2. Ahvaz Research center of thalassemia & hemoglobinopathy
Sickle Cell Anemia
Ahvaz Research center of thalassemia & hemoglobinopathy
Dr. Bijan Keikhaei

3. Acute and Chronic Complications of Sickle Cell Disease

4. Oxidative Stress in SCD

5. CHRONIC VASCULAR INFLAMMATION SYNDROME
SICK RED BLOOD CELL SYNDROME
CHRONIC VASCULAR INFLAMMATION SYNDROME
Sickle RBC
WBC
Platelet
Coagulation Factors

6. Decreased NO Bioavailability
Decreased NO production
Increased NO consumption
Scavenging by free Hb
Oxidant consumption

7. Pathophysiology of SCD
Hbs
(α2βS2) Low oxygen tension
+O² O²
Polymerization of
Deoxygenated Hbs
Irreversibly
Sickled cells
Micro-vascular obstrucion
Acute crises
Chronic progressive
organ damage
Hemolysis
Anemia
Vaso-occlusion

8. SCD Phenotypes Hemolysis Endothelial Syndrome: Stroke
Pulmonary Hypertension
Priapism
Leg Ulcer
Viscosity vaso-occlusion syndrome:
ACS
AVN
Vaso-occlusive pain crisis

9. Acute severe anemia
pallor, weakness, and lethargy; fatalities are common
Splenic sequestration crisis
Aplastic crisis
Hyperhemolytic crisis

10. Acute splenic sequestration:
Definition:
acute illness associated with hemoglobin fall ≥2g/dl and with acutely enlarged spleen
Moderated thrombocytopenia is often present
Reticulocytosis equal or greater than normal
Treatment:
Red blood cell transfusion

11. Acute severe anemia Splenic sequestration crisis :
In pat. whose spleen has not yet undergone fibrosis.
Can occur in first few weeks and cause death before SCD is diagnosed
10 to 15% mortality rate, occurring before transfusions can be given
Recurrent in 50 %of survivors; as a result, splenectomy is recommended after the first acute event .

12. Acute severe anemia Aplastic crisis :
characterized by transient arrest of erythropoiesis, leading to abrupt reductions in HB and red cell precursors in BM, and low reticulocytes in peripheral blood (retic <1.0 % )
Infection with human parvovirus B19,

13. Acute severe anemia Aplastic crisis :
Other causes of transient aplasia are infections by Streptococcus pneumoniae, salmonella, streptococci, and Epstein-Barr virus
Affected patients require acute transfusion therapy. Reticulocytes typically reappear within 2 to 14 days .

14. Acute severe anemia Hyperhemolytic crisis :
Refers to the sudden exacerbation of anemia with reticulocytosis.
Rare, its cause is unknown, and some experts doubt its existence.
Most such cases probably reflect occult splenic sequestration or aplastic crisis detected during a period of resolving reticulocytosis
Association of G6PD deficiency

15. Infection Bacteremia : caused by S. pneumoniae ,H influenzae type b
Presents with leukocytosis, a left shift, aplastic crisis, sometimes disseminated intravascular coagulation, and is associated with a mortality rate of 20 to 50 %.
The risk of recurrent S. pneumoniae sepsis and death is increased in patients who have had previous sepsis.
Bacteremia can be associated with episodes of acute chest syndrome

16. Infection Meningitis –caused by S. pneumoniae and occurs in bacteremia
Bacterial pneumonia – Causes :Mycoplasma pneumoniae, Chlamydia pneumoniae , Legionella and Respiratory viruses , while S. pneumoniae and H. influenza type b are uncommon

17. Infection Osteomyelitis –
Due to infection of infarcted bone with Salmonella species; Staphylococcus aureus< 25 % Osteomyelitis usually affects long bones, often at multiple sites . It may be difficult to distinguish osteomyelitis from vaso-occlusive events involving bone.

