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Diagnosis of hemolytic anemia in adults

Diagnosis of hemolytic anemia in adults
Author:
Wilma Barcellini, MD
Section Editor:
Robert A Brodsky, MD
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Dec 2022. | This topic last updated: Jul 08, 2022.

INTRODUCTION — Hemolytic anemia is defined as anemia due to a shortened survival of circulating red blood cells (RBCs) due to their premature destruction. There are numerous causes of hemolytic anemia, including inherited and acquired conditions, acute and chronic processes, and mild to potentially life-threatening severity. Occasionally the cause will be obvious from the history, physical examination, or findings on the peripheral blood smear, but often the ultimate diagnosis requires a synthesis of all of this information and additional laboratory testing.

The key clue that suggests that hemolysis is the cause of the anemia is an increase in the reticulocyte count that is not explained by recent bleeding or recent correction of iron or other nutrient deficiency, or other causes (pregnancy, acclimatization to altitude). Reticulocytosis should be expressed as an absolute number rather than a percentage, and it should be related to the hemoglobin and hematocrit values. Patients may also have evidence of RBC destruction including increased lactate dehydrogenase (LDH) and unconjugated bilirubin, decreased haptoglobin, and RBC shape changes on the peripheral blood smear.

The causes of hemolytic anemia and a diagnostic approach to the adult with unexplained hemolytic anemia are discussed here. Other topic reviews present general approaches to determining the cause of anemia and diagnosis of specific types of hemolytic anemia:

General approaches:

General approach, child – (See "Approach to the child with anemia".)

General approach, adult – (See "Diagnostic approach to anemia in adults".)

Subtypes of hemolytic anemia:

Immune-mediated:

Warm autoimmune hemolytic anemia (AIHA), child – (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis".)

Warm AIHA, adult – (See "Warm autoimmune hemolytic anemia (AIHA) in adults".)

Paroxysmal cold hemoglobinuria – (See "Paroxysmal cold hemoglobinuria".)

Cold agglutinin disease – (See "Cold agglutinin disease".)

Drug-induced hemolytic anemia – (See "Drug-induced hemolytic anemia".)

Heritable/genetic:

Hemoglobinopathies – (See "Prenatal screening and testing for hemoglobinopathy" and "Diagnosis of thalassemia (adults and children)" and "Diagnosis of sickle cell disorders".)

RBC membrane abnormalities – (See "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

RBC enzyme disorders – (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Pyruvate kinase deficiency".)

Congenital dyserythropoietic anemia (CDA) – (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Congenital dyserythropoietic anemia'.)

Other/less common:

Microangiopathic hemolytic anemia (MAHA) such as thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or drug-induced thrombotic microangiopathy (DITMA) – (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Hemolysis associated with blood transfusion – (See "Hemolytic transfusion reactions" and "Approach to the patient with a suspected acute transfusion reaction".)

Paroxysmal nocturnal hemoglobinuria (PNH) – (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

CONCEPTUAL FRAMEWORK — Causes of hemolysis can be categorized in various ways, including whether the abnormality is intrinsic or extrinsic to the red blood cell (RBC) (intracorpuscular versus extracorpuscular defects), whether the condition is inherited or acquired, whether the hemolysis is acute or chronic, whether the mechanism involves immune destruction due to antibodies (immune versus non-immune mechanism), and whether the hemolysis occurs in the vasculature or in the reticuloendothelial macrophages in the liver and spleen (intravascular versus extravascular hemolysis). Most of the inherited conditions are intracorpuscular, and most of the hemolysis by an immune mechanism is extravascular.

RBC turnover — The typical lifespan of a red blood cell (RBC) is approximately 110 to 120 days (four months). During this time, RBCs are subject to remarkable mechanical stresses as they traverse capillaries and splenic cords much smaller than their diameter, which requires repeated cycles of deformation and elastic recoil. This happens many millions of times over the course of the RBC lifespan.

The properties of the RBC that allow it to withstand this stress include a highly deformable membrane and underlying cytoskeleton, an optimal surface-to-volume ratio, and an enzymatic system that continually restores the proper redox environment of the cell. The optimal membrane surface is approximately 40 percent greater than that of a perfectly spherical cell of equivalent volume. RBC volume is regulated by ion pumps and channels that control the entry of water and cations including sodium, potassium, calcium, and magnesium. Metabolic enzymes generate ATP needed by the cation pumps; 2,3-BPG, which regulates oxygen uptake and release by hemoglobin; and reducing capacity (eg, glutathione, NADPH), to protect the oxygen-rich RBC from oxidant injury [1].

Normal aging of RBCs results in age-dependent RBC destruction. This typically occurs at a rate of approximately 1 percent of RBCs daily. The percentage of RBCs that are cleared from the circulation can be increased dramatically in hemolytic states, especially when an enlarged spleen is contributing to hemolysis [2]. (See "Red blood cell survival: Normal values and measurement".)

Hemolysis occurs when the RBC is unable to maintain its intact structure during passages through the circulation and reticuloendothelial system. Hemolysis by any mechanism stimulates a compensatory increase in RBC production via increased erythropoietin (EPO) secretion by the kidney. EPO in turn stimulates the bone marrow to produce more RBC precursors, which is followed within a few days by an increase in the reticulocyte count and within an additional one to two days by an increase in the hemoglobin level and hematocrit. (See "Regulation of erythropoiesis" and "Diagnostic approach to anemia in adults", section on 'Reticulocyte production'.)

The occurrence of anemia and its severity is determined by the balance between the extent of hemolysis and the capacity of the bone marrow to amplify RBC production. This balance is illustrated in the following calculations and clinical examples:

RBC survival and turnover rate can be calculated under steady state conditions (eg, when the secretion and response to EPO are intact) from the percentage of reticulocytes and the reticulocyte lifespan (RLS). The RLS increases proportionally as the hematocrit decreases and reticulocytes enter the circulation at progressively earlier stages in their maturation (when the hematocrit is lower, reticulocytes are released earlier from the bone marrow). In the steady state without anemia the typical RLS is approximately one day, after which the cell becomes a mature RBC. In severe anemia, reticulocytes can be released from the bone marrow as much as 1.5 days early ("shift cells"), giving a RLS of 2.5 days.

RBC survival – RBC survival (days) ≈ 100  ÷  [Reticulocytes (percent)  ÷  RLS (days)]

The RLS is 1.0, 1.5, 2.0, or 2.5 days at hematocrits of 45, 35, 25, and 15 percent, respectively (figure 1). For an individual without hemolysis who has a hematocrit of 40 and a reticulocyte count of 1 percent, RBC survival is calculated to be approximately 100 days (100 ÷ [1 ÷ 1] = 100). Corrections for the increased RLS can be made in patients with severe anemia to reflect the degree of reticulocytosis more accurately. (See 'High reticulocyte count' below.)

