INTRODUCTION — One of the most useful ways to classify anemia is whether red cell production is decreased or destruction is increased. Hemolysis is the primary form of red cell destruction.
Among hemolytic anemias, it can be clinically useful to distinguish between immune and non-immune causes. Immune hemolysis generally can be treated by immunomodulatory drugs, whereas non-immune hemolysis does not respond to immune suppression.
This topic discusses non-immune hemolytic anemias in adults. Separate topic reviews discuss:
●General diagnostic approach to anemia – (See "Diagnostic approach to anemia in adults".)
●Hemolytic anemias – (See "Diagnosis of hemolytic anemia in adults".)
●Immune hemolysis – (See "Warm autoimmune hemolytic anemia (AIHA) in adults" and "Cold agglutinin disease" and "Paroxysmal cold hemoglobinuria" and "Hemolytic transfusion reactions".)
DEFINITIONS — General definitions of anemia and red blood cell (RBC) indices are listed separately. (See "Diagnostic approach to anemia in adults", section on 'Basic principles'.)
All RBCs are eventually destroyed, typically after a lifespan of approximately 120 days. During this lifespan, the cells undergo repeated cycles of metabolic and physical stress as they circulate through the capillary microvasculature and splenic sinusoids. Accumulated damage to the RBC membrane leads to culling by splenic macrophages that phagocytose pieces of the RBC membrane and ultimately the entire RBC.
●Hemolysis – Hemolysis refers to premature RBC destruction. An RBC lifespan of <100 days would qualify, although RBC survival is not measured outside of research studies. (See "Red blood cell survival: Normal values and measurement".)
Regardless of the cause of hemolysis, typical findings include increased reticulocyte count (compensatory), high lactate dehydrogenase (LDH) and indirect bilirubin (released from lysed RBCs), and low or undetectable haptoglobin (hemoglobin scavenger protein). These and other findings are summarized in the table (table 1).
●Immune versus non-immune – The Coombs test (also called direct antiglobulin test [DAT]) is generally used to determine whether hemolysis is immune (antibody-mediated) or non-immune. (See "Diagnosis of hemolytic anemia in adults", section on 'Cause not obvious - start with Coombs test'.)
•Immune hemolysis – Immune hemolysis generally refers to antibody-mediated RBC destruction. The antibodies can be autoantibodies (as in autoimmune hemolytic anemia [AIHA]) or alloantibodies, as in hemolytic transfusion reactions or hemolytic disease of the fetus and newborn (HDFN). In immune hemolysis, the Coombs test (DAT) or other test for antibodies on the RBC surface is typically positive.
Antibodies can destroy RBCs by fixing complement and causing the cells to be lysed in the circulation (intravascular hemolysis) or by "opsonizing" the cells and making them susceptible to phagocytosis by macrophages of the reticuloendothelial system in the spleen and liver (extravascular hemolysis).
Destruction of RBCs in the spleen due to hypersplenism, which involves non-antibody-mediated phagocytosis, is generally considered to be non-immune.
•Non-immune hemolysis – Non-immune hemolysis (also called Coombs-negative hemolysis) includes all hemolysis that is not antibody mediated.
Non-immune RBC destruction can occur due to intrinsic properties of the RBC (abnormalities of the membrane, hemoglobin, or metabolic enzymes) or to extrinsic factors including infectious organisms, oxidant drugs, toxins, mechanical or chemical destruction, vascular changes, hypersplenism, or others, as discussed below.
●Intravascular versus extravascular – As noted above, hemolysis can occur within the circulation (intravascular) or in the reticuloendothelial system (macrophages of the spleen and liver; extravascular). In severe cases, hemolysis can "spill over" and occur in both sites.
Intravascular hemolysis is characterized by free heme in the serum and urine. Free heme can cause acute kidney injury from heme pigment. Aggressive hydration and monitoring may be indicated. (See 'General management principles' below.)
●Hemolytic anemia – Hemolysis causes anemia when the RBC destruction is too great to be compensated by RBC production in the bone marrow, or when bone marrow compensation is impaired for another reason. When hemolysis is severe and the bone marrow function is normal, the reticulocyte count can be as high as 20 to 30 percent of RBCs.
CAUSES
Heritable/genetic causes — Most heritable anemias are caused by variants in genes that encode red blood cell (RBC) membrane/cytoskeletal proteins, hemoglobin, or metabolic enzymes, as illustrated in the schematic (figure 1).
Most of these are associated with some degree of non-immune hemolysis. Details of evaluation and management are presented separately.
