SICKLE CELL DISEASE II Flashcards
(clinical features, diagnosis and management)
Result of sickling in Sickle cell disease results in?
These physiological changes result in a disease with the following cardinal signs:
- Anaemia
i. hyperhaemolytic crisis,
ii. Sequestration crisis,
iii. Aplastic crisis
iv. Megaloblastic arrest - Painful vasoocclusive crisis, and
- Multiple organ damage with microinfarcts, including heart, skeleton, spleen, and central nervous system
Clinical presentation SCD
- The overall clinical picture is as a result of increased haemolysis and vaso-occlusion.
- The disease is more severe in patients with HbSS or HbS β0-thalassaemia than in those with HbS β+-thalassaemia or HbSC disease.
- The Arab–Indian haplotype produces a less severe disease than the African haplotypes.
- The high HbF level observed in hereditary persistence of fetal haemoglobin (HPFH) is associated with very mild disease.
- In countries with inadequate healthcare, SCD is associated with high mortality in the first 3 years of life as a result of sepsis and splenic sequestration.
- In the developed world, the typical patient with SCD has moderately severe anaemia, leads a relatively normal life interrupted by ‘crises’ as a result of vaso-occlusion, and
- Has a life expectancy of over 45 years.
Varied features of SCD: Under 6 month of age
Features can vary with age:
Under 6 month of age : Pallor, Jaundice, Hepatosplenomegally, Hand- foot syndrome ( painful swelling of One hand, One hand + foot same side, One hand + foot opposite side.
Varied features of SCD: Under 2 years of age
Under 2 years :
Incidental Anaemia,
Hand-foot syndrome (Dactylitis),
Varied features of SCD: Children and adolescents
Children and adolescents :
Chronic leg ulcers,
Priapism
Proliferative sickle retinopathy,
Bone pain crisis, Femoral head necrosis (avascular)
Osteomyelitis,
Acute chest syndrome.
Varied features of SCD: Adults
Adults :
Painful Vasoocclusive, crisis,
less hyperhaemolytic episodes,
end organ damage ( renal failure)
The clinical manifestations are usually triggered by what?
infections, stress , dehydration and other factors.
What are reasons for infections in SCD?
REASONS FOR INFECTIONS includes :
Relative asplenia (autosplenectomy)
Relative tissue hypoxia
Iron overload
Defective complement system
Clinical presentation: Growth and development
Children with SCA are born with normal weight but fall behind other children by the end of the first year.
The weight deficit persists through adulthood and imparts a thin habitus to the typical patient, although obesity is seen in some cases.
The rate of growth is lower than normal in SCA patients, and the pubertal growth spurt is delayed by 1–2 years, but the final adult height is normal.
Delays also occur in skeletal maturation and onset of puberty, and female patients achieve menarche 1–2 years later than their peers.
Clinical presentation: Neurological complications
Neurological complications
Are an important cause of morbidity in SCD.
Transient ischaemic attacks or stroke due to cerebral infarction or haemorrhage occur in 25% of patients with SCD.
The risk of stroke is increased
with lower baseline haemoglobin,
low HbF level,
high leucocyte count or
high systolic blood pressure.
Clinical presentation: pulmonary complications
Pulmonary complications
Acute and chronic pulmonary complications are the leading cause of death in older patients.
The acute chest syndrome is characterized by hypoxia, tachypnoea, fever, chest pain and pulmonary infiltrate on chest radiographs.
The pathogenesis of acute chest syndrome involves vaso-occlusion, infection or both.
Infections due to Mycoplasma, Chlamydia, Legionella, pneumococcus, H. influenzae and viruses are more likely in children.
Clinical presentation: Hypoxia
Hypoxia due to acute chest syndrome can result in widespread sickling and vaso-occlusion, with risk of multi-organ failure.
Clinical presentation: Priapism
Priapism
Priapism occurs in two-thirds of males with SCD, with a peak incidence in the second and third decades.
It is caused by vasoocclusion leading to obstruction of venous drainage from the penis.
Clinical presentation: Liver
The liver can be affected by:
intrahepatic trapping of sickle cells, transfusion-acquired infection and transfusional haemosiderosis.
Episodes of cholestasis due to intrahepatic sickling can lead to liver failure in rare instances.
Pigmented gallstones are seen in two-thirds of patients, particularly those with HbSS, and can occur in young children.
