Blood Bank II: Autoimmune Hemolytic Anemias

What critical value can indicate hemolysis?

+3 schistocytes

How does drug-adsorption hemolysis work?

1. Drugs attach to RBC membrane 2. Antibody directed to drug induces destruction of RBCs

How do immune complex drug antibodies work?

1. Patient forms antibody to drug 2. Drug-antibody complex adsorb onto RBC membrane 3. Complement activation results in destruction of RBC

How does hemolysis due to cefotetan work?

1. Patient given drug during surgery prophylactically 2. Hemolysis appears 7-10 days later with anemia <4g 3. Second dose typically fatal

How common is cold hemagglutinin disease? What kind of results do we see in hematology?

18% frequency MCHC >36

Do we still see reactions at 37C in patients with cold hemagglutinin disease? What about at AHG?

37C: 2+ AHG: 0

In what populations do we see cold hemagglutinin disease? How do we treat these patients?

Adults Stay out of cold

What are the three classes of immune anemias?

Alloimmune (outside stimulus) Autoimmune (attacking self) Drug induced

What drug can cause drug-independent hemolysis?

Alpha-methyldopa (Aldomet)

What antibody typically causes cold hemagglutinin disease?

Anti-I IgM

What do warm autoantibodies tend to look like with serologic testing?

Antibodies in Rh system

What is anti-IH, and what patients does it show up in?

Antibody specific to I antigen and H antigen Appears in A1 patients

What patient populations are more likely to have warm autoantibodies?

Any

How do we perform serologic testing for patients with warm autoantibodies?

Autoadsorption (best) Alloadsorption (send out) Phenotype/molecular (spendy) Reduce enhancement to just saline and cells

How does drug-independent hemolysis work?

Autoantibody forms after 6 months of taking drug Drug may alter T cell, allowing production of antibodies to self OR drug may mimic red cell enough that autoantibody is formed

Which two forms of immune hemolysis look similar?

Autoimmune Drug induced

What is the treatment for warm autoantibodies?

Avoid transfusion if possible Treat underlying cause Plasma exchange Erythrocyte stimulation

What are some examples of benign cold-reactive antibodies? Of pathologic cold-reactive antibodies?

Benign: anti-I, anti-IH, anti-i Pathologic: anti-I, anti-P, anti-M

What drugs can cause drug-adsorption hemolysis?

Cefotetan (most severe) Streptomycin Penicillin Cephalosporin

What drug can cause drug-induced membrane modification?

Cephalosporin

What patient population is most commonly affected by paroxysmal cold hemoglobinuria? How is it treated?

Children Terminates spontaneously after disease resolves

What are the three autoimmune hemolytic anemias?

Cold agglutinin syndrome Paroxysmal cold hemoglobinuria Warm autoimmune hemolytic anemia

What serological results are seen in patients with drug-induced membrane modification?

DAT: IgG+ C3+ Eluate: Neg Hemolysis: No

What serological results do we see in patients with drug-independent hemolysis?

DAT: IgG+ C3+/- Eluate: positive with all cells Hemolysis: yes (mimics WAIHA)

What serologic results do we see with drug-adsorption hemolysis?

DAT: IgG+ C3- Eluate: Neg Hemolysis: Yes (intra and extravascular)

What serological results do we see with drug-induced immune complex hemolysis?

DAT: IgG+/- C3+ Eluate: Neg Hemolysis: Yes (intravascular)

What chemo drugs can bind RBCs?

Darzalex Chemo drugs ending in -umab

What are the transfusion and treatment recommendations for patients with warm immune hemolysis?

Do not trust serological presentation Transfuse only to support cardiovascular function (not to increase Hgb) Transfuse 'least incompatible' blood slowly - in vivo crossmatch Options: Plasma exchange to remove antibodies Steroids or IVIG to reduce immune process Splenectomy

What antibody is responsible for paroxysmal cold hemoglobinuria?

Donath-Landsteiner 'biphasic autohemolysin' IgG specific to anti-P

What test do we perform for paroxysmal cold hemoglobinuria?

Donath-Landsteiner test Add patient serum, normal serum and patient serum with normal serum to RBCs, let sit for 90 min Heat to 37C for 90 min Lower temperature to 0C for 30 min Reheat to 37C for 60 min Check for hemolysis (positive)

How do some chemo drugs bind RBCs?

Drug is an antibody that attaches to CD38 as its chemotherapy method RBCs have lots of CD38 on surface

How does drug-induced membrane modification work?

Drug modifies RBC membrane so IgG, IgM and IgA can attach

What type of antibodies are most often confused for warm autoantibodies?

Drug-induced antibodies

What are the three forms of drug induced anemia?

Drug-membrane Drug only Membrane only

Clinical manifestation of paroxysmal cold hemoglobinuria

Episodes of hemoglobinuria occur after cold exposure followed by malaise, fever, chills

What results do we typically see in patients with cold-reactive antibodies?

Extra reactivity in reverse type (often 2+ unless high titer) Incompatible immediate spin crossmatch DAT: IgG-, C3+

Clinical manifestation of warm autoantibodies

Extreme anemia (Hgb <7) Jaundice Dizziness Polychromasia

How do cold antibodies affect heart surgery?

Heart surgery is conducted in a cold room with cold blood transfusions

What are the two alloimmune hemolytic anemias?

Hemolytic transfusion reaction Hemolytic disease of the newborn

What class are warm autoantibodies, and do they fix complement?