●Membrane/cytoskeletal proteins – (See "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)
●Hemoglobin – (See "Diagnosis of sickle cell disorders" and "Diagnosis of thalassemia (adults and children)" and "Unstable hemoglobin variants".)
●Enzymes – (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Pyruvate kinase deficiency" and "Rare RBC enzyme disorders".)
Infections (RBC parasites and intracellular bacteria) — Certain infectious organisms can lyse RBCs.
●Malaria parasites (all species)
●Babesia
●Leishmania
●Clostridium perfringens
●Bartonella
These organisms cause hemolysis by different mechanisms.
●Protozoa
•Malaria – In malaria, the parasite attaches to a specific receptor on the RBC surface (for Plasmodium vivax, the Duffy antigen; for Plasmodium falciparum, sialic acid residues on glycophorin A of the MNS blood group) and enters the cell (picture 1), where it grows using the RBC's metabolic machinery and ingesting hemoglobin [1-3]. CD55 is also an essential host factor for P. falciparum invasion [4]. RBCs are lysed when the mature schizont (picture 2) bursts out of the cell. Diagnosis is made by finding the intracellular organisms on the blood smear. (See "Red blood cell antigens and antibodies" and "Pathogenesis of malaria", section on 'Life cycle' and "Anemia in malaria".)
•Babesia – Babesia microti is an intracellular RBC parasite (picture 3 and picture 4) transmitted by deer ticks (Ixodes scapularis), mostly in the Northeast and upper Midwest of the United States, especially in the summer months. The tick may also transmit Lyme disease and ehrlichiosis [5]. Babesiosis can occur in people who are immunocompetent, but the most severe disease is seen in people who are immunocompromised or asplenic [6-10]. (See "Babesiosis: Microbiology, epidemiology, and pathogenesis".)
•Leishmania – Leishmania donovani parasitizes macrophages, not RBCs. The organism is transmitted by the bite of a sandfly, especially in South Asia (India, Bangladesh, and Nepal) and the Horn of Africa (Sudan, Ethiopia, Kenya, and Somalia). Some infections are asymptomatic; others can cause visceral leishmaniasis (also called "kala-azar," meaning "black fever") after a period of weeks to months. Parasite levels can be very high in the spleen, liver, and bone marrow, causing anemia by multiple mechanisms including splenic sequestration, hemolysis, and bone marrow suppression [11]. Hemolysis is thought to be caused by oxidative metabolic products [12]. People who develop kala-azar may have deficiencies in enzymes that are protective against oxidative damage [13]. (See "Visceral leishmaniasis: Clinical manifestations and diagnosis".)
●Bacteria
•Clostridium perfringens – Infection by C. perfringens (formerly called C. Welchii) can cause massive, life-threatening hemolysis. Clostridial sepsis is a medical emergency; people with clostridial sepsis often die within hours of presentation. If there is even the slightest suspicion of clostridial sepsis, parenteral antibiotic therapy should be started immediately (see "Clostridial myonecrosis", section on 'Treatment'). The prognosis is grave; the mechanism of hemolysis is thought to involve the alpha toxin, a phospholipase C enzyme that destroys RBC membrane phospholipids and structural membrane proteins [14].
Infection can occur as a complication of surgery (as a gastrointestinal or genitourinary abscess), pregnancy, or medical conditions such as cancer or diabetes [15-18]. Any site of clostridial infection can cause sepsis and massive hemolysis that is often fatal [19]. The site of infection may or may not be apparent. Signs of systemic illness may be obvious, even if fever is unimpressive. (See "Clostridial myonecrosis", section on 'Traumatic gas gangrene'.)
The laboratory may have difficulty performing chemical assays or pretransfusion testing (crossmatching) due to massive hemolysis [16,20]; the laboratory may attribute this to faulty sample collection.
Within hours of infection, it may be possible to see changes on the peripheral blood smear including hemolyzed "ghost" red cells (picture 5), along with spherocytosis, erythrophagocytosis, phagocytic cells containing bacilli, and toxic changes in the white blood cells [15,16,21-23].
Other findings include disseminated intravascular coagulation (DIC) and acute kidney injury (AKI) failure [24,25].
•Bartonella – Bartonella bacilliformis is a gram-negative bacterium transmitted by the bite of a sandfly, mostly in the Andes Mountains of Peru, Colombia, and Ecuador; with sporadic cases in other South American countries. The organism can infect RBCs intracellularly, possibly mediated by the bacterial flagellum [26]. (See "South American bartonellosis: Oroya fever and verruga peruana".)
