with both warm and cold autoantibodies to RBCs, presents as primary 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. Like the warm antibody disorder, the mixed type is usually steroid responsive, can be treated with splenectomy, and responds to immunosuppressive therapy.

ALLOIMMUNE HEMOLYTIC ANEMIA

Alloimmune hemolytic anemia requires exposure to allogeneic RBCs with subsequent alloantibody formation. In the laboratory, alloantibodies react specifically with the allogeneic RBCs that triggered their production; these antibodies do not react against a patient's own RBCs. A well-known example of this is when the Rh(D)-negative maternal immune system develops immunoglobulin G alloantibodies on exposure to 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 to potentially fatal, producing intrauterine fetal death. The term hydrops fetalis has been used to describe the anasarca seen in severe cases. Transplacental or fetomaternal hemorrhage, the inciting stimulus for maternal alloantibody formation, may occur during amniocentesis, chorionic villus sampling, delivery, or abortion (threatened or otherwise) or even during external cephalic version. Administration of anti-D immunoglobulin G with any fetomaternal hemorrhage event and soon after delivery will suppress maternal alloantibody formation and prevent hemolytic disease of the newborn. Treatment of established hemolytic disease of the newborn employs intrauterine and intravascular fetal transfusion and may include plasma exchange and/or IV immunoglobulin therapy.

Most adults who develop alloimmune hemolytic anemia have a history of RBC transfusion, which sensitizes patients to allogeneic RBC antigens. A subsequent transfusion can result in immediate alloantibody production, resulting in the fever, chest and flank pain, tachypnea, tachycardia, hypotension, hemoglobinuria, and oliguria seen in the hemolytic transfusion reaction (see chapter 238, "Transfusion Therapy"). In patients with high alloantibody titers, the hemolytic reaction can be immediate. Delayed alloantibody-mediated hemolysis is possible, with hemolytic transfusion reaction symptoms presenting 3 to 7 days after transfusion (see chapter 238).

DRUG-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 237-4).¹⁸ Drug-induced hemolytic anemia can result in either a positive or negative direct antigen test and can be difficult to distinguish from autoimmune hemolytic anemia, so a careful review of current medications is important in patients with a new hemolytic anemia.

Patients with severe hemolysis and anemia require hospitalization and further evaluation. In all cases, stop the offending drug immediately. In the event that medications are required for treatment of patients in the ED 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.

The two classic syndromes associated with microangiopathic hemolytic anemia are thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS).^19,20 Both syndromes involve platelet aggregation in the microvascular circulation via mediation of von Willebrand factor. Microangiopathic hemolytic anemia or schistocyte-forming hemolysis occurs from fragmentation of RBCs during travel through these partially occluded arterioles and capillaries. Although TTP and HUS are clinical syndromes with characteristic features, overlap does occur, sometimes making differentiation difficult. TTP is more common in adults, whereas HUS is more common in children. TTP typically induces more prominent neurologic effects, with deposition of platelet aggregates in a broader distribution, whereas HUS more specifically affects the renal system.

THROMBOTIC THROMBOCYTOPENIC PURPURA

The classic pentad for TTP includes CNS abnormalities, renal pathology, fever, microangiopathic hemolytic anemia, 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.

Pathophysiology

The pathophysiology of TTP is connected to a specific metalloprotease ADAMTS-13 (a disintegrin and metalloproteinase 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 vascular endothelial cells. Its function is to cleave von Willebrand factor that has been unfolded by shear stress within the microvasculature of arterioles and capillaries. Without this cleavage function, unfolded von Willebrand factor 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 activity alone does not reliably trigger TTP; often other precipitating or contributing factors are important, including pregnancy, 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 pregnancy combined with the decreased ADAMTS-13 activity level may set the stage for TTP in pregnancy. TTP is rare during pregnancy, seen in <1 per 100,000. Published literature offers conflicting opinions as to when TTP most commonly occurs during pregnancy—either during the second trimester or early in the third 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 gestation should raise suspicion for TTP.

Human immunodeficiency virus infection, particularly with progression to acquired immunodeficiency syndrome, is associated with the microangiopathic anemia and thrombocytopenia that characterize TTP. On testing, 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 with microangiopathic hemolytic anemia and thrombocytopenia in the setting of human immunodeficiency virus/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 been associated 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 with calcineurin inhibitors such as cyclosporine, risperidone, clopidogrel, lansoprazole, valacyclovir, mitomycin, infliximab, and ticlopidine.²⁰ Ticlopidine in particular is thought to induce autoantibody formation against ADAMTS-13 as well as microvascular endothelial cell injury in genetically susceptible individuals within 2 to 12 weeks of starting the medication. Clopidogrel use can also incite microvascular endothelial cell injury within 2 weeks of use. Ticlopidine has been associated with more severe thrombocytopenia and microangiopathic hemolysis than clopidogrel, whereas clopidogrel has produced more significant renal insufficiency not readily responsive to plasma exchange therapy.³³ Days to weeks may be required to achieve remission in ticlopidine/clopidogrel-associated TTP cases.

Clinical Features

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

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

Treatment

Plasma exchange therapy is very effective in TTP with the goal to achieve a normal platelet count.^20,21 Daily plasmapheresis (plasma exchange) of 40 mL/kg or up to 1.0 to 1.5 times a patient's plasma volume is performed and then either weaned in frequency or stopped once normal counts are reached for 2 to 3 consecutive days. Infusion of plasma replaces defective or insufficient ADAMTS-13, and removal of plasma rids the body of defective ADAMTS-13, autoantibodies against the metalloprotease, and large von Willebrand factor 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 be considered for patients with plasma allergy after specialist consultation and review.

