1.Sickle Cell Anemia and its management- Basics.pptx

Sickle cell anemia with transfusion aspects.xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

1. SICKLE CELL ANEMIA: MODULE DEPARTMENT OF TRANSFUSION MEDICINE.

2. SICKLE CELL ANEMIA BASICS:

3. OBJECTIVES:- Problem statement. Association with other diseases. Types of sickle cell anemia. Pathogenesis. Clinical features and lab diagnosis.. Transfusion Management. National Program for sickle cell disease prevention. Structure of Haemoglobin S. International program on sickle cell disease.

4. SICKLE CELL DISEASE It’s a common hereditary hemoglobinopathy caused by point mutation in Beta globin, that promotes the polymerization of deoxygenated haemoglobin , leading to Red cell distortion. Hemolytic anemia. Microvascular obstruction Ischemic tissue damage. Point mutation in sixth codon of Beta globin ,that leads to the replacement of glutamate residue with valine residue.

5. PROBLEM STATEMENT. Most prevalent in United states, there about 70,000 individuals, with sickle cell disease in United states. About 8-10% of African Americans, or roughly 2 million individuals, are heterozygous for HbS. In certain population in Africa the prevalence of heterozygosity is as high as 30%. Population studies have, shown that sickle hemoglobin mutation, has arisen independently at 6 times in areas in which falciparum malaria is endemic. First describe in, Nilgiri Hills of Northen Tamil Nadu,1952,widespread among people of Deccan plateau of Central India, with a smaller focus in the north of Kerela and Tamil Nadu, tribal population.(Maharashtra, Gujrat, Odisha, Chhattisgarh.)

6. Structure of Haemoglobin S. Substitution of valine in place of glutamic acid in 6 th position (Beta6 glu-val )of beta chain. Alters the solubility and characterstics of Hb(alpha2 beta2) resulting in polymerization of HbS forming tactoids . In case of low oxygen tension, deoxygenation, HbS polymerizes,and distorts red cells,to an elongated sickle cell, When the O2 tension becomes normal, these HbS polymers, dissolve the sickle cell, reverts to its normal round shape.

7. ASSOCIATION WITH OTHER DISEASES. Malaria:- Metabolically, active intracellular parasites, consume these O2 and decrease intracellular ph., both of which promote Hb sickling, these distorted and stiffened cells, may be cleared more rapidly. Metabolically active intracellular parasites consume O2, and decrease intracellular ph , both of which promote hb sickling, these distorted and stiffened cells may be cleared more rapidly by phagocytes in spleen & liver, helping to keep parasite loads down. Impairs the formation of membrane knobs containing a protein, made by the parasite called PfEM-1,these membrane knobs are implicated in adhesion, of infected red cells, decreasing the adherence.

8. TYPES OF SICKLE CELL ANEMIA . SICKLE CELL CARRIER . Who is virtually symptom free, contains <50% of HbS in red cells. Key note:- Presence of other Hb like HbF , reduces while HbC & HbD increases the propensity of sickling. Sickle cells have altered , rheological properties,these cells don’t alter their shape,(during their passage from splenic circulation)which predisposes to statis and vascular occlusion. SICKLE CELL ANEMIA. This is the homozygous state, SS ,one gene each from both the parents, clinically these patient manifest, early in life since HbS, is more than 70% in the red cells. SICKLE CELL TRAIT. This is a heterozygous state, one gene from one parent ,is for HbS, while the other gene is for HbA . Amount of HbS is 25-40% and clinical picture is mild and may remain undetected. SICKLE CELL DISEASE O ne gene is of HbS, which may be in combination, with normal, HbA or abnormal gene of beta thalassemia alpha thalassemia, HbD , Hb E HbC,HbQ,or any other haemoglobinopathy & includes all sickle cell anemia, sickle cell trait, sickle cell thalassemia or HbS -D and HbS -E disease.

9. PATHOPHYSIOLOGY. Polymerization of deoxygenated HbS. Sickle cell deformity. Increased blood viscosity. Sickle cell –endothelial cell adherence. Role of white cells and platelets.