Oxidant drugs and toxins — Drugs with oxidant potential can cause hemolysis. Common examples include primaquine, dapsone, and phenazopyridine; others are listed in the table (table 2). Hemolysis is exacerbated by glucose-6-phosphate dehydrogenase (G6PD) deficiency, but oxidant drugs can cause hemolysis even if G6PD levels are normal. (See "Drug-induced hemolytic anemia", section on 'Oxidant injury'.)
Evaluation for G6PD deficiency and management are discussed separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
Toxins in certain venoms from insect bites and stings can cause a DIC-like picture with a coagulopathy and hemolytic anemia. Examples include:
●The scorpion Hemiscorpius lepturus, found in hot and humid regions of the Middle East. (See "Scorpion envenomation causing skin necrosis, hemolysis, DIC, and acute kidney injury (Middle East)".)
●Snakebite (several species). (See "Snakebites worldwide: Clinical manifestations and diagnosis" and "Snakebites worldwide: Management".)
Treatment is supportive along with antivenom, with hydration and hemodynamic support as needed. (See 'General management principles' below.)
Fragmentation — Abnormalities of the vasculature can cause RBCs to become fragmented, forming schistocytes (picture 6). Sometimes these are referred to as helmet cells, or the blood smear will be described as showing poikilocytosis. The International Council for Standardization in Haematology notes that the RBCs can be small, irregular triangular or crescent-shaped cells with pointed projections and lack of central pallor [27].
The "gold standard" for schistocyte determination is examination of a suitably prepared peripheral blood smear by an experienced observer. Automated cell counters can often detect schistocytes, especially when they represent 1 percent or more of RBCs [28-31].
The anemia caused by fragmentation of RBCs caused by abnormalities in the vasculature is referred to as microangiopathic hemolytic anemia (MAHA). (See "Diagnosis of immune TTP", section on 'MAHA and thrombocytopenia'.)
Causes of RBC fragmentation are listed in the table (table 3). Common causes include:
●Thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP)
●Systemic disorders associated with activation of intravascular clotting
●Vascular abnormalities caused by hemangiomas or intravascular devices
●Physical, thermal, or osmotic injury
The cause is often apparent from the clinical setting; if not, it should be fully investigated. While a rare schistocyte may be seen in a normal blood smear (due to fragmentation of a cell during sample preparation), schistocytosis is never normal and may indicate a life-threatening condition such as TTP or DIC.
Management of fragmentation hemolysis is primarily directed at the underlying disease or event, as discussed in the following sections.
Primary TMAs — Thrombotic microangiopathies (TMAs) are disorders in which small vessel thrombosis causes mechanical shearing of RBCs as they traverse through microthrombi, as illustrated in the scanning electron microscopy image (picture 7). Thrombocytopenia is also present. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
Primary TMAs are summarized in the table (table 4). They include:
●Thrombotic thrombocytopenic purpura (TTP)
●Complement-mediated TMA (C-TMA)
●Drug-induced TMA (DITMA), including TMA from quinine, certain chemotherapy drugs, and others (table 5)
●Shiga toxin-induced hemolytic uremic syndrome (HUS)
They are distinguished by presenting features and specific laboratory testing, including testing for ADAMTS13 activity. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)", section on 'Evaluation for primary TMA syndromes' and "Drug-induced thrombotic microangiopathy (DITMA)".)
Systemic conditions
●Severe infections or DIC – Disseminated intravascular coagulation (DIC) is characterized by activation of the coagulation cascade, usually due to the release or increased expression of tissue factor. This is followed by the deposition of fibrin and platelet thrombi within small vessels, and mechanical shearing of red cells on the fibrin strands (picture 7). DIC has a variety of causes (table 6), the most common of which are sepsis, trauma, malignancy, and obstetric complications. Vascular lesions can also cause DIC. Coronavirus disease 2019 (COVID-19) is under study as a possible cause of a TMA-like syndrome. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "COVID-19: Hypercoagulability", section on 'Virchow's triad' and 'Hemangiomas and other vascular lesions' below.)
●Cancer – Blood vessels supplying malignant tumors are thought to be structurally abnormal and may cause fibrin stranding and fragmentation hemolysis similar to DIC [32]. Some cancers promote a hypercoagulable state; in severe cases, there may be migratory superficial thrombophlebitis or (Trousseau syndrome). The hypercoagulable state is primarily due to release of tissue factor and cancer procoagulant from tumor cells. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".)