Severe TTP may require additional interventions such as RBC transfusion, anticonvulsants, antihypertensives, and hemodialysis. Avoid platelet transfusions, except in life-threatening bleeding or intracranial hemorrhage, because acutely worsened thrombosis can lead to renal failure and, potentially, death. Aspirin can exacerbate hemorrhagic complications in the setting of severe thrombocytopenia but can still 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.

Outcome

TTP relapse, defined as a new case onset >30 days after completion of remission-achieving plasma exchange therapy, is seen in 20% to 50% of cases, most often within 2 years after the initial episode. Patients with ADAMTS-13 activity levels <10% are at increased risk for relapse.²³ Triggers for relapse may be the same as those inciting original cases. Relapses may present with milder symptoms and less severe hematologic findings. 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 exchange therapy, but fetal mortality has remained high secondary to placental microvascular occlusion, ischemia, and infarction. TTP may relapse with subsequent pregnancy, so affected women should be counseled accordingly. Because of this association, females of child-bearing age presenting with microangiopathic hemolytic anemia and thrombocytopenia should be assessed for an unsuspected pregnancy.

HEMOLYTIC-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 infectious diarrhea, often 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 is sometimes alternatively labeled verocytotoxin in the literature. Other less common causes of diarrhea-associated HUS include Shigella, Yersinia, Campylobacter, and Salmonella. Atypical HUS occurs in older children and adults; may be difficult to distinguish from TTP because of extrarenal involvement; is caused by other infectious organisms, such as Streptococcus pneumoniae and Epstein-Barr virus; or may have a noninfectious 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 fresh spinach, prepackaged raw cookie dough, as well as lettuce, cheddar, and ground beef found in fast food have been 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 after drinking water from a municipal source contaminated by E. coli O157:H7.

Pathophysiology

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 The ensuing colonic inflammation produces the characteristic hemorrhagic colitis associated with E. coli O157:H7 and other Shiga toxin–producing bacteria. Shiga toxin, once absorbed into the systemic circulation, binds with greatest affinity to receptors found on the surfaces of glomerular and renal tubular epithelial and endothelial cells and, to a lesser extent, to receptors lining cerebral and colonic epithelial and endothelial cells and pancreas. Molecular mimicry may exist between human CD36, an antigen found on endothelial cells and 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 epithelial and endothelial cell receptors with high affinity for Shiga toxin creates a vicious cycle of thrombosis, and microangiopathic hemolytic anemia via shearing of RBCs over microthrombi contributes to tissue ischemia and necrosis. Microthrombi within the pancreas have been postulated to cause pancreatic β-cell death and subsequent deficits in insulin secretion. Thus, patients with HUS may present with hyperglycemia consistent with new-onset diabetes mellitus. Some may even go on to have chronic insulin requirements with increased morbidity and mortality rates.³⁸

Clinical Features

Onset of HUS is typically 2 to 14 days after diarrhea develops, so patients may present during the diarrheal illness phase, with abdominal cramps, with or without bloody diarrhea, and, often, without fever. For the patient with nonbloody diarrhea, testing stool for fecal leukocytes can reveal occult inflammatory colitis, thereby prompting stool culture, specifically for E. coli O157:H7.³⁵ For the patient with bloody diarrhea, the results of stool testing for Shiga toxin–producing bacteria, including E. coli O157:H7, can guide medical treatment, alert providers that the complication of HUS should be anticipated, and aid in the cause of public health disease monitoring and outbreak prevention. In addition to the studies required for diagnosing hemolytic anemia, electrolyte and renal function panels should be obtained to detect nephropathy and associated electrolyte disturbances, while urinalysis should be examined for RBCs, RBC casts, protein, and other evidence of acute nephropathy.³⁵

Treatment

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 found that 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

Outcome

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 poor outcome, with permanent renal failure or neurologic damage occurring in about half of patients and a morality 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

A prosthetic heart valve may create turbulent blood flow with high shear stress across the valve. Older generation mechanical heart valves were subject to deterioration that produced subsequent hemolysis, but hemolysis associated with current prosthetic heart valve models is most often attributed to paravalvular leak. 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 after mitral valve replacement, hemolysis may occur at both clinically insignificant and significant levels.

Macrovascular hemolysis can also occur after intracardiac patch repair or aortofemoral bypass; in patients with coarctation of the aorta, severe aortic valve disease, or ventricular assist devices; and in patients requiring 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 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 laboratory findings are consistent with intravascular hemolysis (Table 237-1).

Patients with ongoing mild macrovascular hemolysis should receive supplemental iron and folate to promote healthy reticulocytosis. By reducing the heart rate, β-blocker therapy may decrease RBC shear stress in the presence of a prosthetic valve and thereby mitigate hemolysis. Pentoxifylline, a xanthine derivative that reduces blood viscosity and improves RBC flexibility and deformability, can reduce hemolysis associated with prosthetic heart valves.⁴³ Hemolysis associated with extracorporeal circulation typically begins during the procedure, but such patients may or may not exhibit symptoms until hours afterward. In particular, dialysis patients treated in the outpatient setting may present to the ED for evaluation and treatment of symptoms caused by hemolysis. Severe macrovascular hemolysis may necessitate blood transfusion, whether during an isolated episode or repeat episodes.

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