RBC turnover – The rate of RBC turnover is the reciprocal of RBC survival:

RBC turnover rate (percent/day)  =  100  ÷  RBC survival (days)

In adults, the normal rate of RBC turnover is approximately 1 percent per day, and the maximal sustainable capacity of the bone marrow to increase RBC production in an adult is approximately 5 percent per day (ie, approximately five times normal). In children, the bone marrow capacity can increase RBC production up to eight times normal.

Reticulocytosis (increase in the production of new RBCs, evidenced by appearance of reticulocytes in the peripheral blood) requires adequate iron and vitamins (B12, folate) for RBC production, along with a normally functioning bone marrow and adequate erythropoietin production. Reticulocytosis may not occur in individuals who are deficient in iron, vitamin B12, or folate; those with concomitant bone marrow abnormalities (from infection or primary bone marrow disorders); and those with inadequate erythropoietin production (from chronic kidney disease). (See 'Hemolysis without reticulocytosis' below.)

There are several free applications that calculate the reticulocyte index from the reticulocyte percentage and hematocrit, allowing identification of inadequate bone marrow compensation.

Additionally, a bone marrow responsiveness index (BMRI) has been calculated as ([absolute reticulocyte count] × [patient Hb/normal Hb]) to discriminate an anemia with effective erythropoiesis from those with ineffective erythropoiesis, such as in congenital dyserythropoietic anemia. The BMRI has been extended to other hemolytic conditions including autoimmune hemolytic anemia (AIHA) and hereditary spherocytosis [3-5]. (See 'High reticulocyte count' below.)

Additional information about the pathogenesis of specific types of hemolytic anemia are discussed in separate topic reviews. (See "Hereditary spherocytosis", section on 'Pathophysiology' and "Pathogenesis of paroxysmal nocturnal hemoglobinuria" and "Pathophysiology of thalassemia" and "Cold agglutinin disease", section on 'Pathogenesis' and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Pathogenesis'.)

Intracorpuscular versus extracorpuscular causes of hemolysis — Classifying hemolytic anemias according to whether the abnormality resides within the RBC itself (intracorpuscular) versus external to the RBC (extracorpuscular) is helpful because it incorporates the patient history; it also allows the clinician to determine whether the hemolysis is reversible, whether transfused RBCs will also be affected, and whether the treatment should be directed at a specific RBC defect or at another condition (eg, an infection or drug).

The table lists the causes of hemolytic anemia classified by whether the underlying cause is intracorpuscular or extracorpuscular (table 1).

Intracorpuscular causes include abnormalities of hemoglobin structure and function, membrane structure and function, and cytoplasmic composition including metabolic mechanisms controlling RBC volume and redox potential. (See 'Intracorpuscular' below.)

Extracorpuscular causes are those in which external factors lead to premature loss of membrane, membrane structural damage, volume gain or loss, changes in the solubility of hemoglobin, and changes in the redox state of cellular proteins. (See 'Extracorpuscular' below.)

Intracorpuscular — Intrinsic (intracorpuscular) RBC causes are those in which the altered properties of the RBC are responsible for hemolysis. These defects include the following three major categories [6,7]:

Hemoglobinopathies – Hemoglobinopathies include sickle cell disease (SCD), thalassemia, and unstable hemoglobin variants. These affect the solubility of hemoglobin. When hemoglobin becomes insoluble, it can precipitate and damage the RBC membrane. Some abnormal hemoglobins are less able to recover from oxidant challenge, leading to the formation of Heinz bodies (denatured hemoglobin), as in Hgb Köln. (See "Diagnosis of sickle cell disorders" and "Diagnosis of thalassemia (adults and children)" and "Unstable hemoglobin variants".)

RBC membrane/cytoskeletal disorders – Disorders that affect the structure of the RBC membrane and underlying cytoskeleton include hereditary spherocytosis (HS), hereditary elliptocytosis (HE), and hereditary stomatocytosis (HSt). These conditions may be associated with a suboptimal membrane surface-area-to-volume ratio (eg, HS) or a defect in a membrane protein with ion channel function such as Band 3 that may alter salt and water handling, leading to altered surface-membrane-to-volume ratio. (See "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

End-stage liver disease or cirrhosis can lead spur cell anemia with severe hemolysis resulting from altered lipid metabolism. The membrane changes render erythrocytes less flexible and prone to hemolysis. Spur cell anemia due to end-stage liver disease has a poor prognosis and is often fatal within a few weeks if liver transplantation is not performed.

RBC metabolic abnormalities – Metabolic abnormalities include deficiency of glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PK). These defects affect the metabolic capacity of the RBC, which promotes solute transport and recovery from oxidant damage. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Pyruvate kinase deficiency" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

The vast majority of the intracorpuscular RBC causes are inherited, and conversely, the majority of the inherited disorders are intracorpuscular. Exceptions include rare conditions such as paroxysmal nocturnal hemoglobinuria (PNH), an acquired intracorpuscular abnormality caused by expansion of a clone of RBCs that are hypersensitive to complement lysis; acquired alpha thalassemia in the setting of myelodysplasia, an acquired intracorpuscular abnormality caused by expansion of a clone of RBCs that harbor a genetic variant in the gene that encodes alpha globin; and hereditary TTP, an inherited condition in which abnormalities in the microvasculature lead to episodes of microangiopathic hemolysis. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)" and "Hereditary thrombotic thrombocytopenic purpura (TTP)".)

Extracorpuscular — Extrinsic (extracorpuscular) causes are those in which the RBCs are normal but are destroyed due to mechanical, immunologic, infectious, or metabolic/oxidant damage. These abnormalities are almost always acquired. The major extracorpuscular causes of hemolysis include:

Antibody-mediated – Antibodies directed against RBC membrane components (eg, autoimmune hemolytic anemia [AIHA], alloimmune hemolytic anemia, acute hemolytic transfusion reaction [AHTR], delayed hemolytic transfusion reaction [DHTR], some drug-induced hemolytic anemias). (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Pathogenesis' and "Cold agglutinin disease", section on 'Pathogenesis' and "Immunologic transfusion reactions" and "Drug-induced hemolytic anemia".)

Less common antibody-mediated disorders include mixed AIHA (with concomitant warm and cold autoantibodies) and paroxysmal cold hemoglobinuria (PCH). (See "Paroxysmal cold hemoglobinuria" and "Warm autoimmune hemolytic anemia (AIHA) in adults".)

Administration of Rho(D) immune globulin to an RhD-positive individual (eg, for treatment of immune thrombocytopenia) or administration of intravenous immune globulin (IVIG) can also promote antibody-mediated RBC destruction. (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'Anti-D as an alternative to IVIG' and "Intravenous immune globulin: Adverse effects", section on 'Hemolysis'.)

Severe forms of AIHA are associated with solid organ transplant and hematopoietic stem cell transplantation.

Drug induced hemolytic anemia – Several drugs may induce hemolytic anemia, including historically well-described drugs and newer drugs such as immune checkpoint inhibitors. (See "Drug-induced hemolytic anemia".)

