Transcript Autoimmune Hemolytic Anemias

Heme-Onc Subspeciality Rounds
Dr.Chaudhry
Dr.Vysetti
Case
HPI:57 Yr old male from Philippines gets admitted for evaluation of progressively
worsening fatigue and shortness of breath -2 wks.
- Had a mild sore throat and headache about a week ago which resolved on its own.
- Low grade fevers
- ROS otherwise negative
PMH:
- Gout
PSH:
-Hand surgery involving the joints.
Case
Meds:
1.Allopurinol 100mg po qdaily
2.Tylenol Prn.
Family History:
Non contributory
Social History :
Moved to US about a year ago.
Currently unemployed.
lives with his wife who is a nurse.
Case
Vitals : Afeb P:102 B.p 80/50 98% on RA
Exam : Gen: Positive for Icterus and pallor.No enlarged Lymphnodes
RS:CTA
CVS:S1S2 no murmers
GI :Soft, Spleen palpable 4 cm below the left subcostal margin.liver not palpable.Otherwise
Nontender ,BS +
CNS : No focal deficits.
Ext :No pedal odema.
Labs on admission :
CBC : Hgb 3.3 and Hematocrit of 13.5 (MCV – 98.2,MCH-41.9,MCHC-42.7,Bands 7%,Monocytes of
31%,Neutrophils -52%)
CMP : Na :123,K:4.2 ,HCO3 17, Cl 93,BUN 18 and Creat 1.1,Total Bili 3.3,Alkphos 99,AST and ALT wnl.
PT 18.7 & INR – 1.6
Hospital Course
Diagnostic Work up :
-LDH -1145,
-Haptoglobin <6 ,
-Retic count : 13.6
- PBS:clumping of RBC’s at room temp which resolved upon warming the slides.No Schistocytes.
Hospital Course
Follow up :
-Daily CBC’s,Total Bilirubin,Serum haptoglobulin and LDH.
-RBC count and platelets remain low but stable.
-H&H – 6.0 -9.8 Most recent -6.4
-Haptoglobulin <6 until recently reported as 27 (ref 36-195)
-LDH down to 464 from 1145.Recent uptrending 634.(132-268)
-Total Bilirubin 6.8-3.5.(0.0-1.0)
Autoimmune hemolytic Anemia
-Autoimmune hemolytic anemia (AIHA) refers to a collection of disorders characterized by the
presence of autoantibodies that bind to antigens on patient's own erythrocytes, leading to
premature red cell destruction
- Immune Disorder caused by antibodies directed against unmodified autologous red cells.
Pathophysiology
IgG antibodies are relatively poor activators of complement and recognised more readily by the
Fc Receptors on the phagocytic cells.So in turn destroyed by Phagocytes of the RES.
IgM-sensitised RBC’s generally are associated with both intravascular and extravascular
hemolysis.Intravascular because IgM unlike IgG more readily activate the complement pathway
and produce intravascular hemolysis.Extravascular hemolysis occurs from RES being activated
by the complement bound on the surface of the RBC.
Spleen is the principal site of IgG associated extravascular hemolysis and Kupffer cells in the
liver are the principal effectors of IgM associated extravascular hemolysis.
Classification of Immune hemolytic Anemia
Warm AIHA
Idiopathic Vs Secondary
Cold AIHA
CAS :Idiopathic Vs Secondary
PCH : Idiopathic Vs Secondary
Mixed AIHA
Drug Induced immune hemolytic anemia
Alloantibody-induced immune hemolytic anemia
Secondary causes: Infections, Autoimmune , Lymphoproliferative disorders.
Diagnosis
►
Clinical Presentation and lab evidence of hemolysis
►
Serologic evidence of an Autoantibody
Clinical Presentation
-History : Recent Meds and Infections & Systemic illness.
-Physical findings : Anemia,Jaundice, Organomegaly.
-Lab evaluation
. Retic count-Increased
. PBS –Spherocytes,Schistocytes,Cold Agglutinins.
