15. Sickle Cell Disease and Haemoglobinopathies Flashcards
Describe a normal HbA molecule, and thus what haemoglobinopathies are.
Describe the 2 groups of haemoglobinopathies: sickle cell disease and thalassaemias.
What are the genetics behind sickle cell disease?
4 globin chains: 2 α, 2 β. 4 haem molecules - one bound to each chain. Haemoglobinopathies: abnomalites affecting globin chains.
Sickle cell: presence of HbS (β chain mutation), painful crises, systemic vasculopathy, end organ damage, reduced life expectancy.
Thalassaemias: reduced/absent production of α or β chains -> imbalance -> ineffective erythropoiesis. Effects of anaemia. Effects of iron overload in transfused pts.
HbS: substitution of glutamate by valine in position 6 of the globin gene on chromosome 11. Hb forms polymers -> sickle shape RBC. Autosomal recessive inheritance pattern, carriers are asymptomatic.
What is the pathophysiology of HbS: why do sickle shapes form, and what 2 effects can this have?
What are some precipitating factors of sickle cell?
How is sickle cell diagnosed (clinically and or lab-based)?
When HbS is deO2 (e.g. in venous capillaries) it undergoes polymerization (gelation/crystallization) resulting in long polymers that deform the structure of RBC -> sickle shape. This can lead to vaso-occlusion/infarction, or haemolysis. Free Hb binds NO -> vasculopathy.
Hypoxia, HbS concentration/dehydration (less fluid so get stuck more), acidosis.
Clinical: Family hx, recurrent pain
Laboratory: anaemia, haemolysis (high bilirubin, high LDL, raised reticulocytes and undectectable haptoglobin), blood film, Hb electrophoresis/sickle solubility test (-ve = can see lines behind testtube of solution, +ve = can’t).
NB: haptoglobin binds free Hb released from erythrocytes with high affinityand thereby inhibits its oxidative activity. Haptoglobin-Hb complex is removed by reticuloendothelial system (mostly spleen)
What are some emergency presentations of someone with sickle cell?
What is a sickle cell crisis? What are the signs/symptoms, and precipitatinng factors?
How would you manage a sickle cell crisis? What would you monitor and investigate?
Pain/acute painful crisis (vasoocclusion, bone pain). Acute deterioration of anaemia: sequestration (intersplenic pooling of blood), aplastic crisis. Overwhelming sepsis. Acute chest syndrome. Stroke. Fat embolism syndrome/multi-organ failure. Renal impairment. Priapism. Acute visual loss.
Blood vessels blocked/ defective RBC damage organs. Rapid onset of bone pain; bone marrow infarction. Variable severity and duration (hrs-wks). Fever, bone tenderness +/- swelling, hypertension, tachycardia, tachypnoea. Precipitating factors: infections, skin cooling, dehydration, deoxygenation, stress.
Analgesia within 30mins from presentation. Parenteral opiate analgesia often required. Monitor vital signs, temp, fluid intake, analgesia use + pain score, sedation/urinary retention/restlessness. Ix: FBC + reticulocytes, U+Es/LFT, LDH, CRP, group and save, blood cultures? CXR?
What is acute chest syndrome?
Describe the pathophysiology of it.
How is it managed acutely?
Vaso-occlusive crisis of pulmonary vasculature commonly seen in pts with sickle cell anaemia. Most common cause of death in sickle cell pts. Commonly manifests with pulmonary infiltrate on a CXR. Incresed risk of death and chronic lung disease. Symptoms: CP, SoB, fever, cough.
Brought about by infection/asthma/hypoventilation -> inflammation/hypoxia/acidosis -> vasoocclusion within pulmonary microvasculature. Cycle. Fat embolism and pulmonary thrombi can exacerbate this.
Adequate analgesia, incentive spirometry - reduces ACS in pts admitted with vasoocclusive crisis. O2 therapy. NIV (non-invasive ventilation) valuable even if no severe hypoxia. Fluid management. Abx. Transfusion: TUT (top up transfusion) valuable, Extx (exchange transfusion) recommended for moderate/severe ACS.
What is overwhelming hyposplenic sepsis? What can cause it? What measures are needed to treat/manange it?
Acute deterioration of anaemia:
1) Sequestration. What is this? How is it managed?
2) Aplastic crisis (pic). What is this? How is it managed?
Splenic auto-infarction from a v. young age (most < 3yrs) -> functional asplenia. Can be caused by pneumoccal, meningococcal and haemophilius influenzae. Fulminant; 50% mortality. Febrile, coma, altered sensorium, seizures. Urgent abx tx. Prophylactic penicillin V. Vaccination.
