Sickle Cell Disease and Complications

Andres J Rubio, Zoe Finer

Sickle Cell Disease (SCD) Basics 

  • Pathogenesis: Recessive mutation in β-globulin of hemoglobin => structurally abnormal Hgb (HbS). Homozygosity for HbS (Hb SS) is the classic form of sickle cell disease, but compound heterozygosity with other abnormal hemoglobin genes can cause atypical or mild SCD.
  • Epidemiology:
    • Often linked to Sub-Saharan Africa, but also in other regions with high malaria burden (Central/South America, Caribbean, Middle East, Mediterranean, India).
    • Roughly 1/365 African Americans have SCD, 1/13 (8-10%) of African Americans have sickle cell trait.
  • Pathogenesis of sickling: Decreased O2 => HbS polymerization => RBC sickling & decreased RBC deformability => hemolysis and microvascular occlusion.
  • Most common complications of SCD: acute chest syndrome, CVA, VTE (DVT, PE), pain crisis, ARF, sickle cell nephropathy, renal papillary necrosis, acute on chronic anemia, avascular necrosis, priapism, PH, hepatobiliary complications.
  • Diagnosis: Anemia on CBC, Hgb electrophoresis, periph blood smear.

Evaluation and initial management in hospitalized patient

  • Hx: if pain crisis, try to identify precipitating factor (commonly stress, dehydration, infection, hypoxia, substance use). SCD patients can be hospitalized for non SCD reasons so keep broad DDX.
  • Labs: LDH, CBC, retic, smear, consider infectious workup (UA, BCX), Hgb S level and compare to baseline (if c/f acute chest), Maintain active type and cross given probability of antibodies.
  • Imaging: recommend CXR and other imaging based on symptoms. Consider CT PE, MRI for hip pain to eval avascular necrosis, Abdominal U/S or CT abdomen to eval splenic / renal infarct.
  • Consult Benign Hematology Team on admission. Look for care coordination note in summary tab.
  • Typically, ok to continue hydroxyurea if uncomplicated pain crisis, consider holding if cytopenias or infection.
  • Due to concern for iron overload, development of alloantibodies, and risk of hyperviscosity necessary to be conservative with blood products. Typically will only transfuse PRBCs for hgb drop >2 from baseline OR if pt is symptomatic.
  • VTE ppx as patients are at high risk of VTE.
  • Daily I/O (due to risk of volume overload / pulmonary edema).
  • Check care coordination or clinic notes for inpatient pain management plan.
  • Continue folic acid 1mg daily.

Caring for SCD patients in Primary Care

  • BP goal <130/80.
  • Referral to SCD clinic for disease modifying therapy and coordination of annual SCD visit.
  • Annual screen for end-organ damage: renal function, proteinuria, s/s PH and obtain TTE if concerned, LFTs / ferritin, yearly eye exam.
  • Annual screen for Vitamin D deficiency.
  • Ensure uptodate on vaccinations: (SHiN) strep pneumo, H Flu, N meningitidis, COVID, flu, Hep A and Hep B.
  • SCD patients are at higher risk of co-morbid HTN, DM2, obesity, constipation, cognitive impairment, chronic pain, VTE.
  • Consider referral for genetic counseling and reproductive health planning.
ComplicationSigns/SxPathogenesisWorkupManagement
Acute Chest Syndrome (PNA, intrapulmonary sickling, pulmonary fat embolism) New radiodensity on chest imaging AND either fever +/- respiratory symptoms (hypoxia, tachypnea, cough, chest pain)
- of note, infiltrate on CXR may initially be negative, absence does not eliminate possibility 		Vaso-occlusion in pulmonary microvasculature (=> deoxygenation => sickling => vaso-occlusion)

Precipitants:
infection (PNA - chlamydia, bacteria, mycoplasma), pulmonary infarction, PE, fat embolism, and pain crisis 		CBC, CXR, assess for s/s DVT, assess for indwelling catheter, order HbS with lab workup (drives tx)

Other:
consider CTAPE, ECG 		1. C/s heme
2. Supplemental O2 (>95%) and incentive spirometry
2. D5 ½ NS @ 150-250cc/hr (caution to avoid pulmonary edema)
3. Transfuse 1-2 units if stable O2 requirements and Hgb is below baseline or <10, also consider exchange transfusion (heme team can help)
4. Pain control: see pt's pain plan, consider PCA
5. Immediate Abx - CAP coverage (vs HAP if risk factors) [3rd gen cephalosporin + macrolide]
TIA Or Stroke Focal seizures, hemiparesis, speech deficit, any new neurologic insult Chronic vasoocclusion => endothelial damage => Intimal hyperplasia => vascular stenosis + occlusion of vasculature by sickle cells. Vascular + oxidative injury => activation of coagulation cascade.