. Bone Marrow – r/o Malignancy.Erythroid Hyperplasia.
. UA – If Intravascular hemolysis -Hemoglobinuria
. Direct Globulin Test(Coomb’s) – identifies the presence of antibodies and/or complement
on the surface of the erythrocyte.
. Other – elevated total bilirubin,AST and decreased Haptoglobin
. Immunohematologic studies
-
Autoantibodies
- Two major types, each with specific characteristics, are produced in AIHA:
- IgG antibodies : Generally react with protein antigens on the RBC surface at 37 c and so
called "warm agglutinins“.
- IgM antibodies: Generally react with polysaccharide antigens on the RBC surface only at
temperature 0-4 c and so called "cold agglutinins.”
Factors affecting the rate and location of erythrocyte
destruction:
Characteristics of the autoantibody
- Antibody isotype (eg, IgG, IgM, IgA)
- Antibody titer (high vs. low)
- Thermal reactivity (optimal binding temperature)
- Ability to fix complement
. Characteristics of the erythrocyte antigen
- Specificity of the antigen
- Surface density of the antigen
. Characteristics of the reticuloendothelial (RE) clearance
- Preferential location of clearance (hepatic vs. splenic)
Direct Antiglobulin test
- The RBCs of the patient are washed free of adherent proteins and reacted with
antiserum or monoclonal antibodies prepared against the various immunoglobulins,
particularly IgG and a fragment of the third component of complement, C3d.
- Positive test –Presence of an autoantibody
- Further the sample is tested seperately with reagents specific for anti IgG and Anti-C3d.
Anti-IgG
Anti-C3
Antigen
Occurrence
Comment
Warm AIHA.
Antibody (Ab) is
IgG
+
-
Rh protein complex
Drugs: penicillin,
aldomet; not in SLE
+
+
Glycoprotein
Less common AIHA
Ab is IgG which
fixes complement
-
+
Polysaccharide
Cold agglutinin
disease
Cold agglutinins in
serum. Ab is IgM
+
P blood group
polysaccharide
Paroxysmal cold
hemoglobinuria
Donath Landsteiner
may be pos. Ab is
IgG*
Drug-related
immune hemolysis
Antibody found
with enzymetreated RBCs Ab is
low affinity IgG
Drug-related
immune hemolysis
Drug needed to
detect antibody in
serum. Ab is IgG or
IgM
Multiple causes
May require more
sensitive test for
presence of
antibodies
-
±
±
-
±
±
-
Protein
Protein + drug
Any of above
Warm Agglutinin Disease
Incidence - 50%-70% cases
Etiology : Idiopathic Vs Secondary( CLL,Hodgkins,NHL,Autoimmune )
Clinical course :Insidious onset with waxing and waning course Vrs Fulminant hemolysis.
Diagnosis : Positive DAT and lab evidence of hemolysis.
-Rx:
- Steroids, If no response to steroids next line of Rx includes splenectomy and cytotoxic drugs.
- Splenectomy has a response rate of 60-75%(removal of site of hemolysis )
- Cytotoxic drugs in people who failed steroids and/or splenectomy- response rate
of 40-60%(Cyclophosphamide and Azathioprine)
- Other therapies :Rituximab (Anti –CD20 monoclonal AB),Plasmapheresis,?IVIG,Danazol
- PRBC transfusions limited to life threatening hemolytic anemia.
Cold AIHA
CAS
- More common
- Middle-elderly
- Prim Vs Sec (MC)
- IgM
- Max reactivity in the cold but
reactive up to 30 c
-
Resistant to Rx
PCH
- Less common
- Children
- Often follows a URI
- IgG (DL)
- Biphasic hemolysin
demonstrated by incubation in
cold followed by incubation at 37
c in presence of C.
- Supportive Rx.
CAS
Incidence : 16-32%
Etiology :
Primary Vs Secondary
-Infections: Mycoplasma,EBV,Influenza,HIV,E.coli,listeria
-Lymphoproliferative : CLL,Lymphomas,Waldenstrom’s.
