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.
Hemolytic anemias can be classified as immune (antibody mediated) or non-immune. 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:
●Diagnostic approach to anemia – (See "Diagnostic approach to anemia in adults".)
●Diagnosis of hemolytic anemia – (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 — Anemia definitions 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 approximately 120 days. Each day, they 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 versus hemolytic anemia – Hemolysis refers to premature RBC destruction. An RBC lifespan of <100 days qualifies, 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). The table summarizes these findings (table 1). When hemolysis is severe and bone marrow function is normal, the reticulocyte count can reach 20 to 30 percent of RBCs.
Hemolytic anemia occurs when hemolysis is too great to be compensated by RBC production in the bone marrow, or when bone marrow compensation is impaired for another reason.
●Immune versus non-immune hemolysis – 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 – 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 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 – Non-immune (Coombs-negative) hemolysis includes all non-antibody-mediated hemolysis.
Non-immune hemolysis can result from intrinsic properties of the RBC (abnormalities of the membrane, hemoglobin, or metabolic enzymes) or extrinsic factors including infectious organisms, oxidant drugs, toxins, mechanical or chemical destruction, vascular changes, hypersplenism, or others.
●Intravascular versus extravascular – Intravascular hemolysis occurs within the circulation. Extravascular hemolysis occurs in the reticuloendothelial system (macrophages of the spleen and liver). Severe hemolysis can "spill over" and occur in both sites.
Intravascular hemolysis releases free heme, which can cause acute kidney injury from heme pigment. Aggressive hydration and monitoring may be indicated. (See 'General management principles' below.)
Heritable/genetic causes — Heritable anemias are generally caused by variants in genes that encode red blood cell (RBC) membrane/cytoskeletal proteins, hemoglobin, or metabolic enzymes (figure 1).
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)".)
Infections (RBC parasites and intracellular bacteria) — Certain infectious organisms can lyse RBCs.
•Malaria – Plasmodial parasites attach to receptors on the RBC surface (for Plasmodium vivax, the Duffy antigen; for Plasmodium falciparum, sialic acid residues on glycophorin A of the MNS blood group). CD55 is also an essential host factor for P. falciparum invasion . They grow inside the RBC (picture 1) using the RBC's metabolic machinery and ingesting hemoglobin [2-4]. RBCs are lysed when the mature schizont lyses the RBC (picture 2). Diagnosis is made via 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 parasites (picture 3 and picture 4) are transmitted by deer ticks (Ixodes scapularis), mostly in the Northeast and upper Midwest of the United States, especially in the summer. The tick may also transmit Lyme disease and ehrlichiosis . 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"). Parasites cause anemia by multiple mechanisms including splenic sequestration, hemolysis, and bone marrow suppression . Hemolysis is thought to involve oxidative metabolic products . People who develop kala-azar may have deficiencies in enzymes that are protective against oxidative damage . (See "Visceral leishmaniasis: Clinical manifestations and diagnosis".)
•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 mechanism of hemolysis is thought to involve alpha toxin, a phospholipase C enzyme that destroys RBC membrane phospholipids and structural membrane proteins .
Infection can complicate surgery (gastrointestinal or genitourinary abscess), pregnancy, cancer, or diabetes [15-18]. Any site of infection can cause sepsis and fatal hemolysis . (See "Clostridial myonecrosis", section on 'Traumatic gas gangrene'.)
The laboratory may have difficulty performing chemical assays or pretransfusion testing (crossmatching) due to massive hemolysis; this may be confused with faulty sample collection [16,20].
Within hours, the peripheral blood smear may show hemolyzed "ghost" red cells (picture 5), spherocytosis, erythrophagocytosis, phagocytic cells containing bacilli, and toxic changes in white blood cells [15,16,21-24]. Disseminated intravascular coagulation (DIC) and acute kidney injury (AKI) can occur [25,26].
•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 . (See "South American bartonellosis: Oroya fever and verruga peruana".)
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".)
