Sickle cell disease

Sickle cell disease


Sickling syndromes





Diagnosis / Clinical features




Sickle cells (90%), boat cells (90%), Howell-Jolley bodies (100%), Pappenheimer bodies (90%), Target cells (95%), nucleated red cells (90%), spherocytes (30%)


SS-a/aa, SS-a/-a


Hypochromia and microcytosis


Clinical severity similar to SS



Sickle cells uncommon, some boat shaped cells, hypochromia, microcytosis, prominent target cells and basophilc stippling. Pappenheimer bodies if hyposplenic

Diagnosis confirmed if HbS and Hb A are both present with more HbS than HbA


Mild phenotype, severity correlates with amount of HbA




Microcytichypochromic, targets and sickles

Hb A2 – 4-5.6

HbF 5-15

Similar in severity to HbSS


Sdb0 thal







Similar to SB-thal, but with a low A2


SD Punjab


V Var

up to 110

Anisocytosis, poikilocytosis, target cells and sickle cells

HbF may be as high as 20%

HbD > HbS

Clinically resembles mild SS


SO Arab



Blood film similar to HbSS


HbS>O Arab

Severe sickle cell disease



Frequent targets (100%)Crystals (20%), occasional sickle cells (15%), SC poikilocytes (50%) (misshapen cells with complex forms with crystals jutting out), irregularly contracted cells (90%), nucleated red cells (50%)

Milder vaso-occlusve complications

Higher incidence of retinopathy

Non sickling phenotypes








Target cells, rarely sickle cells

HbS > E

Generally asymptomatic with mild haemolysis and no major morphological abnormailty




Hb F 15-25%

High HbF protects against sickling

S G Philadelphia



HPLC with peaks at Hb A, A2, S and G-phili

No clinical significance




Numerous target cells and irregularly contracted cells, occasional nrbcs, haemoglobin C crystals

Clinically mild chronic haemolytic anaemia

C Bthal


Resembles beta thal intermedia depending on the severity of the b thal mutation

Diagnosis – B+ HbC > HbA; diagnosisng B0 thal can be more problematic (HbCC is microcytic)




Hypochromia, microcytosis, variable target cells and irregularly contracted cells




§        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



§        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



§        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



§        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