Complement Mediated Coagulation (PNH, aHUS) Flashcards
1
Q
What part of the immune system
is complement a part of ?
A
- innate immune system
- over 30 soluble and membrane bound proteins
- provides defense against bacteria, fungi and viruses
- many regulatory proteins that are either soluble or membrane bound
- mutations and autoantibodies frequently lead to disease
- ex: PNH, aHUS
2
Q
What is the clinical manifestation
of coagulation cascade disorders ?
A
- often associated with thrombosis
- highlights the close association between coagulation cascade and complement
3
Q
Which membrane complement regulators
have been linked to human disease ?
A
- CD55
- limits CD5 convertase and ultimately prevents formation of the MAC complex
- CD59
- major inhibitor of the terminal complement pathway
- inhibits pore formation in MAC
- CD46
- accelerates the decay of C3 convertase
- it is expressed on all cells except erythrocytes
- Thrombomodulin
- endothelial cell receptor
- helps with activation of protein C
- regulates Factor I mediated CDb inactivation
4
Q
What are the soluble complement regulators ?
A
- Factor H
- regulates the alternative pathway
- disrupts C3 convertase
- Factor I
- synthesized in the liver
- regulates all pathways in complement
- inactivates C3b
- Factor B
- cleaved by Factor D to generate C3 convertase of alternative pathway
5
Q
Which complement molecule seems to be
the connection between the cascade and coagulation ?
A
- C5a anaphylotoxin
- how it does it:
- increase inflammatory cytokines
- downregulates ADAMTS-13
- generates tissue factor and PAI-1
- decreases levels of Protein S, increase protein C resistance
- activates thrombin
6
Q
What aspects of the coagulation cascade
can activate complement ?
A
- Factor XII interacts with C1 of the classical pathway
- Thrombin cleaves C3 and also generates C5a in the absence of C3
- Fibrinolytic factors (plasmin, kallikrein)
- directly cleave C3
7
Q
How do complement-mediated hemolytic anemias
lead to thrombosis ?
A
- free hemoglobin results in platelet activation as well as:
- inhibition of ADAMTS13
- release of endothelial and red cell procoagulants
- increased levels of tissue factor
- oxygen reactive species
- depletion of nitric oxide
8
Q
What is PNH ?
A
- acquired clonal hematopoietic stem cell disorder
- caused by mutations in the GPI-anchored proteins on surfaces of affected cells
9
Q
What gene is PIGA located on ?
A
- X chromosome
- gene product of one of 7 enzymes involved in GPI anchor biosynthesis
- IMP
- virtually all PNH cases are associated with PIGA mutations
10
Q
What are other mutations that cause
PNH other than PIGA ?
A
- mutations on CD59 and CD55
- these are GPI-anchored proteins and are key in complement regulation
- due to their absence on erythrocytes
- PNH manifest with chronic hemolyitic anemia
- caused by alternative complement pathway activation on mutant erythroid membranes
11
Q
How long can the mutant RBC s in PNH circulate ?
A
- unlike foreign RBCs PNH erythrocytes circulate for 6-60 days
- they are protected by factor H
- so patients with decreased levels of factor H have worse hemolytic disease
12
Q
What other disorder is closely associated
with PNH ?
A
- acquired aplastic anemia
- autimmune entity
- characterized by depletion of hematopoietic stem cells
13
Q
What tests should be ordered in PNH ?
A
- Gold standard: flow cytometry
- cocktail of antibodies against individual GPI-anchored proteins
- FLAER
- variant antibody that binds to the GPI anchor
- helps detect loss of GPI anchored proteins
14
Q
What was the historical test for PNH and
what is the principle behind it ?
A
- Ham test
- principle: PNH cells are more vulnerable to acidified serum which serves to activate the alternative complement pathway
- thus incubation with acidified serum causes hemolysis that is not observed with normal erythrocytes
- test lacked sensitivity and specificity
15
Q
What are the general manifestations of PNH ?
