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Professors Baba Inusa
Guy’s and St Thomas’ NHS Foundation Trust
Introduction to Haemoglobinopathies
Case Scenarios slides and group comments
Pathophysiology -Therapeutic targets
Vaso-occlusion in SCD
Management strategy
Summary
VOCs can be managed by hydration, supplemental oxygen and non-medical techniques
1. Okomo U & Meremikwu MM. Cochrane Database Syst Rev 2017;CD005406; 2.Gallagher PG. Blood 2015;126:2775–6; 3. NIH Publication No 02-2117. NIH, Bethesda, MD, USA, http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf
Hydration1 Supplemental
oxygen3
Non-medical
techniques3
Hot baths
Massages
Distraction
Deoxygenation of HbS is critical for the
formation of sickle-shaped RBCs
Therefore, supplemental oxygen
can relieve pain during a VOC
Dehydration of RBCs is an important contributor to the
sickling process2
SCD patients often have reduced kidney function,
which impairs fluid balance control
Oral or IV fluids can relieve pain during a VOC
Appropriate monitoring is needed to avoid fluid
overload
VOCs can lead to many different acute and chronic complications
1. The Voice of the Patient FDA report 2014 The complications highlighted in green are some of those most driven by VOCs
“I can deal with the pain, but
what…I’m most concerned
about is the fact that my
organs are dying, my tissues
are dying, every time I’m
having a sickle cell episode”1
Retinopathy
Acute chest syndrome
Acute splenic
sequestratio
n
Pulmonary hypertensio
n
Priapism and
impotence
Heart disease
Vertebral body
collapse
Nephropathy
Liver failureArthropath
y
Leg ulcers
Chronic pain
Chronic anaemia
Avascular necrosis
Risk of infection
Overt and silent stroke
5
When I found out? I was really, really upset…… That is when I suddenly started to think about mortality and everything. SS what is that? I got the books and read
everything.I don’t want to manage the sickle cell, I just want it
completely gone. I just want to know how he is going to be and to be free of sickle cell and be his normal self
because he is a lovely boy and he is trying his best in the school and everything so this sickle cell thing is like
an obstacle in his way and I just want it gone.”
Is there a cure for my child sickle cell?
6
When I found out? I was really, really upset…… That is when I suddenly started to think about mortality and everything. SS what is that? I got the books and read
everything.I don’t want to manage the sickle cell, I just want it
completely gone. I just want to know how he is going to be and to be free of sickle cell and be his normal self
because he is a lovely boy and he is trying his best in the school and everything so this sickle cell thing is like
an obstacle in his way and I just want it gone.”
Is there a cure for my child sickle cell?
7
Result of Neonatal blood spot tests
1. You as the nurse receives the result of the NBS blood tests from the laboratory showing FS
2. The mother was confirmed as HbAS at ANC
◦What other test results do you need before visiting the parents?
◦Depending on your finding what are the next steps for disclosure ?
Factors that Lead to Sickle Cell Vasculopathy Can Be Potential Targets of Therapy
Ab, antibody; ESL-1, E-selectin ligand-1; FcyR, Fc receptor for immunoglobulin G; PSGL-1, P-selectin glycoprotein ligand-1; RBC, red blood cell; MHC 1, major histocompatibility complex class I; ROS, reactive oxygen species.
Looney MR, Matthay MA. Nature Medicine. 2009;15:364-366.
E selectin
RBC
⍺M𝛽2
Sickle cell
RBC
ESL-1
Vascular
occlusion Tissue
hypoxia
RBC
ligand?
PlateletNeutrophil
Platelet
ligand?
FcyR
engagement
MHC I
antige
n
MHC I
Ab
Endothelial
permeability
ROS
Cell adhesion“Sickling”
HbF induction
Inflammation
Oxidative stress
P selectin
PSGL-1
Adapted from Looney MR, Matthay MA. Nature Medicine.
2009;15:364-366.
