Sickle Cell Complications

General Approach – all patients

Pain-coping behaviors in children and adults with sickle cell disease are not typical. Often they use distraction (e.g. eating, watching TV, using smart phone).
For the stable patient, consider butterfly needles for blood draws, sparing veins from IVs (i.e. preserve veins whenever possible).
Give supplemental O₂ only for hypoxia (blunts bone marrow response).
Any and all organ systems may be affected: Neuro (stroke), ENT (infection), Pulm (pulmonary hypertension, acute chest syndrome), Cor (hypertension), GI (cholelithiasis/cholecystitis), GU (priapism), Heme (vaso-occlusive crisis), Musculoskeletal (osteonecrosis, osteomyelitis), etc.
Evaluate for aplastic crisis with CBC (anemia) and reticulocyte count (bone marrow response). If anemic below baseline and a reduced reticulocyte count, (reticulocytes less than 1% or absolute reticulocyte count less than 10,000 per microL), consider aplastic crisis.

Background care

Pneumococcal vaccination – decreases the risk of invasive pneumococcal disease by up to 90%

Penicillin – prophylaxis due to asplenia; PCN BID in children less than 5 years of age drastically decreases pneumococcal risk. After age 5 years, there is a dramatic decline in the incidence of pneumococcal infection, probably because of a better immunologic response to encapsulated organisms such as S. pneumoniae.

Folate supplementation – the average RBC lifespan in SCD is 12 days, compared to 120 days in non-affected individuals. More turnover (10 x) requires more substrate.

Hydroxyurea – promotes production of HbF, which is not susceptible to sickling as is HbS. Decreases morbidity, mortality. Less common side effects are neutropenia, bone marrow suppression, elevation of hepatic enzymes, anorexia, nausea, vomiting and infertility.

Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012; Figure 1.

Dangerous Complications of Sickle Cell Disease

Splenic sequestration – 5 months to 2 years (median is 18 months)

Presentation

Occurs when RBCs flow into, but not out of spleen (RBCs pool and sickle).
Present as rapidly enlarging spleen, an acute drop in hemoglobin by 2 g/dL. May result in shock and death.

Management

Treat shock, transfuse PRBCs. Careful of re-perfusion syndrome, in which the perfused patient dumps damaged RBCs back into circulation.
Splenectomy to prevent recurrence (untreated, 50% recurrence rate)

Sequestration crisis, transfusion, and patient’s autotransfusion after perfusion restored:

Ischemic Stroke 2- 5 years old – up to 20% have silent brain infarcts

Infants may be screened for vasculopathy by transcranial doppler ultrasound and given regimen of regular blood transfusions to keep HbS levels below 30% (may reduce risk fi stroke by 90%).

Presentation

May have baseline cognitive impairment, with or without evidence of infarct
Usually present with focal neurologic deficits, often misinterpreted as having pain (e.g. “doesn’t want to move his arm”).

Management

CT in ED, MRI as inpatient
Transfusion goals: a) increase the hemoglobin concentration to approximately 10 g/dL and b) decrease the percentage of HbS RBCs to < 30%
Start with simple transfusion PRBCs; possibly will need exchange transfusion
Thrombolysis with tPA is not recommended for children < 18 years of age with ischemic stroke due to sickle cell (more important to treat cause; not FDA approved)
Anticoagulation may be considered specifically for patients with cerebral venous sinus thrombosis.

Acute Chest Syndrome – 2 to 4 years of age, some genotypes later

Presentation

New pulmonary infiltrate with one other feature: fever, chest pain, shortness of breath, hypoxia
13% require mechanical ventilation, 3% mortality rate.

Management

Supportive (pulmonary toilet, supplemental oxygen, non-invasive positive pressure ventilation, mechanical ventilation prn)
IV antibiotics initially (nearly impossible to distinguish from pneumonia on presentation)
Exchange transfusion in severe cases
Dexamethasone may reduce need for serial blood transfusions

Fever/bacteremia – median age 6 to 7 years

Functional asplenia by age 4. Vaccines, prophylactic antibiotics (up to age 5) decrease morbidity/mortality. Patients always at risk for infection, bacteremia from encapsulated organisms and parasites.

