Hemolysis Flashcards
What is the physiological function of ADAMTS13?
Cleaves ultra high MW vWF to limit plt aggregation and thrombus growth in microvasculature (or prevents microvascular thrombosis) .
Name 8 symptoms or end organ damage that results from hemolysis in PNH
- Thrombosis
- Renal dysfunction
- Erectile dysfunction
- Pulmonary hypertension
- Fatigue
- Dysphagia
- Abdominal pain
- Hemoglobinuria
- Iron deficiency
Why is hemolytic disease in the newborn mild with ABO incompatibility?
Fetal ABO antigens NOT fully developed→ lack of antigens on fetal RBCs and therefore hemolysis is mild and ABO HDN usually presents with neonatal jaundice with no or mild anemia that can be treated with phototherapy (Reason why neonates have weak reactions on ABO forward blood grouping)
ABO antigens are expressed on a variety of other tissues and thus would sequester maternal anti A/B Abs reducing Abs bound to fetal RBC
Eculizumab side effects
headache, nasopharyngitis, back pain and nausea (nitric oxide)
increases the risk of life-threatening Neisserial infections.
Canadian Indications for Eculizumab in PNH
- transfusion dependent
- thrombosis related to PNH
- renal failure (due to pigment nephropathy)
-pulmonary HTN
-large PNH clone (> 50% granulocytes and > 10% red blood cells) and significantly elevated lactate dehydrogenase and increased reticulocyte count - hemolytic PNH with:
>LDH > 1.5xULN
>severe anemia < 90
>symptoms associated with hemolysis.
Why do patients on Eculizumab still have extravascular hemolysis?
Eculizumab compensates for CD59 (very effective in stopping intravascular hemolysis) but NOT compensating for CD55.
Therefore, C3d deposition on PNH red cells and subsequent extravascular hemolysis occurs.
As such, 50% of PNH patients on Eculizumab develop a positive DAT (positive C3d, negative IgG) with ongoing mild-moderate anemia.
What are FIVE other treatment strategies for TTP if pt is refractory to PLEX?
IST 1. Glucocorticoids 2. Rituximab 3. Vincristine 4. Splenectomy Others: CycA, Bortezomib, Cyclophosphamide
Affecting VWD-plt interaction
1. Caplacizumab
Replace ADAMTS-13
1. Recombinant ADAMTS-13 if hereditary TTP
Patient with TTP, ADAMTS13 level low, negative for Ab, potential causes?
- Hereditary TTP (ie. low levels, with no inhibitor)
- Low titre Ab levels
- The inhibitor may have been neutralized by ADAMTS13 or anti-idiotype antibodies present in blood product transfusions.
- The inhibitor reduces ADAMTS13 protein stability or increases clearance rather than blocking enzymatic activity (ie, a “non-neutralizing” inhibitor).
What are two proteins that are defective in atypical HUS?
Factor H- most common, impair interaction with C3b Membrane Cofactor Protein Factor I Factor B (activating mutation) C3 (activating mutation) Thrombomodulin
You have a young female patient with PNH who has become pregnant. What are the advantages and disadvantages of starting Eculizumab in this patient?
pos-high rate of fetal survival and a low rate of maternal complications.
neg-category C, drug detected in cord blood and Increased dosing in T3. Increased risk of infection.
Benefits appear to outweigh harm.
Why doesn’t splenectomy work in cold agglutinin disease?
The liver, not the spleen, is the organ of red cell destruction in cold agglutinin disease; as a result, splenectomy is generally of no value. Splenectomy may be of value in the rare patient with cold agglutinin disease in whom the autoantibody is IgG, rather than IgM
Second most common organism to cause HUS after E.coli 0157:H7?
Strep pneumo, 5-15% in children
Higher mortality and more long-term morbidity than E. coli–associated HUS.
Diagnostic criteria for CAPS?
(i) involvement of 3 or more organs, systems, or tissues;
(ii) development of symptoms simultaneously or in < 1 week;
(iii) confirmation by histopathology of small vessel occlusion in at least 1 organ or tissue;
(iv) laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant; or anti-cardiolipin or anti-β-2-glycoprotein 1 antibodies).
Women with PNH plans to become pregnant, what would you advise re: antepartum and postpartum anticoagulation?