*O2 delivery to the brain is dependent on total Hgb concentration and % of HbS (transfusion goal of Hgb 10, HbS 15-20%) 		1. STAT non-con CTH to assess for hemorrhage vs moyamoya vasculopathy vs LVO
2. CBC
3. MRI 		Sx onset <4-5h:
1. Prompt blood transfusion (simple, exchange, or apheresis) within 2 hours*. If Hgb <8.5, simple transfusion to goal >10 (followed by apheresis). If Hgb >8.5, consider apheresis (decrease possibility of hyperviscosity syndrome*)
2. If hemorrhage on CTH => c/s heme and NSG
3. If no moyamoya vasculopathy, but LVO present => eval for thrombectomy + simple transfusion to achieve Hgb 10, exchange transfusion to reach HbS level 15-20%*
4. If moyamoya vasculopathy, simple transfusion to achieve Hgb 10, exchange transfusion to reach HbS level 15-20%*
For 24-72H onset: O2, transfuse for Hgb >10 and exchange transfusion for HbS 15-20%
Aplastic Crisis Sx: Dyspnea, weakness, fatigue
Signs: tachycardia, pallor, acute drop in Hgb, low reticulocyte count, non-palpable spleen, functional systolic murmur 		Decrease in erythropoiesis (can be due to Parvovirus B19 infection or other infections causing transient arrest of erythropoiesis) (lasts 2-14 days) Trend CBC (often <6) and reticulocyte count (often <1.0%), check CMP, hemolysis evaluation 1. C/s benign heme
2. Blood transfusion
3. Continue folic acid 1mg PO daily
4. Pain management
Splenic Sequestration Crisis LUQ pain, hypotension, acute-onset severe hemolytic anemia Occlusion of splenic vessels => pooling of RBC within spleen Reticulocyte count (high vs in aplastic crisis would be low), consider abdominal imaging to eval splenic infarct 1. C/s benign heme
2. IVF
3. Consider simple blood transfusion
Pain Crisis / Vaso-occlusive Crisis Typically acute, localized, severe pain, can be gradual Causes: (HIDISC)
Hypoxia, Ischemia, Dehydration, Infection, Stress, Cold 		Hx to identify trigger, VS, CBC, CXR, infectious workup.
Consider can't miss diagnoses (acute chest, CVA, PE, renal / splenic infarct). 		1. Aggressive, prompt pain mx: opioids, NSAIDs (reference pain plan in EPIC)
2. Encourage PO intake, if cannot consider IVF
3. Supplemental O2
4. Consider transfusion if Hgb drop >2 and low RC
Osteonecrosis / Avascular Necrosis (most often hip, sometimes shoulder) Chronic groin/hip/buttock/thigh pain with weight bearing that progresses to occurring at rest Sickling => disruption of bone microcirculation and increased intraosseous pressure due to bone marrow hyperplasia => end artery occlusion => necrosis PEx: pain and limited ROM with internal rotation and abduction of hip
Labs: normal WBC ct, ESR, CRP
Imaging: Xray (may appear normal early on), MRI 		1. Pain control
2. Consider outpatient ortho referral
3. Disease modifying therapy if not already on
Osteomyelitis Fever, leg pain (often in pt w hx of bone infarction, avascular necrosis, or gastroenteritis) Low blood flow => microinfarctions => nidus for infection
Asplenia => staph aureus and salmonella 		CBC,
CT/MRI,
blood/bone cultures 		1. Cultures
2. Antistaph therapy + 3rd-gen cephalosporin for salmonella coverage
Splenic Infarct Acute LUQ pain Stressor (high altitude, hypoxia, dehydration) => splenic artery occlusion CBC, Retic Ct, Tbili and DBili, Abdominal U/S or CT 1. Hydration, supplemental O2, analgesia
2. Consider future splenectomy (may recur), monitor for development of splenic abscess
Priapism Sustained unwanted painful erection lasting >4 hours Most often due to low-flow priapism (thought due to sickling of RBCs in venous sinuses => high pressure and prevention of outflow) History (precipitating factors: dehydration or medications), Physical exam, CBC and retic count, possible duplex U/S 1. Emergent urology c/s for sympathomimetic injection vs aspiration vs shunt
2. Analgesia
3. IVF if dehydrated, O2 if hypoxic
4. Disease modifying therapy outpatient
Renal Papillary Necrosis Macroscopic hematuria +/- flank pain
Often patient has sickle cell nephropathy 		Decreased O2 in renal medulla => sickling => RPN => hematuria U/A with microscopy, Creatinine, renal imaging 1. Microscopic hematuria => hydration
2. Macroscopic hematuria => bedrest and aggressive hydration
3. Consider exchange blood tx to lower %HbS
4. Outpatient - start disease modifying therpay for SCN (reduce proteinuria, delay/prevent CKD)
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