ACQUIRED HEMOLYTIC ANEMIAS

Table -1 outlines these conditions, which include antibody-mediated (immune) hemolytic anemias; fragmentation hemolysis, either microvascular or macrovascular; anemias resulting from direct toxic effects; anemias resulting from mechanical injury; and anemia that is the result of abnormal splenic function (hypersplenism).

The general laboratory evaluation of patients with suspected hemolysis is reviewed here; the characteristic results for each type of anemia will be discussed below.

1. Complete blood count (CBC): The anemia that occurs may be mild or severe; verify normal/abnormal white blood cell count and platelet count.

2. Reticulocyte count: This is the single most useful test in ascertaining the presence of hemolysis and a normal bone marrow response; this should be elevated and can be as high as 30 to 40 percent.

3. Review of the peripheral blood smear: Most hemolytic disorders are associated with changes in the morphology of the red blood cells (RBCs); typical changes may include:

a. Spherocytes: These are the most common morphologic abnormality in hemolytic diseases; they will be most abundant in patients with warm antibody immune hemolysis and those with hereditary spherocytosis.

b. Schistocytes:These are fragmented RBCs that result from direct trauma within the vasculature, most often in the microvasculature (known as microangiopathic hemolytic anemia, MAHA), but can also occur in the macrovasculature; schistocytes are markers of nonimmune hemolysis.

4. Unconjugated (indirect) bilirubin: This should be elevated in the presence of hemolysis as a result of heme catabolism; the direct (conjugated) bilirubin should be normal unless there is concomitant hepatic or biliary dysfunction.

5. Haptoglobin: This binds to the protein globin that is released when hemoglobin is catabolized, so this should be low or absent in the presence of hemolysis; it is an acute-phase reactant so it may be deceptively elevated.

7. Lactic dehydrogenase (LDH): This should be elevated in hemolysis; it can be a relatively sensitive marker used to follow the course of a hemolytic disease.

There are three types of antibody-mediated, so-called immune, hemolytic anemias:

1. Warm antibody hemolytic anemia. These antibodies are reactive at body temperature.

2. Cold antibody hemolytic anemia. These antibodies react with the patient's RBCs at temperatures below normal body temperature.

3. Drug-induced immune hemolytic anemia. Certain drugs can cause an immune reaction in some patients that results in destruction of their RBCs.

Immune hemolytic anemias are characterized in the laboratory by the Coombs antiglobulin test, also known as the direct Coombs test, or direct antiglobulin test (DAT). This test demonstrates the presence of immunoglobulin (IgG) or complement (C3) on the surface of the RBC. It is only positive in immune-mediated hemolytic anemias. The indirect Coombs test is primarily used for pretransfusion screening for antibodies; it demonstrates the presence of free antibodies in the patient's serum. Immune hemolysis is typified by abundant spherocytes on the peripheral blood smear.

This disease is characterized by the presence of antibodies directed against IgG and/or C3 that are deposited on the surface of the RBC. It comprises 70 percent of all cases of immune hemolytic anemia. These antibodies react with the RBCs at 37°C. After the antibody-RBC interaction, the RBCs are trapped and destroyed in the spleen.

Patients of any age may be affected, but warm antibody hemolytic anemia is most likely to occur in older adults, women more often than men. Most often it is idiopathic; however, up to 25 percent of affected patients have an underlying disease that affects the immune system such as chronic lymphocytic leukemia, Hodgkin or non-Hodgkin lymphoma, or systemic lupus erythematosus (SLE). In adults, the disease is typically relapsing. In young children, it often follows an acute infection or immunizations and is unlikely to recur.

The clinical presentation and course of disease are highly variable depending on the severity of the anemia and how rapidly it develops. Many patients will have a mild anemia with splenomegaly. In this setting, the Coombs test will be positive for IgG but not C3, and the indirect Coombs test will be negative. Life-threatening anemia can also occur with hemoglobin levels less than 7 g/dL and a reticulocyte count greater than 30 percent. These patients may have marked splenomegaly, pulmonary edema, and mental status changes. Venous thrombosis can also occur. Patients with severe hemolysis generally have a Coombs test that is positive for both IgG and C3, and the indirect Coombs test is also often positive. Rare patients have Evans syndrome, where there is coexistent immune destruction both of RBCs and platelets by different antibodies.