Paroxysmal nocturnal hemoglobinuria (PNH) – PNH is caused by a somatically-acquired variant in the phosphatidylinositol glycan anchor biosynthesis, class A (PIGA) gene, resulting in a deficiency of glycosylphosphatidyl-inositol-anchored proteins (GPI-AP), including complement regulatory proteins CD55 and CD59. The disease is characterized by chronic intravascular hemolysis, increased susceptibility to infections, bone marrow failure, and deep vein thrombosis (DVT). (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

Hypersplenism – Stasis, trapping, and destruction of RBC in an enlarged spleen (hypersplenism). The spleen is also the major site of removal of warm antibody-coated red cells and most of the intracorpuscular defects. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

Mechanical trauma – Mechanical trauma to the RBCs secondary to high velocity jets (malfunctioning cardiac valves, ventricular assist devices); fibrin stands across vessels that shear RBCs in disseminated intravascular coagulation (DIC); or platelet microthrombi in TTP, hemolytic uremic syndrome (HUS), or drug-induced thrombotic microangiopathy (DITMA). (See "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Fragmentation'.)

Oxidant exposure – Exposure to compounds with oxidant potential (eg, aniline dyes, dapsone, phenazopyridine) in individuals with an underlying metabolic defect such as G6PD deficiency, congenital methemoglobinemia, or unstable Hgb variants (eg, sulfonamides), as well as those without an underlying defect. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Unstable hemoglobin variants" and "Methemoglobinemia", section on 'Acquired causes'.)

Infectious diseases – Destruction of RBC by pathogens such as malaria, babesiosis, bartonellosis, or clostridium perfringens (picture 1). (See "Non-immune (Coombs-negative) hemolytic anemias in adults".)

Toxins and poisons – Less common causes include snake and insect bites, certain toxins, thermal burns, and copper poisoning (eg, Wilson disease). Although rare, Wilson disease should be considered in every child and young adult presenting with hemolytic anemia, since this complication can be fatal [8]. (See "Drug-induced hemolytic anemia".)

Immune versus non-immune — Immune hemolysis generally refers to RBC destruction by antibodies and/or complement proteins bound to the RBC surface. Immune hemolysis is characterized by a positive direct antiglobulin test (DAT; also called direct Coombs test) and/or a positive indirect antiglobulin test (also called indirect Coombs test, or, in the setting of pretransfusion testing, referred to as an antibody screen).

Site of RBC destruction — The site of hemolysis can be intravascular (within the circulation) or extravascular (via the reticuloendothelial macrophages and monocytes of the liver, spleen, bone marrow, and lymph nodes). The site often determines the clinical severity and immediate management needs of the patient. This is because the site of RBC destruction determines whether the byproducts of RBC destruction such as free hemoglobin will be routed through the reticuloendothelial system or will be liberated directly into the circulation.

If products of hemolysis are liberated into the circulation, they will appear as free serum hemoglobin or heme and urinary hemoglobin, heme, or hemosiderin. The serum and urine may be pink or darker brown. (See 'Diagnostic approach' below.)

Free hemoglobin or heme in the circulation can cause significant damage to the kidney, causing acute renal failure, and can trigger DIC or increase the risk of thrombosis [9,10]. (See 'Immediate management issues before the cause is identified' below and 'Thrombotic complications' below.)

The site of RBC destruction is one of the main determinants of clinical severity. As an example, RBC destruction in AIHA is generally extravascular, as reticuloendothelial macrophages progressively phagocytize small pieces of RBC membrane that are opsonized with autoantibodies. In contrast, in hemolysis from mechanical trauma (eg, prosthetic heart valve, marching, bongo drums), the lysis can be immediate and complete within the circulation, before the RBCs reach the reticuloendothelial system. Likewise, in conditions in which the membrane attack complex (MAC) of complement creates a hole in the RBC membrane (eg, paroxysmal nocturnal hemoglobinuria [PNH], paroxysmal cold hemoglobinuria [PCH], and severe forms of cold agglutinin disease) a large component of intravascular hemolysis is likely. Generally, extravascular hemolysis is less severe than intravascular one.

However, in many cases there is a component of both intravascular and extravascular hemolysis, especially when hemolysis is severe. The site of RBC destruction thus is helpful in determining the cause of hemolysis and the need for more aggressive therapy but typically is not diagnostic of a specific condition.

Intravascular hemolysis

Definition and clinical findings – Intravascular hemolysis refers to hemolysis that occurs primarily within the vasculature. This occurs when there is a considerable amount of structural damage to the RBC membrane (eg, mechanical shearing, complement MAC) or when the reticuloendothelial system becomes overwhelmed [11]. When severe, intravascular hemolysis is characterized by pink or brown serum and dark urine with free serum and urine hemoglobin [12]. The pink color is due to oxyhemoglobin and the brownish color is due to the oxidized form, methemoglobin.

Free hemoglobin binds to haptoglobin, and the hemoglobin-haptoglobin complex is rapidly removed by the liver, leading to a reduction in plasma haptoglobin, often to undetectable levels (see 'High LDH and bilirubin; low haptoglobin' below). Dimers of alpha-beta globin that are not bound by haptoglobin are small enough (molecular weight 34,000 daltons) to be filtered by the glomerulus and appear in the urine as hemoglobinuria.

Urine hemosiderin may be seen several days after an episode of intravascular hemolysis, as renal tubular cells take up the heme, degrade it, store it as hemosiderin, and eventually are shed into the urine. Urine hemosiderin is detected using Prussian blue staining (iron stain) of the urine sediment. (See 'Immediate management issues before the cause is identified' below.)

Causes – Causes of intravascular hemolysis include the following (table 1):

Direct trauma, as in bongo drummers and march hemoglobinuria (runners' or foot-strike hemolysis)

Shear stress, as in defective mechanical heart valves

Heat damage, as in thermal burns

Complement-induced lysis, as in paroxysmal nocturnal hemoglobinuria (PNH)

Osmotic lysis following infusion of hypotonic solutions

Lysis from bacterial toxins (eg, clostridial sepsis)

Lysis from exposure to high concentrations of copper

Thrombotic microangiopathies (TMA) including TTP, HUS, or drug-induced TMA

Acute hemolytic transfusion reaction

Administration of Rho(D) immune globulin to RhD-positive individuals, such as for treatment of immune thrombocytopenia (ITP)

Immune hemolysis that overwhelms the reticuloendothelial system

Extravascular hemolysis — Extravascular hemolysis refers to hemolysis that occurs primarily via macrophages of the reticuloendothelial system in the liver, spleen, bone marrow, and lymph nodes. Severely damaged RBCs, especially those coated with complement, are primarily destroyed in the liver, an organ that receives a larger proportion of the cardiac output than the spleen. Poorly deformable RBCs such as spherocytes or sickled cells are primarily destroyed in the spleen, in the cords of Billroth. These unique vascular channels end blindly, unlike other vascular channels in the body. The only way for a RBC with a diameter of 7 to 8 microns to escape from these cords and return to the general circulation is to deform sufficiently to pass through 2 to 3 micron slits in the walls of the cords (picture 2). Senescent or damaged RBCs remain in the cords and are phagocytosed by monocytes and macrophages.