●CAPS – The catastrophic antiphospholipid syndrome (CAPS) can also produce microangiopathic hemolysis and a DIC-like picture. Germline variants in genes regulating complement have been found in up to 50 percent of patients [33]. Evaluation and management are presented separately. (See "Catastrophic antiphospholipid syndrome (CAPS)".)
●Severe hypertension – Microangiopathic hemolysis and thrombocytopenia can be caused by severe hypertension [34]. Hypertension may be primary or secondary to an underlying disorder such as scleroderma renal crisis. The presumed mechanism is the associated endothelial/vascular injury, which in turn, leads to fibrin strand formation, shearing of RBCs, and the trapping and removal of platelets. (See "Moderate to severe hypertensive retinopathy and hypertensive encephalopathy in adults", section on 'Mechanisms of vascular injury' and "Kidney disease in systemic sclerosis (scleroderma), including scleroderma renal crisis".)
In one study involving 97 people with severe hypertension, 27 percent had MAHA [35]. MAHA correlated with disease severity; compared with the people who did not have MAHA, those with MAHA had higher blood pressure, higher creatinine levels, and a greater need for dialysis (58 versus 3 percent). Rapid control of the blood pressure is critical. (See "Evaluation and treatment of hypertensive emergencies in adults" and "Management of severe asymptomatic hypertension (hypertensive urgencies) in adults".)
Pregnancy-related disorders — Hemolysis is not a component of normal pregnancy, but pregnancy-associated disorders can cause microangiopathic hemolysis, typically accompanied by thrombocytopenia and other clinical findings (coagulopathy in DIC; hypertension and proteinuria in severe preeclampsia; elevated liver enzymes in HELLP syndrome). Evaluation and management are discussed separately.
●Unclear cause – (See "Thrombocytopenia in pregnancy", section on 'Determining the likely cause(s)' and "Anemia in pregnancy", section on 'Other anemias'.)
●DIC – (See "Disseminated intravascular coagulation (DIC) during pregnancy: Clinical findings, etiology, and diagnosis" and "Disseminated intravascular coagulation (DIC) during pregnancy: Management and prognosis".)
●Preeclampsia – (See "Hypertensive disorders in pregnancy: Approach to differential diagnosis" and "Preeclampsia: Clinical features and diagnosis" and "Preeclampsia: Antepartum management and timing of delivery" and "Preeclampsia with severe features: Expectant management remote from term".)
●HELLP syndrome – (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)
Hemangiomas and other vascular lesions — The Kasabach-Merritt phenomenon was first described in 1940 as a syndrome of consumptive coagulopathy with capillary hemangiomas [36]. However, more modern investigations have shown that this phenomenon is more typically associated with kaposiform hemangioendotheliomas, an aggressive form of giant hemangioma [37-39]. In approximately half of infants affected, the angiomas are noted at birth. Common locations in order of frequency include the trunk (including retroperitoneum), arms and shoulders, legs, and face/neck. In addition to RBC fragmentation, the Kasabach-Merritt phenomenon causes severe thrombocytopenia, hypofibrinogenemia, and elevated fibrin degradation products. Treatment is discussed separately. (See "Tufted angioma, kaposiform hemangioendothelioma (KHE), and the Kasabach-Merritt phenomenon", section on 'Kasabach-Merritt phenomenon'.)
Less common vascular lesions causing hemolysis include atrioventricular malformations, calcific aortic stenosis, left atria myxoma, and cardiac metastases [40].
Intravascular devices — Certain intravascular devices can fragment RBCs by shear stress, turbulence, or direct mechanical trauma, especially via impact on a foreign, nonendothelialized surface:
●Hemodialysis – Damage to red cells is an unavoidable side effect of extracorporeal hemodialysis. Acute hemolysis can also occur, mostly due to mechanical issues (eg, obstructions within the extracorporeal circuit, kinking of blood tubing, excessive flow, improper cannula or catheter dimensions) [41].
Hemodialysis can also cause hemolysis if certain contaminants are present in the water. (See 'Liver and kidney disease' below.)
●TIPS – Transjugular intrahepatic portosystemic shunts (TIPS) and coil embolization [42,43]. One series described microangiopathic hemolysis in approximately 10 percent of people with a TIPS; the hemolysis disappeared after 12 to 15 weeks [42].
●Cardiopulmonary bypass – A syndrome of fever, acute intravascular hemolysis, leukopenia, and systemic inflammation can occur in some patients following cardiopulmonary bypass, referred to as postperfusion syndrome. Some patients develop pulmonary dysfunction and acute respiratory distress syndrome. The mechanism is thought to involve binding and activation of complement on the RBC surface that occurs as blood is passed through the oxygenator [44].
