Heme 05: Sickle Cell Disease

Front 1

How did they originally diagnose Sickle Cell Disease?

Back 1

Putting a rubber band around a finger will cause hypoxia, causes cells to sickle, go from 15% → 90% sickled

Front 2

What are the steps of the pathophysiology for Sickle Cell Disease?

Back 2

1) Endothelial activation by SS-RBCs and other inflammatory mediators
2) Recruitment of adherent leukocytes
3) Activation of recruited neutrophils and other leukocytes (monocytes or iNKT cells)
4) Interactions of sickled RBCs w/ adherent neutrophils
5) Vascular clogging by heterotypic cell-cell aggregates composed of SS-RBCs, adherent leukocytes, and possibly platelets
6) Increased transit time to greater than the delay time for deoxygenation-induced hemoglobin polymerization, propagating retrograde vaso-occlusion
7) Ischemia as a result of the obstruction creates a feedback loop of worsening endothelial activation

Front 3

What happens during the first step of Sickle Cell Disease?

Back 3

1) Endothelial activation by SS-RBCs and other inflammatory mediators

Front 4

What happens during the second step of Sickle Cell Disease after the endothelium is activated?

Back 4

2) Recruitment of adherent leukocytes

Front 5

What happens during the third step of Sickle Cell Disease after adherent leukocytes are recruited?

Back 5

3) Activation of recruited neutrophils and other leukocytes (monocytes or iNKT cells)

Front 6

What happens during the fourth step of Sickle Cell Disease after activation of recruited neutrophils and leukocytes?

Back 6

4) Interactions of sickled RBCs w/ adherent neutrophils

Front 7

What happens during the fifth step of Sickle Cell Disease after the endothelium is activated?

Back 7

5) Vascular clogging by heterotypic cell-cell aggregates composed of SS-RBCs, adherent leukocytes, and possibly platelets

Front 8

What happens during the sixth step of Sickle Cell Disease after the vascular clogging?

Back 8

6) Transit time becomes greater than the delay time for deoxygenation-induced hemoglobin polymerization, propagating retrograde vaso-occlusion

Front 9

What happens during the seventh step of Sickle Cell Disease after the retro-grade vaso-occlusion?

Back 9

7) Ischemia as a result of the obstruction creates a feedback loop of worsening endothelial activation

Front 10

What happens to the vessel wall during Sickle Cell Disease?

Back 10

- Oxidative endothelial cell damage (ROS)
- Increased inflammation
- Increased cell adhesion and tissue factor expression
- Loss of vasoregulation
- Intimal hyperplasia
- Platelet and leukocyte adhesion
- Propagation of fibrin clot
- Entrapment of rigid sickle RBCs
- Dysregulation of NO pathway

Front 11

What happens to the RBCs during Sickle Cell Disease?

Back 11

- Sickle-RBC adhesion
- Abnormal shear
- Entrapment of rigid sickle RBCs

Front 12

What happens to the plasma during Sickle Cell Disease?

Back 12

- ↑ Serum free hemoglobin
- Propagation of fibrin clot

Front 13

Case: 8 month-old girl w/ SCD was admitted to ED w/ pallor noted by mother. She has not been ill other than a slight cold. She has been a little less active.

On physical examination, where do you look for pallor?

Back 13

- Conjunctiva
- Mucous membranes
- Palms
- Soles

Front 14

Case: 8 month-old girl w/ SCD was admitted to ED w/ pallor noted by mother. She has not been ill other than a slight cold. She has been a little less active.

Her spleen on exam appears to be somewhat enlarged. What questions might you ask of the family?

Back 14

- History of enlarged spleen? If they've had it before it is more likely to do it again
- Splenic sequestration?
- Is it new?

Front 15

Case: 8 month-old girl w/ SCD was admitted to ED w/ pallor noted by mother. She has not been ill other than a slight cold. She has been a little less active.

What lab studies may be helpful? What's the first thing to order from the lab?

Back 15

- Type + Cross-match for blood transfusion
- CBC
- Reticulocyte count

Front 16

How do you treat Sickle Cell Disease?

Back 16

Hypoxia, dehydration, and fever increase sickling, so:
- Treat hypoxia with O2
- Give fluids, oral or IV, to prevent dehydration in the cells (enhances sickling) and in the patient
- Antipyretics for fever (causes enzymatic reactions to speed up)

Front 17

What should kids with Sickle Cell Disease avoid?

