Haemolytic anaemias Flashcards
What are the signs of haemolysis?
- Reduced Hb
- Reduced hematocrit (proportion of blood volume occupied by RBCs)
Increased serum bilirubin (Jaundice) - Gall stones
- Increased LDH
- Depletion of haptoglobin and hemopexin – specific for intravascular haemolysis
- Haemoglobinemia – specific for intravascular haemolysis
- Haemoglobinuria – specific for intravascular haemolysis
What are the signs of compensatory hematopoiesis in a patient with haemolytic anaemias?
Intramedullary hematopoiesis
- The bone marrow becomes hypercellular.
- In severe chronic hemolytic anemia, hematopoiesis extends into the marrow of long bones and skull.
- In the skull, this leads to a chipmunk-like face, frontal bossing (protruding forehead and maxilla).
Extramedullary hematopoiesis:
- In severe chronic hemolytic anemia, hematopoiesis extends into spleen and liver (outside the bone marrow). These organs will enlarge as a consequence
- Hepatosplenomegaly may also occur because of increased extravascular hemolysis.
Reticulocytosis: Increased erythropoiesis in the bone marrow as compensation for hemolysis leads to an increase in reticulocytes in the blood.
Haptoglobin and hemopexin synthesis: In patients with hemolytic anemia due to increased intravascular destruction, haptoglobin and hemopexin will get consumed. To compensate, the liver synthesizes more haptoglobin and hemopexin.
What are the causes of haemolytic anaemia?
Genetic disorders:
- Hereditary spherocytosis
- G6PD deficiency
- Thalassemia
- Sickle cell disease
- Paroxysmal Nocturnal Hemoglobinuria
Infections:
- Malaria
Autoimmune Haemolytic Anemia
- Cold (IgM): results in intra-vascular haemolysis via complement
- Warm (IgG): results in extra-vascular haemolysis
Microangiopathic Haemolytic Anaemia (MAHA) ( results in Intra-vascular haemolysis)
- TTP: check ADAMTS13
- HUS: Previous E Coli Infection, Check for Uraemia
- DIC: DIC Panel of Coag Time, Fibrinogen Levels, Plt Levels, D Dimers
- (HELLP) Eclampsia: Check BP, Urine Pregnancy Test
- HIT: previous heparin use
Drugs
- Methyldopa
- Quinine
- NSAIDS
- Interferon
- RIbavarin
[Hereditary spherocytosis]
Hereditary spherocytosis is the most prevalent haemolytic anaemia of people of Northern European descent (approximately 1 in 5000).
___________ are a characteristic feature.
RBC membrane is not anchored properly to cytoskeleton, lipid is lost by vesiculation, resulting in spherical, less deformable RBCs. This is caused by mutations of proteins (__________ -50%, ____________ - 25%, ______________ -25%) that cause cytoskeleton instability in RBCs.
Spherocytes cannot traverse the ______________, break down and are engulfed by splenic macrophages.
Patients with HS develop splenomegaly because of increased macrophage-phagocytosis of spherocytes.
Migration of spherical RBC through the main blood stream is not impaired.
Abnormally shaped RBCs (spherocytes)
Ankyrin;
spectrin;
anion exchanger;
splenic sinuses
[Hereditary spherocytosis] What are the investigations of hereditary spherocytosis?
Peripheral Blood Smear
- In a peripheral blood smear the RBCs appear smaller and lack the central pallor that is present in normal RBCs.
- As a result, they are hyperchromic and they show both an increased thickness and an increase in MCHC (mean corpuscular hemoglobin concentration).
Osmotic fragility test: Exhibit increased osmotic fragility
[Hereditary spherocytosis] What is the management of hereditary spherocytosis?
Splenectomy (partial splenectomy) reliably corrects anemia although spherocytes persist in the circulation.
- Splenectomy cures the anemia but doesn’t correct the abnormal RBC shape.
- Splenectomy is postponed until the age of four to minimize risk of infections with Gram-positive encapsulated organisms (Pneumococci).
Polyvalent pneumococcal vaccine should be administered two weeks before splenectomy to prevent S. pneumoniae infection.
Folic acid supplements also important.
[Sickle cell anaemia]
Point mutation: Negatively charged glutamic acid (Glu) at position 6 in the beta globin protein is replaced by the _________________.
The association of two normal alpha globin chains with two mutant beta globin chains results in HbS (Sickle hemoglobin).
Polymerization and sickling: HbS polymerizes under ______________.
- ß6-Valine (a hydrophobic residue) interacts with neighboring hydrophobic residues.
- Intermolecular bonding leads to the build up of long polymerized chains of Hb, which deforms the RBC causing sickling, and transforms the RBC into abnormal, rigid, sickle shape.
RBC dehydration and RBC death:
- The deforming process induces an increase in cytoplasmic calcium, which in turn activates a calcium-activated potassium channel called KCa3.1 (KCNN4).
- Potassium ions are lost through the open KCa3.1 channel.
- Water is dragged along with it. The RBC dehydrates leading to more sickling, and many of these dehydrated cells will die.
