Sickle cell disease
Sickling syndromes
Diagnosis § Blood film § Normal at birth § Sickle cells – variable numbers – less when there is a lower MCHC § Boat cells – elongated with pointed ends § Target cells and Howell-Jolley bodies develop by 1 year § § § Beta globin chain disorder – glutamine to valine substitution at the 6th residue of beta globin § Sickle solubility test § Blood + PO4 buffer containing reducing and lysis agents § Sickle Hb is induced to sickle by the reducing agent and gets trapped in red cells § Normal Hb is lysed § Centrifuge and read § Any sickle Hb results in turbidity § Cannot reliably detect <15%, therefore not suitable for babies or massively transfused patients § HPLC § Separates by cation exchange chromatography § Identifies variant Hbs by change in electrical charge § Change in gradient of buffer means Hb attached to column will elute at different times § Enables provisional identification and quantification § Confirmatory tests § Alkaline electrophoresis – pH 8.2-8.6 § Previously used as a screening technique § Provisional ID of A, F, S/G/D, A2/C/E/O-arab § Acid electrophoresis – pH 6.0-6.2 § Separates S and D/G § Separates C and E § Iso-electric focusing § Suitable for neonates § More expensive, but separates more variants than electrophoresis § Newborn screening § Heel prick § HbSS and HbSBo-thal – FS pattern § HbSBo-thal - low MCV and increased A2 § HbAS – FAS pattern § HbSB+-thal –FSA pattern § HbSC – FSC pattern § Prenatal screening
Pathophysiology § Intracellular polymeristaion of deoxy HbS due to reduced tissue oxygenation and pH § Initially reversible, but repeated sickling damages the red cell membrane § Damage causes § movement of potassium and water out of the cell by the gardos pathway and potassium-chloride co-transport, leading to dehydration of red cells. § extracellular expression of proteins usually only found intracellularly (eg. Phosphatidylserine – activation of coagulation cascade) § Haemolysis – nitric oxide scavenging and endothelial dysfunction § Release of haem iron induces transcription factors eg NFKB which results in increased expression of E selectin, VCAM-1 and ICAM-1, which increase leucocyte recruitment with increased occlusion of the microcirculation § Abnormal adherence to vascular endothelium via VCAM-1, thrombospondin and fibronectin. § Increased vWF and FVIII § Increased platelets § Red cell survival 4-25 days
Complications § Anaemia § Aplastic crisis § Parvovirus B19 § Reticulocytopenia 5days after exposure, lasts for 7-10days § Followed by lifelong immunity § Splenic sequestration § 6-12 months § Risk of recurrence, therefore splenectomy may be recommended § Superimposed haemolysis if G6PD § Reduced epo if renal insufficiency § Acute pain § Higher frequency in HbSS, low HbF, high Hb, a-thal § Dactylitis in children § EBT not normally helpful for an acute episode § Analgesia should be given within 30 minutes and control achieved within 60 minutes § Pain, RR and sedation should be assessed every 20minutes until control § Paracetamol and NSAIDs should be used with opiates (unless nephropathy) § Pethidine avoided because of risk of seizures § Adjuvants eg. Laxatives, anti-histamines, anti-emetics § If PCA, most should be given as boluses § Fluids can normally be given orally 60mls/kg/24 hours § Oxygen if sats less than 95% § Avoid cannulation of feet because of risk of ulcers § Monitor 2 hourly for pain, RR sedation and saturation § Consider incentive spirometry if back/ chest pain § Infections § Strep pneumoniae, haemophilus, meningitis, salmonella, mycoplasma and Chlamydia pneumoniae are all commonly isolated § Neurological § Infarct or haemorrhage in 25% by 45 years, 11% by 20 years § Increased blood flow velocity can be detected by TCD with flow rates of >200cm/sec correlating with high risk of stroke § Prevent 90% of strokes with pre-emptive maintenance transfusions – STOP 1 § Risk of stroke reappears once transfusion stopped – STOP 2 § Screen all children 2-16yrs, annually or 6 monthly if results ‘conditional’ § As the skull mature the TCD window closes, making it inappropriate for most adults § Not as useful for predicting haemorrhagic strokes § In infarctive strokes – immediate exchange transfusion is warranted § Hamorrhagic strokes are often subarachnoid and may require surgical intervention of an aneurysm. (moya moya) § High risk of recurrence and EBT program recommended § Silent infarcts on MRI causing neuropsychiatric and neurocognitive impairment, also predictive of stroke.
