Approach
Once the diagnosis of haemolytic anaemia has been determined, a haematological consultation is warranted.
All aetiologies of haemolytic anaemia require some degree of supportive care. Supportive care includes folic acid supplementation. Folic acid is useful for patients with a high reticulocyte count, as it is rapidly depleted in the setting of increased red cell production.
Blood transfusion and plasmapheresis are considered to be rescue (emergency) therapies in patients with autoimmune haemolytic anaemia.
Acquired: direct antiglobulin test (Coombs') positive
A positive direct antiglobulin test indicates an immune-mediated disease process.
The treatment for these subtypes of haemolytic anaemia consists of supportive care plus removal of the insult (infection, drug, etc.), if one is present. Corticosteroids can lead to decreased antibody production and resolution.[37] Rituximab should be considered for patients refractory to 3 weeks of corticosteroid therapy. Splenectomy removes the site of significant antibody production and the predominant site of red blood cell (RBC) destruction, if patients do not respond to initial therapies.[37][38] Splenectomy is typically not effective in cold autoimmune haemolytic anaemia (AIHA) because extravascular haemolysis occurs in the liver.[37][38][46] Approximately one third of patients may relapse after splenectomy.[37][38]
Autoimmune haemolytic anaemia: warm and cold
Initial management of AIHA includes the removal of the insult, if present. Management of an underlying condition may include treating infection in warm AIHA or treating lymphoma in cold AIHA.
Patients with warm AIHA, and most patients with cold AIHA, will also require pharmacological management in addition to removal of the insult.[10][37][46] A corticosteroid may be used in warm or cold AIHA (with or without rituximab). Warm AIHA is much more likely to respond to corticosteroids than cold AIHA.[38] Sutimlimab (a humanised monoclonal antibody that selectively targets and inhibits complement component 1 [C1]-activated haemolysis) can, therefore, be considered as an alternative to corticosteroids in patients with cold AIHA.[46][47] Treatment with sutimlimab for up to 2 years resulted in sustained improvements in anaemia and haemolysis, although markers of anaemia and haemolysis returned to close to baseline after discontinuation of sutimlimab.[48][49] Sutimlimab increases susceptibility to serious infections; patients prescribed sutimlimab must be immunised against encapsulated bacteria (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae) at least 2 weeks before beginning treatment. Respiratory tract infection, viral infection, diarrhoea, dyspepsia, cough, arthralgia, arthritis, and peripheral oedema are common with sutimlimab. Sutimlimab is approved by the US Food and Drug Administration (USFDA) as the first treatment for use in patients with cold agglutinin disease to decrease the need for red blood cell transfusion due to haemolysis. Sutimlimab is approved by the European Medicines Agency for the treatment of haemolytic anaemia in adult patients with cold agglutinin disease.
Remission of AIHA can be seen within 1-3 weeks of treatment with corticosteroid therapy. Once the haemolysis is corrected, corticosteroids must then be tapered. Absence of response by 21 days should be considered a corticosteroid failure.[37][38] Taper corticosteroid in unresponsive patients at 21 days.[38] Close monitoring for relapses is required for a few weeks, with slowing of corticosteroid taper if signs of possible relapse develop.
Many patients may benefit from effective corticosteroid-sparing therapy prior to consideration of splenectomy.[37] Rituximab should be considered for patients with warm or cold AIHA who are refractory to 3 weeks of corticosteroid therapy, and for those patients who relapse during or after corticosteroid tapering.[37][38] One meta-analysis that evaluated response to rituximab in observational studies reported overall response rates of 79% for warm AIHA and 57% for cold agglutinin disease.[50] Approximately 50% of patients received concomitant corticosteroids. A subsequent meta-analysis of two randomised controlled trials concluded that combination therapy with rituximab and corticosteroid may increase the rate of complete haematological response compared with corticosteroid alone (very low-certainty evidence) in patients with newly diagnosed warm AIHA.[51] Infusion-related reactions and infections have been reported in patients with AIHA receiving rituximab therapy.[50][52]
Third, and subsequent, lines of therapy for patients with warm AIHA include azathioprine, ciclosporin, danazol, and mycophenolate.[37][38]
Supportive therapies include cold avoidance in patients with cold AIHA; avoid active cooling for fever.[37][38] Consideration should be given to the use of a blood warmer in patients with cold AIHA.[37]
Folic acid supplementation is widely practised, and is recommended in some guidelines.[37][38]
Blood transfusion and plasmapheresis are considered to be rescue (emergency) therapies in patients with AIHA. Transfusion may be considered if anaemia is life-threatening; uncertainty regarding matching should not delay transfusion.[37][38] Plasmapheresis may be considered in severe haemolysis requiring repeated transfusions, but its effects are transient. Plasmapheresis may serve as bridging therapy while immunotherapy is instituted.
AIHA: haematological malignancy
Reported most frequently in patients with chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL).[53] CLL treatment options include a conservative (watch and wait) approach, chemoimmunotherapy, targeted therapies, and stem cell transplant. For patients with NHL, lymphoma type and remission status will influence the decision to direct therapy towards the malignancy or to AIHA.[53] See Chronic lymphocytic leukaemia and Non-Hodgkin's lymphoma.
AIHA: infection
Supportive care together with treatment for the infection is used to address the cause of haemolysis. Corticosteroids may be indicated in specific circumstances (e.g., patients with severe and persistent cold haemagglutinin disease secondary to atypical and mycoplasma pneumonia).[53] See Malaria infection, Babesiosis, Bartonella infection, Leishmaniasis, Bacterial meningitis in adults, and Atypical pneumonia (non-COVID-19).