RBCs destroyed in the spleen are usually phagocytosed in their entirety and digested within phagosomes of macrophages. Most of the hemoglobin is degraded to release heme, with each molecule of heme converted to equimolar amounts of biliverdin, iron, and carbon monoxide via the action of microsomal heme oxygenase [13-16].

The biliverdin is immediately reduced to unconjugated bilirubin by the enzyme biliverdin reductase and is released into the plasma. (See "Bilirubin metabolism".)

Under normal circumstances, the iron is efficiently released from macrophages into the plasma, mediated by the iron export protein ferroportin. It is transported to the bone marrow and used in the production of new RBCs. In patients with the anemia of chronic disease/inflammation, iron release is impaired due to the action of hepcidin, resulting in impaired iron mobilization for new RBC production. (See "Regulation of iron balance" and "Anemia of chronic disease/anemia of inflammation", section on 'Hepcidin (primary regulator of iron homeostasis)'.)

The carbon monoxide formed from heme breakdown initially binds to the hemoglobin of intact RBCs as carboxyhemoglobin. It is subsequently released in the pulmonary capillaries and excreted into the expired air.

LIST OF CAUSES — The major causes of hemolytic anemia include:

Autoimmune

Warm autoimmune hemolytic anemia (AIHA)

Cold agglutinin disease (CAD)

Paroxysmal cold hemoglobinuria (PCH)

Congenital hemolytic anemias

Alpha thalassemia

Beta thalassemia

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

Hereditary spherocytosis (HS)

Hereditary elliptocytosis (HE)

Hereditary stomatocytosis (HSt)

Hereditary xerocytosis (HX)

Pyruvate kinase (PK) deficiency

Sickle cell disease

Unstable hemoglobin variants

Disseminated intravascular coagulation (DIC)

Drug-induced hemolytic anemias

Drug-induced immune hemolysis

Drug-induced hemolysis associated with G6PD deficiency

Drug-induced thrombotic microangiopathy (DITMA)

Transfusion-related hemolysis

Acute hemolytic transfusion reaction (AHTR)

Delayed hemolytic transfusion reaction (DHTR)

Other conditions

Clostridial sepsis

Mechanical hemolysis from aortic stenosis or prosthetic heart valve

Mechanical hemolysis from marching or bongo drumming

Osmotic lysis from hypotonic infusion

Paroxysmal nocturnal hemoglobinuria (PNH) receiving anti-complement therapy

RBC parasite (eg, malaria, Babesia)

Snake bite

Thrombotic microangiopathy (TMA) such as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS)

Spur cell anemia from end-stage liver disease

These can be classified in a number of ways, including mechanism (intracorpuscular versus extracorpuscular; immune versus non-immune), site of hemolysis (intravascular versus extravascular), and acuity/duration (acute versus chronic). (See 'Conceptual framework' above.)

DIAGNOSTIC APPROACH

Overview of the evaluation — Some patients with especially severe anemia (hemoglobin <6 g/dL) or other worrisome findings may require immediate life-saving interventions before hemolysis has been diagnosed and/or the cause identified [17]. Importantly, life-saving interventions such as transfusion for severe anemia; plasmapheresis for possible thrombotic thrombocytopenic purpura (TTP); or vigorous hydration and diuresis for an acute transfusion reaction should not be withheld while confirming the diagnosis. (See 'Immediate management issues before the cause is identified' below.)

Recognizing and diagnosing hemolytic anemia in patients with a classic presentation is straightforward. However, for many patients, the exact timing of the onset of anemia may be unclear, the red blood cell (RBC) morphology may be unrevealing, or there may be several possible diagnoses under consideration. Other patients may have more than one cause of anemia, one of which may blunt the normal reticulocyte response to hemolysis.

The diagnosis of hemolytic anemia is suspected in a patient with chronic or new onset symptoms of anemia (eg, fatigue, weakness, shortness of breath), a low hemoglobin level, and an increased reticulocyte count that is not explained by accelerated RBC production due to recent bleeding; repletion of iron, vitamin B12, folate, or copper; or administration of erythropoietin. Reticulocytosis (expressed as absolute number) may be absent or inadequate to Hb levels in conditions with lack of bone marrow compensation.

Additional laboratory testing is often used to confirm the diagnosis of hemolytic anemia and to determine the likely cause. Testing to confirm hemolysis may be done simultaneously (increased unconjugated bilirubin and lactate dehydrogenase [LDH], and decreased haptoglobin) with testing to determine the cause, or sequentially. (See 'Laboratory confirmation of hemolysis' below and 'Post-diagnostic testing to determine the cause' below.)

Once the diagnosis of hemolytic anemia is relatively certain, our approach to determining the cause and providing immediate interventions is as follows (algorithm 1):

Rapidly identify and triage individuals with potentially life-threatening conditions that require urgent involvement of a specialist (often a hematologist or transfusion medicine physician), such as a thrombotic microangiopathies (TMA), disseminated intravascular coagulation (DIC), or an acute transfusion reaction.

Obtain a thorough history and physical examination targeted to potential causes of hemolysis.

If the patient has a clear history of life-long anemia or classic findings on the peripheral blood smear that suggest one of the hereditary hemolytic anemias due to hemoglobinopathy, metabolic defect, or membrane defect, pursue specific testing for the likely condition.

For other patients, obtain a direct antiglobulin (Coombs) test (DAT) to determine whether the anemia is immune or non-immune.

If the DAT is positive, immune hemolysis is the likely diagnosis. Some patients may require additional testing to identify associated conditions.

If the DAT is negative, perform specific diagnostic tests suggested by the patient history and physical examination. These may be obtained sequentially or simultaneously depending on the urgency of the evaluation.

Other laboratory testing that reveals one of the specific causes of hemolysis is also strongly supportive and in many cases sufficient for diagnosis (see 'Post-diagnostic testing to determine the cause' below); in some cases this may be available at the time of the initial evaluation and in others it may be obtained as part of the evaluation.

Hematologic consultation should be obtained in virtually all patients with a new onset of hemolysis, since sudden and life-threatening worsening of anemia may occur, requiring urgent coordination between treating clinicians, clinical pathologists, and transfusion medicine or blood bank personnel for appropriate management. Hemolysis may also be the first sign of an underlying systemic disorder (eg, thrombotic thrombocytopenic purpura, systemic lupus erythematosus, chronic lymphocytic leukemia) and may require an urgent intervention to prevent death or disease-related complications.

History and physical examination — A systematic approach, starting with a thorough history and physical examination is the cornerstone of the evaluation. Helpful clues from the history and physical examination include the following, if present:

Rapid onset of symptoms of anemia in the absence of bleeding is consistent with brisk hemolysis.

