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