The treatment of warm antibody hemolytic anemia depends on the degree of anemia that develops and the ability of the patient to hemodynamically tolerate anemia. When there is only mild anemia, no treatment is necessary. When significant hemolysis is present, the first-line treatment is prednisone, 1.0 mg/kg per day. About 75 percent of patients will respond to steroid therapy, but up to one-half of these will relapse after the steroids are tapered. Transfusion of red blood cells is difficult in these patients because they will be impossible to crossmatch. Transfusion is indicated for symptoms of angina, congestive heart failure, mental status changes, orthostasis, or hypoxia. In this setting, the patient is slowly transfused with the best match available; acute transfusion reactions can occur. Splenectomy is the second-choice treatment for patients who fail or cannot tolerate steroids. Immunosuppressive drugs such as azathioprine and cyclophosphamide are occasionally used. Treatment of any underlying immunologic disease may also help control the hemolytic anemia. Death in these patients results from severe anemia that cannot be corrected, immunosuppression, venous thrombosis, or underlying immunologic disease.

Cold-reactive antibodies, those that react maximally at temperatures between 4° and 20°C and not usually above 32°C, account for 10 to 20 percent of patients with immune hemolytic anemia. There are two types of diseases where this occurs: cold agglutinin disease and paroxysmal cold hemoglobinuria. These antibodies react with the RBCs in the superficial microcirculation where it is cool, then the hemolysis occurs when the red blood cells reenter the central circulation and are warmed.

This can be an acute, transient disease mostly seen in younger people or a chronic disease primarily in older patients. It is typically caused by an IgM antibody, and the Coombs test will only be positive for C3, because the IgM will not be attached to the RBCs at warmer temperatures. The acute form of this disease is mostly seen in patients with Mycoplasma pneumonia or infectious mononucleosis. The IgM antibodies are directed against the I antigen or i antigen on the RBC surface, respectively. Only rare patients develop significant hemolysis, but severe anemia and renal failure can occur. The acute form of this disease is self-limited. Chronic cold agglutin disease is more common than the acute form and primarily occurs in patients with underlying lymphoid neoplasms. These patients typically have a mild to moderate anemia that results from hemolysis occurring in portions of the body exposed to lower temperatures (acrocyanosis). These patients should be kept in a warm environment, and treatment is directed against the underlying disease. Some of the hemolysis may respond to treatment with prednisone.

This disease is characterized by acute episodes of hemolysis following exposure to cold. Two groups of patients can be affected by this disease: (1) those with congenital or tertiary syphilis that is untreated, or (2) patients with viral illnesses such as mumps or measles. In this disease, the immune hemolysis is caused by an IgG antibody called the Donath-Landsteiner antibody, which is directed against the P-antigen complex on the RBC surface. Clinically, after exposure to cold, affected patients will have hemoglobinuria, chills, fever, and pain involving the back, legs, and abdomen. The direct Coombs test is only positive during an acute attack. When associated with syphilis, this disease goes away after appropriate antibiotic therapy. Now most commonly seen in patients with viral infections, the hemolysis is self-limited but can cause transient severe anemia.

Many drugs have been directly linked to immune hemolytic anemia. There are three types of reactions that can occur and result in hemolysis:

Autoantibody induction. Alpha-methyldopa is the prototype drug of this reaction, and 10 to 20 percent of patients taking moderate-to-high doses will develop a positive direct Coombs test. In this drug reaction, the RBCs become coated with an IgG that is directed against the Rh complex. Other drugs that can cause this are l-dopa, procainamide, ibuprofen, diclofenac, and thioridazine. Generally, it takes an extended period of drug exposure to develop the positive Coombs test, and only a small number of those patients will develop severe hemolysis. The hemolysis ceases after the drug is stopped, but the Coombs test may remain positive for a year or more.

