Hemolytic Anemias 2

Question 1

Describe how a DAT works

Answer 1

Testing if patient RBCs have IgG and/or C3 antibodies bound to their surface. If they do, when adding IgG and C3 specific Abs, the cells will agglutinate.

Question 2

5 examples of DAT+ hemolysis

Answer 2

Warm AIHA
CAD
PNH and PCH
Transfusion reactions
Drug induced hemolysis

Question 3

6 Examples of DAT- hemolysis

Answer 3

DAT-negative AIHA (1-10%)
Hemoglobinopathies
Enzymopathies
MAHA
Toxins
IgA or IgM dependent hemolysis

Question 4

Most common DAT result in warm AIHA?

Answer 4

IgG+
C3+

Question 5

describe pathophysiology of warm AIHA

Answer 5

Patients have a panagglutinating IgG antibody directed against a common antigen on RBC surface (like Rh and others). These bind at body temperature, causing enhanced destruction of Ab-coated RBCs by macrophages in the spleen

Question 6

First line Treatment for warm AIHA

Answer 6

Steroids. Takes 7-25 days to respond, and 75-80% of patients respond. Very slow taper

Question 7

Second line therapy for warm AIHA (5)

Answer 7

Rituximab
Splenectomy
IVIG
MMF
Sirolimus

Question 8

Patients with warm AIHA secondary to autoimmune lymphoproliferative syndrome (ALPS) have a high response rate to what treatment?

Answer 8

Sirolimus

Question 9

Pathophysiology of Cold Agglutinin disease

Answer 9

IgM antibodies directed against RBCs I antigen that are active below body temperature. Causing RBC agglutination and extravascular hemolysis.

Question 10

In secondary cold AIHA. What are the two most common infections?

Answer 10

Mycoplasma
Mono (EBV)

Question 11

Patient with hemolytic anemia, livedo reticularis. Smear shows RBC agglutination. DAT is +C3 but negative for IgG. Most likely diagnosis and test to confirm?

Answer 11

Cold agglutinin disease (cold AIHA)
Thermal amplitude test

Question 12

What is a clinically significant result on thermal amplitude test for cold AIHA?

Answer 12

1:64 or greater

Question 13

Management of cold AIHA

Answer 13

Avoid cold
Transfuse as needed
Plasmapheresis for severe cases
Benda + Ritux if associated with underlying B cell disorder
Sutimlimab

Question 14

What is the indication for sutimlimab?

Answer 14

In cold AIHA, useful for temporizing patients requiring transfusions for severe symptoms or those who can’t take immunosuppression, or refractory to immunosuppression, or those that require rapid action to improve symptoms and relieve transfusion burden

Question 15

Pathophysiology of PCH

Answer 15

Immune mediated intravascular hemolytic anemia because of IgG that binds RBC P antigen in a cold environment and fixes complement.

Question 16

Mechanism of action of sutimlimab?

Answer 16

Targets C1s protein, a protease that activates the classic complement pathway. Treats the anemia, hemolysis, and fatigue of cold AIHA, but doesn’t get rid of the cold agglutinin

Question 17

You see a patient present with nausea, vomiting, back pain, weakness, dark urine, and evidence of hemolytic anemia. They had a viral URI about 10 days prior. DAT shows IgG negative and C3 positive. What is the test to confirm the most likely diagnosis?

Answer 17

Donath Landsteiner test: AutoAb taht binds to RBCs and fixes complement at cold temperatures and dissociates upon warming.
Diagnosis is PCH

Question 18

Treatment for PCH

Answer 18

Typically self-limited
Supportive care for acute episodes
Avoid cold
If there is no rapid recovery, can offer steroids or rituximab

Question 19

Pathophysiology of PNH

Answer 19

PIG-A mutation seen in a pluripotent stem cell causing the lack of GPI anchors in that cell, meaning complement inhibitory proteins CD55 and CD59 are not present.
This mutation is not sufficient for PNH, this clone needs to undergo expansion. Then there is a complement driven hemolytic anemia

Question 20

Aside from hemolytic anemia, what are other clinical features seen in PNH?

Answer 20

Dark/red urine
bone marrow failure
Thrombosis, typically in unusual sites (highest risk with PNH cells >50%)
Smooth muscle dystonia (vascular constriction, pHTN)

Question 21

First line Treatment for PNH

Answer 21

Eculizumab, Ravulizumab

Question 22

Mechanism of action of Eculizumab and Ravulizumab

Answer 22

C5 complement inhibtor. Inhibitrs the terminal complement pathway, blocking intravascular hemolysis, doesn’t treat bone marrow failure or extravascular hemolysis

Question 23

Second line therapy for PNH after eculizumab or ravulizumab

Answer 23

Pegcetacoplan (C3 inhibitor)
Iptacopan (factor B inhibitor)

Question 24

What treatment was approved in 2024 for PNH to be used in addition to eculizumab or ravulizumab?

Answer 24

Danicopan