8
Clinical Complications
Infection/Sepsis
Splenic Sequestration
Ischemic Stroke
Dactylitis
VOEACSGallstonesPriapismFe OverloadAplastic Crisis
Pulmonary HypertensionNephropathyAVNLeg UlcersChronic Lung DiseaseMulti Organ FailureHemorrhagic Stroke
Pediatrics
Adults
Splenic Sequestration Crisis
• Acute, life-threatening anemia
• RBCs trapped within the spleen
• Occurs mainly in younger children
with HbSS, but also in older children
and adults with HbSC and
HbSb+thal
• May be associated with infection,
hypovolemic shock and death
• Signs: Sudden drop of hemoglobin
~2g/dl, weakness, pallor,
tachycardia, tachypnea,
A VOC has four distinct phases, which can last for a total of 12 days
Day
Resolving phase
Established phase
Initial phase
Prodromal phase
0
1
2
3
4
5
6
7
8
9
10
-2 -1 0 1 2 3 4 5 6 7 8 9 10
Ca
teg
oric
al p
ain
sc
ale
1. Prodromal phase1
▪ Symptoms include numbness, paresthesia, and aches
▪ May be asymptomatic
4. Resolving phase1
▪ Pain severity decreases
2. Initial phase1
▪ Patients reach peak pain severity
▪ Increased
anxiety
3. Established phase1
▪ Patients maintain peak pain severity
▪ Signs of joint effusion and inflammation
ACS, acute chest syndrome; MOF, multiorgan failure1. Ballas SK et al. Blood 2012;120:3647–56
Recurrent crises with no intermediate pain1
Chronic pain1
Prodromal Initial Established Resolving Initial Established Resolving
Ca
teg
oric
al p
ain
sc
ale
Crisis day Crisis day100 98765421–1–2 3
2
4
6
10
8
1098765421–1–2 3
Prodromal Initial Established Resolving Initial Established Resolving
Ca
teg
oric
al p
ain
sc
ale
Crisis day Crisis day100 98765421–1–2 3
2
4
6
10
8
1098765421 3
Common timing for onset of complicationseg ACS, MOF, relapse, death
Note: Permission for figures to be requested
Suitable analgesia for VOC management must be selected on a case-by-case basis
1. NIH Publication No 02-2117. NIH, Bethesda, MD, USA, http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf; 2. Kawadler JM et al. Br J Haematol 2019;186:360–362
NSAID, non-steroidal anti-inflammatory drug
1Assess the patient’s level of painDifferent scales exist for ranking
pain1
Wrong-Baker
faces
Memorial pain
assessment
card
2 Options for analgesia1
Composite
pain index
Captures pain location, intensity, duration and frequency in a single
number2
1: No hurt 2: Hurts a little bit 3: Hurts a little more
4: Hurts even more 5: Hurts a whole lot 6: Hurts worst
Pain scale
Least
possible
pain
Worst
possible
pain
Relief scale Mood scale
Best
moodWorst
moodComplete
reliefNo
relief
Mild-to-moderate pain
Moderate pain
Moderate-to-severe pain
▪ Non-opioids eg NSAIDs, paracetamol (acetaminophen)
▪ Opioid/NSAID combinations egcodeine, hydrocodone, oxycodone
▪ Opioids, eg morphine, hydromorphone
Pain is subjective
Suitable analgesia for VOC management must be selected on a case-by-case basis
1. NIH Publication No 02-2117. NIH, Bethesda, MD, USA, http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf; 2. UK NICE guidelines https://www.nice.org.uk/guidance/cg143/resources/sickle-cell-disease-managing-acute-painful-episodes-in-hospital-pdf-35109569155525; 3. Telfer P et al. J Clin Med 2019;8:doi:10.3390/jcm8101728
ER, emergency room
3Choose a suitable analgesic, dose
and mode of administration1
Offer analgesia within 30 minutes of
presentation (UK NICE2)
Rapid pain relief may be achieved using intranasal and oral
opioids in the ER, rather than parenteral opioids, especially
for children3
4Continually assess the
patient’s response1
Analgesic administere
d
Assess every 30 minutes until
satisfactory relief
Assess every 4 hours after
relief reportedIf severe pain is still reported,
consider: (UK NICE2)
▪ Bolus opioid dose▪ Patient-controlled
analgesia
▪ Which analgesia has the patient already used for this particular VOC?
▪ Which analgesia has the patient received for previous VOCs?