Hapten-induced immune hemolysis. Penicillin is the classic drug associated with this reaction. Immune hemolysis can develop in patients receiving large intravenous doses of penicillin or penicillin-type antibiotics and usually starts 1 to 2 weeks after the therapy begins. The patient forms an antibody against the offending drug, then the antibody combines with the drug-RBC complex and causes hemolysis. Other drugs that can cause hemolysis by this mechanism include oxacillin, ampicillin, methicillin, carbenicillin, and some cephalosporins. The hemolysis stops when the drug is discontinued.

Innocent bystander immune hemolysis. Quinidine is the prototype drug for this reaction. Antibodies (IgG or IgM) are formed against the drug, then the drug-antibody complex binds to the RBC and hemolyzes it. Other drugs linked to this mechanism include quinine, isoniazid, sulfonamides, hydrochlorothiazide, antihistamines, insulin, chlorpromazine, tetracycline, acetaminophen, hydralazine, probenecid, cephalosporins, fenoprofen, and sulindac. Even a small dose of the drug can cause hemolysis; however, these drugs are very commonly prescribed and the associated hemolysis is very rare.

This type of hemolytic anemia is associated with a variety of disorders; however, the mechanism leading to hemolysis is consistent. The fragmentation of RBCs results from their passage through abnormal arterioles: usually there is damage to the vessel wall or endothelial surface or fibrin has been deposited in the arteriole. Schistocytes are characteristically found on the peripheral blood smear.

Those diseases will be discussed separately; however, TTP and HUS may well represent variant clinical presentations of a single disease. In selected patients, the specific diagnosis may be impossible to establish.

TTP is a heterogeneous clinical syndrome characterized by this pentad of symptoms and signs:

1. Microangiopathic hemolytic anemia (MAHA) with characteristic schistocytes on the peripheral blood smear and a reticulocytosis

3. Renal abnormalities including renal insufficiency, azotemia, proteinuria, or hematuria

5. Neurologic abnormalities including headache, confusion, cranial nerve palsies, seizures, or coma

TTP has been diagnosed in patients of all ages but occurs most commonly in ages 10 to 60. Women are affected more commonly than men. The course of the disease is typically acute and fulminant, lasting days to months, but it can be chronic and relapsing in 10 percent of patients. The overall survival rate is 80 percent, but the course is rapidly fatal in some patients. The majority of patients diagnosed with TTP have no apparent predisposing condition. In a small number of patients, TTP has been linked to genetic predisposition, pregnancy, immunologic diseases (SLE, rheumatoid arthritis, Sjogren syndrome), or infections (viral, Mycoplasma pneumonia, subacute bacterial endocarditis, human immunodeficiency virus).

The pathogenesis of TTP is uncertain, but the presence of one or more platelet aggregating agents is likely responsible. Several abnormalities of the vascular endothelium and endothelial cell function have been implicated, including the release and presence of large von Willebrand multimers, decreased production of prostacyclin, inadequate fibrinolysis as a result of deficient tissue plasminogen activator (tPA) production, the presence of a platelet agglutinating protein, and deficient production of IgG molecules. Whatever the etiology, the result is the deposition of hyaline material within the lumina of capillaries and arterioles. These microthrombi are made of platelets and a small amount of fibrinlike material. These deposits may be found in any tissue but occur most frequently in the heart, brain, kidneys, pancreas, and adrenal glands.

The diagnosis of TTP is established clinically by the presence of the signs and symptoms listed above. Treatment should begin immediately based on these clinical and laboratory features. Biopsies are sometimes done of the gingiva, kidney, or bone marrow but are not essential to establish the diagnosis and should not delay therapy.

Clinically, the neurologic abnormalities are the most common presenting complaint, but hemorrhagic signs and symptoms and those referable to anemia are also common presentations. Laboratory studies will reflect the presence of MAHA with an anemia of variable degree (the hemoglobin will be less than 6 g/dL in one out of three patients), reticulocytosis, elevated indirect bilirubin, elevated LDH, negative Coombs test, and the presence of schistocytes on the peripheral smear (the diagnosis of TTP is doubtful without schistocytes). Thrombocytopenia, reflective of the intravascular microthrombi, is often severe with the count less than 20,000/mL (mm3) in 50 percent of patients. A mild leukocytosis with a left shift is common. The blood urea nitrogen (BUN) and creatinine are typically elevated to a mild to moderate degree. Urinalysis usually shows some degree of proteinuria and may show microscopic hematuria. Coagulation screening tests should be normal.