Back 17

- Avoid cold swimming pools and Lake Michigan
- Avoid cold temperatures

Front 18

If you make a diagnosis of splenic sequestration, what therapy is indicated?

Back 18

O2 even if their SaO2 is 99%

Front 19

Case: 8 month-old girl w/ SCD was admitted to ED w/ pallor noted by mother. She has not been ill other than a slight cold. She has been a little less active.

If you can't palpate the spleen because she was uncooperative, which of the lab studies help you differentiate sequestration from RBC aplasia?

Back 19

Reticulocyte count

Front 20

What is a common life-threatening complication of Sickle Cell Disease? How common / who is most likely to get it?

Back 20

Splenic Sequestration
- Up to 1% of children w/ SCD
- SS > SC
- Usually infants (as early as 5 weeks)

Front 21

What are the features of Splenic Sequestration in Sickle Cell Disease?

Back 21

- Greater than 2g drop in hemoglobin d/t splenic RBC pooling
- Rapidly enlarging spleen
- Can progress to shock and death if untreated
- Often recurs

Front 22

What happens to the hemoglobin in Sickle Cell Disease patient with Splenic Sequestration?

Back 22

- Greater than 2g drop
- Caused by splenic RBC pooling

Front 23

How do you treat Splenic Sequestration in a patient with Sickle Cell Disease?

Back 23

- Short term: fluids, oxygen, RBCs / blood transfusion
- Long term: splenectomy (after one or two sequestration events)

Front 24

What are the effects of doing a blood transfusion on a Sickle Cell Disease patient with Splenic Sequestration?

Back 24

- Transfusion reverses process in hours
- Transfuse w/ aim to raise Hemoglobin 3g, may result in rapid shrinkage of spleen
- Final Hemoglobin value 2-3g higher than target (d/t RBC/Hb released from spleen

Front 25

How do you prevent / detect early a Splenic Sequestration event in patients with Sickle Cell Disease?

Back 25

- Newborn screening for SCD (all 50 states)
- Teach mom and dad how to feel for spleen at first visit

Front 26

What does Parvovirus B19 infection cause in a Sickle Cell Disease patient?

Back 26

Aplastic Crisis
- Infects erythroblasts in the BM
- They will require a blood transfusion to live

Front 27

What is the most likely etiologic agent for a Sickle Cell Disease patient with an aplastic crisis?

Back 27

Parvovirus B19

Front 28

How do you cure Sickle Cell Disease?

Back 28

Bone marrow transplant
- HLA identical sibling w/ HbAA or HbAS

Front 29

How do you treat Sickle Cell Disease?

Back 29

Transfusion increases HbA and reduces HbS
- HbS <30% prevents stroke recurrence

Hydroxyurea (only approved drug)

Bone Marrow Transplant to cure from HLA identical sibling who is AA or AS

Front 30

What are the effects of Hydroxyurea?

Back 30

- Decreases sickled cells
- Reduces number of vaso-occlusive incidents
- Reduces acute chest incidents
- Induction of HbF
- ↓ Neutrophil and reticulocyte counts
- ↓ Adhesiveness of circulating neutrophils and reticulocytes
- ↓ Hemolysis
- Nitric Oxide (NO) release w/ local vasodilation and improved vascular response

(A→B→C and D→E→F)

Front 31

Case: 3yo Hmong girl presents with microcytic anemia. She has been treated w/ iron with no effect. Her mother also has a history of anemia. The child's screen was positive for Bart hemoglobin consistent w/ a 2 gene deletion.

Why is it important that we order molecular studies to define the alpha gene deletions?

Back 31

- There is no clinical difference if genes are deleted in cis or in trans

- But the genetic counseling implications are huge
- If deleted in cis and mother or daughter have children with a man who also has similar α-thalassemia trait, potential for HbH disease (if his deletions are trans) or embryonic lethal 4 gene deletion if cis

Front 32

If a patient has cis α-thalassemia trait (2 deletions on same gene), then what are the implications depending on if they mate with someone who also has α-thalassemia trait?

Back 32

- If man has trans deletions: potential for HbH disease
- If man has cis deletions: potential for embryonic lethal 4 gene deletion