W3L6 - Haemolytic Anaemia: Extrinsic Defects Flashcards
Extrinsic Haemolytic Anaemia
Extrinsic haemolytic anaemia results from external factors outside of the RBC that cause the premature destruction of the RBC May be: - intravascular - extravascular - combined
Mediation of Extrinsic Haemolytic Anaemia
Mediated by a number of mechanisms
- physical or mechanical damage to RBC
- immune mediated processes
- antagonistic plasma substances
Physical or Mechanical Trauma to RBC
Includes mechanisms that result in physical damage the RBC
- microangiopathic haemolytic anaemia
- traumatic cardiac haemolytic anaemia
- March haemoglobinuria
- thermal Injury
Characterised by fragments of RBC (schistocytes)
Microangiopathic Haemolytic Anaemia
Damaged endothelium of small blood vessels leads to fibrin deposits within the vessel
Flow forces RBC past fibrin strands => physical damage to cell
Membrane sliced open, when seals forms schistocytes
Damaged RBCs removed via extravascular haemolysis
Severely damaged RBCs undergo intravascular haemolysis
Disseminated Intravascular Coagulation (DIS)
Consumptive coagulopathy Complex cycle of clotting & fibrinolysis Many inciting causes - trauma - sepsis - neoplasia etc. Intravascular fibrin deposition Results in physical damage to RBC => schistocyte formation
Haemolytic Uraemic Syndrome
Most commonly occurs in children (< 5 y.o.)
Occurs after E. coli infection => acute renal failure
Localised intravascular coagulation
=> localised microangiopathic haemolytic anaemia
Concurrent thrombocytopenia
March Anaemia
Caused by mechanical damage to RBC Trauma to RBC within capillaries of the feet Results from prolonged marching/running - => schistocyte formation - => haemoglobinuria Commonly results in reticulocytosis
Immune Haemolytic Anaemias
Haemolysis is caused by antibody production by the body against it’s own RBC
- => subsequent anaemia
Antibody Mediated Haemolytic Anaemia
- autoimmune haemolytic anaemias (AIHA)
- alloimmune haemolytic anaemias (AlloIHA)
- drug induced
Autoimmune Haemolytic Anaemias - Classification
Classified according to optimal temperature (OT) for antibody reactivity
Warm reactive antibodies: OT: 35-40°C
Cold reactive antibodies: OT: <30°C
Autoimmune Haemolytic Anaemias - Warm Type
Most common form of AIHA (70%)
May be idiopathic (primary) or secondary to other disorders
- e.g. SLE, CLL
RBCs sensitised with IgG and/or complement (less commonly IgM, rarely IgA)
Haemolysis is predominantly extravascular (spleen, liver)
Opsonised RBC are phagocytosed by macrophages in Fc mediated process
Optimum in vitro reaction temperature is 37˚C
Autoimmune Haemolytic Anaemias - Warm Type Clinical Features
May occur:
- at any age; most > 40 y.o.; peak ~70 y.o.
Varying severity
- mild to severe
Clinical findings commonly reflect anaemia
- e.g. weakness, tiredness, jaundice etc.
Spleen is often enlarged (splenomegaly)
May occur alone (idiopathic) or with other diseases (e.g. SLE, ulcerative colitis, CLL, non haematopoietic tumours
Autoimmune Haemolytic Anaemias - Warm Type Laboratory Findings
FBC - anaemia - moderate-severe, normocytic normochromic - anisocytosis (↑ RDW) - hyperchromic subpopulation - reticulocytosis Blood film - spherocytes - ↑ polychromasia (reticulocytosis) Bone Marrow: - erythroid hyperplasia - decreased M:E ratio Other Tests: - direct antiglobulin test: positive - osmotic fragility: increased - unconjugated bilirubin: increased
Autoimmune Haemolytic Anaemias - Cold Type
May be benign or pathological
Pathological cold type comprises minority of AIHA
May be idiopathic (primary) or secondary to other disorders
Predominantly IgM (± complement)
In vitro RBC may lyse at 20-30°C
Autoimmune Haemolytic Anaemias - Cold Type Benign
Laboratory phenomenon
- i.e. patient not affected
Agglutination becomes apparent after blood sample is collected & temperature of the samples decreases
Some samples can be reversed by warming of cold samples
Some samples need to be kept warm from collection until processing
Autoimmune Haemolytic Anaemias - Cold Type Pathological
May occur:
- at any age
- either sex
Varying severity
- mild to severe
Haemolysis only with decrease temperature
May affect extremities
- numbness, tingling & pain
- acrocyanosis (purple discolouration) of the skin
Clinical findings commonly reflect anaemia
- e.g. weakness, tiredness, jaundice etc.
