SM 213 Thrombotic Microangiopathies Flashcards
What are thrombotic microangiopathies?
TMA’s are a heterogeneous group of disorders characterized clinically by a triad of:
Microangiopathic hemolytic anemia
Thrombocytopenia
Organ Injury
What is seen on slides in TMA?
Fragments of RBC’s called schistocytes
What area of the Nephron is suspectible to TMA?
Glomerular microvasculature
What are the 3 types of TMA’s?
TTP = Thrombotic Trombocytic purpura
HUS = Hemolytic Uremic Syndromes
Other TMA’s
What are the two types of HUS?
D+HUS (Diarrhea due to Shigatoxin) and Atypical HUS (Due to defect in Complement Regulatory Proteins)
What can cause the “other” TMA’s?
Pre-eclampsia and anti-VEGF drugs
What is found in the blood of patients with TTP?
Patients with TTP have large circulating multimers of vWF
What is the trigger for TTP?
Endothelial cells releasing multimers of vWF, normally chopped up by ADAMTS13 (now deficient)
Why do clots of vWF form and clog microvasculature in TTP?
Low enzymatic activity of ADAMTS13 either due to birth defect or due an auto-antibody to ADAMTS13
What forms clots in TTP?
Multimers of vWF forming microclots
What are symptoms of TTP?
Schistocytes (fragments of RBC’s)
Low platelets
Fever
What is used to diagnose TTP?
Measuring activity of ADAMTS13 and finding low activity
Explain the pathophysiology of HUS?
Thrombi form in the small capillaries and arterioles leading to ischemia to the Glomeruli
Due to either Shigatoxin or CRP deficiencies
What toxin is associated with HUS?
Shiga-toxin
What strain of E. coli causes HUS?
O157:H7 - the shiga-toxin producing strain of E. coli that produces HUS
Which population is mostly effected by HUS?
Pediatric populations
How does Shiga-toxin work?
Ingest bacteria
Toxin enters the circulation
Toxin binds to Gb3 receptor on glomerulal endothelial cells
Platelet clots form
Why do children tend to be effected by Shiga-toxin?
More expression of the Gb3 receptor = more targets for Shiga-toxin
Can EAEC cause HUS?
Yes, if they acquire the shigatoxin gene, as was the case in Germany in 2011
What causes atypical HUS?
By definition, HUS not caused by Shigatoxin
Which is more common, aHUS or shigatoxin-mediated HUS?
Shigatoxin mediated HUS
Is atypical HUS heritable?
Yes
What part of the immune system is dysregulated in aHUS?
Abnormalities in complement regulation cause aHUS
What’s worse, aHUS or normal HUS?
aHUS, both in terms of mortality and complications in surviving patients
What are the 3 complement pathways?
Classical - immune complex
Lectin - microbes
Alternatives - implicated in HUS
What is the complement system?
An ancient defense system
Where do the complement pathways converge?
All 3 pathways converge on C5b-9
When is the alternative complement pathway active?
Always, but it is regulated by other proteins
How is the alternative complement pathway altered in aHUS?
A mutation in a protein(s) that inhibit the alternative complement pathway or antibodies against these proteins lead to overactivity of the aHUS
Causes endothelial cell damage
What type of cells are damaged by aHUS?
Endothelial cells are damaged by constititutive alternative complement pathway activation, leading to generation of more immune signals
Why do some patients with a mutation that predisposes aHUS not develop aHUS?
Two hit hypothesis
Which form of TMA has normal ADAMTS13?
HUS
Which form of TMA has low ADAMTS13?
TTP
What bacteria other than E. coli can cause HUS?
Strep. pneumoniae - neuraminidase can damage the endothelium
What nutrient deficiency can predispose HUS?
B12 deficiency
Why is the kidney particularly susceptible to thrombotic injury?
Extremely high vascular flow, since it filters the entire circulation several times every week
How are Podocytes connected to fenestrated endothelium in a healthy kidney?
Podocytes are normally intimately associated with underlying fenestrated endothelium, forming interdigated slits with their foot processes
What is the most potent growth factor for endothelial cells, and what cells make it?
VEGF is the most potent growth factor for endothelial cells, and it’s made by Podocytes at high levels
Where are VEGF receptors found?
The Glomerular basement membrane contains lots of VEGF receptors, but they are also found throughout the body
Why can’t full VEGF knockouts be used in a mouse model?
The mouse dies during embryonic development because VEGF is needed for embryonic development
How are VEGF knockout mice created?
Only knockout VEGF in the podocyte cells so it otherwise develops normally
What is the role of VEGF in TMA?
VEGF protects the glomerular capillary from TMA by promoting eNOS activity as well as protecting against damage to the glomerular endothelium
What is the pathopneumonic finding for TMA?
Endotheliosis
How was VEGF studied in adult filtering glomeruli?
Anti-cancer that act as VEGF inhibitors (antibodies) can knockout VEGF to see the effect of VEGF on adult filtering glomeruli
Caused endotheliosis
What were the side effects of VEGF blocker drugs?
Dose-dependent proteinuria that could even be nephrotic range
Severe HTN - consistent with a RAAS reflex response to decreased perfusion at Glomeruli
What class of drugs can cause TMA?
VEGF inhibitors
What does endotheliosis cause?
Bloodless glomeruli (lacking blood flow) with fibrous material deposited in and around the capillary endothelium
Why do VEGF blockers cause endotheliosis?
The capillaries in the glomeruli are filled with microthrombi due to loss of both eNOS activity and the protective effects VEGF has on the glomerular basement membrane, destroying the blood supply to the glomeruli
What is the role of VEGF in the glomeruli with respect ot TMA?
VEGF prevents clotting the Glomeruli
Do anti-VEGF agents affect every patient?
Nope, only a very small subset
What form of TMA effects pregnant women?
Pre-eclampsia
How does Pre-eclampsia start?
In the placenta
Spiral artery needs to remodel
In pre-eclampsia, artery remodelling is flawed
Leads to Hypoxia
VEGF Decoy (SLFT1) is secreted into the bloodstream
VEGF Decoy prevents binding of VEGF to the VEGF Receptor, causing TMA
How does pre-eclampsia cause TMA?
In pre-eclampsia, hypoxia leads to secretion of a VEGF decoy (SLFT1) into the neonatal bloodstream that prevents VEGF from binding VEGF Receptors in the neonatal glomeruli, causing endotheliosis and TMA
What are the 3 protective pathways against TMA?
ADAMTS13
Complement Regulatory Proteins
VEGF-VEGF Receptor signaling
What defect is aHUS associated with?
A defective complement regulatory pathway can cause aHUS
How is TTP treated?
Infuse plasma contained ADAMTS13
Rituximab to inhibit formation of Antibodies against B cells
How is aHUS treated?
Infuse the missing complement regulatory protein via plasma contain the missing protein
Add Eculizamab, a C5 inhibitor
How does Eculizamab treat aHUS?
Eculizamab is a C5 inhibitor, which blocks the common part of the complement pathway, to prevent thrombi form forming in aHUS
How should anti-VEGF TMA be treated?
Discontinue the drug and never start it again
How should pre-eclampsia TMA be treated?
Deliver the baby
Remove the VEGF decoy from the baby via column
What is the classic TMA patient?
A young woman with neurological symptoms, low platelet count, and shcitocytes on blood smear
What are Schistocytes?
Fragments of RBC’s