The salient features in the differential diagnosis of TTP are outlined in Table 188-2.

The diagnosis of TTP represents a medical emergency. Patients should be treated by experienced specialists. Rapid transport to a tertiary care center is indicated. Some centers have a policy of initially admitting all TTP patients to an intensive care unit. The foundation of therapy for TTP is plasma exchange transfusion. Some patients will respond favorably to plasma infusions alone, and these can be given until the exchanges can be initiated. The plasma exchange uses fresh-frozen plasma (FFP) or fresh unfrozen plasma (FUP). The plasma is thought to provide a substance that the patient is lacking or remove an unknown toxic substance. These exchanges may be required daily for a period of several months. TTP patients are also treated with prednisone (or methylprednisolone), 1 mg/kg per day, and antiplatelet therapy consisting of aspirin or dipyridamole. Refractory patients may receive immunosuppressive therapy such as vincristine, azathioprine, or cyclophosphamide. Splenectomy is sometimes done but has little correlation with clinical improvement. Supportive care includes the transfusion of packed red blood cells as needed and hemodialysis if indicated. Platelet transfusions should be avoided, unless there is uncontrolled hemorrhage, because they can aggravate the thrombotic process. Clinical and hematologic progress in patients with TTP is assessed by improvement in neurologic and renal function, decrease in the reticulocyte count, decrease in the LDH, and increase in the platelet count.

HUS is a disease mainly of infancy and early childhood, with a peak incidence between 6 months and 4 years of age. An adult form also exists. The overall mortality rate is 5 to 15 percent, and the prognosis is worse in older children and adults. HUS is one of the most common causes of acute renal failure in childhood. HUS is characterized by acute renal failure, microangiopathic hemolytic anemia, fever, and thrombocytopenia.

In children, the development of HUS often follows a prodromal infectious disease, usually diarrhea or an upper respiratory infection. Diarrhea, particularly that associated with Escherichia coli serotype 0157:H7, as well as with Shigella, Yersinia, Campylobacter, and Salmonella, may be antecedent. Other implicated bacteria and viruses include Streptococcus pneumoniae, varicella, echovirus, and coxsackie A and B. Some cases of HUS are familial, with a genetic or HLA-type predisposition.

As noted above, HUS and TTP may actually be clinical variations of the same disease. Like TTP, HUS is pathologically identified by microthrombi, consisting of platelet aggregates, that occlude the arterioles and capillaries. In HUS, the microthrombi are confined mostly to the kidneys; in TTP, they occur throughout the microcirculation. The platelet-fibrin hyaline material is found in the afferent arterioles and glomerular capillaries. A defect in the vascular endothelium is thought to cause these platelet aggregates. It is not precisely known how the endothelial damage occurs, but the toxins released from bacteria or viruses have been implicated. The damaged endothelial cells are then thought to release large and ultralarge vonWillebrand factor multimers that lead to platelet aggregation.

Like TTP, HUS is primarily a clinical and laboratory diagnosis. The signs and symptoms of acute renal failure predominate. Although neurologic dysfunction is not a key feature of HUS, it does occur in up to one-third of HUS patients at some point in the course of their disease. Laboratory studies reflect the presence of MAHA. Thrombocytopenia is present but generally not to the degree seen in TTP. The BUN and creatinine will be markedly elevated, and urine, if present, will contain protein and red blood cells. Coagulation studies are usually normal.

The treatment of HUS primarily consists of early dialysis for management of renal failure and general supportive care. Up to 90 percent of HUS patients with acute renal failure will eventually regain normal renal function. Plasma exchange or infusion is not usually used in the treatment of childhood HUS. HUS is rarely a recurrent disease, but it has been known to recur in patients who have undergone renal transplantation.