AIHA: drug-induced
Offending drugs affect the immune system, resulting in the production of RBC autoantibodies.[12]
The most commonly implicated drugs include cephalosporins, diclofenac, rifampicin, oxaliplatin, and fludarabine.[12][54] The inciting drug should be discontinued. Haematological improvement may be evident within 1-2 weeks.[53] It is unclear whether corticosteroids are of benefit.[53] The decision to prescribe a corticosteroid should be informed by severity of haemolysis and strength of clinical suspicion that haemolysis is drug-induced.[53]
Acquired: direct antiglobulin test (Coombs') negative
A negative direct antiglobulin test suggests a non-immune disease mechanism. Non-immune haemolysis will not respond to immune suppression; therefore, corticosteroids are not indicated in most of these subtypes. Treatment for these aetiologies consists primarily of supportive care, along with removal of an offending agent if present.
Some aetiologies require more directed therapy
Drug-induced non-immune haemolytic anaemia: drugs can induce non-immune destruction of RBCs, usually by oxidative stress.[30] Therapy consists of discontinuation of culprit drug(s) and supportive care until the haemolysis process ends. Unlike in immune-mediated drug-induced haemolysis, corticosteroids and splenectomy are not generally useful and the emerging therapies, which target the immune system, are not indicated.
Infection or bacterial toxin: supportive care together with treatment for the infection is used to address this cause of haemolysis.
Footstrike (march) haemolysis: resolves when exceptional physical exertion stops.
Thermal injury, osmotic lysis: therapy consists of supportive care and removal of the insult.
Liver disease: consider splenectomy in patients with liver disease. Liver disease may cause haemolysis through acquired membrane defect or splenomegaly. Consensus guidelines have considered portal hypertension to be a contraindication to laparoscopic splenectomy, but there is some evidence to suggest that this may no longer be the case.[55][56][57] Consult local guidance.
Prosthetic valve haemolysis: subclinical haemolysis is not uncommon, even with more contemporary prostheses (≥5% in some studies).[22] It is generally well tolerated, so significant worsening suggests possible valve dysfunction requiring urgent evaluation by a cardiologist. Medical and supportive therapy is usually appropriate for patients with mild prosthesis-related haemolysis.[22] Patients with severe symptomatic haemolysis, despite maximal medical therapy, require invasive treatment informed by the type of prosthesis and the haemolytic mechanism.
Thrombotic thrombocytopenic purpura: clinical syndrome characterised by microangiopathic haemolytic anaemia and thrombocytopenic purpura.[58] A combination of plasma exchange therapy, with the intent of stopping the causative process, and corticosteroids is the mainstay of treatment.[59] See Thrombotic thrombocytopenic purpura.
Paroxysmal nocturnal haemoglobinuria (PNH): haemolytic anaemia characterised by evidence of intravascular haemolysis such as haemoglobinuria and elevation of plasma lactate dehydrogenase. First-line therapies for paroxysmal nocturnal haemoglobinuria, eculizumab and ravulizumab, are monoclonal antibodies to the fifth component of complement. Eculizumab and ravulizumab improve health-related quality of life and increase transfusion independence.[60][61] The complement C3 inhibitor, iptacopan, and complement factor B inhibitor, pegcetacoplan, are also first-line options for PNH. See Paroxysmal nocturnal haemoglobinuria.
Inherited disorders
Treatment for these disorders varies by pathophysiology. Supportive care with transfusions as needed is an important adjunct, as with all aetiologies of haemolytic anaemia.
Red cell membrane disorders (hereditary spherocytosis, elliptocytosis, pyropoikilocytosis)
Splenectomy will often result in significant decrease in haemolysis.[62] Indications for splenectomy in patients with hereditary spherocytosis include severe anaemia/transfusion dependence. The decision will be premised upon quality of life issues and spleen size in patients with moderate hereditary spherocytosis.[62] See Hereditary spherocytosis.
Red cell enzyme defects (glucose-6-phosphate dehydrogenase deficiency [G6PD], pyruvate kinase deficiency)
G6PD deficiency: common inciting drugs in G6PD deficiency are sulfa drugs, nitrofurantoin, and salicylates.[63] These should be pre-emptively avoided and discontinued if in use. Other possible triggers include naphthalene, fava beans, nitrites, dapsone, ribavirin, phenazopyridine, or paraquat.[28][64] See Glucose-6-phosphate dehydrogenase deficiency.
Pyruvate kinase deficiency therapy is primarily supportive, including transfusions. Splenectomy may be considered for severe cases.[65]
Mitapivat, an oral pyruvate kinase activator, is the first disease-modifying therapy approved by the USFDA for the treatment of haemolytic anaemia in adults with pyruvate kinase deficiency. Approval was based on results from phase 3 trials that demonstrated, respectively: improved haemoglobin response in 16 (40%) participants receiving mitapivat compared with placebo; and a reduction in transfusion burden by at least 33% in 10 (37%) participants.[66][67] Common adverse reactions include decreases in oestrone and oestradiol in men, increased urate, back pain, and arthralgia.
Haemoglobinopathies (sickle cell anaemia, thalassaemia)
Supportive care is the primary therapy, alongside reducing the threat of infection. Adjunctive therapies in sickle cell crises can include oxygen, pain control, aggressive hydration, and treatment of any concurrent stressors (e.g., infection). See Sickle cell anaemia.
How to insert a peripheral venous cannula into the dorsum of the hand.
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