W3L6 - Haemolytic Anaemia: Extrinsic Defects

Question 1

Extrinsic Haemolytic Anaemia

Answer 1

Extrinsic haemolytic anaemia results from external factors outside of the RBC that cause the premature destruction of the RBC
May be:
- intravascular
- extravascular
- combined

Question 2

Mediation of Extrinsic Haemolytic Anaemia

Answer 2

Mediated by a number of mechanisms

• physical or mechanical damage to RBC
• immune mediated processes
• antagonistic plasma substances

Question 3

Physical or Mechanical Trauma to RBC

Answer 3

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)

Question 4

Microangiopathic Haemolytic Anaemia

Answer 4

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

Question 5

Disseminated Intravascular Coagulation (DIS)

Answer 5

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

Question 6

Haemolytic Uraemic Syndrome

Answer 6

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

Question 7

March Anaemia

Answer 7

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

Question 8

Immune Haemolytic Anaemias

Answer 8

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

Question 9

Autoimmune Haemolytic Anaemias - Classification

Answer 9

Classified according to optimal temperature (OT) for antibody reactivity
Warm reactive antibodies: OT: 35-40°C
Cold reactive antibodies: OT: <30°C

Question 10

Autoimmune Haemolytic Anaemias - Warm Type

Answer 10

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

Question 11

Autoimmune Haemolytic Anaemias - Warm Type Clinical Features

Answer 11

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

Question 12

Autoimmune Haemolytic Anaemias - Warm Type Laboratory Findings

Answer 12

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

Question 13

Autoimmune Haemolytic Anaemias - Cold Type

Answer 13

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

Question 14

Autoimmune Haemolytic Anaemias - Cold Type Benign

Answer 14

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

Question 15

Autoimmune Haemolytic Anaemias - Cold Type Pathological

Answer 15

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

Question 16

Autoimmune Haemolytic Anaemias - Cold Type Pathological Laboratory Findings

Answer 16

FBC
- mild-moderate anaemia
- spurious macrocytosis (MCV)
- altered RBC sub populations
- reticulocytosis
Blood film:
- aggregates of RBC
- poikilocytosis
- ↑polychromasia
Bone Marrow:
- erythroid hyperplasia

Question 17

Combined Type AIHA

Answer 17

~7% of patients with AIHA have both warm (IgG) and cold (IgM) simultaneously
Referred to as:
- ‘mixed-type’ AIHA
- ‘combined warm & cold’ AIHA

Question 18

Evan’s Syndrome

Answer 18

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

Question 19

Primary Cold Agglutinin Disease

Answer 19

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)

Question 20

Alloimmune Haemolytic Anaemia Examples

Answer 20

Haemolytic transfusion reactions

Haemolytic disease of the newborn

Question 21

Drug Induced Immune Haemolytic Anaemia

Answer 21

~12% of immune haemolytic anaemia
Three main mechanisms
- autoantibody induction
- drug adsorption
- immune complex formation

Question 22

Drug Induced Immune Haemolytic Anaemia - Autoantibody Induction

Answer 22

Most common mechanism
- associated with aldomet (α- methyldopa) in 12-13% of patients
- 1-3% => AIHA
- autoantibody
- positive DAT
Examples:
- methyldopa
- chlorpromazine
- ibuprofen
- levodopa

Question 23

Drug Induced Immune Haemolytic Anaemia - Drug Absorption

Answer 23

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

Question 24

Drug Induced Immune Haemolytic Anaemia - Immune Complex Formation

Answer 24

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

Question 25

Antagonistic Plasma Factors

Answer 25

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

Question 26

Antagonistic Plasma Factors - Malaria

Answer 26

4 common species
- plasmodium vivax, P. falciparum, P. ovale. P. malariae
Direct RBC destruction due to parasite replication
=> Intravascular haemolysis
Incite increased extravascular haemolysis