1) Painful enlargement of spleen and drop in Hb ≥ 2g/L (high reticulocytes). Children (78% first events in < 2 yrs). Mortality 12%. Recurrence 50%. Management: early detection, parental education, urgent blood transfusion, splenectomy (if recurrent).
2) Temporary cessation of red cell production. 42 yo pt in pic: infection with HPV B19. Common childhood illness (“slapped cheek” disease (pic)). Infection of red cell precursors in bone marrow -> pure red cell aplasia -> low reticulocytes. Lowest Hb 15d post infection. Epidemics/siblings. Mx: urgent blood tx.
What is beta thalassaemia major?
Beta thalassaemia can cause severe anaemia - what effects does this have?
Regular transfusions are needed from early life to maintain Hb >10g/dL but what is the main risk of this?
Lack of production of β chains (usually due to point mutations in β globin genes on chromosome 11). Precipitation of unpaired α chains. The α chain inclusions are toxic to red cell progenitors. Ineffective erythropoiesis.
Growth failure.
Plasma volume expansion: worsening anaemia, heart failure.
Bone marrow expansion: “thalassaemic facies”, poor dentition, bone disease, extramedullary haemopoiesis. (pic)
Death in 1st-2nd decade without transfusion.
Transfusional iron overload. In β thalassaemia major without chelation, effects of haemosiderosis (form of iron overload disorder) appear by end of 1st decade. Death in teens/early 20s due to severe CF or arrhythmia.
What are the clinical sequelae of iron overload?
List some iron chelating agents.
How is iron status assessed (3 ways)?
Pituitary: impaired growth, infertility.
Thyroid: hypoparathyroidism
Heart: cardiomyopathy, cardiac failure
Liver: hepatic cirrhosis
Pancreas: diabetes mellitus
Gonads: hypogonadism.
Desferoxamine (continuous infusion), Deferiprone (oral), Deferassirox (oral), combination.
Liver biopsy (invasive, risk). Serum ferritin (quick, cheap, available, acute phase protein - non specific). Cardiac/liver MRI = gold std (pic).
What is α thalassaemia? Describe the 4 different severities.
4 α globin genes (2 from each parent) on chromosome 16. Reduced production of α chains = excess β cains but less toxic.
1 α gene defective: α thalassemia minima - silent carrier, no sympyoms. Low MCV, no evidence of iron deficiency. Dx by genetic testing.
2 α genes defective: α thalassaemia minor - mild microcytic hypochromic anaemia
3 α genes defective: HbH disease, 2 unstable Hbs (tetramers) present: HbBarts (γ4) and HbH (β4), which have higher affinity for O2. Microcytic hypochromic anaemia. Exercise capacity limited.
4 α genes defective: stillborn with hydrops fetalis, all HbBarts (γ4).
HbH seen most in SE Asia and Middle East.
What severities of α thalassaemia are these images depicting?
What is thalassaemia intermedia?
L: homozygous α 0 thalassaemia (–/–), 4 α genes defective, incompatible with life, hydrops fetalis.
R: HbH disease (α-/–), 3 α genes defective. Microcytic hypochromic anaemia of variable severity. HbH inclusion bodies. Tendency for iron overload.
Group of conditions, significant anaemia due to β thalassaemia but not transfusion dependent. Increased iron absorption -> risk of iron overload disproportionate to transfusion history.
Usually combination of severe disease with favourable factors or a mild condition with additional adverse characteristics e.g. β thalassaemia major with α thalassaemia trait = less α/β imbalance, OR β thalassaemia trait with triplicate α chains = more α/β imbalance. (pic)
What is the significance of antenatal screening/heel prick test?
ID all pregnancies at risk of clinical significant haemoglobinopathy. Offer partner screening and genetic counselling to affected couples. ID at birth all children with sickle cell: penicillin prophylaxis, immunisation, parent education.
What results are shown in the sickle solubility test on the L, and the electrophoresis HPLC on the R?
SST: L = -ve (can see lines behind tube), R = +ve (can’t see lines)
HPLC: peaks correspond with different Hbs:
top = carrier trait
middle: sickle cell. Retained some HbF as protective factor.
bottom = has sickle cell b/c Hb not very functional, so HbS more expressed phenotypically. But milder disease.
What do you deduce from this hx and CXRs?
Acute chest syndrome: (vaso-occlusive crisis of the pulmonary vasculature commonly seen in patients with sickle cell anemia) see bad bilateral pulmonary infiltrations, sickling and infarcting more, need exchange transfusion.