18. Infectious risk (preventive and therapeutic measures)
Penicillin prophylaxis (50 to U/kg/day) as soon as the age of 2 months is reached
Anti-pneumococcal vaccine
Prevenar (7-valence vaccine) 2, 3, 4 m
Pneumo 23 (23-valent vaccine) at 2 y of age and every 5 y

19. Pulmonary complications
Pulmonary arterial circulation has low oxygen tension and low pressure in a slow-flow system, is ideally suited to facilitate polymerization of sickle hemoglobin, causing both acute and chronic pulmonary manifestations that collectively are the most common cause of death in SCD

20. Pulmonary complications
Pulmonary complications – major cause of mortality (20-30% of deaths)

21. Pulmonary complications
Acute chest syndrome
Clinical manifestations : chest pain-a new infiltrate on chest radiograph- fever>38.5 -Tachypnea, wheezing, or cough

22. Pathogenesis of ACS
Atelectasis secondary to painful rib, vertebral, sternal infarctions (pain→hypoventilation→atelectasis→hypoxia→
pulmonary infarction)
Pulmonary Infection 30%
Pulmonary Infarction 16%
Fat embolism 8%
Thromboembolic disease (pulmonary emboli documented by V/Q scanning and autopsy series)
Pulmonary oedema

23. Clinical presentation at diagnosis of ACS
Fever 80%
Cough 62%
Tachypnea 45%
Chest pain 44%
Limb pain 37%
Abdominal pain 35%
Wheezing 26%
Rib or sternal pain 21%
Cyanosis 2%

24. ACS management Oxygen therapy Fluid management Pain management
Antibiotic therapy
Bronchodilator
Transfusion/Exchange therapy
Incentive spirometry
Noninvasive ventilation/mechanical ventilation
Nitric oxide (NO)…
Corticosteroids

25. Oxygen therapy Wide indication (hypoxia precipitates sickling)
Systematic prescription or required when SaO2<90%
Administered to 85% of the patients in the National ASC study group

26. 1 to 11/2 times daily fluid requirement
Hydration
Blood viscosity
Pulmonary oedema 
1 to 11/2 times daily fluid requirement
2 liters / m2 / day

27. Antibiotic therapy
Infectious agents identified in 30% episodes of ACS
→ Broad spectrum antibiotics including C3G + macrolide are required
→ Diagnostic tests (blood cultures, nasopharyngeal and sputum samples for bacterial and viral cultures) should be obtained whenever possible

28. Bronchodilator therapy
Prevalence of airway hyperreactivity (detected by methacholine tests) in the sickle cell population is quite high (75% in recent reports)
Airway hyperreactivity is associated with a high risk of developing ACS

29. Transfusion/Exchange therapy
Increase the oxygen carrying capacity
Lower the fraction of sickle red blood cells
Improves oxygenation

30. Severe Acute Chest Syndrome with Respiratory Distress

31. Acute Chest Syndrome 48 hr after Exchange Transfusion

32. Pulmonary HTN in SCD
Was for many yrs thought to be part of “Chronic sickle cell lung disease”
Originally defined by a TRV > 2.5 m/sec
Observed in 1/3 of HbSS and 10-25% of HbSC adults
10-22% of HbSS children and adolescents
Overlap in some with LV diastolic dysfunction

33. Pulmonary Hypertension in SCD

34. Hepatobiliary complications
Acute hepatic episodes :
Viral hepatitis, cholecystitis, choledocholithiasis with CBD obstruction
Benign cholestasis: severe, asymptomatic hyperbilirubinemia without (fever, pain, leukocytosis, hepatic failure)
resolves without consequence in 7 to 10 days.
Acute sickle hepatic crisis : acute right upper quadrant pain, nausea, low grade fever, tender hepatomegaly, and jaundice (T bilirubin <15 mg/dL ,ALT< 300 IU/L ) , resolve within 3 to 14 days.

35. Hepatobiliary complications
Acute hepatic episodes :
Hepatic sequestration crisis : right upper quadrant pain, rapidly increasing hepatomegaly, and a falling hematocrit
Intrahepatic cholestasis : associated with hepatic ischemia, is more common in adults (fever, right upper quadrant pain, leukocytosis, severe hyperbilirubinemia, and abnormal LFT), can progress to liver failure, has poor prognosis Exchange transfusion

36. Hepatobiliary complications
Chronic liver disease: intrahepatic trapping of sickle cells, transfusion-acquired infection, transfusional hemosiderosis, and autoimmune liver disease .
Cholelithiasis :usually asymptomatic, can occur in 3 to 4y of age

37. “Benign” Hyperbilirubinemia.
Marked hyperbilirubinemia of up to 57 mg/dL, in most cases predominantly conjugated with only a mild elevation in ALT levels,
The hyperbilirubinemia resolved Spontaneously within 2 to 8 weeks with no subsequent recurrences.
It is possible that these cases represent a benign variant of intrahepatic cholestasis.