Discuss the sickle cell trait
Sickle cell trait (HbAS) is a benign condition that has no haematological manifestations and is associated with normal growth and life expectancy.. Impaired urine-concentrating ability and haematuria can occur.
Discuss the HbSC disease
HbC is found among individuals of African descent and the compound heterozygote state HbSC accounts for 25–50% of patients with SCD.
The vaso-occlusive complications seen in patients with HbSC resemble those of HbSS but are less severe.
Splenomegaly and the risk of sequestration can persist into adult life.
Of particular note is the higher incidence of proliferative retinopathy in HbSC beginning in the second decade.
Peripheral blood smear reveals frequent target cells, intraerythrocytic crystals and rare sickle cells.
Sickle cell–b-thalassaemia
Sickle cell–β-thalassaemia compound heterozygotes account for less than 10% of patients with sickle syndromes.
The majority of these patients have the β+-phenotype, with the proportion of HbA ranging from 3% to 25%.
The clinical phenotype is mild and disease severity correlates with the amount of HbA present.
The clinical manifestations of less frequent HbS-β0 genotype are similar in severity to those of HbSS.
Sickle cell anaemia with coexistent a-thalassaemia
Co-inheritance of α-thalassaemia (–α/αα or –α/–α) with SCD is common, and such patients have less severe anaemia and demonstrate hypochromia and microcytosis.
In general, the clinical severity is similar to that seen in HbSS patients with a normal complement of α-globin genes.
Discuss Sickle cell–HPFH
Approximately 1 out of 100 patients with HbSS has an elevated HbF level due to deletional or non-deletional mutations that maintain γ-globin gene expression after birth.
Such individuals have 20–30% HbF and < 2.5% HbA2. The haemoglobin level is normal with microcytosis, and target cells are observed in peripheral smear.
The clinical course is benign, and vaso-occlusive complications are rare because of the inhibition of sickling by elevated HbF.
Discuss Sickle cell–Hb Lepore disease
Co-inheritance of Hb Lepore with sickle cell mutation produces a clinical picture similar to that of S-β-thalassaemia but with a low HbA2 level.
Discuss Sickle cell–HbD disease
Of all the D or G haemoglobins, HbD Punjab (D Los Angeles) alone interacts with HbS to produce moderately severe haemolytic anaemia in compound heterozygotes.
Target cells and irreversibly sickled cells (ISCs) are observed in the peripheral smear, and the clinical manifestations resemble mild sickle cell anaemia.
Discuss Sickle cell–HbO Arab disease
HbO Arab resembles HbC on alkaline electrophoresis and produces a moderately severe haemolytic anaemia in association with HbS.
The disease is more severe than HbSC, and numerous sickled erythrocytes are observed on peripheral smear.
Discuss Sickle cell–HbE disease
HbSE disease causes mild haemolysis and no remarkable abnormality of red blood cell morphology.
HbE makes up only 30% of the total haemoglobin because of the thalassaemic nature of the mutation.
Patients are generally asymptomatic, although occasionally significant vaso-occlusive complications and anaemia have been observed.
Diagnosis: Haematology FBC and PBF
Peripheral blood findings (PBF)
Anaemia develops, (normochromic, normocytic) and sickle or cigar-shaped ISCs can be observed in the peripheral blood by 3–4 months of age as HbF declines.
Average reticulocyte count is 10% (4–20%) and normoblasts may be observed.
Red cells are microcytic in the presence of coexisting α-thalassaemia or iron deficiency. The red cell morphology in HbSC disease is characterized by predominant target cells and rare ISCs.
The white cell count is elevated (12–20 × 109/L) as a result of an increase in mature neutrophils.
The platelet count is also elevated to 300–500 × 109/L as a result of decreased splenic function.
Clotting factors Increased
The erythrocyte sedimentation rate (ESR) is consistently low.
Diagnosis: Haemoglobin electrophoresis
How can HbS be identified and how can HbD be differentiated from HbG
Distinction cannot be made between Hb what and what?
HbS can be identified by cellulose acetate electrophoresis at pH 8.4
HbD and HbG have the same electrophoretic mobility with this method, but can be distinguished using citrate agar electrophoresis at pH 6.2 or thin-layer isoelectric focusing
Distinction cannot be made between HbSS and HbS β0-thalassaemia on electrophoresis
The diagnosis of S-β0-thalassaemia is suggested by microcytosis and elevated HbA2, and confirmed by finding β-thalassaemia trait in one of the parents.