●Ventricular assist device – The incidence of severe hemolysis after the use of ventricular assist device implantation is low and has been estimated at approximately 3 percent [45,46]. (See "Short-term mechanical circulatory assist devices".)
●ECMO – Extracorporeal membrane oxygenation (ECMO) can cause direct mechanical trauma to RBCs and/or activation of coagulation on the circuit. (See "The role of TEE in the management of extracorporeal membrane oxygenation".)
●Percutaneous thrombectomy – Certain thrombectomy devices that fragment and macerate a clot can also cause mechanical trauma to RBCs [47,48]. (See "Coronary artery bypass graft surgery: Prevention and management of vein graft stenosis", section on 'Thrombolysis and thrombectomy'.)
●Prosthetic heart valves – Hemodynamic turbulence can lead to microangiopathic hemolytic anemia and thrombocytopenia, sometimes referred to as the Waring blender syndrome (picture 8) [49]. This is most often seen in patients with leaky prosthetic valves or other foreign materials [50,51]. Because of the high pressure gradient, it is usually assumed that aortic valve prostheses cause more hemolysis than mitral prostheses, although dysfunctional prosthetic mitral valves can also cause microangiopathic hemolysis [52]. In some cases, mitral valve replacement or re-repair may be indicated. (See "Overview of the management of patients with prosthetic heart valves", section on 'Hemolytic anemia'.)
Foot strike or hand strike — Repetitive, forceful physical impact can lyse RBCs [53-55]. The classic example is march hemoglobinuria (also called foot-strike hemolysis, runners hemoglobinuria). This can be caused by marching, jogging, or marathon running, especially on hard surfaces with poorly cushioned shoes [56-58]. Bongo drumming is another example. This rarely causes severe anemia, and it can often be remedied by changing the footwear or location of running [59]. Some individuals who develop march hemolysis have underlying RBC disorders [57,60-64]; if hemolysis or hemolytic anemia does not resolve with interruption of the foot strike or hand strike activity, further evaluation for other causes of anemia should be pursued.
Thermal and osmotic injury — Inadvertent over-heating of RBCs can cause heat denaturation. This is rare. Causes may include:
●Heating of RBC units prior to transfusion with temperatures >45°C (>113°F), such as with improperly set blood warming devices.
●Extensive thermal burns [65].
Heat stroke is unlikely to cause elevations of body temperature high enough to cause hemolysis.
Abrupt changes in blood osmolality can cause hemolysis because RBCs will swell or shrink as free water enters or leaves the cell.
●Low serum osmolality with RBC hyperhydration and swelling can occur in:
•RBC transfusion with a hypotonic solution infused together with the red cells.
•Freshwater drowning associated with water taken in through the lungs.
•Hemodialysis with inadvertent use of a very dilute dialysate [66].
●High serum osmolality with RBC dehydration can occur in:
•RBC transfusion with concentrated (hypertonic) solutions.
•Saltwater drowning.
•Hemodialysis with a very concentrated dialysate [66,67].
The resulting change to RBCs is a form of xerocytosis. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Other causes of xerocytosis'.)
Management requires rapid recognition and restoration of isotonicity as quickly as possible. Hemodialysis may be helpful in severe cases.
Hypersplenism — Hypersplenism refers to splenic pooling or sequestration of blood cells to a degree that causes one or more cytopenias. The spleen is often enlarged (splenomegaly) and congested with blood, but hypersplenism and splenomegaly do not always coexist. All of the normal splenic functions are thought to be accentuated in an enlarged spleen, including sequestration of RBCs as well as increased destruction and clearance by splenic macrophages, a form of extravascular hemolysis. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)
Hypersplenism can be caused by liver disease, especially cirrhosis with increased portal pressure, and portal or hepatic vein thrombosis with portal hypertension [68]. Other causes are listed in the table (table 7).
In addition to findings common to all types of hemolysis, additional changes characteristic of hypersplenism:
●The complete blood count (CBC) may also show mild thrombocytopenia and neutropenia.
●The blood smear may show spherocytes, formed when portions of the RBC membrane are removed, and teardrop-shaped RBCs, formed by cell membrane distortion as cells traverse the splenic cordal-sinus barrier.
Management is usually supportive, with treatment of the underlying cause and avoidance of interventions that could further worsen hepatic or splenic function. For individuals with significant splenomegaly, avoiding high-impact activities and reducing the risk of falls may be indicated. Splenectomy is generally reserved for people with massive splenomegaly or severe cytopenias. It should be appreciated that massive splenomegaly is frequently associated with expansion of the plasma volume; as a result, the hemoglobin concentration may give a falsely low estimate of the actual red cell mass. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Indications'.)