38. HYPERAMMONEMIA CAUSED BY ZINC DEFICIENCY
Patients with sickle cell anemia have hyperzincuria and systemic zinc deficiency caused by increased renal loss of zinc,which may lead to zinc deficiency.
Deferoxamine therapy may also increase fecal losses of zinc.A recent study of 104 patients with sickle cell disease indicated that 44% had low plasma levels of zinc.
Zinc is a cofactor for ornithine transcarbamylase, a urea cycle enzyme,and inhibition of the urea cycle with resultant hyperammonemia may occur with
zinc deficiency.

39. Renal complications
The primary event is occlusion of vasa recta capillaries in renal medulla.
The normal medullary environment has both a low oxygen tension and high osmolality (osmotically dehydrating the red cells, thereby increasing the concentration of HbS) .

40. Renal complications The manifestations :
Painless hematuria due to papillary infarcts
Renal infarction, papillary necrosis, and renal colic
Nephrogenic diabetes insipidus lead to polyuria
Focal glomerulosclerosis lead to end-stage renal disease
Renal medullary carcinoma

41. Bone complications
The skeletal system is frequently involved due to one or both of two factors: accelerated hematopoiesis and bone infarction.
The extended hematopoietic marrow resulting from chronic hemolysis leads to tower skull, bossing of forehead, and fish-mouth deformity of vertebrae.
These effects cause widening of medullary space, thinning of trabeculae and cortices and osteoporosis
Infarction and necrosis of bones: Excruciating pain
Hand-foot syndrome or dactylitis: the most common initial symptoms
It is important to distinguish this syndrome, which resolves spontaneously, from osteomyelitis
Osteonecrosis of lang bones : occurs with equal frequency in the femoral and humeral heads
The femoral heads more commonly undergo progressive joint destruction due to chronic weight bearing

43. Dermatologic complications
Leg ulcers:
occur after age of ten
near medial or lateral malleolus
frequently bilateral
begin spontaneously or occur after trauma
may become infected
resistant to healing
tend to be recurrent
associated with venous incompetence

46. Priapism Defined as an unwanted painful erection
Two peaks : between the ages 5 and 13 and the ages 21 and 29
Onset :acute, recurrent, acute on chronic, or stuttering
Duration :1.6 and 7.0 hours, rare > 24 hours.
Engorgement affects the corpora cavernosa and usually spares the glans penis and corpus spongiosum.

47. Pathophysiology of Priapism
• The penis is composed of 3 corporeal bodies: 2 corpora cavernosa and 1 corpus spongiosum. Erection is the result of smooth-muscle relaxation and increased arterial flow into the corpora cavernosa, causing engorgement and rigidity • Priapism. Corporeal relaxation causes external pressure on the emissary veins exiting the tunica albuginea, trapping blood in the penis and causing erection

48. Treatment saline irrigation
injection of alpha- agonist drugs such as phenylephrine,Epinephrine
Pseudoephedrine HU
Argentine
Glutamine
Blood Transfusion
Surgery

49. Retinopathy Retina manifestations : proliferative retinopathy,
retinal artery occlusion,
retinal detachment and hemorrhage .
vitreous hemorrhage

50. Risks Associated with Transfusion
RBC antigen alloimmunization risk
Viral risk
Iron overload

51. PROGNOSIS Infection – 48 % Stroke – 10 %
median survival: men 53y and women 58 y
Increased risk of early death: acute chest syndrome, renal failure, seizures, a baseline white blood cell count >15,000/microL, and a low level of fetal hemoglobin
Causes of death
Infection – 48 %
Stroke – 10 %
Complications of therapy – 7 %
Splenic sequestration – 7 %
Thromboembolism – 5 %
Renal failure – 4 %
Pulmonary hypertension – 3 %