Jaundice is consistent with brisk hemolysis that overwhelms the capacity of the reticuloendothelial system to convert heme to storage iron. Mild jaundice is also present in chronic hemolysis.

Dark urine and highly increased LDH is consistent with intravascular hemolysis.

Recent blood transfusion suggests possible acute hemolytic transfusion reaction; transfusion in the previous four weeks also raises the possibility of a delayed hemolytic transfusion reaction.

Initiation of a new medication with potential for causing hemolysis suggests possible drug-induced etiology.

History of hemolytic anemia or unexplained anemia in family members suggests an inherited disorder; this is more likely if multiple first degree family members are affected.

History of pigmented gallstones or presence of gallstones implies chronic hemolysis that overwhelms the reticuloendothelial system.

Splenomegaly suggests expansion of the reticuloendothelial capacity.

However, the absence of these features does not eliminate the possibility of hemolytic anemia. Patients with chronic compensated hemolytic anemia may have minimal to no symptoms of anemia, a negative family history, no new drugs, and no evidence of jaundice or splenomegaly.

Laboratory confirmation of hemolysis — There is no single specific diagnostic test for hemolytic anemia. However, most experts consider the diagnosis to be accepted if most of the following findings are present:

Anemia that is not due to another obvious cause.

Increased reticulocyte count that is not explained by accelerated RBC production due to recent bleeding; repletion of iron, vitamin B12, folate, or copper; or administration of erythropoietin.

Signs of RBC destruction such as increased lactate dehydrogenase (LDH), low haptoglobin, increased unconjugated bilirubin.

Additional test results that are consistent with a specific cause of hemolytic anemia (schistocytes or spherocytes on peripheral blood smear; free hemoglobin or pink serum; newly positive direct antiglobulin [Coombs] test [DAT]; hemoglobin analysis demonstrating an abnormal hemoglobin) are highly supportive and in some cases diagnostic if present, but their absence does not exclude the possibility of hemolysis. (See 'Post-diagnostic testing to determine the cause' below.)

CBC/blood smear review — All patients for whom the diagnosis of hemolytic anemia is considered will have had a complete blood count. In the majority of cases, this will include a white blood cell (WBC) count, platelet count, and RBC indices. Hemolysis will be associated with some degree of anemia in the majority of cases, especially when it first occurs, when there is a delay in the production of new RBCs to compensate for hemolysis, and, if it is severe, when the bone marrow cannot fully compensate. (See 'RBC turnover' above.)

Review of the peripheral blood smear is an extremely valuable tool for determining the presence and cause of hemolytic anemia. In many cases, findings on the blood smear are essential to providing life-saving treatment. Examples include:

Thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP) or drug-induced TMA (DITMA) have microangiopathic hemolysis with schistocytes.

Infections such as malaria or Babesia have visible microorganisms on a thick smear.

Bite cells suggest hemolysis due to an oxidant drug in a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Microspherocytes suggest warm autoimmune hemolytic anemia (warm AIHA) or drug-induced hemolytic anemia.

Spherocytes, elliptocytes, and stomatocytes suggest hereditary RBC membrane disorders.

RBC agglutination suggests cold-agglutinin disease.

Abundant spur cells in conjunction with severe liver disease suggest spur cell anemia.

An initial evaluation for the cause of anemia may have already occurred in some individuals for whom the likelihood of hemolysis was thought to be low or for whom hemolysis was not considered initially. The discussion herein presumes that other common causes of anemia have been evaluated or excluded based on the clinical history, examination, or laboratory testing. (See "Diagnostic approach to anemia in adults".)

High reticulocyte count — A high reticulocyte count implies an accelerated production of RBCs in the bone marrow. Increased reticulocytes is a typical finding in hemolytic anemia but is not specific for hemolysis; the bone marrow can also increase RBC production in response to bleeding, nutrient repletion (eg, vitamin B12, folic acid, iron), or erythropoietin administration. The absence of reticulocytosis does not eliminate the possibility of hemolysis, as some individuals have concomitant bone marrow suppression or reduced bone marrow function that interferes with production of reticulocytes. (See 'Hemolysis without reticulocytosis' below.)

The degree of reticulocytosis can be estimated from the peripheral blood smear, as reticulocytes are larger than mature RBCs, lack central pallor, and have a bluish tint (polychromasia) (picture 3). The count can be quantified from a manual count on a peripheral blood smear stained for reticulin (picture 4) or by an automated counter. Many counters automatically provide the reticulocyte count. (See "Automated hematology instrumentation", section on 'Automated counting of reticulocytes'.)

Reticulocytes can be expressed as a percentage of RBCs or as an absolute number; these numbers can be corrected for the degree of anemia and the lifespan of the reticulocytes in the circulation. In cases of markedly increased reticulocytosis or failure of the bone marrow to produce reticulocytes, any of these measures is likely to be a relatively good indicator of the degree of reticulocytosis. However, the corrections make the count more accurate, and in some cases are essential to determining whether reticulocytosis is truly increased:

Reticulocyte percentage – The reticulocyte percentage conveys the percentage of all RBCs that are reticulocytes. Since it is relative to the total RBC count, it may be artificially increased in severe anemia and artificially decreased if the patient is not anemic. The normal reticulocyte percentage in a patient without hemolysis is in the range of 1 to 2 percent. In patients with hemolysis and an otherwise intact bone marrow, reticulocyte percentage is at least 4 to 5 percent, and often considerably higher. This was illustrated in case series such as the following:

A series of 109 individuals with autoimmune hemolytic anemia, in which the median reticulocyte percentage at diagnosis was 9 percent [18]. However, the range was large (0.4 to 92 percent) and approximately one-fifth had a reticulocyte percentage <4 percent.

A subsequent series of 308 patients with AIHA found that reticulocytopenia was associated with a severe anemia (Hb <6 g/dL), indicating an inadequate bone marrow compensation that possibly contributed to the clinical severity [4,5].

Corrected reticulocyte count – The reticulocyte percentage is a relative number. For any given number of reticulocytes, a lower the total number of RBCs (the denominator) will raise the percentage of these RBCs that are reticulocytes. Thus, the reticulocyte percentage can be multiplied by the patient's hematocrit divided by a normal hematocrit (eg, 45 percent) to give a corrected reticulocyte percentage. As an example, if reticulocytes are 10 percent in a patient with a hematocrit of 22.5 percent, the corrected count can be calculated as follows:

10 percent x (22.5 percent ÷ 45 percent) = 10 percent x 0.5 = 5 percent.

Absolute reticulocyte count – The absolute reticulocyte count has the advantage of accurately reflecting the degree of reticulocytosis regardless of the degree of anemia and the number of RBCs [19,20]. The normal absolute reticulocyte count is between 25,000 to 75,000/microL (ie, approximately 1 percent of an absolute RBC count of 5,000,000 cells/microL). An example of the utility of this measure is a severely anemic patient with a hematocrit of 18 percent, a RBC count of 2,000,000/microL, and reticulocyte count of 3 percent. While the reticulocyte count of 3 percent appears high, the absolute reticulocyte count is only 60,000/microL (ie, 3 percent of 2,000,000), which is in the normal range and does not reflect an adequate bone marrow compensation.