Spleen is seldom prominently enlarged
May occur alone (idiopathic) or with other diseases
Autoimmune Haemolytic Anaemias - Cold Type Pathological Laboratory Findings
FBC - mild-moderate anaemia - spurious macrocytosis (MCV) - altered RBC sub populations - reticulocytosis Blood film: - aggregates of RBC - poikilocytosis - ↑polychromasia Bone Marrow: - erythroid hyperplasia
Combined Type AIHA
~7% of patients with AIHA have both warm (IgG) and cold (IgM) simultaneously
Referred to as:
- ‘mixed-type’ AIHA
- ‘combined warm & cold’ AIHA
Evan’s Syndrome
Autoimmune haemolytic anaemia and immune thrombocytopenia and/or immune neutropenia Age at onset 19-88 y.o. M:F 40:60 IgG 43%, IgG + C3d 53%, Negative 4% May be primary or secondary Secondary, many underlying causes - autoimmune disease - immunodeficiency - lymphoma - miscellaneous
Primary Cold Agglutinin Disease
Onset 30-92 y.o. M:F 45:55 Hb: 45-156 g/L IgM 90%, IgG 3.5%, IgA 3.5% Transformation to lymphoma 3.5% (over 10 years)
Alloimmune Haemolytic Anaemia Examples
Haemolytic transfusion reactions
Haemolytic disease of the newborn
Drug Induced Immune Haemolytic Anaemia
~12% of immune haemolytic anaemia Three main mechanisms - autoantibody induction - drug adsorption - immune complex formation
Drug Induced Immune Haemolytic Anaemia - Autoantibody Induction
Most common mechanism - associated with aldomet (α- methyldopa) in 12-13% of patients - 1-3% => AIHA - autoantibody - positive DAT Examples: - methyldopa - chlorpromazine - ibuprofen - levodopa
Drug Induced Immune Haemolytic Anaemia - Drug Absorption
Drug or its metabolites bind to protein on RBC membrane Creates an immunogenic complex Antibodies produced to complex => extravascular haemolysis DAT positive Examples - cephalosporins - diclofenac - penicillins
Drug Induced Immune Haemolytic Anaemia - Immune Complex Formation
Drug or metabolite with low affinity for cell membrane combines with plasma protein Antibodies form, combine with RBCs in nonspecific manner Complexes activate complement Examples - acetaminophen = paracetamol - antihistamines - cephalosporins - chlorpromazine
Antagonistic Plasma Factors
Factors/substances/organisms within the blood that can have deleterious effects on RBC leading to haemolysis
Commonly intravascular but may be extravascular
Includes:
1. Chemicals
- oxidative: e.g. naphthalene, phenol, cresol
- non-oxidative: e.g. Lead, copper, arsenic
2. Animal Venoms
- may have direct action on membrane phospholipid or act via DIC
3. Infectious agents
- bacterial toxins
Antagonistic Plasma Factors - Malaria
4 common species
- plasmodium vivax, P. falciparum, P. ovale. P. malariae
Direct RBC destruction due to parasite replication
=> Intravascular haemolysis
Incite increased extravascular haemolysis