A
- most patients have chronic hemolysis with bursts of hemoglobinuria
- patients with bone marrow failure exhibit low levels of chronic hemolysis
- reticulocyte count is elevated
- but not to the level you would expect for the degree of anemia
- morphologically the cells look normal
- clinical symptoms of anemia
16
Q
Clinical findings in PNH include what ?
A
- anemia (intravascular and extravascular)
- venous thrombosis
- intraabdominal veins ex: mesenteric
- cerberal veins
- deep venous thrombosis
- pulmonary embolism
- dermal veins
- arterial thrombus
- smooth muscle distonia
- chronic kidney disease
17
Q
What factors are important in identifying the
degree of hemolysis in PNH ?
A
- size and type of PNH clone
- degree of complement activation
18
Q
What is the most common site of thrombosis
in PNH ?
A
- hepatic vein thrombsosi
- Budd Chiari Syndrome
19
Q
What is the treatment of choice for PNH ?
A
- Eculizumab
- used in patients with severe hemolytic anemia and thrombosis
- must be infused every 2 weeks IV (limitation)
- mechanism:
- binds the terminal complement component C5 and blocks MAC formation
IMP
- due to absence of CD55 PNH erythrocytes are susceptible to opsonization by CD3b and thus extravascular hemolysis when they are on eculizumab
- known to have chronic extravascular hemolysis
20
Q
What is the only cure for PNH ?
A
- hematopoietic stem cell transplantation
21
Q
What is atypical hemolytic
uremic syndrome ?
A
- it is a thrombotic microangiopathy
- includes a heterogeneous group
- presentation is typically MAHA, thrombocytopenia and organ damage
- peripheral smear shows schistocytes, anemia and thrombocytopenia
- in order to diagnose atypical hemolytic uremic syndrome you must exclude other TMAs
22
Q
What is the pathophysiology of
atypical HUS ?
A
- disease of excessive activation of the APC
- can be from inherited mutations in APC proteins or in autoantibodies
- requires a two hit model
- mutations and autoantibodies are not enough to cause it
- what are common triggers:
- pregnancy
- inflammation
- autoimmunity
- surgery
23
Q
What tests should be ordered
for aHUS ?
A
- it is a clinical diagnosis of exclusion
- modified Ham test
- use PNH erythrocytes (sensitive to complement)
- mix them with aHUS patient serum (activated)
- cells do not release dye due to complement induced death
- has been initially shown to differentiate well between aHUS and TTP
24
Q
What is the differential diagnosis of
aHUS /
A
- TTP
- Shiga-toxin producing E.coli induced HUS
- Secondary causes of microangiopathy:
- DIC
- Drugs
- Malignancy
- Slceroderma-associated renal crisis
- Malignant hypertension
25
Q
What is considered a severe ADAMTS13 deficiency ?
A
- usually level <10%
- inherited : Upshaw-Schulman Syndrome
- acquired: IgG autoantibodies against the molecule
- more common than inherited
IMP: if ADAMTS13 is >10% and shiga-toxin is negative than aHUS should be considered
26
Q
What are the clinical findings in
aHUS ?
A
- aHUS patients usually manifest by age 18
- generally have anemia, thrombocytopenia and acute kidney injury
- other possible presentations
- peripheral gangrene
- arterial stenosis
- dilated cardiomyopathy
- cardiorespiratory arrest
- neurologic, pulmonary and gastrointestinal complications
27
Q
What is the treatment for
aHUS ?
A
- severe, life-threatening emergency requiring immediate treatment
- plasma exchange can help in some cases but lasting complement mediated damage to the kidneys and CNS often persist and may lead to death
- Eculizumab is the treatment of choice
28
Q
How is failure to respond to PLEX diagnosed ?
A
- most frequently used criteria:
- failure to achieve a hematologic response (improvement in platelet count, decrease in LDH) over the first 4-5 days
- progressive end-organ damage while on PLEX
- ADAMTS13 <10%