Presentation

Any fever in a child or adult with sickle cell is bacteremia until proven otherwise, regardless of results of viral respiratory panel results (co-infections and super-infections are common)

Encapsulated bacteria – vaccine preventable

Streptococcus pneumoniae accounts for the majority (40-60% cases). Often symptoms are vague, fever, nausea, vomiting, diarrhea.
Haemophilus influenzae type b often presents as bacteremia, pneumonia, and/or meningitis.
Neisseria meningitidis is less common, and initially presents with vague flu-like symptoms. Rapidly progresses to septic shock, DIC, and purpura fulminans.

Encapsulated bacteria – no vaccine available

Salmonella (food contamination), Klebsiella (opportunistic), Pseudomonas (opportunistic), Capnocytophaga (dog bites), Bordetella (respiratory variant and cats), Escherichia coli (food contamination)

Parasites and atypicals

Babesia (tick-borne), Cytomegalovirus (opportunistic), Mycoplasma pneumoniae (respiratory), Mycobacterium tuberculosis (respiratory)

Management

IV access, blood cultures, immediate empiric antibiotics, and admission.
Ceftriaxone 50 mg/kg (bacteremia); 75 mg/kg (focal infection); 100 mg/kg (suspected meningitis) up to 2 g/kg.
Vancomycin 15 mg/kg for suspected meningitis
Clindamycin for cephalosporin allergy, 10 mg/kg

Osteomyelitis – 90% before 10 years of age

Presentation

Difficult to distinguish osteomyelitis from vaso-occlusive crisis, and even osteonecrosis, as all can present with pain, inability to ambulate.
Favoring osteomyelitis: fever, soft tissue edema, erythema, point tenderness to palpation.
Encapsulated organisms are common.
Avascular necrosis occurs in up to 10% of children with sickle cell disease. The natural progression of disease is: vaso-occlusion of supplying vessel which causes microfractures, collapse of cancellous bone, and finally collapse of the contour of the articular surface with chronic pain and loss of normal function.
Interestingly, the entire epiphysis is often involved. Femoral heads are most common sites. Other common sites include humeral head and the distal tibia. Less common but important considerations are the mandible, elbow, and vertebrae.

Management

Plain films, biomarkers (CBC, CRP, ESR)
If concern for osteomyelitis, admission for MRI

Priapism – mean 15 years of age

Presentation

Common, possibly up to half of boys and men with sickle cell have experienced priapism (reporting bias).
Majority of cases are low-flow, ischemic priapism.
Often provoked by vaso-occlusive crisis, sexual activity, fever, dehydration, drug use, or associated with normal daily sleep-associated tumescence.

Management

Fluids, pain control.
If not rapidly controlled, needle aspiration, irrigation with phenylephrine (standard priapism aspiration/infusion technique)
Exchange transfusion for refractory cases (although has not been proven to decrease time to detumescence)

Hemorrhagic stroke – average age, adolescents throughout 20s

Presentation

Intracranial hemorrhage is more likely in older adolescents and adults with sickle cell disease. Etiologies include hemorrhagic transformation of a previous ischemic stroke, or a primary subarachnoid, intraventricular, or parenchymal hemorrhage.
Presentations vary and may be non-focal (severe headache) or typical (focal neuro deficits).

Management

Reverse any previous anticoagulants
Maintain platelet count above 100,000/microL
Angiography as needed for culprit lesion
Neurosurgical consultation
Despite optimal treatment, mortality may be as high as 50%

Specific Treatment Modalities

Analgesia

Typically sickle cell pain is managed at home with NSAIDs and sparingly with opioids. Patients who come to the ED often exhibit more morbidity and are opioid-tolerant.