Venoms from certain insect bites and stings can cause a DIC-like picture with a coagulopathy and hemolytic anemia; these include:
●Hemiscorpius lepturus, a scorpion 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 with antivenom, hydration, and hemodynamic support. (See 'General management principles' below.)
Fragmentation — Vasculature abnormalities can fragment RBCs, forming schistocytes (also called helmet cells or poikilocytes) (picture 6). The RBCs can be triangular or crescent-shaped with pointed projections and lacking central pallor .
The gold standard for schistocyte determination is examination of a suitably prepared peripheral blood smear by an experienced observer. Automated cell counters can detect schistocytes, especially when they represent ≥1 percent of RBCs [29-32].
Fragmentation anemia is referred to as microangiopathic hemolytic anemia (MAHA). (See "Diagnosis of immune TTP", section on 'MAHA and thrombocytopenia'.)
The table lists common causes including (table 3):
●Microangiopathies such as thrombotic thrombocytopenic purpura (TTP)
●Systemic disorders with activation of intravascular clotting such as DIC
●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. A rare schistocyte may be seen in a normal blood smear (due to fragmentation of a cell during sample preparation), but schistocytosis is never normal and may indicate a life-threatening condition.
Primary TMAs — In thrombotic microangiopathies (TMAs), microthrombi mechanically shear RBCs, as illustrated in the scanning electron microscopy image (picture 7). Thrombocytopenia is also present. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
The table lists primary TMAs including (table 4):
●Complement-mediated TMA (C-TMA)
●Shiga toxin-induced hemolytic uremic syndrome (HUS)
Presenting features and laboratory testing, including testing for ADAMTS13 activity are discussed separately. (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)".)
●Severe infections or DIC – DIC involves activation of the coagulation cascade, usually from release or expression of tissue factor. Fibrin deposition and formation of platelet thrombi cause mechanical shearing of red cells on the fibrin strands (picture 7). Causes of DIC include sepsis, trauma, malignancy, and obstetric complications (table 6). (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Cancer – Tumor blood vessels are structurally abnormal and may cause fibrin stranding and fragmentation hemolysis similar to DIC . Some cancers cause 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 – Catastrophic antiphospholipid syndrome (CAPS) can produce microangiopathic hemolysis and a DIC-like picture. Germline variants in genes regulating complement have been found in up to 50 percent of patients . (See "Catastrophic antiphospholipid syndrome (CAPS)".)
●Severe hypertension – Severe hypertension can cause microangiopathic hemolysis . The presumed mechanism is endothelial/vascular injury, which causes fibrin strand formation and shearing of RBCs. (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 . MAHA correlated with disease severity; compared with controls, those with MAHA had higher blood pressure, higher creatinine, and greater likelihood of dialysis (58 versus 3 percent). (See "Evaluation and treatment of hypertensive emergencies in adults" and "Management of severe asymptomatic hypertension (hypertensive urgencies) in adults".)
Pregnancy disorders — Pregnancy-associated disorders that can cause MAHA are discussed separately.
●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: Delaying delivery in pregnancies 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 as a consumptive coagulopathy with capillary hemangiomas . However, this phenomenon is more typically associated with kaposiform hemangioendotheliomas, an aggressive form of giant hemangioma [38-40]. In approximately half of infants affected, the angiomas are noted at birth, commonly on the trunk, retroperitoneum, arms, shoulders, legs, face, and neck. The Kasabach-Merritt phenomenon causes MAHA with severe thrombocytopenia, hypofibrinogenemia, and elevated fibrin degradation products. (See "Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP)", section on 'Kasabach-Merritt phenomenon'.)
Less common vascular lesions causing hemolysis include atrioventricular malformations, calcific aortic stenosis, left atrial myxoma, and cardiac metastases .
Intravascular devices — Certain intravascular devices can fragment RBCs by shear stress, turbulence, or direct mechanical trauma, especially with a foreign nonendothelialized surface:
●Hemodialysis – Damage to RBCs is an unavoidable side effect of extracorporeal hemodialysis. Acute hemolysis can also occur with obstructions within the extracorporeal circuit, kinking of blood tubing, excessive flow, or improper cannula or catheter dimensions .