Adult HUS. When HUS occurs in adult patients, it can be difficult or impossible to differentiate between HUS and TTP. HUS is diagnosed when there is prominent renal failure and minimal neurologic dysfunction. Of adults diagnosed with HUS, two-thirds are women. Associated factors are the use of oral contraceptive agents, preeclampsia, eclampsia, other obstetric complications, and the postpartum period. HUS also rarely occurs in association with the chemotherapeutic drug mitomycin C and in other cancer patients who may or may not have received chemotherapy. The renal failure in adults with HUS may be reversible, even after as long as 1 year.

Microangiopathic hemolytic anemia (MAHA) can occur in pregnancy as a complication of preeclampsia, eclampsia, or placental abruption. The presence of preeclampsia, hemolysis, elevated liver enzymes, and low platelet counts is known as the HELLP syndrome. The HELLP syndrome can occur with minimal signs or symptoms of preeclampsia. The pathogenesis is not entirely known, but preeclampsia can be associated with microvesicular fatty infiltration of the liver and with localized or systemic endothelial damage that can lead to MAHA. Untreated, HELLP can result in hepatic failure or rupture, disseminated intravascular coagulation (DIC), or congestive heart failure. Treatment begins with prompt delivery of the infant followed by supportive care.

MAHA occurs in about 25 percent of patients with DIC. The degree of hemolysis that occurs in DIC is much less than that seen in TTP or HUS. The basic pathology in DIC is the deposition of fibrin in the microvasculature. Fragmentation and hemolysis of the RBCs occur as they pass through the microcirculation. Schistocytes, reflective of MAHA, are often found on the peripheral smear of patients with DIC, but their absence does not rule out DIC. Along with the factor replacement therapy required in DIC, patients with significant hemolysis and anemia will require transfusion of packed red blood cells to maintain adequate circulation and oxygenation.

MAHA can be seen in patients with widely disseminated cancer. Gastric adenocarcinoma is the malignancy most frequently associated with MAHA, although it also occurs with adenocarcinomas of the lung, breast, and of unknown primary. The pathogenesis is uncertain, but hypotheses include the following: vessels that supply malignant tumors may be structurally abnormal; circulating tumor cells may damage the endothelial surface; or tumor cells may give off factors that promote platelet aggregation and microvascular changes. Patients with MAHA due to widespread malignancy have a very poor prognosis.

MAHA can be seen in vascular diseases such as SLE, polyarteritis nodosa, Wegener granulomatosis, and scleroderma. In this setting, damage to the endothelial surface is thought to result from deposition of immune complexes and fibrin in the microcirculation.

Patients with malignant or accelerated hypertension can develop MAHA as a result of narrowing and hardening of the afferent arterioles and swelling of the endothelial cells. This hemolysis subsides after normalization of the blood pressure.

Traumatic hemolysis can occur in patients with artificial heart valves or severe calcific aortic stenosis. Some degree of hemolysis occurs in up to 10 percent of patients with aortic prostheses; mechanical valves are more likely to cause hemolysis than porcine valves. Mitral valve replacements cause less hemolysis because of the lower pressure gradient. Hemolysis can also occur in patients with prosthetic patches in the heart and, rarely, in patients who have undergone aortofemoral bypass. The hemolysis that occurs in this setting is generally mild and well tolerated. These patients should receive supplemental iron and folate. If the hemolysis is severe, the defective valve may have to be replaced.

Destruction of red blood cells occurs commonly in the course of many infectious diseases. Those disease with the most profound effect on RBCs will be reviewed here.

Transmitted by mosquitoes, malaria is the world's most common cause of hemolytic anemia. Red cell hemolysis results from direct parasitization of the RBCs. Hemolysis also results from direct parasitization of RBCs in babesiosis, which is transmitted by ticks or blood transfusions. Infection with Bartonella is also associated with direct parasitization of RBCs and resultant hemolysis.

Haemophilus influenzae type B infection can produce hemolysis by altering the RBC surface. The capsular polysaccharide of the bacterium binds to the RBC surface, then antibodies destroy the bacterium as well as the RBC. Those with H. influenzae meningitis have the greatest potential to develop severe hemolysis.