10. Red cells containing HbS. Passage through microcirculation in spleen. Low oxygen tension. Deoxygenation of HbS. Sickling occurs. Cells pass through circulation, with good oxygen tension(other organs) Desickling . Various cycle of sickling and desickling,cell membrane affected,change in membrane permeability),irreversible sickling., Sickled RBC’s Cont …

11. Cont … Sickled RBC’s adherence to endothelium. Poor RBC deformability, aggregates, of rigid red cells are formed. Blood viscosity increases, vascular statis, leading to vascular occlusion. Vaso-occlusive crises, occlusion of microcirculation of hands , feet,spleen , head of femur, renal papillae. Infarction of various organs,& tissue damage in various organs. . Macrophage phagocytosis. Extravascular hemolysis in spleen. Chronic hemolytic Anemia. Increased mechanical fragility Intravascualar hemolysis + Platelet activation, Increase platelets Alteration in function en white cell count. Splenic infarct Autospleenctomy Spleenic function diminished. Hypospleenism

12. CLINICAL FEATURES AND DIAGNOSIS:- Chronic hemolytic anemia. Vaso occlusive events. Growth and development delay. Autosplectomy . Recurrent leg ulcers. Avascular necrosis. Dactylitis(Hand foot syndrome). Jaundice and liver enlargement. Renal papillary necrosis. Salmon patches. Intraretinal haemorrhage . CRISES:- Sickling crisis. Hemolytic crisis. Aplastic crisis. Sequestration crisis.

13. Haematologic findings:- Diagnostic tests:- NCNC to mildly hypochromic red cells. Mild APK. Sickle cells(30-40%) Boat shaped /oat shaped cells /(pump sickle cells) Crescent or sickle shaped cells. Many target cells. Howell Jolly bodies. Sickling test. (Reducing agent like 2% sodium metasulphite or sodium dithionite. Hb electrophoresis.

14. National Program for sickle cell disease prevention:-

15. To improve care of all SCD patients for their better future and to lower, the prevelance of the disease, through multifaced coordinated approach,towards screening and awareness strategies. Vision: Eliminate sickle cell disease, as a public health program in India, before 2047, there is need to increase the awareness about the disease in community. Objectives : Provision of affordable and accessible care to all SCD patients ,to ensure quality of care for SCD patients, to reduce the prevelance of SCD.

16. TRANSFUSION AND TRANSPLANTATION:

17. TRANSFUSION MANAGEMENT:- PRBC transfusion,play an important role,in the treatment of some acute illness in patients with SCD,in addition a timely blood transfusion may be life saving in severe complications. PRBC should be transfused,if the hb >1-2 g/ dl,below the basline.any sign of cardiovascular compromise. Indications:- Cardiovascular compromise. Hyperhemolysis . Hepatic and splenic sequestration. Aplastic crisis. Leuckocyte depleted blood,packed RBC are recommrnded ,&where available,Rh,kell antigen matched,sickle negative cells are preferred. DGHS TECHNICAL MANUAL

18. Cont … Slow correction of anemia , 4-5 ml/kg PRBC over 4 hrs,often with furosemide or isovolumic partial exchange transfusion, may be needed to prevent preci [ pitation of heart failure. Simple transfusion of 10 ml/kg of PRBC raises the Hb by 2gm/dl. PRBC transfusion,at a dose of 10 ml/ kg,for hb <4-5g/dl, and signs of cardiovascular compromise should be done. Transfusion may be needed,for Hb <7-8 gm/dl for patients with high baseline Hb sickle levels. Post transfusion,Hb levels,<8-9 g/dl is generally recommended,to avoid the risk of hyperviscosity . DGHS TECHNICAL MANUAL .

19. Since sickle cell are poorly deformable, simple red cell transfusion that increase the Hb levels to>10-11 g/dl, may cause hyperviscosity in patients not receiving chronic transfusions and should be avoided. Partial exchange transfusion by erythrocytapheresis , to achieve Hb 10 gm/dl and keep Hb sickle RBC less than 30%.,remove central and venous catheter as soon as possible after exchange transfusion to reduce the risk of thrombosis. For stable patients, simple transfusion to achieve post transfusion Hb appro 10g/dl, with hb 6-7 g/dl. DGHS TECHNICAL MANUAL

20. Initial visit. (Regardless of planned transfusion). Obtain blood type ,antibody screen, and extended red cell antigen profile (genotyping preferred). Prior to transfusion. Obtain pretransfusion antibody screen. Match red cell units for: Rh(D,C,E or D,C/c, E/e) and K at minimum. Any other, clinically significant alloantibodies previously detected . After transfusion. Patient should be counselled return for symptoms of HTR(increased jaundice, scleral icterus ,fatigue, dark urine, pain).Ideally obtain ,type and screen, within 1-3 months to screen for new alloantibody formation. Best practices. Patient should carry a card, with primary institution blood center, for other hospitals to obtain transfusion history, and stating she/he: ASH GUIDELINES:2020 Requires Rh and K matched red cells. Requires additional antigen matching, if alloimmunized . Recommendations on transfusion management .