Isoelectric focusing (IEF)
is in general, used only to a limited extent, mainly for neonatal screening or in specialist laboratories
Automated high-performance liquid chromatography (HPLC)
is increasingly replacing haemoglobin electrophoresis as the initial investigative procedure in laboratories analysing large numbers of samples.
Diagnosis: Sickling
Sickling of red cells can be induced by sealing a drop of blood under a coverslip to exclude oxygen or by adding 2% sodium metabisulphite.
Both these tests are unable to distinguish sickle cell trait from sickle cell anaemia and cannot be used for primary diagnosis
Diagnosis: The solubility test
The solubility test for HbS utilizes a reducing agent such as sodium dithionite, which is added to the haemolysate. The deoxy-HbS is insoluble and renders the solution turbid.
Both these tests are unable to distinguish sickle cell trait from sickle cell anaemia and cannot be used for primary diagnosis
CHEMISTRY Lab Investigations
The serum levels of unconjugated bilirubin and lactate dehydrogenase are elevated
Haptoglobin is decreased.
IMAGING STUDIES Lab Investigations
a) X-rays may demonstrate areas of infarction for painful bones.
b)Magnetic resonance imaging (MRI) demonstrates areas of avascular necrosis for the femoral and humeral heads and may distinguish between osteomyelitis and bony infarction for painful bones. C
c)Abdominal sonogram is useful to document spleen size and the presence of biliary stones.
d) Transcranial Doppler ultrasonography is very useful in selecting patients at risk for stroke to participate in a chronic transfusion program.
Values outside the reference range depend on the method used and are lower for duplex Doppler (180 cm/s) than for non–duplex Doppler (200 cm/s).
All children with SCD should be tested.
General Management
I. COUNSELING- GENERAL AND GENETIC
Parent should understand the risk of having HBSSHelp make informed decision
Prevent Unwanted pregnancy through family planning
PRENATAL DIAGNOSIS/ PRE-MARITAL COUNSELING.In the 1st 3 months of pregnancy: Chorionic villus sampling (CVS)Ammniocentesis
II. PREVENTION OF COMPLICATIONS
a) Pneumococal septicaemia -
-Prophylactic penicillin to infants (10% resistance) and
Pneumococal vaccine at late stages
b) Malaria
i) ITNs, ii) Chemoprophylaxis, iii) Folate prophylaxis
Definitive Management
- Vasoocclusive crisis is treated with vigorous hydration and analgesics.
These fluids should be given intravenously, and treatment must be in an inpatient setting. - Pain control is best achieved by the administration of opioids.
Morphine is the drug of choice. Morphine dosing has to be individualized.
Intravenously, hourly at first. After 24-48 hours, as pain is controlled, equivalent doses of sustained-release oral morphine should be given.
Morphine elixir can be used to control breakthrough pain.
- Chronic pain is managed with long-acting oral morphine preparations and acetaminophen and non steroidal anti-inflammatory drugs (NSAIDs).
The addition of tricyclic antidepressants may reduce the dose and need for opiates by interfering with pain perception. Many patients with chronic pain are depressed, and lifting the depression has a salutary effect on the pain.
- Non pharmacological approaches such as physical therapy, heat and cold application may be helpful
Prevention of infection improves chances of survival in SCD.
Penicillin prophylaxis, commencing in infancy and continued until age 5 years or early teens, and the use of a pneumococcal vaccine at age 2 years with a booster dose at age 5 years greatly reduces the frequency of infections with S pneumoniae.
Management of Anemia in SCD
Anaemia is usually well tolerated.
Folic acid supplementation may raise the Hb level and support a healthy reticulocyte response.
Treat the cause of the Hyperhaemolysis.
Patients with coexisting iron deficiency should be given iron supplements.
An adequate overall diet is essential.
Blood transfusion (simple, exchange or hypertranfusion program) is indicated only in specific situations such as acute chest syndrome, stroke, abnormal findings on transcranial Doppler in children (for stroke prevention), pregnancy, and general anesthesia.
The aim is to decrease the concentration of Hb S to 30% or less.
OTHER RADICAL TREATMENT/PARTIAL CURE OF SCD
Chronic and repeated transfusion leads to alloimmunization and iron overload and is associated with the risk of transfusion-transmitted infectious agents.