§ Pulmonary § Acute chest syndrome § Hypoxia, tachypnoea, fever, chest pain, pulmonary infiltrates, wheezing, cough § Bronchodilator therapy § Incentive spriometry § PE § Chronic lung disease – fibrosis § ? secondary to recurrent infections § Restrictive and obstructive – HRCT and PFTs § Pulmonary hypertension – NEJM 2004; increased TR jet >2.5m/sec § Also seen in other haemolytic states, therefore possibly related to release of free Hb and nitric oxide scavenging resulting in endothelial dysfunction § Assoc with increased risk of death § Assoc with intensity of haemolysis § Screening is indicated in non-crisis steady states § NT-proBNP may prove to be a useful screening tool § May benefit from EBT § Hepatobiliary § Intrahepatic sickling § RUQ syndrome § High bili and ALT secondary to hepatocyte destruction § EBT probably best treatment § TTI § Iron overload § Pigment gallstones § Pregnancy § Steady state Hb falls in pregnancy § Painful episodes may become more common § Higher rate of pre-eclampsia § Consider EBT if ++pain +/- preeclampsia § Fetal risks § Abortion, still birth, IUGR § Prophylactic transfusions do not alter outcome § Beware drug toxicity in the neonate § Renal § Hyposthenuria § Destruction of the vasa recta in early life § Presents as nocturia and enuresis § Papillary necrosis § Haematuria § Usually left kidney § Sickle nephropathy § Proteinuria leads to nephrotic syndrome § Progression to renal failure delayed by ACE-I § BP control § Avoid NSAIDs § Priapism § Caused by obstruction of venous drainage § Usually affects the corpora cavernosa alone § Persistent if > 3hours § May require aspiration, fistula formation, exchange transfusion § To prevent recurrence – etiliferine, cyproterone § Ocular § Higher risk in SC and SB+-thal § Proliferative retinopthy, may require laser or vitrectomy § Central retinal artery occlusion § Hyphaema = sickling of blood on the anterior chamber, requires urgent washout § Bone § Leg ulcers § Painful § Dependant on intensity of haemolysis § Surgery § A simple top-up transfusion to a Hb 10 is probably adequate § If Hb >10 and major surgery, consider EBT
Treatment § Immunisation § Pneumococcal § H influenzae § Hepatitis B § Influenza § Prophylactic penicillin § Folic acid § TCD § Ophthalmology review § Transfusion § Sickle negative blood § Matched for Rh antigens and kell § Exchange transfusion § Removes ISCs from participating in new vaso-occlusive events § Reduces haemolysis § Increases oxygen carrying capacity § Decreases blood viscosity § Target = S% <30% and Hb <10 § Iron neutrality § Fluid neutrality § Aim to exchange 1.5 red cell volumes § Chronic exchange- usually 1 blood volume every 4 weeks § Analgesia § Hydroxyurea § JAMA 2003 – 40% reduction in mortality at 9 years in patients taking HU § NEJM 1995 – HU reduced crisis frequency from 4.5 – 2.5/ year § Inhibits ribonucleotide reductase leading to S-phase arrest and stimulates HbF production § Also increases erythrocyte water content and deformability which reduces adherence to vascular endothelium and reduces expression of soluble VCAM-1 and reduces wcc § Decreases Pain, ACS, transfusion and hospitalisations § Improves survival § 5-azacytidine § Increases HbF but concerns regarding carcinogenic effects § Decitabine § Analogue of 5-azacytidine § Iv or sc § Increases HbF including patients who have failed to respond to HU § Long-term risks not yet known § Butyrate § Shows promise but administration requires central venous access § Sodium phenlybutyrate = oral, but 30-40 tablets/ day = poor compliance § Gardos channel inhibitors § ICA-17403/ senicapoc § Blocks Ca dependant K efflux, limiting loss of Ca, K and water § Preliminary results suggest less haemolysis but no effect on vaso-occlusive rate § BMT and gene therapy § Recent trials have shown long term survival 90% § Matched siblings only available in <15% § ? role of cord blood § Psychosocial support
§ Antenatal screening
§ Current trials
§ ICA17043 § Vasoactive drugs – nitrous oxide, sildenafil § Statin – increases nitrous oxide § Anti-inflammatory drugs that inhibit NFKB
Unstable haemoglobinopathies § AD inheritance § Individually rare § Precipitate spontaneously or with oxidative stress (Heinz bodies) § Suspect in a patient with non-spherocytic haemolytic anaemia § Diagnostic test – isopropanol stability test § False positive in neonates due to high Hb
Acquired Haemoglobinopathies § Carboxyhaemoglobin § Carbon monoxide § 200x greater oxygen affinity and less rapidly dissociates § Functional hypoxia § 100% oxygen to improve partial pressure in blood § Hyperbaric oxygen if life threatening § Methaemoglobinaemia § Offending drugs include nitrates, nitrites, aniline dyes, sulphonamides § Oxidise ferrous iron to ferric which results in Hb being converted to metHb § metHb usually maintained at <1% by 2 enzyme dependant pathways § exposure to offending agent oxidises haem and overwhelms NADH-diaphorase system, resulting in metHb formation § 10-20% - cyanosis § >30% - headaches, dizzy, dyspnoea, tachycardia § >50% obtundation § >70% lethal § Reduced sats with normal arterial PaO2 § Blood appears brown § Also a congenital form due to the enzyme deficiency § Best treatment is methylene blue, which activates the normally quiescent pathway
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