Transfusion in Sickle cell anemia Dr. Soheila zareifar Department of pediatric hematology/oncology Shiraz university of medical sciences Qeshm 2018

Transfusion in Sickle Cell In sickle cell disease transfusions improve blood flow by reducing the proportion of red cells capable of forming sickle hemoglobin polymer. This limits hemolysis and the endothelial damage that result from high proportions of sickle polymer-containing red cells. Additionally, transfusions are used to increase blood oxygen carrying capacity in sickle cell patients with severe chronic anemia or with severe anemic episodes. 

Transfusion in Sickle Cell However, transfusion carries risks, many of which are greater in individuals with SCD than in the general population. The approach to transfusion in SCD must balance these benefits and risks, both in decisions regarding when to transfuse and in the practical aspects of how transfusions are administered. Used correctly, transfusion can prevent organ damage and save the lives of sickle cell disease patients. Used unwisely, transfusion therapy can result in serious complications.

INDICATIONS FOR TRANSFUSIONS The two primary goals of transfusion are: 1. Management of severe anemia to correct the low oxygen-carrying capacity caused by severe anemia. 2. Management of sudden severe illness to improve microvascular perfusion by decreasing the proportion of sickle red cells in the circulation. In the clinical setting, transfusions are often used to address both indications.  

Decision for transfusion 1. EPISODIC (EMERGENCY) TRANSFUSION 2. PREPARATION FOR GENERAL ANESTHESIA 3. CHRONIC TRANSFUSION THERAPY 4. CHRONIC DEBILITATING PAIN 5. CONTROVERSIAL/EQUIVOCAL INDICATIONS

EPISODIC (emergency)TRANSFUSIONS Management of severe anemia Management of severe illness

Management of severe anemia Most common: a. Acute splenic sequestration b. Acute hepatic sequestration c. Transient red cell aplasia episodes (Aplastic crisis ) d. Hyper hemolysis, is associated with infection e. Acute chest syndrome f. Increased hemolysis during painful crises

EPISODIC TRANSFUSIONS Management of sudden severe illness Transfusions to improve tissue oxygenation and perfusion are indicated in these seriously ill patients Acute chest syndrome Acute ischemic stroke Sepsis Acute priapism Acute multi-organ failure syndrome Mesenteric (“girdle”) syndrome Acute intrahepatic cholestasis Pregnancy?? transfusion therapy to women who experience frequent complications during pregnancy.

EPISODIC TRANSFUSIONS Management of sudden severe illness Target Hb 10-11 g/dl is effective in preventing progression to acute respiratory failure in SS patients with mild ACS if it is given early in the illness and should be considered in patients with a PaO2 <90 on room air. Exchange transfusion is recommended in patients with features of severe ACS, those who fail to respond to initial simple transfusion, or patients with a higher Hb (>9 g/dl) where there is little leeway for simple transfusion. There is no evidence as to the optimal %HbS target post-exchange transfusion. In practice, a target of <30–40% is often used, but clinicians should be guided by the clinical response .

PREPARATION FOR GENERAL ANESTHESIA A multi-institution study recently compared perioperative complications among patients with sickle cell disease undergoing major surgery (e.g. cholecystectomy). Patients were randomized to an aggressive transfusion arm (decrease hemoglobin S to below 30 percent) or to a conservative transfusion arm (hemoglobin S approximately 60 percent; hemoglobin corrected to 10 gr/dl). The control patients did not receive perioperative transfusions. Complications occurred in all groups, but were substantially more frequent in the non-transfused patients. There was no difference between the conservatively or aggressively transfused patients with respect to perioperative complications. However, alloimmunization occurred more frequently in the aggressively transfused group.

PREPARATION FOR GENERAL ANESTHESIA The recommendation from this study is that all sickle cell disease patients undergoing major surgery be prepared in advance with transfusion to correct their anemia to a hemoglobin of approximately 10 gm/dl and hemoglobin S percent to approximately 60 percent. No standard practice guidelines have been developed for patients undergoing minor procedures or for patients with hemoglobin SC disease. The generally accepted practice is to not use preoperative transfusion therapy in healthy hemoglobin SC patients, nor for limited minor surgery in stable hemoglobin SS patients.

CHRONIC TRANSFUSION THERAPY Indicated for several conditions in which the potential medical complications outweigh the risks of alloimmunization, infection and iron overload. The goal of these programs is to maintain the hemoglobin S at 30-50 percent, depending on the specific disorder. Transfusions are usually repeated every 3-4 weeks.

CHRONIC TRANSFUSION THERAPY Primary and secondary stroke prevention Secondary prevention of silent cerebral infarction in children with SCD Secondary prevention of overt stroke in children with SCD Prevention of recurrence of stroke Recurrent ACS Frequent painful crises( ≥3 times a year because of vaso-occlusive crises are at increased risk of early death) Pulmonary hypertension and chronic lung disease Vital organ failure

Primary stroke prevention The STOP trial demonstrated that chronic transfusion therapy reduces the occurrence of first stroke in children with a rate of high blood flow through the circle of Willis cerebral arteries, as measured by Doppler ultrasonography. This was the first application of chronic transfusion therapy to prevent potential complications of sickle cell disease.  

Prevention of recurrence of stroke Chronic transfusion therapy for children who suffer vaso-occlusive stroke decreases the recurrent stroke rate from 90 percent to less than 10 percent. Initially, the hemoglobin S level is maintained at 30 percent or less for approximately 5 years. Well-controlled studies have not determined the duration or percent level of hemoglobin S required for long-term treatment of these patients. Pilot studies allowing the hemoglobin S to rise to 50 percent in patients with stable neurologic disease are on-going.