Clostridium perfringens (welchii) infection can result in severe hemolysis by direct lysis of red blood cells. The organism releases enzymes that acutely degrade the phospholipids of the RBC membrane bilayer and the proteins in the structural membrane. This infection is seen most commonly in patients with acute cholecystitis, after surgery involving the biliary tree, after abortions, and in uterine infections. Clinically, the patient may have acute hemodynamic collapse and profound intravascular hemolysis. Clostridium septicemia has a mortality rate over 50 percent.

M. pneumoniae and infectious mononucleosis are associated with cold agglutin disease, as described above.

Many viral infections can be accompanied by hemolytic anemia, including measles, cytomegalovirus, varicella, herpes simplex, coxsackie, and human immunodeficiency virus.

Insect, spider, and snake bites. Acute intravascular hemolysis can occur following bites/stings of bees, wasps, the southern black widow spider, and the brown recluse spider. The bites of American snakes, pit vipers and coral snakes, are known to cause coagulation abnormalities but rarely cause hemolysis. The bite of the cobra snake does cause intravascular hemolysis.

Copper. Copper has a direct hemolytic effect on red blood cells. Copper sulfate contamination from copper pipes can taint hemodialysis fluid, and copper sulfate is sometimes used in suicide attempts. Patients with Wilson disease experience transient episodes of hemolysis as a result of their elevated copper levels.

Oxidative hemolysis of RBCs can result from exposure to a number of drugs that cause the formation of methemoglobin. These drugs oxidize ferrous hemoglobin (+2) to ferric hemoglobin (+3), which is methemoglobin. Methemoglobin cannot bind oxygen, so the oxygen-carrying capacity of the blood is decreased. A large number of commonly used drugs can cause methemoglobinemia, but not at therapeutic doses (Table -3). Toxic methemoglobinemia occurs when more than 1 percent of the hemoglobin has been oxidized to the ferric form. Clinically, methemoglobinemia should be suspected in patients who are cyanotic without cardiopulmonary disease. This cyanosis is not relieved by oxygen. The venous blood appears chocolate brown. The arterial blood gas will reflect a normal PO2, but decreased oxygen saturation. Table -4 shows the clinical effects of acute methemoglobinemia. Levels of methemoglobin greater than 20 to 30 percent of the total hemoglobin should be treated. Methylene blue is given intravenously at a dose of 1 to 2 mg/kg in a 1% solution over 5 min. Methylene blue reduces methemoglobin back to oxygen-carrying hemoglobin through a series of reactions.

Temperatures above 47°C cause direct damage to erythrocytes by denaturation of the cytoskeletal protein, spectrin. This can occur in patients with extensive burns. Within 24 h of the burns, acute hemolytic anemia can develop with gross hemoglobinuria and spherocytes and schistocytes on the peripheral blood smear.

March hemoglobinuria. This type of hemolysis can occur in soldiers and joggers and in karate and conga-drumming enthusiasts. Red blood cell destruction is the result of direct trauma to the cells in the vessels of the feet or hands. These patients rarely become anemic but do have hemoglobinuria after strenuous exercise or activity.

Cardiopulmonary bypass. Patients who have been on cardiopulmonary bypass can develop a postperfusion syndrome that consists of acute intravascular hemolysis, leukopenia, and fever. This hemolysis is thought to result from the activation of complement as blood passes through the oxygenator.

There are many disease states that result in splenic enlargement (Table -5). The main function of the normal spleen is to filter defective red blood cells and foreign particles and to participate in antigen processing and antibody synthesis. When the spleen is enlarged, its activity is increased, a condition known as hypersplenism. Hypersplenism results in the sequestration of red blood cells as well as platelets and white blood cells. Unlike the platelets and white blood cells, which can survive within the spleen and be released back into the circulation, the sequestered red blood cells are not metabolically self-sufficient and are prematurely destroyed within the spleen. Hemolysis within the spleen is greatest when the splenomegaly is caused by inflammatory states or splenic congestion due to elevated portal pressure.