Options include:

Intranasal Fentanyl 2 mcg/kg
Morphine1 mg/kg/dose every 15-30 min titrated to effect
Hydromorphone015 mg/kg/dose every 15-30 min titrated to effect
Ketamine3 mg/kg (subdissociative dose) as an adjunct

Simple Red Blood Cell Transfusions

Goal is to dilute HbS red blood cells with functional HbA red blood cells to interrupt cycle of hypoxia, sickling, and occlusion.

For severe complications, may start with simple PRBCS transfusion of 5-10 mL/kg. Careful in potential sequestration (see above)

Exchange Transfusion

Goal is to replace patient’s blood manually (traditional, time- and effort-consuming) or by automated erythrocytapheresis (more effective, especially with large volumes) . Used when goal is to decrease Hb S concentration to less than 30%

Iron Chelation

Each unit of packed red blood cells can introduce approximately 250 mg of elemental iron. This is usually of concern in patients with chronic routine transfusions or recurrent need for acute transfusion.

Iron overload can cause cardiac, liver, and endocrine disorder. Serum ferritin levels give an estimate of total body stores and may be used to drive therapy. Various chelating agents are available; deferoxamine is common.

Hydroxyurea

Discharged patients should be evaluated for the need for hydroxyurea therapy, as it can reduce the incidence of acute chest syndrome, transfusion requirement, and mortality when compared with those on placebo. It is typically indicated for most children, and for adults with recurrent pain episodes.

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Selected References

Splenic Sequestration

Al-Salem AH. Splenic complications of sickle cell anemia and the role of splenectomy. ISRN Hematol. 2011;2011:864257. doi: 10.5402/2011/864257. Epub 2010 Oct 31. PMID: 22084706; PMCID: PMC3200071.

Brousse V, Elie C, Benkerrou M, Odièvre MH, Lesprit E, Bernaudin F, Grimaud M, Guitton C, Quinet B, Dangiolo S, de Montalembert M. Acute splenic sequestration crisis in sickle cell disease: cohort study of 190 paediatric patients. Br J Haematol. 2012 Mar;156(5):643-8.

El Hoss S, Brousse V. Considering the spleen in sickle cell disease. Expert Rev Hematol. 2019 Jul;12(7):563-573. doi: 10.1080/17474086.2019.1627192. Epub 2019 Jun 14. PMID: 31195851.

Kane I, Nagalli S. Splenic Sequestration Crisis. [Updated 2021 Apr 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021

Owusu-Ofori S, Remmington T. Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. Cochrane Database Syst Rev. 2017 Nov 7;11(11):CD003425

Powell RW, Levine GL, Yang YM, Mankad VN. Acute splenic sequestration crisis in sickle cell disease: early detection and treatment. J Pediatr Surg. 1992 Feb;27(2):215-8; discussion 218-9.

Solanki DL, Kletter GG, Castro O. Acute splenic sequestration crises in adults with sickle cell disease. Am J Med. 1986 May;80(5):985-90.

Ischemic Stroke

DeBaun MR et al. Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia. N Engl J Med 2014; 371:699-710

DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014;371(8):699-710. doi:10.1056/NEJMoa1401731

Farooq S et al. Neurologic Complications of Sickle Cell Disease. Current Neurology and Neuroscience Reports (2019) 19: 17

Acute Chest Syndrome

Al-Salem A. (2016) The Acute Chest Syndrome in Sickle Cell Anemia. In: Medical and Surgical Complications of Sickle Cell Anemia. Springer, Cham.

Heilbronner C, Berteloot L, Tremolieres P, Dupic L, de Saint Blanquat L, Lesage F, Odièvre MH, de Marcellus C, Fourgeaud J, de Montalembert M, Grimaud M, Moulin F, Renolleau S, Allali S, Oualha M. Patients with sickle cell disease and suspected COVID-19 in a paediatric intensive care unit. Br J Haematol. 2020 Jul;190(1):e21-e24. doi: 10.1111/bjh.16802.

