Haemolytic Anaemia Flashcards
(19 cards)
Define anaemia.
Anaemia is a reduction in one or more of the major red blood cell (RBC) measurements obtained
as a part of the complete blood count (CBC): hemoglobin concentration, hematocrit, or
RBC count.
- Hgb = expression of amount (g/dL).
- Hct = expression of volume (% or decimal fraction).
- RBC = expression of number (number/mm3)
List the causes of haemolysis.
- Hereditary causes fall into 3 broad categories:
Inherited RBC defects (membrane defects) - hereditary spherocytosis, elliptocytosis, pyropoikilocytosis
Enzyme deficiencies - glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency
Haemoglobinopathies - sickle cell anaemia, thalassaemia.
- Acquired haemolytic anaemia can be subdivided into immune and non-immune aetiologies:
Autoantibodies are the cause of immune-mediated haemolytic anaemias, most often as part of other autoimmune conditions (e.g., SLE, rheumatoid arthritis, scleroderma) or related to a lymphoproliferative disorder (non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia).
Immune haemolytic anaemias can be divided into warm- or cold-reacting antibodies, depending on the temperature at which the antibody binds most avidly to the RBCs.
Alloimmune haemolytic anaemias include haemolytic disease of the newborn or transfusion reaction.
Many drugs are associated with haemolysis, some through immune-mediated mechanisms and others through non-immune-mediated mechanisms.
Other non-immune-mediated causes of acquired haemolysis include infection, trauma in various forms (MAHA - see later card), hypersplenism and liver disease.
Paroxysmal nocturnal haemoglobinuria is a rare disorder resulting in an acquired RBC membrane defect and subsequent haemolysis.
Summarise the pathophysiology of haemolytic anaemia.
- Haemolytic anaemia results from either intravascular or extravascular RBC destruction.
Extravascular haemolysis results from accelerated red cell destruction by cells of the reticuloendothelial system, due to immune targeting by antibodies, as occurs in a warm autoimmune haemolytic anaemia.
- E.g. autoimmune haemolysis is most often due to extravascular destruction of red cells coated with an autoantibody (Coombs’ positive).
- E.g. hereditary causes of haemolytic anaemia, including membrane defects, enzyme mutations, and haemoglobinopathies, generally result in anaemia due to significantly shortened RBC lifespan and removal of senescent red cells by the spleen.
Intravascular haemolysis results from red cell destruction within the vasculature, due to complement-mediated lysis or direct red cell trauma from a prosthetic heart valve or microangiopathic process.
- Intravascular haemolysis results in the release of RBC LDH (lactate dehydrogenase) and Hb into the circulation, which can result in haemoglobinuria. Free Hb is bound by haptoglobin, resulting in the decrease in haptoglobin that is observed in many intravascular causes of haemolytic anaemia.
List the major causes of microcytic, normocytic and macrocytic anaemia.
Microcytic: either iron deficiency or thalassaemia.
Normocytic: either blood loss or anaemia of chronic disease.
Macrocytic: either alcohol, haemolysis or B12 / folate deficiency.
Summarise the investigational findings of haemolytic anaemia.
Generic signs (can differ based on type of anaemia):
Increased RBC destruction: • High LDH • Low haptoglobin • High Bilirubin • Positive DAT • High MCV • BF: Spherocytes, polychromasia, RBCs fragments
Increased RBC production:
• High Reticulocytes.
• Erythroid hyperplasia in the bone marrow
Describe the direct and indirect antiglobulin (Coombs’) tests.
Direct: Pt blood sample taken, plasma removed to isolate RBCs coated with antibody, antihuman globulin added, +ve = agglutination
Indirect: Pt blood sample taken, RBCs removed to isolate plasma w/ free antibodies, antihuman globulin and animal RBCs added, +ve = agglutination.
Summarise the inheritance pattern, epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of G6PD deficiency.
G6PD deficiency:
• X-linked inheritance disorder.
• The commonest enzymatic disorder of red cells affecting 400-500 million people worldwide.
• The highest prevalence is in the Middle East, Tropical Africa and Asia.
• G6PD is a metabolic enzyme involved in the pentose phosphate pathway , important in red
blood cell metabolism.
• G6PD protects red cells from harmful effects of reactive oxygen radicles.
• G6PD is only source of NADPH in red cells
• Heterozygosity associated with resistance to malaria
Clinical manifestations:
• Haemolysis usually precipitated by an oxidative stress:
Drugs: eg primaquine, sulphonemaides, aspirin , quinine,etc
Infections
Food: fava beans (Favism)
• May present as neonatal jaundice.
• Anaemia, Jaundice in older age.
Diagnosis:
• Evidence of haemolysis: high LDH, retix and low
haptoglobin
• DAT –ve (non immune haemolysis).
