Miscellaneous

Question 1

Inherited causes of HLH (Haemophagocytic lymphohistiocytosis)?

Answer 1

• Familial (FHL)

- Immune deficiency syndromes (Eg Griscelli syndrome II)

Question 2

-Acquired causes of HLH (Haemophagocytic lymphohistiocytosis)?

Answer 2

• Infections (eg leishmanial)
  - Tumours (eg EBV associated lymphomas)
  - Autoimmune disorders (eg SLE)

Question 3

What are the clinical manifestations of HLH (Haemophagocytic lymphohistiocytosis)?

Answer 3

• Organ infiltration by T cells causing
  - Haemophagocytosis (Macrophages engulfing red cells)
  - Cytokine storm (By T cells and macrophages)
• These effects result in: Fever, hepatosplenomegaly, lymphadenopathy, bone marrow failure (And many more)

Question 4

-Pathogenesis of HLH (Haemophagocytic lymphohistiocytosis)?

Answer 4

Perforin is an essential protein in inducing apoptosis by CTLS or NKs

• Perforin failure
• CTLs cannot execute apoptosis, causing upregulation
• Homeostasis of cytotoxic lymphocyte responses becomes deregulated
  - Clonal and polyclonal expansion of CTLs

Question 5

Describe the pathophysiology of paroxysmal nocturnal haemoglobinuria (PNH)

Answer 5

• Deficiency in the glycosylphosphatidylinositol (GPI) anchor found on marrow stem cells
• This deficiency leads to a deficiency of GPI-linked proteins (Such as the membrane inhibitor of reactive lysis (MIRL) aka CD59)
• Red cells that descend from these stem cells also lack GPI and GPI-linked proteins, so become sensitive to lysis by complement. (especially MIRL/CD59, DAF/CD55)

Question 6

Clinical features of paroxysmal nocturnal haemoglobinuria (PNH)?

Answer 6

• Chronic intravascular haemolysis
• Anaemia
  - Nitric oxide depletion
  - Thrombosis at unusual anatomical sites
  - Bone marrow failure (BMF) and cytopenia

Question 7

-Treatment of PNH-anaemia?

Answer 7

• Iron and folate supplements
  - Blood transfusion
  - Inhibition of haemolysis (Steroids or Complement inhibitors)
  - Eculizumab: mAb: C5 inhibitor.

Question 8

-Describe how gene therapy is being used in the treatment of SCD

Answer 8

• A psuedotyped lentivirus is used to inject wild-type Beta globin genes into HSCs, along with control sequences such as LCRs
• Lentiglobin BB305 has shown promising results
  - Vector derived haemoglobin production improves clinical picture

Question 9

Give an example of a novel approach for the treatment of sickle cell

Answer 9

Prevention of vaso-occlusion by P-selectin inhibitor Crizanlizumab

Question 10

What are the main psychosocial problems in children with Sickle Cell Disease?

Answer 10

• Emotional challenge: Coming to terms with the illness
• Cognitive impairment leads to educational problems, where extra support may be required
• Adherence to treatment is also a problem

Question 11

Explain the treatment of PNH

Answer 11

• Iron and folate supplements, Blood transfusion: to correct anaemia
• Eculizumab: mAb: C5 inhibitor.
• This mAb blocks the terminal complement pathway
• Membrane attack complex is not formed as a result
• This stops haemolysis mediated by complement
• Steroids can also be used to inhibit haemolysis

Question 12

How is PNH diagnosed?

Answer 12

clinical features:

- Chronic intravascular haemolysis - Anaemia
			- Nitric oxide depletion
		- Thrombosis at unusual anatomical sites
		- Bone marrow failure (BMF) and cytopenia

-Diagnosis confirmed with flow cytometry: presence of CD55 and CD59