Corrected absolute reticulocyte count – The more severe the anemia, the younger the reticulocytes are when they are released into the circulation, and hence the longer their lifespan in the circulation. The absolute reticulocyte count can be corrected for the reticulocyte lifespan (RLS), also called the reticulocyte maturation time (RMT). The RLS is 1.0, 1.5, 2.0, or 2.5 days at hematocrits of 45, 35, 25, and 15 percent, respectively (figure 1). (See 'RBC turnover' above.)

In a patient with a hematocrit of 18 percent and an absolute reticulocyte count of 60,000/microL, the RLS is approximately 2.5 days; thus, the corrected absolute reticulocyte count is (60,000 ÷ 2.5 = 24,000/microL), which is inappropriately low.

Reticulocyte production index (RPI) – The RPI makes corrections for both the hematocrit and the reticulocyte lifespan (calculator 1):

RPI  =  Reticulocytes (percent)  x  (HCT ÷ 45)  x  (1 ÷ RMT)

The RPI in an individual without hemolysis or blood loss is approximately 1. A value in excess of 2 to 3 is considered increased, whereas a value <2 in a patient with anemia is considered inappropriately low [18].

There are several free applications that calculate the reticulocyte index from the reticulocyte percentage and hematocrit, allowing the identification of inadequate bone marrow compensation. A bone marrow responsiveness index (BMRI) has been calculated as [(absolute reticulocyte count) × (patient Hb/normal Hb)] to discriminate an anemia with effective erythropoiesis from those with ineffective erythropoiesis, such as congenital dyserythropoietic anemia (CDA). The BMRI has then been extended to other hemolytic conditions including AIHA and hereditary spherocytosis [3-5].

The use of the reticulocyte percentage and absolute reticulocyte count are discussed in more detail separately. (See "Diagnostic approach to anemia in adults".)

High LDH and bilirubin; low haptoglobin — The other major typical finding in hemolytic anemia aside from reticulocytosis is evidence of RBC destruction from breakdown products. Hemolysis releases lactate dehydrogenase (LDH) and hemoglobin from RBCs. Hemoglobin is bound by circulating haptoglobin, which facilitates heme recycling; hemoglobin is converted to bilirubin as part of the degradation and heme recycling process (figure 2).

Thus, high LDH and bilirubin and low haptoglobin are all consistent with hemolysis as summarized in the table (table 2). Caveats include:

LDH and bilirubin – High LDH and bilirubin are not very specific for hemolysis, as there are numerous other possible causes of these abnormalities (table 3). When bilirubin elevation is due to hemolysis, the elevation is predominantly in the indirect (unconjugated) bilirubin. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

Haptoglobin – The normal range for serum haptoglobin is wide. A low haptoglobin is likely to be due to hemolysis, and an undetectable haptoglobin level is almost always due to hemolysis. In a series of 100 patients with various medical conditions, a haptoglobin level of 25 mg/dL provided the best cutoff between hemolytic and non-hemolytic disorders [21]. The sensitivity and specificity of a haptoglobin ≤25 mg/dL were 83 and 96 percent. However, a normal or increased haptoglobin does not eliminate the possibility of hemolysis because haptoglobin is an acute phase reactant that can be increased in the setting of inflammation (see "Acute phase reactants"). Other causes of low haptoglobin include hepatic insufficiency, abdominal trauma, and congenital ahaptoglobinemia [22].

In one series of reports, the combination of an increased serum LDH and a reduced haptoglobin was 90 percent specific for diagnosing hemolysis, while the combination of a normal serum LDH and a serum haptoglobin >25 mg/dL was 92 percent sensitive for ruling out hemolysis [21,23].

Immediate management issues before the cause is identified — Certain management issues may need to be addressed before the specific cause of hemolytic anemia is definitively established. Importantly, life-saving interventions should not be delayed while awaiting the results of diagnostic testing.

Rate of hemoglobin decline – It is important to have a sense of the rate of decline in the hemoglobin level to manage the patient properly. Individuals with a very slow decline in hemoglobin may be able to adapt to and tolerate severe anemia without end organ ischemia, whereas those with brisk hemolysis and a rapid drop in hemoglobin level may be quite symptomatic and require more aggressive treatment and accelerated evaluation, even if the absolute hemoglobin level is not that low.

Transfusion – Patients with severe anemia (hemoglobin <6 g/dL, higher hemoglobin in some cases with heart or lung disease) should be transfused with RBCs, especially if there is active bleeding, symptoms of organ ischemia, or ongoing brisk hemolysis. It may be appropriate to obtain a pre-transfusion blood sample that can be stored for later analysis, particularly if an inherited cause of hemolytic anemia is suspected. For patients with possible immune-mediated hemolysis for whom crossmatch compatible blood cannot be identified, blood designated for immediate release can be transfused. This and other alternatives such as RBC genotyping or autoadsorption are discussed in more detail separately. (See "Transfusion in individuals with complex serologies on pretransfusion testing", section on 'Identification of blood for transfusion' and "Pretransfusion testing for red blood cell transfusion", section on 'Emergency release blood for life-threatening anemia or bleeding'.)

Plasma exchange – In cases of presumed thrombotic microangiopathy (TMA; ie, microangiopathic hemolytic anemia and thrombocytopenia), diagnostic testing may take hours to days. The use of therapeutic plasma exchange for a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP) and information regarding the diagnostic evaluation are presented separately. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Complement blockade – C5 inhibition with eculizumab or ravulizumab should be considered in patients with thrombotic microangiopathy (TMA) with ADAMTS13 activity >10 percent and suspected complement-mediated TMA (CM-TMA) or paroxysmal nocturnal hemoglobinuria (PNH). (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS", section on 'Role of terminal complement blockade' and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)

Proximal complement inhibition (anti C1s) with sutimlimab is used in cold agglutinin disease (CAD). (See "Cold agglutinin disease".)

Hydration and hemodynamic support – For individuals with apparent severe intravascular hemolysis (eg, acute hemolytic transfusion reaction [AHTR] due to ABO incompatible transfusion), free hemoglobin in the circulation can cause renal failure, hypotension, and disseminated intravascular coagulation. Aggressive hydration and other supportive measures are discussed separately. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Suspected acute hemolytic reaction' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment' and "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)

Post-diagnostic testing to determine the cause

Obvious cause- proceed to specific testing — In some of the obvious/classic presentations of hemolytic anemia, it may make sense to proceed directly to specific diagnostic testing (algorithm 1):

Anemia and thrombocytopenia with numerous schistocytes (picture 5) on the blood smear suggests a TMA such as TTP, HUS, or drug-induced TMA. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Rapid onset of fever, back pain, dark urine, and pink plasma following a blood transfusion suggests an AHTR. (See "Hemolytic transfusion reactions", section on 'Acute hemolytic transfusion reactions' and "Approach to the patient with a suspected acute transfusion reaction", section on 'Acute hemolytic transfusion reaction (AHTR)'.)