• Blood film: Blister cells, bite cells and Heinz bodies,
non-spherocytic haemolytic anaemia.
• Enzyme assay (not in acute crisis) falsely high G6PD
levels (2-3/52 post haemolysis)
Treatment: Stop precipitating factors > folic acid > blood transfusion > splenectomy
Summarise the inheritance pattern, pathophysiology, clinical manifestations, diagnosis and treatment of pyruvate kinase deficiency.
Pyruvate kinase deficiency:
• Autosomal recessive disorder
• Reduced ATP production in RBCs
causing rigidity
Clinical:
Anaemia which is variable
Gall stones, jaundice
Diagnosis:
Enzyme assay
Treatment :
Symptomatic: folic acid +/- BT
Splenectomy in some cases
What is the difference between sickle cell anaemia and thalassaemia?
Describe the structure of haemoglobin.
SICKLE CELL DISEASE:
• An inherited mutation of the globin genes leading to a qualitative abnormality of globin synthesis
THALASSAEMIA :
• An inherited mutation of the globin genes leading to a quantitative abnormality of globin synthesis
- Haemoglobin has 2 alpha chains (4 genes in total) and 2 beta chains (2 genes in total).
Summarise the inheritance pattern, pathophysiology, clinical manifestations and treatment of sickle cell disease.
SICKLE CELL DISEASE: • Autosomal Recessive. • Beta globin chain defects, where glutamic acid is replaced by valine in position 6 (point mutation), forming HbS. • Exposure to low oxygen, causes Hb to precipitate to long crystals causing sickle cells.
Clinical manifestations: • Variable (phenotype/genotype) • Haemolytic anaemia • Vaso-occlusive disease: painful bony crisis, infants dactylitis . Acute chest crisis. Splenic sequestration crisis. Stroke. Haemolytic crisis Aplastic crisis -Parvo B19 • Chronic renal impairment (sickle nephropathy) • Infections (auto-splenectomy) • Retinopathy • AVN of the joints • Cardiac disease
Treatment: • Folic acid • Prophylactic antibiotics (auotsplenectomy) • Transfusion- HbS is a low affinity HB, low Hb well tolerated. • Exchange transfusion- certain indications. • ACEI- nephropathy • Hydroxycarbamide • New drugs: voxelotor, crizanlizumab • Bone marrow transplant in children and adolescents.
Describe the change in haemoglobin gene expression over time starting at conception.
- Following conception, epsilon and zeta haemoglobin initially predominate.
- These quickly decline and alpha and gamma predominate for the rest of pregnancy. Meanwhile, beta exists at low levels.
- After birth, gamma decreases and beta increases.
- By 48 weeks postnatal, only alpha and beta remain.
List 2 methods for the diagnosis of haemoglobinopathies.
Haemoglobinopathies can be diagnosed using HPLC or gel electrophoresis.
*Two methods are needed for confirmation of a Hb variant
Summarise the inheritance pattern, pathophysiology, clinical manifestations and treatment of thalassaemia.
- Autosomal recessive
Pathophysiology = quantitative defects:
1. Reduced synthesis of a normal globin chain
alpha or beta thalassaemia
2. Absent synthesis of a normal globin chain
alpha 0 thalassaemia or beta 0 thalassaemia
3. Unequal alpha and beta globin chain production
- Remember there are 4 alpha genes (2 from each parent) and 2 beta genes (1 from each parent). Genes can be mutated or missing entirely).
- For beta thalassaemias: 1 beta gene missing or mutated = thalassaemia trait, 2 beta genes mutated (not missing) or 1 mutated and 1 missing = beta thalassaemia intermedia, both missing = beta thalassaemia major
- For alpha thalassaemias: 4 alpha genes missing = Hb Barts (causes hydrobes faetalis which is incompatible with life), 3/4 missing is known as haemoglobin H disease (moderate to severe anaemia), 2/4 is thalassaemia trait and 1/4 is silent carrier. Don’t bother learning about alpha mutations.
Clinical manifestations: B-thal Major: • Presents early in life • Failure to thrive • Poor weight gain • Developmental delay. • Haemolytic anaemia. • Jaundice • Extramedullary haematopoiesis Hepatoslenomegaly , thalassaemic facies.
B-Thal intermedia:
Variable presentation
Severe anaemia( BT dependent )
or mild anaemia.
B-Thalassaemia trait:
Mild asymptomatic anemia
Treatment: • Regular Blood transfusion 3-4 weekly to prevent extramedullary haematopoiesis, NB risk of iron overload. • Iron chelation therapy. • Folic acid, prophylactic antibiotics. • Gene therapy. • Allogenic stem cell transplant.
Summarise hereditary spherocytosis.
• Autosomal dominant.