Liver and kidney disease — Liver disease can cause hemolysis by several mechanisms; the two major mechanisms include RBC membrane alterations and hypersplenism.
Alterations in RBC membrane are caused by changes in the cholesterol and phospholipid content of the membrane bilayer. The cholesterol increase is usually proportionately greater, producing an elevation in the cholesterol-to-phospholipid ratio, impaired membrane fluidity, and damaged fatty acids [68-71].
These changes produce target cells (picture 9), spur cells (picture 10), burr cells (picture 11), and stomatocytes (picture 12). Details of the cell morphology and mechanisms of formation are illustrated in the figure (figure 2) and discussed in detail separately. (See "Burr cells, acanthocytes, and target cells: Disorders of red blood cell membrane", section on 'Pathophysiology (burr cells and acanthocytes)'.)
●Spur cell anemia – Spur cell anemia is associated with end-stage liver disease. It is caused when excess membrane cholesterol accumulates. Median survival is measured in weeks to months but can be reversed with liver transplantation. (See "Burr cells, acanthocytes, and target cells: Disorders of red blood cell membrane", section on 'RBC changes in liver disease'.)
●Stomatocytosis – In stomatocytosis, which can be caused by liver disease or alcohol ingestion, there is a reduction in the RBC surface area-to-volume ratio that leads to trapping in the microvasculature of the spleen and phagocytosis by reticuloendothelial macrophages. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Other causes of stomatocytosis'.)
Hemolysis is usually mild, and other causes of anemia may also be present, including anemia of chronic disease/anemia of inflammation, blood loss from gastrointestinal bleeding (eg, from varices), and iron deficiency. (See "Hemostatic abnormalities in patients with liver disease".)
●Wilson disease – High levels of copper in Wilson disease are associated with fulminant liver failure and non-immune hemolysis. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)
Kidney disease can cause anemia by several mechanisms, many of which are unrelated to hemolysis. Mechanisms of hemolysis in kidney disease include:
●Microangiopathic – Microangiopathic hemolytic anemia can be due to a thrombotic microangiopathy or other systemic disorder such as uncontrolled hypertension. (See 'Primary TMAs' above and 'Systemic conditions' above.)
●Uremia – Uremia may produce a modest shortening of red cell survival. This may be due in part to increased osmotic fragility that can be reversed by hemodialysis [72].
●Hemodialysis – Hemolysis can be precipitated by contaminants in water used for hemodialysis. A case report from the 1970s described hemolysis precipitated by chloramine in tap water [73]. Oxidative RBC damage due to alterations in glutathione metabolism has been implicated [74,75]. (See "Contaminants in water used for hemodialysis", section on 'Disinfectants added to drinking water'.)
PNH — Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, clonal, hemolytic anemia in which RBCs lack surface proteins that protect against complement-mediated lysis. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria".)
Clinical findings include unexplained intravascular hemolysis, thrombosis in an atypical location, or nonspecific symptoms attributable to hemolysis (fatigue, abdominal pain, erectile dysfunction). Flow cytometry provides diagnostic confirmation by demonstrating lack of glycosylphosphatidylinositol (GPI)-anchored proteins, which are reduced or absent on blood cells in PNH. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)
Management involves assessing and treating thrombotic complications and use of complement blockade. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)
EVALUATION — The pace of the evaluation (including whether testing can be done sequentially or simultaneously) and need for immediate hematologist input depends on the acuity of presentation and likelihood of specific diagnosis.
Although most individuals with hemolytic anemia can be readily treated and recover, some of the conditions discussed below are potentially life-threatening and must be evaluated and treated rapidly.
The discussion below presumes an initial evaluation that determines the person has Coombs-negative (direct antiglobulin test [DAT]-negative) hemolysis, as illustrated in the figure (algorithm 1).
Assess disease severity — The major red flags for potentially life-threatening hemolytic anemia include:
●Possible life-threatening infection requiring systemic antibiotics, especially systemic clostridial infections. (See 'Infections (RBC parasites and intracellular bacteria)' above.)
●Hemodynamic instability, rapidly declining hemoglobin, or hemoglobin <7 to 8 g/dL, which would generally require transfusion. (See 'Transfusion for severe anemia' below.)
●Significant intravascular hemolysis, which can potentially cause acute kidney injury (AKI) or a disseminated intravascular hemolysis (DIC)-like picture. (See 'Kidney protection in intravascular hemolysis' below.)