▪ Are any analgesics contraindicated? (eg NSAIDs are contraindicated with renal failure)
▪ Does the patient have an individual care plan?
SCD patients may choose not to seek help for VOCs
1. Haywood Jr C et al. J Nat Med Assoc 2009;101:1022–33; 2. ASH State of Sickle Cell Disease 2016 report. Available at http://www.scdcoalition.org/report.html; 3. Wright J et al. Br J Haemtol 2004;126:878–80
Stigmatization HCP knowledge Expense
▪ 63% of nurses believe that
drug addiction is common
amongst SCD patients1
▪ Healthcare staff are more
likely to believe that SCD
patients exaggerate pain
compared with cancer
patients1
▪ In a systematic review:– 26% of patients
thought that hospital
staff lacked
knowledge of SCD1
– 49% of nurses acknowledged poor
understanding of
SCD1
▪ Total lifetime costs for
an average SCD
patient of 45 years
are estimated at
nearly
$1 million2
▪ Financial concerns
can lead patients to avoid the healthcare
systemSpecialized SCD day care units are associated with better pain
management and reduced hospitalization, versus the ER3
Prevention of VOCs is preferable to management
HydroxyureaBlood
transfusion
Practical
approaches
Practical lifestyle approaches can help to prevent VOCs
1. Bender MA & Seibel GD. Sickle Cell Disease. In: Pagon RA et al. GeneReviews; Seattle: University of Washington 1993–2017; 2. Gallagher PG. Blood 2015;126:2775–6; 3. Tewari S et al. Haematologica 2015;100:1108–16; 4. Jenerette CM et al. Nurs Res Pract2011;270594
HydroxyureaBlood
transfusion
Practical
approaches
Hydrate1
Reduce stress4 Sleep4
Stay warm3
▪ Use stress-coping techniques, such as yoga
▪ Monitor tiredness and rest when needed
▪ Dehydration of RBCs is an important
contributor to the sickling process2
▪ Maintain adequate daily fluid intake
▪ Be aware of risk factors for
dehydration, eg exercise or air
travel
▪ Cold temperatures trigger
vasoconstriction and reduce blood
flow, promoting deoxygenation▪ In addition to temperature, other
environmental factors eg wind
speed have been linked to VOCs
Limitations
• Dehydration, cold, stress and fatigue cannot be totally avoided in daily life
• These approaches are not disease-modifying, and have not been evaluated in clinical trials
Blood transfusions can prevent the complications of VOCs
1. Ware RE et al. Lancet 2017:390;311–23; 2. Adams RJ et al. N Engl J Med 1998;339:5–11 TCD, transcranial doppler
HydroxyureaBlood
transfusion
Practical
approaches
Aim: Increase oxygen-carrying capacity, restore blood volume and
reduce sickle erythropoiesis1
Single ‘top-up’ transfusion1
• ACS
• Transient aplastic crises
• Severe anaemia
• Acute splenic sequestration
Long-term transfusion1
• Strokes
• Abnormal TCD
• Multi-system organ failure
The STOP trial2
• Transfusion vs supportive care for patients without stroke history but
with TCD velocity ≥200 cm/s
• 92% reduction in risk of first
stroke with transfusion• Study terminated early to allow
patients to switch from
supportive care to transfusion
Blood transfusions can have short- and long-term adverse effects1
1. Ware RE et al. Lancet 2017:390;311–23
HydroxyureaBlood
transfusion
Practical
approaches
Short-term adverse effects
Volume overload
Acute haemolytic
reactions
Acute non-haemolytic
reactions
RBC alloimmunization
Long-term adverse effects
Delayed haemolytic
reactions
Iron overload
Transmission of infections
Hydroxyurea is a mainstay for the prevention of VOCs
1. Charache S et al. N Engl J Med 1995;332:1317–22; 2. Thornburg CD et al. Blood 2012;120:4304–10
19*Hospitalizations per 100 person-years
HydroxyureaBlood
transfusion
Practical
approaches
Hydroxyurea was the first FDA-approved pharmacological therapy for SCD