Risk of thrombosis is 10%
Post-partum- LMWH proph/intermediate for ALL women with PNH
Antepartum-
- pts with thrombosis (need therapeutic dose)
- large PNH clones (> 50%)
- prior history of VTE
- recurrent prior late fetal loss
In AIHA, what are 2 causes for DAT Neg
Low titre antibody
Low affinity antibody (dissociate from the surface during washing)
Non IgG/IgM antibody (usually IgA)
If patient had mechanical valve, what 3 things can confirm valve hemolysis?
- Transthoracic echocardiogram showing valvular damage/regurgitation
- Transesophageal echo
- Plasma free hemoglobin
- PBS–>Lack of thrombocytopenia, MAHA
C3 positive DAT, what is the DDX?
- Warm AIHA w/ subthreshold IgG deposition
- Cold-agglutinin disease
- Paroxysmal cold hemoglobinuria
- Drug-immune hemolytic anemia: ternary- immune complex type (can be severe hemolysis)
IgG positive DAT (C3 negative), what is the DDx?
- Warm AIHA
2. Drug-immune hemolytic anemia: hapten/drug adsorption type or autoantibody type (usually mild hemolysis)
4 Treatments for cold AIHA
- Avoidance of cold
- Steroids (30% remission rate)
- Ritux
- PLEX (to remove anti-IgM)
- Chlorambucil
- Cyclophosphamide
- BR, FCR etc. if underlying LPD found.
Do not work: Splenectomy (kupffer cells of liver site secondary site of hemolysis), IVIG
Role of CD 55 and CD 59 as complement regulators.
CD55—> accelerates the destruction of C3 convertase CD59—> inhibits the membrane attack complex.
3 mechanisms by which pts experience thrombosis in PNH?
Lack of 2 GP-anchored proteins:
(1) uro-kinase plasminogen activator receptor, the lack of which may decrease local fibrinolysis
(2) tissue factor pathway inhibitor, the lack of which may increase the procoagulant activity of tissue factor.
Others:
1) PNH plts are hyperactive
2) RBC phospholipids released during intravascular hemolysis also may initiate clotting.
What is FLAER with respect to PNH flow?
It is now also a routine to include the fluorescein-labeled aerolysin (FLAER) assay in flow cytometry, which exploits a property of aerolysin, the principal virulence factor of the bacterium Aeromonas hydrophila.
*FLAER binds selectively with high affinity to the GPI anchor of most cell lineages
4 drugs implicated in MAHA
- Tacrolimus
- Sirolimus
- Mitomycin (chemo for GI malignancy)
- Gemcitabine
Others: Plaxix and ASA implicated in TTP
10 organisms that can cause hemolytic anemia
Bacterial
- Clostridium (alpha toxin, brillant red plasma)
- Gram pos- Strep, enterococcus
- Salmonella (may be DAT pos)
- Mycoplasma (IgM, cold aggulitinin, I antigen)
- EBV (IgM directed against i antigen)
- Syphilis (Donath-Lansteiner, IgG against P antigen, PCH, C3+ and paradoxically IgG neg)
- Rocky mountain spotted fever (DIC)
- Others: CMV, HIV, rubella, HSV, varicella, Flu A
Parasites
- Malaria (direct RBC infestation, hemoglinuria=black water fever)
- Babesiosis (maltese cross)
- Bartonellosis (2 clinical stages: an acute hemolytic anemia and a chronic granulomatous phase)
A pt with DAT positive AIHA, presents with reticulocytopenia. What is the mechanism?
A minority of pts manifest a transient reticulocytopenia early in the course of AIHA. Causes:
1) auto- Ab titers increase more quickly than the bone marrow’s reticulocyte response
2) due to rapid destruction of retics by the autoantibody.
Factors in the PLASMIC score
1.Platelet count <30 x 109/L
2. Hemolysis
Reticulocyte count >2.5%, haptoglobin undetectable, or indirect bilirubin >34.2 µmol/L
3.Active cancer within the past year (0)
4. History of solid-organ or stem-cell transplant (0)
5. MCV <9.0 x 10-14 L
6. INR <1.5
7. Creatinine <176.8 μmol/L
score <5 generally does not require further workup