Lifelong anemia, splenomegaly, and RBC morphology typical of one of the inherited disorders such as spherocytes (picture 6), elliptocytes (picture 7), or stomatocytes (picture 8) suggests a congenital RBC membrane/cytoskeletal defect. (See "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

A blood smear characteristic of sickle cell disease (picture 9) or thalassemia (picture 10) in a patient with classic findings suggests a hemoglobinopathy. (See "Diagnosis of sickle cell disorders" and "Diagnosis of thalassemia (adults and children)".)

A rapid drop in hemoglobin level after exposure to a drug known to cause hemolysis suggests drug-induced hemolytic anemia, which may be due to glucose-6-phosphate dehydrogenase (G6PD) deficiency (table 4). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Hemoglobinuria associated with pancytopenia or acute onset thrombosis (especially abdominal vein or central venous sinus thrombosis) suggests paroxysmal nocturnal hemoglobinuria (PNH), which is evaluated with flow cytometry. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Flow cytometry/FLAER'.)

Cause not obvious - start with Coombs test — In some cases, the cause of hemolysis may be less clear. As examples, the presence of numerous spherocytes could indicate autoimmune hemolytic anemia or hereditary spherocytosis.

For such individuals, we use the direct antiglobulin (Coombs) test (DAT) to distinguish between hemolysis due to an immune mechanism (eg, AIHA) and hemolysis that is less likely to be due to an immune mechanism (algorithm 1).

The DAT is used to determine whether patient RBCs are coated with IgG, complement, or both. The assay is performed by taking washed patient RBCs and incubating them with anti-human IgG and anti-human C3d antibodies. In AIHA, anti-human antibodies and/or anti-C3d antibodies form bridges (agglutination) between red cells by binding the human antibodies on the patient's red cells. Agglutination is graded visually as negative to 4+, as is illustrated in the figure (figure 3). Less frequently, RBC may be coated with IgM or IgA, and their presence is revealed by specific antisera.

A DAT should be obtained in all patients who present with anemia, laboratory evidence of hemolysis (ie, increased lactate dehydrogenase, increased indirect/unconjugated bilirubin, reduced haptoglobin), and an absence of schistocytes on the peripheral blood smear. It is important to distinguish between warm-AIHA and cold agglutinin disease. (See "Cold agglutinin disease".)

Coombs test interpretation

Warm AIHA – Warm AIHA is generally due to an IgG that binds to RBCs at a temperature around 37°C, and the DAT is typically positive with anti-IgG antisera or IgG plus complement at low titer.

Cold agglutinin disease – Cold agglutinin disease is due to an IgM autoantibody that has an optimum temperature of reaction at 4° C (thermal range 4 to 34°C) and strongly activates complement. The DAT is positive with anti-complement antisera and a high titer of cold agglutinins is found in the serum (picture 11). Typically, spontaneous agglutination of RBCs occurs at room temperature, sometimes invalidating automated blood counts and raising the diagnostic suspect.

Mixed AIHA – Mixed forms of AIHA show common characteristics of warm and cold autoantibodies, with a DAT positive for both IgG and complement, along with high titer cold agglutinins. As an exception, paroxysmal cold hemoglobinuria (PCH) is due to an IgG that binds to RBCs in the cold but causes severe intravascular hemolysis at 37°C. PCH is diagnosed with the Donath-Landsteiner test. (See "Paroxysmal cold hemoglobinuria", section on 'Evaluation and diagnosis'.)

Atypical forms – Atypical AIHA forms include:

IgA driven – IgA-driven cases are due to an IgA antibody, which is frequently but not always associated with an IgG.

Warm IgM – AIHAs due to IgM with a thermal range close to body temperature (warm IgM) are rare and cause extremely serious AIHA that is potentially fatal. These IgM antibodies are able to strongly activate complement in vivo and cause massive intravascular hemolysis. They may appear weakly positive for complement on the DAT or may be DAT negative, possibly delaying diagnosis.

DAT-negative – The DAT can be performed with various methods, the most classic being the test tube with polyspecific and monospecific antisera (anti-IgG, anti-complement, anti-IgA, and anti-IgM). More sensitive tests can reveal smaller amounts of antibodies bound to RBCs; these tests include microcolumn and solid phase tests; these are widely used in routine diagnosis. More sophisticated methods involve washing RBCs with low ionic strength solutions (LISS), improving the ability to detect low affinity autoantibodies, and experimental tests such as immunoradiometric assays, ELISA, and cytometry. Despite these methodological improvements, 5 to 10 percent of AIHAs remain DAT-negative, making diagnosis especially challenging.

False-positive DAT – The DAT may be falsely positive after the administration of various immunoglobulin-containing therapies:

Intravenous immune globulin (IVIG)

RhD immune globulin

Antithymocyte globulin

Daratumumab

The DAT may also be falsely positive in diseases with elevated serum gamma globulins or paraproteins.

Moreover, the DAT may be positive due to alloantibodies in patients who have recently been transfused, such as during delayed hemolytic transfusion reactions (DHTRs) and in the hemolytic disease of the fetus and newborn (HDFN).

The DAT may be positive without clinical evidence of AIHA in a small percentage of healthy blood donors (<0.1 percent) and in hospitalized patients (0.3 to 8 percent).

Selected testing to further narrow the diagnosis — Other features that may be useful to test for in narrowing the diagnostic possibilities include the following:

Evidence of intravascular hemolysis (eg, pink serum, positive serum free hemoglobin, positive urine dipstick for heme, positive urine for hemosiderin) suggests one of the following:

AHTR

Overwhelming bacterial infection (eg, from clostridium perfringens)

Paroxysmal nocturnal hemoglobinuria (PNH)

Paroxysmal cold hemoglobinuria (PCH)

Red to brown urine in a patient with a normal plasma color may be due to transient hemolysis (if the samples were not evaluated simultaneously) or to a cause other than intravascular hemolysis (eg, myoglobinuria, beet ingestion).

Splenomegaly suggests a congenital, infectious, or neoplastic process. (See "Evaluation of splenomegaly and other splenic disorders in adults".)

Abnormal finding on blood smear:

Spherocytes (picture 6), microspherocytes, and elliptocytes (picture 7) suggest AIHA, assessed by DAT; or hereditary spherocytosis, assessed by tests for reduced eosin-5-maleimide (EMA) binding, increased osmotic fragility, and/or genetic testing. Elliptocytosis may also suggest myelodysplasia, assessed by bone marrow evaluation with chromosomal analysis. (See "Warm autoimmune hemolytic anemia (AIHA) in adults" and "Hereditary spherocytosis" and "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)".)

Acanthocytes (spur cells) (picture 12) and target cells suggest liver disease. (See "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Liver and kidney disease'.)