CF :
-Mild chronic hemolytic anemia exacerbated by cold environmentepisodes of acute
hemolysis common in winter months.
-Clinical presentation corresponds with the immune response to an infectious agent.
-Symptoms appear 2-3 wks after the infections begins(corresponding to Cold Agglutinin titre)
and resolve 2-3 wks later.
CAS
Diagnosis
-
Typically Clumping of the RBC even before
the antisera is added and dissolution of the
clumping upon warming indicates the
presence.
- Positive DAT with Anti –C3 and often negative
for IgG.
- IgM can be Monoclonal and Polyclonal.
- Antigens usually “ I “ on adult RBC
Treatment
- Avoidance of cold exposure.
-
- Therapy directed against secondary causes.
- Immunosuppression with
chlorambucil,cyclophosphamide.
-Steroids are rarely helpful.
-Splenectomy-? Since extravascular hemolysis
(IgM mediated )occurs in Liver.
-Plasmapheresis
- Rituximab has shown success.
PCH
Incidence -Rare 2-10%
Children MC affected
Etiology:
- Idiopathic Vrs Secondary
- Infections Measles,Mumps,EBV,CMV,VZ,Adeno,Influenza,Mycoplasma,Hemophilus.
Diagnosis :
- DAT: positive with Anti-C3 but is generally negative for anti-IgG unless performed at
colder temperatures.
- Donath Landsteiner AB –Biphasic hemolysin
- Antigen is P present on most of RBC
Rx :
- Generally self limited.No need for aggressive measures.
Drug Induced IHA
-
MC drugs : Alpha methyl dopa,PCN,2nd & 3rd Cephalosporins
Rarely Levodopa,Diclofenac.
CF:Variable MC subacute onset but rarely acute hemolysis.
Prognosis –Excellent.
-
Therapy –Stop drug and rarely empiric course of steroids
-
-
.
Hospital Course
Diagnostic Work up:
- CMV IgG > 5.0 (ref <0.9) IgM Pending.
- EBV cap AB,IgG- 1: 10,240 & IgM- Neg
- Bone marrow Biopsy (Day 6)-Flow cyto:Small population of monoclonal B cell (1%).Final
reports – negative for Acute leukemia,MDS,LPD,plasma cell dyscrasia.
- Cold agglutinin titres 1:512
-Preliminary results : ID antibody as Anti-S
-Mycoplasma IgG and IgM –ve.
-Hep A,B and C – Non reactive
- HIV – Non reactive
- PNH :r/o by flow cytometry
- SPEP : unremarkable .Low IgM
- Donath Landsteiner Antibody negative r/o PCH..
- HIT panel negative (was ordered because of low platelet count).
Hospital Course
Admitted to ICU
Inetially transfused 4U of PRBC which brought his H/H to 6/13
- High dose IV steroids initiated on Day 3 x 3 d following by high dose oral
prednisone (60mg po daily).
On day 2 pt had to be intubated because of ?TRALI ,was weaned off the
ventilator over couple of days.
The pt continued to require daily transfusions.(received 17 U Prbc’s so far
since admission).
Plasmapheresis initiated on Day 3 continued for total of 7 days.
Relative stabilisation of H&H after Plasmapheresis was initiated
Held for a couple of days and reinitiated because of persisting Hemolysis.
Danazol started on Day 3 (200mg po BID)
Cyclophosphamide (100mg po q daily) started on Day 10.
Rituximab (Received 3 doses so far
-
Hospital Course
Follow up :
-Daily CBC’s,Total Bilirubin,Serum haptoglobulin and LDH.
-RBC count and platelets remain low but stable.
-H&H – 6.0 -9.8 Most recent -8.0 and is stable
-Haptoglobulin <6 until recently reported as 27 (ref 36-195)
-LDH down to 464 from 1145.Recent uptrending 634.(132-268)
-Total Bilirubin 6.8-3.5.(0.0-1.0)
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