IgG May or may not fix complement

What class of antibodies are seen with drug-adsorption hemolysis? Do they fix complement?

IgG (IgM with penicillin) No

What kind of antibodies are seen in drug-induced immune complex hemolysis? Do they fix complement?

IgM Yes

What diseases are associated with warm autoantibodies?

Insidious Trauma Surgery Pregnancy Infection Cancer

What complication is commonly seen with drug-induced immune complex hemolysis?

Kidney failure

How can we resolve blood bank results for cold hemagglutinin disease?

Let blood settle for 60 minutes

What diseases are cold hemagglutinin disease (CHD) associated with?

Lymphoproliferative disorder Mycoplasma pneumoniae Idiopathic

Why would we want to know if benign cold antibodies are present?

May need to differentiate them from pathologic antibodies (RA, lupus)

What DAT results might occur with paroxysmal cold hemoglobinuria?

Mixed results due to intense hemolysis

Clinical manifestation of cold hemagglutinin disease (CHD)

Moderate chronic hemolytic anemia Purple extremities Weakness Jaundice Reynaud's phenomenon

What kind of cancer are the drugs that bind to RBCs designed to treat?

Multiple myeloma

Do patients with warm autoantibodies tend to have a history of transfusion?

No

How do we interpret the results of a cold screen?

No reaction with cord RBCs: Anti-I No reaction with adult RBCs: Anti-i No reaction with A1, B or AB cells: Anti-IH

What is the difference between paroxysmal cold hemoglobinuria and paroxysmal nocturnal hemoglobinuria?

Paroxysmal cold hemoglobinuria is due to cold-acting antibodies Paroxysmal nocturnal hemoglobinuria is due to a membrane defect that causes complement-mediated hemolysis

How do we determine if an antibody is warm reactive or cold reactive?

Perform screen without enhancement and look for stage at which antibody activity dissipates

What are the clinical findings of immune hemolysis?

Positive DAT Evidence of hemolysis Possible ABO discrepancy Schistocytes Reticulocytes Increased bilirubin, LDH Hemoglobinemia Hemoglobinuria

How do we resolve cold antibodies?

Pre-warm immediate spin crossmatch and reverse type

What drugs can casuse drug-induced immune complex hemolysis?

Quinidine Phenacetin

How common is drug-induced membrane modification? Are there any symptoms?

Rare No symptoms

What kind of sample must we use to determine if a patient has drug-induced immune complex hemolysis?

Serum - contains complement

Compare and contrast benign vs. pathologic cold reactive antibodies

Similarities: both enhanced with albumin and enzyme, both typically IgM Benign: most common, low titer Pathologic: less common, high titer (>1000)

What are the transfusion and treatment recommendations for patients with cold immune hemolysis?

Skip immediate spin testing Run slowly through blood warmer Keep patient warm

How do we treat drug-induced antibodies?

Stop taking drug

What diseases are associated with paroxysmal cold hemoglobinuria?

Syphilis Mumps Chickenpox Infectious mono

What is a characteristic sign of the presence of drug-induced antibodies?

Tea-colored plasma

What seven parameters can help us distinguish between forms of immune hemolytic anemia?

Thermal amplitude (is it hot or cold?) Benign vs. pathologic Ig class Complement fixation Specificity Titer Underlying disease process

What are the transfusion and treatment recommendations for drug-induced immune hemolysis?

Transfusion recommended in most cases Plasma exchange may also help remove drug Stop taking drug

Clinical manifestation of drug-induced antibodies

Very fast hemolysis Possible death

What does paroxysmal cold hemoglobinuria typically follow?

Viral infection

What percent of patients with drug-independent hemolysis develop WAIHA? What percent have a positive DAT?

WAIHA: 0.8% DAT: 15%

What type of antibodies are we more concerned about in the blood bank, and why?

Warm antibodies: harder to find compatible blood, treatment requires far more intervention

Warm vs. cold antibodies: what is their frequency and when are they more common?

Warm: 70%, summer Cold: 15%, winter

Warm vs. cold antibodies: What is the ideal reaction temperature?

Warm: >32C Cold: <30C

Warm vs. cold antibodies: what is their serological reactivity?

Warm: AHG Cold: Immediate spin

Warm vs. cold antibodies: What type of immunoglobulin are they (typically)?

Warm: IgG Cold: IgM

Warm vs. cold antibodies: DAT results?

Warm: IgG+; C3+/- Cold: IgG-; C3+

Warm vs. cold antibodies: what are the most common culprits?

Warm: anti-Rh Cold: anti-I, anti-P

Warm vs. cold antibodies: what clinical presentations do we see with these?

Warm: exhausted, anemic Cold: purpling of extremities

Warm vs. cold antibodies: where is their reaction site?

Warm: extravascular Cold: intravascular and extravascular

Warm vs. cold antibodies: Do they bind complement?

Warm: may bind Cold: does bind

Why do we need to avoid transfusion if a patient has warm autoantibodies?

We can't determine the patient's phenotype due to the autoantibody interfering with serologic testing

What serological results may be seen in patients taking chemo drugs?

Weak positive DAT (poly and IgG) ID and eluate positive with all cells and autocontrol DTT treatment removes antibody and ID becomes negative

What is a cold screen?

Workup for cold agglutinins by testing patient serum with screen cells, autocontrol and cord cells