Blister or "bite" cells (picture 13) suggest oxidant injury in the setting of G6PD deficiency. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

Red cell "ghosts" (picture 1) indicate severe intravascular hemolysis, most often associated with overwhelming bacterial infection (eg, from clostridium perfringens).

Involvement of specialists with expertise in hemolytic anemias, laboratory diagnosis, or genetic testing may be helpful in especially challenging cases.

ATYPICAL PRESENTATIONS — Anemia is often multifactorial, and concomitant disorders that blunt the normal reticulocyte response can call the diagnosis of hemolytic anemia into question. (See 'Hemolysis without reticulocytosis' below.)

In some individuals, compensation for hemolysis may be sufficient to raise the hemoglobin into the normal range. (See 'Hemolysis without anemia' below.)

In other cases, an increased reticulocyte count initially thought to indicate hemolysis may in fact be due to another cause of increased erythropoiesis. (See 'Reticulocytosis without hemolysis' below.)

Hemolysis without reticulocytosis — Hemolytic anemia can be seen in the absence of an appropriate reticulocyte response, often resulting in a more profound degree of anemia [24]. This occurs when the bone marrow is not capable of responding appropriately to anemia. If hemolysis is suspected or confirmed but the reticulocyte count is inappropriately low, there are several possible concomitant conditions that may be responsible for blunting the reticulocyte response:

Iron deficiency (absolute or functional) – (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Diagnosis of iron deficiency in chronic kidney disease" and "Treatment of anemia in nondialysis chronic kidney disease".)

Deficiency of vitamin B12, folate, or copper – (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency'.)

Anemia of chronic inflammation (anemia of chronic disease) – (See "Anemia of chronic disease/anemia of inflammation".)

Alcohol – (See "Hematologic complications of alcohol use".)

Myelodysplasia, aplastic anemia, or other primary bone marrow disorder – (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

Transient red blood cell (RBC) aplasia due to parvovirus infection, which targets erythropoietic precursor cells [25,26] – (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)

Drug-induced bone marrow suppression such as therapy for chronic lymphocytic leukemia (CLL) [27] – (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Anemia'.)

Other settings in which the reticulocyte response may be inappropriately low include an autoimmune hemolytic anemia in which the autoantibody also targets RBC progenitor cells in the bone marrow, or a transient lag in the production of reticulocytes during the first few days of new-onset hemolysis.

Hemolysis without anemia — Hemolysis without anemia can be seen if the bone marrow capacity to increase RBC production is sufficient to overcome the anemia caused by the hemolysis. (See 'RBC turnover' above.)

Despite a normal hemoglobin and hematocrit, hemolysis can still be detected from increased reticulocyte count, increased serum LDH, and decreased serum haptoglobin. An estimate of RBC turnover from the reticulocyte count in non-anemic patients should yield a value of ≤5 or ≤8 percent per day in adults and children, respectively.

Reticulocytosis without hemolysis — A patient thought to have hemolytic anemia based on an increased reticulocyte count may in fact have another cause of reticulocytosis. If the clinical picture is not fully consistent with hemolytic anemia or a specific cause of hemolysis cannot be identified, it may be appropriate to evaluate the patient for other causes of reticulocytosis such as:

Recovery from an episode of bleeding or ongoing bleeding.

Repletion of iron, vitamin B12, or folate in a patient who was deficient.

Administration of erythropoietin.

Recovery from a bone marrow insult such as an infection (eg, parvovirus), medication, or alcohol.

THROMBOTIC COMPLICATIONS — There is a well-known association between hemolytic anemia and thrombosis, which may be seen with either intravascular or extravascular hemolysis. The mechanism(s) are not well understood. Postulated factors include the effects of free plasma heme or hemoglobin, depletion of nitric oxide (NO), splenectomy, antiphospholipid antibodies in some patients with autoimmune hemolysis, and prothrombotic changes in the surface of affected RBCs [28].

Management and prevention of thrombosis in specific disease settings is discussed in separate topic reviews:

Paroxysmal nocturnal hemoglobinuria (PNH) – (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria", section on 'Thrombosis'.)

Sickle cell disease (SCD) – (See "Overview of the pulmonary complications of sickle cell disease", section on 'Venous thromboembolism and pulmonary thrombosis'.)

Autoimmune hemolytic anemia (AIHA) – (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Thromboembolic complications'.)

Hereditary spherocytosis (HS) – (See "Hereditary spherocytosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Autoimmune hemolytic anemia (The Basics)")

SUMMARY AND RECOMMENDATIONS

Types of hemolysis – Hemolytic anemias can be classified according to whether the abnormality is intrinsic or extrinsic to the RBC (intracorpuscular versus extracorpuscular defects), whether the condition is inherited or acquired, whether the hemolysis is acute or chronic, whether the mechanism involves antibody-mediated destruction (immune versus non-immune mechanism), and whether the hemolysis occurs in the vasculature or in the reticuloendothelial macrophages in the liver and spleen (intravascular versus extravascular hemolysis). (See 'Conceptual framework' above.)

Causes – Causes of hemolytic anemia are listed in the table (table 1) and discussed above. (See 'List of causes' above.)

Evaluation – The diagnosis of hemolytic anemia is suspected in a patient with chronic or new onset anemia with reticulocytosis and not due to another obvious cause. There is no single specific diagnostic test for hemolytic anemia. Most experts consider the diagnosis to be accepted if there is reticulocytosis not explained by recent bleeding, nutrient repletion, or administration of erythropoietin; with high lactate dehydrogenase (LDH) and unconjugated bilirubin, low haptoglobin, and in some cases other laboratory findings (table 2). Once the diagnosis is relatively certain, the cause is determined using information from the history and physical examination and directed laboratory testing (algorithm 1). (See 'Overview of the evaluation' above.)

Immediate interventions – Certain interventions may be required before the cause of hemolysis is known, including transfusions, plasma exchange, hydration, and hemodynamic support. Life-saving interventions should not be delayed while awaiting the results of diagnostic testing. (See 'Immediate management issues before the cause is identified' above.)

Further testing – In some of the obvious/classic presentations, it may make sense to proceed directly to specific diagnostic testing to determine the specific cause. If the underlying cause is less obvious, we use the direct antiglobulin (Coombs) test (DAT) to distinguish between immune and non-immune hemolysis, and for those with a negative DAT, we perform directed laboratory testing based on the patient and family history, physical examination; pace and severity of hemolysis; and RBC morphology (algorithm 1). Involvement of specialists with expertise in hemolytic anemias, laboratory diagnosis, or genetic testing may be helpful. (See 'Post-diagnostic testing to determine the cause' above.)

Atypical presentations – It is possible to have hemolysis without reticulocytosis, hemolysis without anemia, and reticulocytosis without hemolysis. (See 'Atypical presentations' above.)

Thrombosis – There is a well-known association between hemolytic anemia and thrombosis, which may be seen with either intravascular or extravascular hemolysis. (See 'Thrombotic complications' above.)

ACKNOWLEDGMENTS — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.

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