Pulmonary hypertension , chronic lung disease Chronic transfusion therapy has been used to decrease the recurrence of pulmonary events in patients experiencing severe acute chest syndrome. While pilot data suggests this therapy is efficacious, rigorous clinical trials have not been completed. The duration of such treatment programs is also unknown. Patients with proven pulmonary hypertension and chronic lung disease should receive long-term chronic transfusion therapy.

Vital organ failure Chronic heart failure is a late complication of sickle cell disease. Transfusion therapy for these patients, along with interventions to improve cardiac function, enhances quality of life. Severe anemia, secondary to chronic renal failure, often becomes debilitating. Erythropoietin therapy is often ineffective, leaving chronic transfusion therapy as the sole option.

CONTROVERSIAL/EQUIVOCAL INDICATIONS Management of acute priapism Preparation for infusion of contrast media Pregnancy Management of "silent" cerebral infarct and/or neurocognitive damage Leg ulcers

Non-indications and contra-indications 1. Chronic steady-state anemia. 2. Uncomplicated acute painful crises. 3. Infections 4. Minor surgery not requiring prolonged general anesthesia (e.g., myringotomy) 5. Aseptic necrosis of the hip or shoulder (except when surgery is required) 6. Uncomplicated pregnancy 7. Leg ulcer 8. Prior to contrast media exposure 9. Sub-clinical neurological damage 11. Priapism

TRANSFUSION METHODS Simple transfusion used for acute anemia or hypovolemia Exchange transfusion is used to alter the hemoglobin level rapidly and to replace sickle cells with normal cells Rapid partial exchange whole blood can be removed from one arm at the same time that donor cells are transfused into the other arm Erythrocytopheresis When to use each method?

Transfusion in Sickle Cell (exchange transfusion) Except in severe anemia, exchange transfusion offers many benefits and is our first choice Phenotypically matched, leuko - depleted packed cells are the blood product of choice. A posttransfusion hematocrit of 30 to 36 percent or less is recommended. Avoid hyper viscosity, which is dangerous to sickle cell patients.

Transfusion in Sickle Cell (exchange transfusion) Bleed one unit (500 ml), infuse 500 ml of saline Bleed a second unit and infuse two units. Repeat. If the patient has a large blood mass, do it again.

Transfusion in Sickle Cell (exchange transfusion) Episodic, acute transfusions to stabilize or reverse complications. Limited studies have shown that aggressive transfusion (get Hgb S < 30%) may help in sudden severe illness. May be useful before general anesthesia.

EXCHANGE TRANSFUSION In children, a practical estimate of the volume required for exchange (whole blood or packed cells reconstituted to a hematocrit of 30-40 percent) is 50-60 mL/kg. In adults, blood can be removed from the patient in 500 mL aliquots, followed by infusion of 500 mL of reconstituted blood; this may be repeated for 6-8 units of transfusion. Alternatively, the following technique can be used:   Bleed one unit (500 mL) of blood from the patient, infuse 500 mL of saline. Bleed a second unit from the patient, infuse two units of blood. Repeat steps 1 and 2; if the patient has a large red blood cell mass, repeat once more.

EXCHANGE TRANSFUSION Usually 6-8 units of blood are needed to exchange and adult. Formulae are available to calculate the exact amount needed depending on body size, pretreatment hematocrit, desired hematocrit, and desired percentage of hemoglobin A. Such devices can be used for pediatric patients if the size of the receptacle is sufficiently small so as not to remove too much blood at one time.

Transfusion in Sickle Cell (chronic transfusion therapy) Stroke Chronic debilitating pain Pulmonary hypertension Setting of renal failure and heart failure

Transfusion in Sickle Cell Inappropriate uses of transfusion: Chronic steady-state anemia Uncomplicated pain episodes Infection Minor surgery Uncomplicated pregnancies Aseptic necrosis

Transfusion Mediated Iron Overload While transfusion may improve disease complications, iron overload is a dreaded and inevitable consequence of ongoing transfusion therapy. Chronically transfused iron overloaded patients with SCD have significantly higher mortality than less transfused counterparts without iron overload, as well as age and race-matched normal controls. Available data suggest that SCD patients are relatively protected from iron- induced cardiac and endocrine organ damage as compared with TM patients.

Potential Factors Modifying Iron Toxicity in SCD Relative distribution of iron loading in RES versus parenchymal cells Levels of NTBI and LPI Coexisting hereditary iron loading defects The impact of ineffective erythropoiesis. The role of hepcidin in the pathophysiology of iron overload in SCD remains controversial. 

Transfusion Mediated Iron Overload The role of hepcidin in the pathophysiology of iron overload in SCD remains controversial.  Although steady-state SCD patients do not exhibit increased hepcidin levels, transfusion acutely up regulates hepcidin mRNA expression. It is unclear whether this increased gene expression results in increased circulating hepcidin and decreased unbound iron immediately post transfusion. Nor is it known whether this transient increase in hepcidin expression is of clinical relevance. Patients with SCD suffer from recurrent infections and ongoing endothelial damage by reperfusion injury that result in a chronic-inflammatory-like state. This is evidenced by increased CRP, IFNγ, IL-1, and IL-6 in steady state and IL-6 and TNF-  increase during crises.

Cumulative transfusions of 120 cc packed RBC/kg Chelation therapy should be considered NIH guidelines (2008) Italian Society of Hematology UK guidelines (Sickle Cell Society) (2010) Transfusion status Serum ferritin Liver iron concentration Cumulative transfusions of 120 cc packed RBC/kg Steady-state level >1000 ng/mL ≥7 mg Fe/g dw When >10 units of blood have been received >1000 ng/mL - At least 20 top-up transfusions