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SM 213 Thrombotic Microangiopathies Flashcards

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1
Q

What are thrombotic microangiopathies?

A

TMA’s are a heterogeneous group of disorders characterized clinically by a triad of:

Microangiopathic hemolytic anemia
Thrombocytopenia
Organ Injury

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2
Q

What is seen on slides in TMA?

A

Fragments of RBC’s called schistocytes

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3
Q

What area of the Nephron is suspectible to TMA?

A

Glomerular microvasculature

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4
Q

What are the 3 types of TMA’s?

A

TTP = Thrombotic Trombocytic purpura
HUS = Hemolytic Uremic Syndromes
Other TMA’s

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5
Q

What are the two types of HUS?

A

D+HUS (Diarrhea due to Shigatoxin) and Atypical HUS (Due to defect in Complement Regulatory Proteins)

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6
Q

What can cause the “other” TMA’s?

A

Pre-eclampsia and anti-VEGF drugs

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7
Q

What is found in the blood of patients with TTP?

A

Patients with TTP have large circulating multimers of vWF

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8
Q

What is the trigger for TTP?

A

Endothelial cells releasing multimers of vWF, normally chopped up by ADAMTS13 (now deficient)

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9
Q

Why do clots of vWF form and clog microvasculature in TTP?

A

Low enzymatic activity of ADAMTS13 either due to birth defect or due an auto-antibody to ADAMTS13

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10
Q

What forms clots in TTP?

A

Multimers of vWF forming microclots

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11
Q

What are symptoms of TTP?

A

Schistocytes (fragments of RBC’s)
Low platelets
Fever

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12
Q

What is used to diagnose TTP?

A

Measuring activity of ADAMTS13 and finding low activity

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13
Q

Explain the pathophysiology of HUS?

A

Thrombi form in the small capillaries and arterioles leading to ischemia to the Glomeruli

Due to either Shigatoxin or CRP deficiencies

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14
Q

What toxin is associated with HUS?

A

Shiga-toxin

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15
Q

What strain of E. coli causes HUS?

A

O157:H7 - the shiga-toxin producing strain of E. coli that produces HUS

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16
Q

Which population is mostly effected by HUS?

A

Pediatric populations

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17
Q

How does Shiga-toxin work?

A

Ingest bacteria
Toxin enters the circulation
Toxin binds to Gb3 receptor on glomerulal endothelial cells
Platelet clots form

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18
Q

Why do children tend to be effected by Shiga-toxin?

A

More expression of the Gb3 receptor = more targets for Shiga-toxin

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19
Q

Can EAEC cause HUS?

A

Yes, if they acquire the shigatoxin gene, as was the case in Germany in 2011

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20
Q

What causes atypical HUS?

A

By definition, HUS not caused by Shigatoxin

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21
Q

Which is more common, aHUS or shigatoxin-mediated HUS?

A

Shigatoxin mediated HUS

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22
Q

Is atypical HUS heritable?

A

Yes

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23
Q

What part of the immune system is dysregulated in aHUS?

A

Abnormalities in complement regulation cause aHUS

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24
Q

What’s worse, aHUS or normal HUS?

A

aHUS, both in terms of mortality and complications in surviving patients

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25
What are the 3 complement pathways?
Classical - immune complex Lectin - microbes Alternatives - implicated in HUS
26
What is the complement system?
An ancient defense system
27
Where do the complement pathways converge?
All 3 pathways converge on C5b-9
28
When is the alternative complement pathway active?
Always, but it is regulated by other proteins
29
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
30
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
31
Why do some patients with a mutation that predisposes aHUS not develop aHUS?
Two hit hypothesis
32
Which form of TMA has normal ADAMTS13?
HUS
33
Which form of TMA has low ADAMTS13?
TTP
34
What bacteria other than E. coli can cause HUS?
Strep. pneumoniae - neuraminidase can damage the endothelium
35
What nutrient deficiency can predispose HUS?
B12 deficiency
36
Why is the kidney particularly susceptible to thrombotic injury?
Extremely high vascular flow, since it filters the entire circulation several times every week
37
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
38
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
39
Where are VEGF receptors found?
The Glomerular basement membrane contains lots of VEGF receptors, but they are also found throughout the body
40
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
41
How are VEGF knockout mice created?
Only knockout VEGF in the podocyte cells so it otherwise develops normally
42
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
43
What is the pathopneumonic finding for TMA?
Endotheliosis
44
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
45
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
46
What class of drugs can cause TMA?
VEGF inhibitors
47
What does endotheliosis cause?
Bloodless glomeruli (lacking blood flow) with fibrous material deposited in and around the capillary endothelium
48
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
49
What is the role of VEGF in the glomeruli with respect ot TMA?
VEGF prevents clotting the Glomeruli
50
Do anti-VEGF agents affect every patient?
Nope, only a very small subset
51
What form of TMA effects pregnant women?
Pre-eclampsia
52
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
53
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
54
What are the 3 protective pathways against TMA?
ADAMTS13 Complement Regulatory Proteins VEGF-VEGF Receptor signaling
55
What defect is aHUS associated with?
A defective complement regulatory pathway can cause aHUS
56
How is TTP treated?
Infuse plasma contained ADAMTS13 | Rituximab to inhibit formation of Antibodies against B cells
57
How is aHUS treated?
Infuse the missing complement regulatory protein via plasma contain the missing protein Add Eculizamab, a C5 inhibitor
58
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
59
How should anti-VEGF TMA be treated?
Discontinue the drug and never start it again
60
How should pre-eclampsia TMA be treated?
Deliver the baby | Remove the VEGF decoy from the baby via column
61
What is the classic TMA patient?
A young woman with neurological symptoms, low platelet count, and shcitocytes on blood smear
62
What are Schistocytes?
Fragments of RBC's

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