1)Leo PL, Cooper C, Songco C: Hemolytic uremic syndrome: Just another case of gastroenteritis? Am J Emerg Med 12:358, 1994.

2)Moake JL: Thrombotic microangiopathies: Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome, in Loscalzo J, Schafer AI (eds): Thrombosis and Hemorrhage. Cambridge, MA, Blackwell Scientific, 1994, pp 517–527.

3)Neild GH: Haemolytic-uremic syndrome in practice. Lancet 343:398, 1994.

4)Reubinoff BE, Sohenker JG: HELLP syndrome—a syndrome of hemolysis, elevated liver enzymes and low platelet count—complicating preeclampsia-eclampsia. Int J Gynaecol Obstet 36:95, 1991.

5)Schwartz RS, Berkman EM, Silberstein LE: The autoimmune hemolytic anemias, in Hoffman R, Benz EJ, Shattil SJ, et al (eds): Hematology: Basic Principles and Practice. New York, Churchill Livingstone, 1991, pp 422–441.

6)White CD, Weiss LD: Varying presentations of methemoglobinemia: Two cases. J Emerg Med 9:45, 1991.

I. Autoimmune hemolytic anemia (antibody-mediated)
     A. Warm antibodies
     B.   Cold antibodies
            1. Cold agglutin disease
            2. Paroxysmal cold hemoglobinuria
      C.   Drug-induced
II. Fragmentation hemolysis
      A. Microangiopathic hemolytic anemia (MAHA)
            1. Thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic
                syndrome (HUS)
            2. Pregnancy-associated hemolysis (HELLP)
            3. Disseminated intravascular coagulation (DIC)
            4. Malignancy-associated hemolysis
            5. Hemolysis in vasculitis
            6. Hemolysis in malignant hypertension
      B. Macrovascular hemolysis
            1. Due to abnormal cardiac valves
III. Direct toxic effects causing hemolysis
        A. Infections
        B. Other toxins–bites, copper
        C. Drug-induced oxidative hemolysis–methemoglobinemia
IV. Mechanical damage causing hemolysis
        A. Heat denaturation
        B. March hemoglobinuria
        C. Cardiopulmonary bypass
V. Anemia due to abnormal splenic function (hypersplenism)

Evans’
Syndrome TTP HUS DIC HELLP

Autoimmune hemolytic anemia           Present                 No                         No                        No                           No
Microangiopathic hemolytic anemia (MAHA)                No                         Prominent           Prominent               Often present                                                                Present
Coombs test                                          Positive                Negative               Negative              Negative                  Negative
Thrombocytopenia                                Present                 Prominent            Present                Present                    Present
Renal abnormalities                              No                         Mild                      Prominent           No                           No
Neurologic abnormalities                    No                         Prominent            No or mild          No                           No
Hepatic dysfunction                              No                         May have              May have             May have                 Prominent
Fever                                                      No                         Present                 Present                May have                 No
Coagulation studies                              Normal                 Normal                 Normal                Abnormal                Normal
Pregnancy-associated                           No                         Can be                   Can be                 Can be                     Always

*Disease descriptions here are based on presence of isolated disease without complications; individual patients often have other problems that make syndromes less readily identified.
Note: TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; DIC, disseminated intravascular coagulation; HELLP, hemolysis, elevated liver functions, low platelets.

Cause of Splenic
Enlargement Disease Example(s)

Splenic congestion due to                Cirrhosis, portal vein thrombosis,
elevated portal pressure                   splenic vein obstruction, conges-
               tive heart failure, Budd-Chiari
               syndrome
Infiltrative disease                             Leukemia, lymphoma, amyloidosis,
               polycythemia vera
Inflammatory states                          Rheumatoid arthritis, SLE, sarcoidosis
Infections                                           Bacterial endocarditis, infectious mono-
               nucleosis, military tuberculosis, malaria,
               schistosomiasis
Hereditary hemolytic anemias                        Sickle cell anemia
Acquired hemolytic anemias                           Autoimmune hemolytic anemia