OTHER RADICAL TREATMENT/PARTIAL CURE OF SCD
Haemopoietic stem cell transplantation (HSCT) after total BM ablation or after partial BM ablation
Gene replacement (Gene therapy) Correction of SCD by gene therapy requires efficient insertion of a gene into repopulating haemopoietic cells and regulated expression in erythropoietic lineage. An anti-sickling haemoglobin, constituting 20–30% of the total haemoglobin, would be enough to produce clinical response.
Management of some complications: acute chest syndrome, strokes and leg ulcers
Acute chest syndrome is managed with analgesics, oxygen, antibiotics, and transfusion.
Strokes are managed with general support and transfusion.
The aim is to lower the concentration of Hb S to less than 30%. An exchange transfusion is usually required. Because of the devastating neurological defect that may result, emphasis is placed on prevention.
Leg ulcers are treated with debridement and antibiotics. Zinc oxide occlusive dressing and leg elevation are employed. Skin grafting may be necessary in recalcitrant cases.
Management of some complications: avascular necrosis, chronic renal failure and priapism
Avascular necrosis of the femoral and humeral heads is treated by not bearing weight at the site. In many cases, surgical intervention with hip replacement or other orthopaedic procedures are needed.
Chronic renal failure is managed with dialysis in the same manner as end-stage renal disease due to other causes.
Priapism is treated with analgesics and hydration. Persistent priapism may require surgical evacuation of the penile corpora. If impotence results, insertion of a penile prosthesis is indicated.
When drug addiction with substance abuse is present, a team approach involving counselors, substance abuse specialists, haematologists, and pain management experts is important.
ANTISICKLING AGENTS IN MANAGEMENT OF SCD
a) POLYMERISATION INHIBITORS
i). Hydroxyurea + EPO-promotes HbF
ii) Butyrates – Enhance Y-gene Expression
b) ANTI-INFLAMMATORY AGENTS
i).NSAID – Inhibit granulocyte Activation
ii) Aspirin – Inhibit Platelet Activation
iii) Hydroxyurea–reduces granulocyte Production (a super drug but it is cytotoxic and cause cause infertility)
iv) Nitric Oxide – Inhibit granulocyte/Platelet Activation
c) ANTI-OXIDANTS Vit E, Vit C – Replenishes Antioxidant Pool
d) RBC IC HYDRATION AGENTS
i) Vasopressin – Hormonal Water Retention ii) Hydroxyurea – Water Retention Effect
e) HB-O2 AFFINITY PROMOTERS Nitric Oxide – Changes HbS configuration
f) VASCULAR RELAXANTS Nitric oxide – relaxes smooth muscle
g) ENDOTHELIAL ADHESION INHIBITORS
i). Hydroxyurea – Down regulates adhesion molecules ii)Monoclonal ab – blocks adhesion receptors
h) LOCAL HERBAL AGENTS (Efficacy not well proven)
Fagara Xanthoxyloides
Niprisan
Ciklavit
Salin-Hb
Discuss Gene therapy
An exciting news for patients with sickle cell disease, and perhaps the most important medical breakthrough of 2023.
The first drug, CASGEVY, a CRISPR/CAS9 based treatment that essentially cures sickle cell disease ( and TDT) was approved by the MHRA, (UK health regulator)today. (information released on 21st Nov. 2023)
It works by ex-vivo, CRISPR/CAS9 mediated inhibition of the transcription factor BCL11A, in CD34+ hematopoetic stem cells, (BCL11A represses post natal HBf production).
The result is remarkable increase in HBf production. Unfortunately treatment costs at this time will be around USD 2million, and only approved for children >12 years
Challenges in management
Premarital Counseling
Prenatal Diagnosis
Early Childhood screening
Adequacy of follow-up care
Challenges of Crises management
VOC adequate production of N/S
Availability of strong analgesia
Drug Addiction
Blood Transfusion reaction time
Hypertransfusion programme
Challenges of drugs
Lack of Vaccine antigens like Pneumovax/Polyvalent antigen, HiB
Fake Drug Syndrome(antibiotics)
Chronic complication management
Malaria Prevention
Challenges of growth & development
Growth & Development
Physical Growth: small stature
Late sexual maturity
Personality development
Poor self-esteem/ self-worth
Social challenges
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Community
School
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