Certain contaminants in the water can cause hemolysis. (See 'Liver and kidney disease' below.)
●TIPS – Transjugular intrahepatic portosystemic shunts (TIPS) and coil embolization can cause hemolysis; one series described MAHA in approximately 10 percent of patients with a TIPS that resolved after 12 to 15 weeks [43,44].
●Cardiopulmonary bypass – Postperfusion syndrome, with fever, acute intravascular hemolysis, leukopenia, and systemic inflammation can occur following cardiopulmonary bypass. 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 as blood passes through the oxygenator .
●Ventricular assist device – Severe hemolysis with a ventricular assist device implantation has been estimated at approximately 3 percent [46,47]. (See "Short-term mechanical circulatory assist devices".)
●ECMO – Extracorporeal membrane oxygenation (ECMO) can shear RBCs and/or activate clotting on the circuit. (See "Extracorporeal life support in adults in the intensive care unit: The role of transesophageal echocardiography (TEE)".)
●Percutaneous thrombectomy – Certain thrombectomy devices can cause mechanical trauma to RBCs [48,49]. (See "Coronary artery bypass graft surgery: Prevention and management of vein graft stenosis", section on 'Thrombolysis and thrombectomy'.)
●Prosthetic heart valves – Hemodynamic turbulence can cause MAHA and thrombocytopenia (Waring blender syndrome) (picture 8) . This is most common with leaky prosthetic valves or other foreign materials [51,52]. Aortic valve prostheses cause more hemolysis than mitral prostheses due to their higher pressure gradient, although dysfunctional prosthetic mitral valves can also cause MANA . 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 [54-56]. The classic example is march hemoglobinuria (foot-strike hemolysis, runners hemoglobinuria) after marching, jogging, or marathon running, especially on hard surfaces with poorly cushioned shoes [57-59]. Bongo drumming is another example. Anemia is rarely severe and can often be remedied by changing the footwear or location of running . An underlying RBC disorder may be present [58,61-65]. If hemolysis does not resolve with interruption of the activity, evaluation for other anemias should be pursued.
Thermal and osmotic injury — Inadvertent overheating of RBCs can cause heat denaturation. This is rare. Causes include:
●Improperly set blood warming devices (temperatures >45°C [>113°F]).
●Extensive thermal burns .
Heat stroke is unlikely to cause hemolysis.
Abrupt changes in blood osmolality can cause lyse RBCs as free water enters or leaves the cell.
●Low serum osmolality with RBC hyperhydration and swelling:
•RBC transfusion combined with a hypotonic solution.
•Hemodialysis with inadvertent use of a very dilute dialysate .
●High serum osmolality with RBC dehydration:
•RBC transfusion combined with a hypertonic solution.
•Hemodialysis with a very concentrated dialysate [67,68].
RBCs undergo 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. Hemodialysis may be helpful in severe cases.
Hypersplenism — Hypersplenism involves splenic sequestration of blood cells that causes one or more cytopenias. The spleen is often enlarged and congested with blood, but hypersplenism and splenomegaly do not always coexist. All normal splenic functions are accentuated, including sequestration of RBCs as well as increased clearance by splenic macrophages. (See "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)
Additional changes with hypersplenism:
●Mild thrombocytopenia and neutropenia.
●Spherocytes, induced by splenic macrophages, and teardrop-shaped RBCs, formed by cell membrane distortion as cells traverse the splenic cordal-sinus barrier.
Management involves treating the underlying cause and avoiding interventions that could worsen hepatic or splenic function. For significant splenomegaly, high-impact activities may be avoided. Splenectomy is generally reserved for massive splenomegaly or severe cytopenias. Massive splenomegaly is frequently associated with expansion of the plasma volume, and the hemoglobin may underestimate the RBC mass. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Indications'.)