Occlusion and ischemia:
- Sickle-shaped red blood cells obstruct capillaries and restrict blood flow to an organ, resulting in ischemia, pain and necrosis leading to _____________________
Hemolytic anemia: Sickled cells, because of their abnormal shape, are lysed in the ___________. The resulting hemolysis leads to anemia.
hydrophobic amino acid valine (Val);
low oxygen conditions;
vaso- occlusive crises (stroke, necrosis of bone, skin ulcers, kidney failure, blindness)
spleen
[Sickle cell anaemia]
What is the clinical manifestations of a patient with sickle cell trait (HbAs)?
These individuals have one normal beta globin gene and one Bs gene. There is a mixture of HbA and HbS at a 60:40 ratio. HbAS only sickle when O2 saturation <40%.
They are usually asymptomatic except under low oxygen conditions.
Survival value in carrying the sickle cell mutation in an endemic malaria area (1 in 10 people of African descent).
[Sickle cell anaemia]
What is the clinical manifestations of a patient with sickle cell disease (HbSS)?
Autosomal recessive hemolytic anemia in an individual with two mutant ßs genes T
hey develop two types of clinical symptoms, those due to destruction of red blood cells (hemolytic anemia) and those due to occlusion of small blood vessels by sickled RBCs.
Symptoms only develop a few months after birth when HbF decreases.
[Sickle cell anaemia]
What is the clinical manifestations of a patient with vaso- occlusive crisis?
Sickled cells are unable to pass through capillaries efficiently and therefore impede the blood flow.
Acute episodes of pain in the abdomen occur due to splenic or liver infarctions.
Pulmonary disease occurs in about 50% of patients.
Plugs of sickled cells block blood vessels to bones resulting in bone destruction (osteonecrosis leading to a fish vertebra appearance). Chronic osteomyelitis (infection of the bone) secondary to the poor blood flow to bones can develop.
Microvascular occlusion in the feet can cause ulcers; in the brain stroke; in the retina it causes blindness; while placental infarctions in pregnant women can lead to fetal loss.
[Sickle cell anaemia] What are the investigations required for patients with sickle cell anaemia?
Sodium metabisulfite (sodium hydrosulfite) screening test: . The compound induces a low oxygen state, which causes the HbS in the RBCs to polymerize, leading to RBC sickling.
Sickle Solubility test: A mixture of hemoglobin S (Hb S) in a reducing solution such as sodium dithionite gives a turbid appearance, whereas normal Hb gives a clear solution.
Hemoglobin electrophoresis : Different hemoglobins migrate differently during electrophoresis.
[Sickle cell anaemia] What is the management of patients with sickle cell anaemia?
Supportive therapy
- Acute painful attacks require supportive therapy with IV fluids and adequate analgesia.
- Morphine is the drug of choice as pain can be very severe.
- Milder pain can sometimes be relieved by codeine, paracetamol and NSAIDs. O2 and antibiotics are only given if specifically indicated.
- Blood transfusions should only be given for clear indications (heart failure, TIAs, strokes, ACS, acute splenic sequestration, aplastic crises, before elective operations and pregnancy).
Prophylaxis
- Prophylaxis is with penicillin 500 mg daily and vaccination with polyvalent pneumococcal and Haemophilus influenzae type b vaccine.
- Folic acid is given to all patients with haemolysis.
Hydroxyurea
- Hydroxyurea increases the production of fetal Hb (HbF, α2γ2) in RBCs of patients with sickle cell disease.
- RBCs will then contain a mixture of HbS and HbF.
- The presence of HbF in the RBCs reduces polymerization of HbS and thereby reduces sickling.
Stem cell transplantation: Children and adolescents younger than 16 years of age who have severe complications (strokes, recurrent chest syndrome or refractory pain) and have an HLA-matched donor are the best candidates for transplantation.
[G6PD deficiency] What are the precipitants of haemolysis?
Infections
Drugs:
- Analgesics: aspirin
- Anti-malarials: primaquine, quinine, chloroquine, pyrimethamine
- Antibiotics: sulfonamides, ciprofloxacin, nitrofurantoin
- Miscellaneous: quinidine, probenecid, vitamin K, dapsone
Favism: eating fava beans (beans contain chemicals that give rise to oxygen free radicals) precipitates hemolysis in individuals with G6PD deficiency
[G6PD deficiency] What are the investigations findings in a G6PD patient?
G6PD and NADPH levels:
- G6PD levels measured in RBCs.
- Beutler’s Fluorescent test: Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies NADPH produced by G6PD under ultraviolet light. When the blood spot does not fluoresce, the test is positive i.e. decreased NADPH, possible G6PD deficiency.
Peripheral blood smear:
- Bite cells (RBCs with a ‘bite’ of membrane missing)
- Blister cells (RBCs with surface blistering of membranes)
- Irregularly shaped small RBCs
- Reticulocytosis: Reticulocytes contain cytoplasmic RNA, which stain with supravital dyes giving rise to a reticular pattern, hence the name reticulocyte.
- Denatured hemoglobin (Heinz bodies): Visible in RBCs when stained with supravital dyes (e.g. crystal violet)
[G6PD deficiency] What is the management of a G6PD patient?
- Any offending drugs should be stopped.
- Underlying infection should be treated.
- Blood transfusion may be life-saving.
- Splenectomy is not usually helpful.