●Thrombosis may complicate severe hemolysis and may be life-threatening.
Determine the cause
Important clues from the clinical history — The following may be helpful:
●Family history of anemia or specific disorder that could be heritable
●New exposures to drugs, including over-the-counter remedies and supplements
●Exposure to foods made from fava beans
●Recent transfusions
●Fever or other systemic symptoms
●Symptoms of severe anemia such as dyspnea or lightheadedness
●Symptoms of thrombotic events (leg swelling, dyspnea, neurologic symptoms)
Review laboratory findings
●Confirm hemolysis – Typical laboratory findings of hemolysis, regardless of the cause, are summarized in the table (table 1) and discussed separately. (See "Diagnosis of hemolytic anemia in adults".)
•Anemia – May be mild or absent if hemolysis is mild or compensatory reticulocytosis is robust.
•Reticulocyte count – Increased, unless there is also a problem that interferes with bone marrow function.
•Lactate dehydrogenase (LDH) – Increased. This is a nonspecific finding; LDH can also be elevated from kidney or liver disease, muscle injury, cancer (especially lymphoma), and pancreatitis.
•Bilirubin – Increased, mostly indirect.
•Haptoglobin – Decreased or undetectable. Haptoglobin is an acute phase reactant and may be increased in severe inflammatory states.
If the clinical picture does not match with the laboratory findings (or if the reticulocyte count is not increased), it may be helpful to repeat the complete blood count (CBC) to verify that hemolysis is present in the patient rather than occurring during the blood draw (in vitro hemolysis). Hemolysis can occur during blood draws when a small-gauge needle is used and the blood draw is rapid, causing red blood cells (RBCs) to be sheared by the collecting needle.
In vitro hemolysis can be due to a traumatic or difficult blood draw, prolonged tourniquet time, use of a narrow gauge needle, choice of a sampling site other than the antecubital fossa, use of a syringe with excessive suction applied to the plunger, forcibly squirting the blood from a syringe into an evacuated tube, and the method of delivery of the blood sample to the laboratory [76,77]. A systematic review of 16 studies concluded that the strongest predictor of hemolysis in blood samples obtained in the Emergency Department was drawing blood through an existing intravenous catheter; use of a butterfly needle for phlebotomy was the most effective means of avoiding in vitro hemolysis [78-80].
●Narrow the diagnosis – If hemolysis is unexplained, the first step is often to obtain a Coombs test (also called direct antiglobulin test [DAT]) as illustrated in the flow chart (algorithm 1). Immune hemolysis is typically Coombs positive; non-immune hemolysis is Coombs negative. (See "Diagnosis of hemolytic anemia in adults", section on 'Cause not obvious - start with Coombs test'.)
Findings from the CBC, blood smear, and other initial testing can also help narrow the diagnostic possibilities.
•CBC – Isolated anemia is seen in heritable/genetic RBC abnormalities; most drug-induced hemolytic anemias; and mechanical, thermal, or osmotic RBC lysis. Leukopenia, leukocytosis, and thrombocytopenia are seen in certain infections, primary thrombotic microangiopathies, systemic and pregnancy-related conditions, hypersplenism, and liver disease.
•RBC morphology – The laboratory may report findings that suggest the cause:
-Spherocytes – Hereditary spherocytosis, drug-induced hemolysis, hypersplenism
-Schistocytes – Thrombotic microangiopathy (TMA), systemic, or vascular condition with RBC fragmentation
-Stomatocytes – Hereditary stomatocytosis, liver disease, certain drugs
-RBC ghosts – Clostridium perfringens sepsis
-Bite cells – Glucose-6-phosphate dehydrogenase (G6PD) deficiency and/or oxidant hemolysis
-Intracellular parasites – Malaria or babesiosis
•Kidney function – Kidney dysfunction suggests a possible TMA such as Shiga toxin-mediated hemolytic uremic syndrome (ST-HUS) or complement-mediated (C-TMA). (See "Thrombotic microangiopathies (TMAs) with acute kidney injury (AKI) in adults: CM-TMA and ST-HUS".)
•Liver function – Liver dysfunction suggests a possible role for hemolytic anemia due to membrane abnormalities and/or hypersplenism. (See 'Liver and kidney disease' above and 'Hypersplenism' above.)
•Coagulation studies – Typically in severe liver disease the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged and the fibrinogen level is low.