21. DEFINITION OF DHTR AND HYPERHEMOLYSIS .( ASH GUIDELINES 2020 ) DHTR:- Significant drop in Hb, within 21 days posttransfusion, associated with1 or more of the following: New red cell alloantibody. Hemoglobinuria. Accelerated increase in percentage Hb S. with contaminant fall in Hb A posttransfusion. Exclusion of alternative cause. Relative reticulocytosis from baseline. Significant increase in LDH from basiline . Hyperhemolysis :- Rapid hemoglobin decline to below the pretransfusion level. Rapid decline of post transfusion HbA levels.

22. PREVENTION OF HTR IN HIGH RISK PATIENTS: ASH GUIDELINES 2020 Patient with life threatening anemia, and high risk of HTR Start erythropoietin, with or without IV iron bed rest, supplemental oxygen, if transfusion, still indicated, consider: Pretransfusion : IVIg (0.4-1g/kg/day.) (total dose 2g/kg ). methylprednilasone / prednilasone . (1-4mg/kg/day.) Transfuse maximum , of 1 unit of extended, matched red cells,(If time allows) and re assess before further transfusion. As anemia allows serial monitoring of Hb, Hct, Hb, fractionation, retic count bilirubin, and LDH. If transfusion, are needed, in the near future, consider, rituximab 375mg/m2 repeated after 2 wks , or weekly x4 doses, fr prevention of additional alloantibody formation. If hyperhemolysis occurs,ecluzimab 900-1200 mg for patients,>=40 kgs,repeat after 1 week is necessary.

23. CONSIDERATIONS FOR MODE OF CHRONIC TRANSFUSION THERAPY.(ASH-2020 GUI) SIMPLE TRANSFUSION MANUAL RED CELL EXCHANGE AUTOMATED RED CELL EXCAHNGE. Peripheral venous access. +/- indwelling central catheter +/- indwelling central catheter. Time consuming for patient Minimal staff training. Time consuming for patient and staff.,Some staff training required. Rapid procedure.Significant staff training required. Iron loading inevitable. Intermediate iron loading. Minimal iron loading possible. Potential circulatory overload. Minimizes blood volume shifts. Maintains isovoluemia . Risk of hyper-viscosity with high Hb targets. Less risk of hyper-viscosity. Less risk of hyperviscosity . Poor control of HbS%. Intermediate control of HbS% Best control of HbS%.

24. Acute Anemia. Simple transfusion to baseline Hb. Acute ischemic stroke. Acute pain. Exchange transfusion, not currently indicated, unless additional complication. Acute chest syndrome. No transfusion, simple or exchange transfusion, depending on severity. Acute priapism. Consider simple or exchange transfusion, if no response to initial treatment. Mutiple organ failure, acute sickle hepatopathy, severe sepsis. Exchange transfusion. SUMMARY OF EMERGENCY INDICATION S OF TRANSFUSION. ASH -2020

25. Consider simple transfusion: Moderate ACS with pre transfusion Hb levels <9gm/dl. Consider automated, or manual RCE:(automated preferred if available) Severe ACS. Rapidly progressive ACS. Moderate ACS with a high pre –transfusion Hb ( eg >9 gm/dl). No improvement after initial simple transfusion. CHOICE OF TRANSFUSION THERAPY IN ACS. ASH GUIDELINES 2020

26. TECHNICAL CONSIDERATIONS WITH IHD-RCE.(ASH-2020) Minimum HCT The guidelines, panel suggests, not decreasing the Hct to <21% and /or no more than 20% from baseline. Isovolumic replacement fluid. Saline or 5% albumin are standard, if hypotension, is a concern, albumin should be considered. To reduce red cell volume needed. Maintain same procedure frequency, and targets for end, Hct and HbS% as with conventional RCE.