BABY-HUG trial (children)2Hydroxyurea
N=152
Placebo
N=147
Rate of VOCs
(median),
n/year
2.5 4.5
Time to first VOC
(median), months3 1.5
Time to second VOC
(median), months8.8 4.6
ACS, n (%) 25 (16) 51 (35)
Blood transfusions,
n (%)48 (32) 73 (50)
MSH trial (adults)1Hydroxyurea vs placebo
5.1-fold 3.4-fold 1.4-fold2.1-fold
There are barriers to the widespread use of hydroxyurea
1. Berthaut I et al. Blood 2017;130:2354–66; 2. Ware RE. Blood 2010:115;5300–11; 3. Walker AL et al. Blood 2016;128:318; 4. Badawy SM et al. Health Qual Life Outcomes 2017;15:136; 5. Mulaku M et al. Arch Dis Child 2013;98:908–14
HydroxyureaBlood
transfusion
Practical
approaches
Known risk of myelosuppression
(can be transient)2
Adverse effects
Potential impairment of spermatogenesis
causing infertility1
Perception of lack of efficacy3
Poor patient adherence to
medication4
Barriers to
HU use
Limited availability in lower-income
countries5
SCD and Stroke
◦ Children with HbSS: 10% have ischemic stroke
◦ Adult neurological events: bleeding>ischemia
Wong W, Powars D. Neuroimaging Clinics of North America,
17:269
Stroke Prevention – Childhood SCD◦ Transcranial Doppler (TCD)
◦ Increased flow in area of vascular
narrowing
◦ Associated with risk of stroke in
children
Stroke Prevention – Childhood SCD◦ Starting transfusion for
>200 cm/sec TCD
reduces stroke -1.5% vs.
16.4% (STOP Study)
Stopping transfusion –
TCDs revert and stroke
risk returns (STOP 2
Study)
NEJM 339:5, 1998 NEJM 353:2769-78, 2005
Stroke Prevention
◦ Annual TCD scans should be performed on all children with
SCD from aged 2 years in accordance with the TCD Standards
and Guidelines attached in Appendix 10.
◦ Indicates for HbSS/Sβothal until at least age 16 years
◦ For those children who are considered to be “high risk”, the risks and benefits of starting regular blood transfusions and/or
other treatments should be fully discussed by an appropriate
multidisciplinary team with parents/carers (A)
◦ Does not discuss duration of transfusion therapy
NHS 2010 – Appendix 10
New information….
◦ TWiTCH: Study reached endpoint: HU non-inferior to
transfusion for primary stroke prevention
◦ SIT: Reduction in overt stroke or new/enlarged areas
of silent ischemia from 4.8 to 2.0 events per 100 years
at risk, corresponding to an incidence rate ratio of
0.41 (95% confidence interval, 0.12 to 0.99; P = 0.04)
1. 1 stroke, 5 new/larger silent infarcts with transfusion
2. 7 strokes, 7 new/larger silent infarcts without DeBaun, NEJM 371:699, 2014
Summary
VOCs are the most common cause of hospitalization for SCD
patients, and can result in many acute and chronic complications
VOCs can be managed using hydration, supplemental oxygen,
appropriate analgesia and non-medical techniques
SCD patients may avoid seeking healthcare assistance during a
VOC because of stigma around opioid use, poor provider
knowledge, and expense
Practical approaches, blood transfusion and hydroxyurea are options for the prevention of VOCs, but there is an unmet need for additional preventative therapies
Summary
Malaria prophylaxis- standard care; Long acting treated bed nets:
Nutrition and Vitamin D supplementation
Stroke prevention using TCD screening and blood transfusion
Hydroxyurea as primary and secondary stroke prevention
investigative- what is the most reliable chemoprophylaxis
Penicillin prophylaxis in children 0-5 reduces Mortality by 70%, coupled with pneumococcal vaccination
Acknowledgments
Professor Baba Inusa
Dr Maria Pelidis
Sharon Ndoro
NataleeMurray
Fiona French
Kemi Ajamufua
Michelle Anderson
Stephanie Quirk
Dr Anna Hurley
Dr HatelBhatt
Luhanga Musumadi
29
Paediatric Sickle Cell and Thalassaemia Team
30
Heroes