Liver and kidney disease
Alterations in the cholesterol and phospholipid content of the membrane bilayer impair membrane fluidity; the cholesterol increase is usually proportionately greater than the phospholipid increase, and fatty acid damage may occur [69-72].
Target cells (picture 9), spur cells (picture 10), burr cells (picture 11), and stomatocytes (picture 12) may occur. The figure illustrates the mechanisms (figure 2). (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, with median survival measured in weeks to months. Liver transplantation can be curative. (See "Burr cells, acanthocytes, and target cells: Disorders of red blood cell membrane", section on 'RBC changes in liver disease'.)
•Stomatocytosis – Stomatocytosis caused by liver disease or alcohol ingestion leads to trapping in 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. Anemia of chronic disease/anemia of inflammation, variceal bleeding, and iron deficiency may coexist. (See "Hemostatic abnormalities in patients with liver disease".)
•Wilson disease – Wilson disease can cause fulminant liver failure and hemolysis from copper toxicity. (See "Wilson disease: Clinical manifestations, diagnosis, and natural history".)
•Uremia – Uremia may modestly shorten RBC survival due to increased osmotic fragility .
•Hemodialysis – A case report from the 1970s described hemolysis precipitated by chloramine in tap water . Oxidative RBC damage due to alterations in glutathione metabolism has been implicated [75,76]. (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 due to loss of complement inhibition. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria".)
Clinical findings include intravascular hemolysis and complications of circulating free heme (thrombosis, fatigue, abdominal pain, erectile dysfunction). Flow cytometry demonstrates lack of glycosylphosphatidylinositol (GPI)-anchored proteins. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)
EVALUATION — The pace of the evaluation, testing sequentially or simultaneously, and need for immediate hematologist input depends on the acuity and likelihood of specific diagnoses. Most individuals can be readily treated and recover, but some conditions are potentially life-threatening and must be evaluated and treated rapidly.
The following discussion presumes Coombs-negative (direct antiglobulin test [DAT]-negative) hemolysis has been established (algorithm 1).
Assess disease severity — Major red flags for potentially life-threatening hemolytic anemia include:
●Infection requiring systemic antibiotics, especially systemic clostridial infection. (See 'Infections (RBC parasites and intracellular bacteria)' above.)
●Hemodynamic instability and need for transfusion (hemoglobin rapidly declining or <7 to 8 g/dL). (See 'Transfusion for severe anemia' below.)
●Significant intravascular hemolysis or a disseminated intravascular hemolysis (DIC)-like picture. (See 'Kidney protection in intravascular hemolysis' below.)
Determine the cause
Important clues from the clinical history
●Family history of anemia or heritable disorder
●New exposures to drugs, including over-the-counter remedies and supplements
●Exposure to foods containing fava beans
●Fever or other systemic symptoms
●Dyspnea or lightheadedness
●Symptoms of thrombosis (leg swelling, dyspnea, neurologic symptoms)
Review laboratory findings
•Anemia – May be mild or absent if hemolysis is mild or reticulocytosis is robust.
•Reticulocyte count – Increased, unless bone marrow function is impaired.
•Lactate dehydrogenase (LDH) – Increased but nonspecific; LDH can be elevated from kidney or liver disease, muscle injury, cancer (especially lymphoma), and pancreatitis.
•Bilirubin – Increased, mostly indirect.
•Haptoglobin – Decreased or undetectable. Haptoglobin may be increased in severe inflammatory states and may be decreased in liver disease and with large hematomas. (See "Acute phase reactants".)
●Artifact – If the clinical picture and laboratory findings are discordant, repeat the complete blood count (CBC) to verify that hemolysis is present rather than artifactual.
Hemolysis can occur during phlebotomy due to [77,78]:
•Blood drawn rapidly through a small-gauge needle
•Traumatic or difficult blood draw
•Prolonged tourniquet time
•Sampling site other than the antecubital fossa
•Forcibly squirting the blood from a syringe into an evacuated tube
•Damage during delivery of the blood sample to the laboratory
A systematic review of 16 studies concluded that the strongest predictor of hemolysis in blood 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 [79-81].