• Is an inherited abnormality of the red blood cell, caused by defects in structural membrane
proteins (RBCs cytoskeleton)
• Deficiency of Beta Spectrin or Ankyrin = RBC becomes more spherical instead of the
biconcave disc shape this affect deformability of RBCs whilst passing through
microcirculation .
• Spherocytes are phagocyted by macrophages and destructed in Spleen , hence reduced life
span.
Clinical manifestations: • Neonatal presentation: anaemia+ jaundice, more severe. • Infancy & childhood presentation: variable severity. Mild: asymptomatic. Moderate: intermittent jaundice, splenomegaly, anaemia. Severe: Transfusion dependent, bone expansion, pigmented gall stones.
Treatment: Blood transfusions Folic acid supplementation Cholecystectomy (gallstones are common) Splenectomy for Tx dependent
Summarise hereditary elliptocytosis.
- Autosomal Dominant
- Functional abnormality in one or more anchor proteins in RBC membrane- Alpha spectrin, Protein 4.1.
- Results in elliptical RBCs.
Clinical manifestations :
Vary from asymptomatic with no or mild haemolysis to severe haemolysis, depending on the genotype.
Treatment: Most are asymptomatic
Folic acid.
Blood transfusions
Splenectomy for Tx dependent
What is the difference between warm and cold autoimmune haemolytic anaemia?
Warm AIHA:
• Is caused by autoantibodies (usually IgG)
that bind red cells optimally in vitro at
37°C (body temperature).
• BF: spherocytes, macrocytes,
• DAT +ve for IgG+/- C3d
Clinical manifestations:
• Acute onset haemolytic anaemia,
jaundice.
Aetiology = secondary (malignancy, infection, drugs or immune).
Malignancy: CLL, lymphoma
Infection: Hepatitis C, HIV, CMV, TB, pneumococcus
Immune: SLE, UC, Sjogren’s, scleroderma, post-transplantation
Drugs: Penicillins, cephalosporins, fludarabine, interferons
Cold AIHA:
• Is caused by autoantibodies (usually IgM)
that bind red cells optimally in vitro at 4°C.
• The IgM Ab is a lower affinity and only
binds at cooler temperatures.
• DAT +ve for C3d >90%.
• BF: Red cell agglutination, a challenge for
identifying the correct ABO group
Clinical manifestations: Haemolytic anaemia Acrocyanosis: cold , painful & often blue fingers, toes, ears, or nose the correct ABO group.
Aetiology = primary or secondary
- Secondary causes: Malignancies(LPD), Infections
(Mycoplasma), Autoimmune disorders
Summarise haemolytic disease of the newborn.
- An alloimmune anaemia where the baby is RhD positive and mum is RhD negative.
Pathophysiology:
• Significant antibodies causing HDN are D,c and kell.
• Severe haemolytic anaemia and jaundice (risk of kernicterus, = brain damage in baby due to bilirubin)
Prevention:
• Close monitoring of antibodies quantity/titres during pregnancy.
• Routine anti-natal Anti-D Prophylaxis (RAADP) at 28 weeks+ anti D for any sensitization events.
Summarise MAHA.
- Microangiopathic haemolytic anaemia (MAHA) is a non-immune acquired haemolytic anaemia.
• Intravascular haemolysis, 2nd to
mechanical injury of the red blood cells whist
passing through fibrin strands deposited in the
small blood vessels.
• BF:Many RBC fragments and low platelets.
Causes include:
disseminated intravascular coagulation thrombotic thrombocytopenic purpura haemolytic uraemic syndrome malignant hypertension preeclampsia HELLP syndrome [haemolysis, elevated liver enzymes, low platelet count] in pregnancy mechanical prosthetic heart valves disseminated carcinoma thermal injury osmotic lysis drugs e.g. tacrolimus and cyclosporine A
Summarise TTP.
Thrombotic thrombocytopenic purpura (TTP) is a medical emergency. It is a pentad of:
- MAHA
- Thrombocytopenia
- Fever
- Renal failure
- Neurological symptoms
• Pathophysiology:
Deficiency of ADAMTS13 cleavage of the
ultra large VWF is defective platelets
aggregation and consumption.
INVESTIGATIONS: • Thrombocytopenia • BF: RBCS Fragments. • Haemolysis screen • DAT -ve • High troponin (due to myocardial necrosis) • Renal failure • Low ADAMTS13 level<5% • CT TAP
TREATMENT
• Immediate plasma exchange (PEX), before confirming the diagnosis.
• Steroids:either IV methylprednisolone (1 g/day for 3 days) or oral prednisolone (e.g.
1mg/kg/day) with an oral proton pump inhibitor)
• Folic acid
• Novel drugs: Caplacizumab, risk of bleeding, induces VWD like picture
• Rituximab: if cardiac or neurological symptoms.
• LMWH and aspirin, once platelets count >50.