•Serum and urine color – The serum and urine should be clear yellow. Free heme makes the serum and urine amber to red, raising concern for intravascular hemolysis. Urinalysis is positive for heme and negative for RBCs. Intravascular hemolysis can be confirmed by testing the serum for free heme, although appropriate treatments should not be delayed while obtaining this testing. (See 'Kidney protection in intravascular hemolysis' below.)
Additional testing to determine the cause — The following may be helpful, depending on the clinical presentation:
●Suspected infection – Appropriate cultures. (See "Clostridial myonecrosis" and "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children" and "Babesiosis: Clinical manifestations and diagnosis".)
●Suspected oxidant hemolysis – G6PD testing. (See "Genetics and pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
●Suspected TMA or DIC – Coagulation studies, ADAMTS13 activity. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Suspected hypersplenism – Splenic imaging. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)
●Suspected PNH – (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)
When to consult hematology — Hematology input should be sought whenever there is evidence of hemolysis and the cause is not apparent. The hematologist can guide further diagnostic testing and assist with any emergency interventions that may be needed.
GENERAL MANAGEMENT PRINCIPLES — Therapy to treat the underlying cause of hemolysis depends on the disease process responsible. (See 'Causes' above.)
In addition to treating the underlying cause, some general management principles also apply, as discussed in the following sections.
Transfusion for severe anemia — Transfusion may be indicated if there is severe anemia with hemodynamic compromise or symptoms of cardiac ischemia, or hemoglobin <7 to 8 g/dL. Transfusions should not be withheld if needed while awaiting the results of diagnostic testing, although it can be helpful to obtain a sample prior to transfusion that can be tested for certain causes. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult" and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion".)
Kidney protection in intravascular hemolysis — Free heme can cause acute kidney injury (AKI) and a disseminated intravascular hemolysis (DIC)-like picture. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury" and "Approach to the patient with a suspected acute transfusion reaction", section on 'Suspected acute hemolytic reaction'.)
Hydration is paramount to reduce the risk of AKI; this and other interventions are presented separately. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury" and "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)
Folic acid for chronic hemolysis — Hemolysis leads to increased proliferation of hematopoietic progenitor cells and red blood cell (RBC) precursors in the bone marrow, which depends on folates for metabolism. Individuals with chronic hemolysis are generally treated with daily folate (typical dose, 1 mg orally per day) unless this would create a significant undue burden.
Low threshold for VTE evaluation — Many hemolytic anemias, especially with severe hemolysis or intravascular hemolysis, are associated with an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). While routine surveillance for these complications is generally not used outside of a clinical trial, there should be a low threshold for evaluating symptoms or findings that suggest venous thromboembolism (VTE).
Examples include leg swelling, unexplained dyspnea, cough, or pleuritic chest pain. Individuals with hemolytic anemia should be educated about these symptoms and the importance of seeking medical attention should they occur. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)
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".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Non-immune hemolysis (also called Coombs-negative hemolysis) refers to several non-antibody-mediated processes that reduce red blood cell (RBC) lifespan. They have typical findings of hemolysis including anemia, increased reticulocyte count, high lactate dehydrogenase (LDH) and indirect bilirubin, and low haptoglobin (table 1), along with a negative direct antiglobulin (Coombs) test. (See 'Definitions' above.)
●Causes – Categories of non-immune hemolysis include:
•Genetic alterations of the RBC membrane, metabolic enzymes, or hemoglobin (figure 1)
•Infectious organisms that directly invade and lyse RBCs
•Mechanical, thermal, and osmotic injury
•Oxidant drugs and toxins (table 2)
•RBC fragmentation from a thrombotic microangiopathy (table 3) or a systemic disorder (table 6)
•Hypersplenism (table 7)
•Liver or kidney disease
Mechanisms and typical findings are discussed above. (See 'Causes' above.)
●Evaluation – The severity of disease determines the pace of the evaluation and need for immediate interventions. After an initial evaluation that determines a person has Coombs-negative (direct antiglobulin test [DAT]-negative) hemolysis (algorithm 1), the next step is to determine the cause. Several clues from the clinical history and initial laboratory testing can be used to narrow the diagnostic possibilities and suggest additional testing that may be helpful. Hematology consultation should be obtained if there is diagnostic uncertainty and/or a need for rapid interventions. (See 'Evaluation' above.)
●Treatment – Management depends on the underlying cause. General management principles include transfusion for severe anemia with hemodynamic compromise or cardiac ischemia, hydration for significant intravascular hemolysis, folic acid supplementation for chronic hemolysis, and having a low threshold for evaluating possible venous thromboembolism. (See 'General management principles' above.)
ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who died 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.