27. CONSIDER INDICATIONS FOR TRANSFUSION IN PREGNANT WOMEN WITH SCD. ASH-2020 Women with previous serious medical , obstetric or fetal complications. Consider prophylactic RCE. Women who are on transfusion regimen before pregnancy for primary or secondary stroke prevention or for the prevention of severe disease complications. Continue pre-pregnancy transfusion program. Twin pregnancies Consider prophylactic RCE as high rate of complications in twin pregnancies. Acute anemia Simple transfusion if Hb <7 gm/dl or >2 gm/dl below baseline Acute chest syndrome,acute stroke, or other complication,repeated pain crisis during pregnancy. Emergency RCE followed by prophylactic transfusion therafter .

28. TRANSFUSION CONSIDERATION DURING PREGENANCY: ASH -2020 Consider prophylactic regular transfusion at pregnancy onset for: History of severe or frequent SCD related complications before current pregnancy. Additional features of high risk pregnancy( eg , comorbidities such as nephropathy.) Consider prophylactic regular transfusion later in pregnancy for: Onset of SCD related complications,(fetal or maternal) during current pregnancy. Transfusion targets Alloimmunization risks: Hb >7 gm /dl, and target HbS level, of <50% Hemolytic disease of the fetus, and newborn is a potential risk with transfusion.

29. Preoperative transfusion consideration: Consider no transfusion: Surgery requiring less than 1 hr of general anaesthesia . Low risk sugery .( arthroscopy,myringotomy tubes). Hb >10gm/ dl,milder genotype ( HBSc or phenotype). Multiple red cell alloantibodies /DHTR.(history) Consider simple transfusion: Moderate or high risk surgery.( tonsillectomy,joint rplacement,abdominal surgery). Hb<9 gm/dl. Severe genotype. Consider red cell exchange: Very high risk surgery.(Neurosurgery or cardiac surgery). Patients needing preoperative transfusion but with, Hb>9-10 gm/dl. Transfusion targets:- Post transfusion target hb (9-11 gm /dl). Preoperative HBS %<30-50% for high risk surgery eor severe phenotype(history of stroke,recurrent ACS or prior severe post –operative complications)

30. IRON OVERLOAD SCREENING WITH CHRONIC TRANSFUSION. Consider serum,ferritin monitoring only: Serum ferritin<1000ng/ ml,particularly if managed with regular exchange transfusion,with neutral or negative net red cell gain. R2,T2OR R2 MRI Use a validated method. Same method should be used over time(every 1-2 years) Useful for titration of iron chelation. &to determine chelation regardless of ferritin level. Consider cardiac MRI: Liver iron content >15 mg/ gdry weight for>2 yrs. H/O ex Evidence of cardiac overloadex ceptionally elevated liver iron. Evidence of end organ damage,resulting from transfusional iron overload. Consider chelation: R2 orR2 liver iron conc >5mg/gm dry weight. T2 cardiac iron<20 ms.

31. SUMMARY OF NON –NEUROLOGICAL INDICATIONS. Recurrent pain crisis Consider if hydroxyurea ineffective or contraindicated. Recurrent acute chest syndrome Consider if hydoxyurea ineffective or contraindicated. Recurrent priapism Consider if lack of response to other treatments. Leg ulcers Consider if lack of response to other treatments or in context of clinical trial Pulmonary hypertension Consider on case by case basis or in context of clinical trial. Post renal or liver transplantation: Consider on case by case basis.

32. QUESTION BANK:

33. MCQ’S Q1) Hyperhemolysis is defined as: Significant drop in Hb within 21 days post transfusion. Rapid haemoglobin decline to below the pretransfusion level. Rapid decline of post transfusion HbA level. Significant LDH arise from baseline. ANS: b,c .

34. Automated red cell exchange is better than simple transfusion because:- RCE quickly and precisely reaches target HBS. RCE maintains isovoluemia. RCE requires specialized equipment's. RCE needs specialized staff. Ans – a,b .

35. Choice of transfusion therapy in ACS:- moderate ACS with pre transfusion Hb level <9gm/dl. Simple transfusion. Automated RCE. Rituximab. Manual RCE. Ans - a.

36. In context of Isovolumeic hemodilution –RCE , which of the following statement is true:- Saline or 5%albumin are standard to use. Saline only. 8% Albumin. 0.9% saline. Answer A only.

37. LONG QUESTIONS: Describe the management protocol as per ASH guidelines 2020 in a patient with life threatning anemia and high risk of HTR. Describe pathophysiology of SCD, and clinical features.

38. SAQ:- Q1.) Enumerate and compare different method of transfusion methods. Q2) Enumerate Electropheresis findings in case of SCD. Q3)Enumerate transfusion consideration in case of pregnancy ACC to ASH guidelines?