Acquired Haemolytic Anaemias

Can be divided into immune or non-immune

Immune Haemolytic Anaemias

·         These can be subdivided into:

·         Autoimmune

·         Alloimmune

·         Drug-induced

Autoimmune Haemolytic Anaemias (AIHA)

·         Caused by antibodies produced by patient’s own immune system

·         Classified according to thermal properties of antibodies:

·         warm antibodies bind to RBC most avidly at 37⁰C

·         cold antibodies bind best below 32⁰C

Warm AIHA:

·         Antibody usually IgG, but may be IgM or IgA

·         Usually facilitate sequestration of sensitized RBCs in spleen

·         May be primary or secondary - autoimmune disorders, HIV, chronic lymphocytic leukaemia (CLL), non-Hodgkin's lymphoma (NHL)

·         Most common type

Incidence:

·         Occurs in either sex but female preponderance reported esp. primary

·         Occurs in all ages

Higher incidence of secondary noted in patients > 45 years

Clinical Features:

·         Haemolytic anaemia of varying severity

·         Tends to remit and relapse

·         Symptoms of anaemia

·         Jaundice

·         Splenomegaly

·         Symptoms of underlying disorder (if 2⁰)

Laboratory Features:

·         Variable anaemia

·         Blood film: polychromasia, microspherocytes

·         Severe cases: nucleated RBCs, RBC fragments

·         Mild neutrophilia, normal platelet count

·         Evan’s syndrome: association with ITP

·         Bone marrow: erythroid hyperplasia; underlying lymphoproliferative disorder

·         Unconjugated hyperbilirubinaemia

·         Haptoglobin levels low

·         Urinary urobilinogen usually increased; haemoglobinuria uncommon

Serological Features:

·         Direct antiglobulin test (DAT; Coomb's test) usually positive

·         DAT: rabbit antiserum to human IgG or complement (Coomb's reagent) added to suspensions of washed RBCs. Agglutination signifies presence of surface IgG or complement

·         RBC may be coated with

·         IgG alone

·         IgG and complement

·         complement only

·         Rarely anti-IgA and anti-IgM encountered

Treatment:

·         Remove/treat underlying cause

·         Corticosteroids - high doses then tapering when PCV stabilizes

·         Splenectomy:

·         patients who fail to respond to steroids

·         unacceptably high doses of steroids to maintain adequate PCV

·         unacceptable side-effects

·         Transfusion

·         Immunosuppressive Drugs:

·         Azathioprine

·         Cyclophosphamide (CTX)

·         Others:

·         plasmapheresis

·         Intravenous immunoglobulin (IVIG)

·         Androgens e.g. danazol

Cold AIHA:

·         Two major types of cold antibody: cold agglutinins and Donath-Landsteiner antibodies

·         Causes either immediate intravascular destruction of sensitized RBCs by complement-mediated mechanisms or sequestration by liver (C3 coated RBCs preferentially removed here)

                                                                                                           

Cold Agglutinins:

^·          IgM autoantibodies that agglutinate RBCs optimally between 0 to 5⁰C. Complement fixation occurs at higher temperatures

^·          Primary - Cold Haemagglutinin Disease (CHAD) or secondary (usually due to infections)

^·          Peak incidence for CHAD > 50 years

^·          Primary usually monoclonal; secondary usually polyclonal

Pathogenesis:

^·          Specificity usually against I/i antigens

^·          Varying severity depending on:

^·          titre of antibody in serum

^·          affinity for RBCs

^·          ability to bind complement

^·          thermal amplitude

^·          Bind red cells in peripheral circulation impeding capillary flow, producing acrocyanosis

Clinical Features:

^·          Chronic haemolysis; episodes of acute haemolysis can occur on chilling

^·          Acrocyanosis frequent; skin ulceration and necrosis uncommon

^·          Mild jaundice and splenomegaly

^·          Secondary cases e.g. Mycoplasma, self-limited

Laboratory Features:

·         Anaemia- mild to moderate

·         Blood film: agglutination, spherocytosis less marked than warm AIHA

·         DAT +ve: complement only

·         Anti-I: idiopathic disease, mycoplasma, some lymphomas

·         Anti-i: infectious mono, lymphomas

Treatment:

·         Keep patient warm

·         Treat underlying cause

·         Alkylating agents: chlorambucil, CTX

·         Splenectomy and steroids generally not helpful

·         Plasmapheresis- temporary relief

·         Transfusion- washed packed cells

Paroxysmal Cold Haemoglobinuria

·         Rare form of haemolytic anaemia

·         Characterized by recurrent haemolysis following exposure to cold

·         Formerly, more common due to association with syphilis

·         Self-limited form occurs in children following viral infections

·         Antibodies usually IgG with specificity for P antigen

·         Biphasic: binds to red cells at low temperatures, lysis with complement occurs at 37C

Drug-induced Haemolytic Anaemia

·         May cause immune haemolytic anaemia by three different mechanisms:

1)      Drug adsorption mechanism e.g. Penicillin

2)      Neoantigen type e.g. Quinidine

3)      Autoimmune mechanism e.g. a - Methyldopa

 

Drug adsorption mechanism

·         Also known as hapten mechanism

·         Drug binds tightly to red cell membrane

·         Antibody attaches to drug without direct interaction with RBC

·         Usually seen in patients receiving high doses of penicillin – substantial coating of RBC with drug

·         Small proportion develop anti-penicillin antibody Ô binds to drug on RBC