●Narrow the diagnosis – Once hemolysis has been documented based on the CBC, reticulocyte count, and blood smear, the next step is to determine the cause. Obvious causes may be apparent on the blood smear; if not, the appropriate next step is often to obtain a Coombs 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'.)
•CBC – Isolated anemia is seen in heritable/genetic red blood cell (RBC) abnormalities; drug-induced hemolysis; and mechanical, thermal, or osmotic RBC lysis.
Leukopenia, leukocytosis, and thrombocytopenia are seen in certain infections, primary thrombotic microangiopathies (TMAs), 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 – 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, oxidant hemolysis
-Intracellular parasites – Malaria, babesiosis
•Kidney function – Kidney dysfunction can accompany 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".)
•Coagulation studies – Liver disease and disseminated intravascular coagulation (DIC) prolong the prothrombin time (PT) and activated partial thromboplastin time (aPTT) and reduce the fibrinogen.
•Pink/red serum and urine – The serum and urine should be clear yellow. Intravascular hemolysis liberates free heme, making the serum and urine amber to red. Urinalysis is positive for heme and negative for RBCs. Free heme in serum is confirmatory; appropriate treatments should not be delayed while obtaining this testing. (See 'Kidney protection in intravascular hemolysis' below.)
Additional testing to determine the cause
●Suspected infection – 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 DIC or TMA – 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 "Splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)
●Suspected paroxysmal nocturnal hemoglobinuria (PNH) – (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)
When to consult hematology — Hematology input should be sought with unexplained hemolysis to guide further diagnostic testing and assist with any emergency interventions that may include plasma exchange.
GENERAL MANAGEMENT PRINCIPLES — Therapy depends on the cause. (See 'Causes' above.)
Transfusion for severe anemia — Transfusion may be indicated if there is severe anemia with hemodynamic compromise, cardiac ischemia, or hemoglobin <7 to 8 g/dL. Transfusions should not be withheld if needed while awaiting diagnostic testing results, although it can be helpful to obtain a sample prior to transfusion. (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. (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 — Increased RBC production requires folates. Individuals with chronic hemolysis are generally treated with daily folate (typical dose, 1 mg orally per day) unless this would create an undue burden.
Low threshold for evaluating DVT/PE — Many hemolytic anemias, especially with severe or intravascular hemolysis, increase the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE). (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".)
Routine surveillance is generally not used outside of a clinical trial, but the threshold for evaluation should be low and individuals with hemolysis should seek medical attention for:
●Unexplained dyspnea, cough, or pleuritic chest pain
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 includes non-antibody-mediated processes that cause anemia, increased reticulocyte count, high lactate dehydrogenase (LDH) and indirect bilirubin, and low haptoglobin (table 1), along with a negative direct antiglobulin (Coombs) test (DAT). (See 'Definitions' above.)
•Genetic alterations of red blood cell (RBC) membrane proteins, enzymes, or hemoglobin (figure 1)
•Infectious organisms that invade and lyse RBCs
•Mechanical, thermal, and osmotic injury
•Oxidant drugs and toxins (table 2)
•Hypersplenism (table 7)
•Liver or kidney disease
Mechanisms and typical findings are discussed above. (See 'Causes' above.)
●Evaluation – Disease severity determines the pace of the evaluation and need for immediate interventions. An initial evaluation identifies Coombs (DAT)-negative hemolysis (algorithm 1). Clues from the history and initial laboratory testing narrow the diagnostic possibilities. Hematology consultation should be obtained if there is diagnostic uncertainty and/or need for rapid interventions. (See 'Evaluation' above.)
●Treatment – Management depends on the cause. General principles include transfusion for severe anemia with hemodynamic compromise or cardiac ischemia, hydration for significant intravascular hemolysis, folic acid for chronic hemolysis, and a low threshold for evaluating thromboembolic complications. (See 'General management principles' above.)
UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.
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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