Martí-Carvajal AJ, Conterno LO, Knight-Madden JM. Antibiotics for treating acute chest syndrome in people with sickle cell disease. Cochrane Database Syst Rev. 2019 Sep 18;9(9):CD006110

Siddiqui AK, Ahmed S. Pulmonary manifestations of sickle cell disease. Postgraduate Medical Journal 2003;79:384-390.

Fever and Bacteremia

Morrissey BJ, Bycroft TP, Almossawi O, Wilkey OB, Daniels JG. Incidence and Predictors of Bacterial infection in Febrile Children with Sickle Cell Disease. Hemoglobin. 2015;39(5):316-9

Savlov D, Beck CE, DeGroot J, Odame I, Friedman JN. Predictors of bacteremia among children with sickle cell disease presenting with fever. J Pediatr Hematol Oncol. 2014 Jul;36(5):384-8.

Shihabuddin BS, Scarfi CA. Fever in children with sickle cell disease: are all fevers equal? J Emerg Med. 2014 Oct;47(4):395-400

Sirigaddi K, Aban I, Jantz A, Pernell BM, Hilliard LM, Bhatia S, Lebensburger JD. Outcomes of febrile events in pediatric patients with sickle cell anemia. Pediatr Blood Cancer. 2018 Nov;65(11):e27379.

Osteomyelitis

Aguilar C, Vichinsky E, Neumayr L. Bone and joint disease in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):929-41

Vaishya R, Agarwal A, Edomwonyi E O, et al. (October 20, 2015) Musculoskeletal Manifestations of SickleCell Disease: A Review. Cureus 7(10): e358. DOI 10.7759/cureus.358

Vanderhave KL, Perkins CA, Scannell B, Brighton BK. Orthopaedic Manifestations of Sickle Cell Disease. J Am Acad Orthop Surg. 2018 Feb 1;26(3):94-101.

Priapism

Arduini GAO, Trovó de Marqui AB. Prevalence and Characteristics of Priapism in Sickle Cell Disease. Hemoglobin. 2018 Mar;42(2):73-77.

Chinegwundoh FI, Smith S, Anie KA. Treatments for priapism in boys and men with sickle cell disease. Cochrane Database Syst Rev. 2020 Apr 6;4(4):CD004198

Rogers ZR. Priapism in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct;19(5):917-28, viii

Hemorrhagic Stroke

Strouse JJ, Hulbert ML, DeBaun MR, Jordan LC, Casella JF. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics. 2006 Nov;118(5):1916-24. doi: 10.1542/peds.2006-1241. PMID: 17079562.

Talahma M et al. Sickle Cell Disease and Stroke. Stroke. 2014;45:e98-e100

General

Ballas S K et al. Sickle cell pain: a critical reappraisal. Blood. 2012; (1) 12: 18

Gong, L., Parikh, S., Rosenthal, P.J. et al. Biochemical and immunological mechanisms by which sickle cell trait protects against malaria. Malar J 12, 317 (2013).

Hequet O et al. Red blood cell exchange in an emergency in sickle cell disease. Transfusion and Apheresis Science 59 (2020) 102996

Howard J. Sickle cell disease: when and how to transfuse. Hematology Am Soc Hematol Educ Program. 2016;2016(1):625-631. doi:10.1182/asheducation-2016.1.625

Koehl B, Missud F, Holvoet L, et al. Continuous Manual Exchange Transfusion for Patients with Sickle Cell Disease: An Efficient Method to Avoid Iron Overload. J Vis Exp. 2017;(121):55172. Published 2017 Mar 14. doi:10.3791/55172

Lanzkron S, Strouse JJ, Wilson R, Beach MC, Haywood C, Park H, Witkop C, Bass EB, Segal JB. Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med. 2008 Jun 17;148(12):939-55

Luzzatto L. Sickle cell anaemia and malaria. Mediterr J Hematol Infect Dis. 2012;4(1):e2012065. doi:10.4084/MJHID.2012.065

Ochocinski D et al. Life-Threatening Infectious Complications in Sickle Cell Disease: A Concise Narrative Review. Front. Pediatr., 20 February 2020