·         DAT +ve and haemolysis may ensue

·         Occurs after 7-10 days of treatment

·         Ceases few days to 2 weeks after drug stopped

Neoantigen type

• Formerly known as immune complex / innocent bystander
• Old theory suggested drug formed immune complex with anti-drug antibody Ô attached non-specifically to red cell Ô destruction by complement
• However where complex displays rare specificity for a particular antigen on RBC e.g. I, antibody does not bind to cells lacking that antibody, even in presence of drug
• Suggests that interaction required component of red cell membrane to bind to antigen recognition site on antibody

Autoimmune mechanism

·         Truly autoimmune in nature

·         Antibody binds to red cell membrane antigens in a manner indistinguishable from sporadic AIHA

·         Alpha-methyldopa responsible for most cases

·         DAT becomes +ve in 8-36% of patients taking drug

·         However, only 0.8% of patients develop clinical haemolysis

·         Induces auotimmune red cell antibodies by unknown mechanisms

Alloimmune Haemolytic Anaemias

·         Two important situations:

·         ABO incompatibility

·         Haemolytic disease of the newborn

                                   

ACQUIRED HAEMOLYTIC ANAEMIA (2)

Non-immune haemolytic anaemias:

·         Paroxysmal nocturnal haemoglobinuria (PNH)

·         Red cell fragmentation syndromes

·         March haemoglobinuria

·         Infections

·         Chemical and physical agents

·         Secondary haemolytic anaemia

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Paroxysmal nocturnal haemoglobinuria (PNH)

·         Acquired haemopoietic stem cell disorder

·         Characterized by increased sensitivity of red cells to haemolysis by complement

Pathogenesis: 

·         Arise as a clonal abnormality of stem cells

·         Disorder a consequence of somatic mutations Ô error in synthesis of the glycosylphosphatidylinositol (GPI) anchor

·         Results in deficiencies of several GPI-anchored membrane proteins – decay accelerating factor (DAF), membrane inhibitor of reactive lysis (MIRL), acetylcholine esterase, leukocyte alkaline phosphatase (LAP)

·         Some of these proteins involved in complement degradation

·         Absence of MIRL plays most critical role

Clinical Features:

·         Haemoglobinuria occurs intermittently precipitated by a variety of events

·         Nocturnal haemoglobinuria uncommon

·         Chronic haemolytic anaemia which may be severe

·         Iron deficiency due to loss in urine

·         Bleeding may occur secondary to thrombocytopenia

·         Thrombosis a prominent feature

Laboratory Features:

·         Pancytopenia

·         Anaemia may be severe

·         Macrocytosis may be present due to mild reticulocytosis

·         Hypochromic, microcytic due to iron deficiency

·         Marrow: erythroid hyperplasia; may be aplastic

·         Urine: haemosiderinuria constant feature; haemoglobin sometimes present

·         Ham’s (acidified serum lysis) test positive

Treatment:

·         Transfusion of washed packed red cells

·         Oral iron

·         Folate supplements

·         Steroids may be of benefit

·         Anticoagulation for thrombotic complications

Course:

·         Variable

·         May transform to acute leukaemia or aplastic anaemia

Red Cell Fragmentation Syndromes

1.      Microangiopathic haemolytic anaemia (MAHA)

·         Intravascular haemolysis due to fragmentation of normal red cells passing through abnormal arterioles

·         Deposition of platelets and fibrin most common cause of microvascular lesions

·         Red cells adhere to fibrin and are fragmented by force of blood flow

·         Underlying disorders:

·         Mucin-producing adenocarcinomas

·         Complications of pregnancy: Preeclampsia, eclampsia, Haemolysis, Elevated Liver enzymes, Low Platelets (HELLP)

·         Disseminated Intravascular Coagulation (DIC)

·         Thrombotic Thrombocytopenic Purpura (TTP)/ Haemolytic Uraemic Syndrome (HUS)

·         Malignant hypertension

·         Drugs: mitomycin, bleomycin, cisplatin

Laboratory Findings:

·         Blood film: schistocytes prominent, spherocytes, reticulocytes, normoblasts

·         Thrombocytopenia

·         Coagulopathy in DIC

Treatment:

·         Treat underlying cause

2.   Traumatic cardiac haemolytic anaemia

·         Seen in patients with prosthetic heart valves, cardiac valvular disorders esp. severe aortic stenosis

·         Due to physical damage of red cells from turbulence and high shear

stresses

·         Haemolytic anaemia usually mild and well compensated

March Haemoglobinuria

·         Due to damage to red cells between small bones of feet

·         Usually during prolonged marching or running

·         Blood film does not show fragments

Infections

·         Cause haemolysis in a variety of ways

·         Ppt acute haemolytic crisis in G6PD deficiency

·         Cause MAHA e.g. meningococcus

·         Direct invasion of red cells by infective organisms e.g. malaria

·         Elaboration of haemolytic toxins e.g. clostridium

·         Production of red cell autoantibodies e.g. viral infections

Chemical and physical agents

·         Certain drugs cause oxidative damage in high doses e.g. dapsone

·         Acute haemolytic anaemia due to high levels of Cu e.g. Wilson’s disease

·         Chemical poisoning e.g. Pb, chlorate or arsine may cause severe haemolysis

·         Severe burns

·         Snake / spider bites

·         Hypophosphataemia

Secondary haemolytic anaemias

·         Red survival shortened in many systemic disorders

·         Renal failure – ‘burr’ cells

·         Liver disease – acanthocytes, target cells

·         Zieve’s syndrome – acute haemolytic anaemia with intravascular haemolysis, hyperlipidaemia and abdominal pain in alcoholics