208: Thromboembolic Microangiopathies

Question 1

What causes TTP?

Answer 1

TTP = thrombotic thrombocytopenic purpura

Caused by deficiency in ADAMTS13 due to genetic mutation or autoantibodies. Requires a trigger to cause TTP

• Without ADAMTS13, you cannot chop up large multipers of Von Wilebrand factor
• This leads to uncontrolled platelet aggregation and thrombus formation

Question 2

What are the 3 types of TMA?

Answer 2

• TTP – Thrombotic Thrombocytopenic Purpura
• HUS – Hemolytic uremic syndrome
  
  • Typical: Diarrhea-associated HUS, caused by shiga toxin
  • Atypical: Not caused by shiga toxin
• Other

Question 3

Decreased activity of which protein could cause endotheliosis (capillaries to fill with endothelial cells)

Answer 3

Decreased activity of VEGF -> Endotheliosis. This can lead to TMA

VEGF stimulates angiogenesis

Genetic susceptibility + anti-VEGF drugs or pregnancy
-> Decreased VEGF activity

Question 4

Which TMA is associated with shiga toxin?

Answer 4

Typical HUS

Question 5

What is the most prominent stimulator of endothelial cell production and podocyte growth?

Answer 5

VEGF

VEGF receptors are highly expressed in the glomerular endothelium

May be inhibited by pregnancy or drugs

Question 6

How does preeclampsia develop?

Answer 6

Abnormal placenta: Abnormal spiral artery remodeling

• -> Hypoxia
• -> Increased sFlt1 (a VEGF receptor decoy)
• -> sFlt1 binds VEGF, decreasing the effective VEGF concentration in the bloodstream
• -> Decreased VEGF activity
  
  • -> Loss of ENOS -> HTN
  • -> Damage to glomerular endothelium or other vascular bed -> Thrombus formation (TMA)

Question 7

A 40 y.o. female presents to the emergency room with numbness in her right arm and a headache. Routine CBC shows anemia and platelets of 60,000. An MRI is performed, which shows no abnormalities.

Which of the following findings helps to confirm diagnosis of a TMA?

A) white blood cell differential

B) blood smear showing RBC fragments (shistocytes)

C) blood chemistry showing abnormal liver function tests

D) high ADAMTS13 enzymatic activity

Answer 7

B) blood smear showing RBC fragments (shistocytes)

Question 8

Which TMA is associated with low ADAMTS13?

Answer 8

TTP - Thrombotic Thrombocytopenic Purpura

Low ADAMTS13 can be caused by genetic mutation or autoantibodies to ADAMTS13

Question 9

_____% of HUS is caused by shiga toxin (typical HUS).

The rest is caused by______________

Answer 9

90% of HUS is caused by shiga toxin (typical HUS).

The rest is caused by abnormalities in complement regulation

Question 10

Why can patients with mutations in ADAMTS13 or complement regulation live their whole life without TMA?

Answer 10

These mutations predispose patients to TMA, but a “trigger” is still required to activate the disease

Question 11

What causes typical hemolytic uremic syndrome?

Answer 11

Shiga Toxin

• Produced by some E. Coli (0157:H7) and Shigella
• Binds to the Gb3 receptor on glomerular endothelial cells
• -> Platelet thrombus formation

Question 12

Why doesn’t everyone on an anti-VEGF agent develop TMA?

Answer 12

Anti-VEGF agents are not bad for everybody

Genetic susceptibility -> TMA due to VEGF therapy

Question 13

What factors normally protect the glomerular microvascular bed?

Answer 13

VEGF

Complement regulatory proteins (Factor H)

ADAMTS13

Question 14

Where does shiga toxin bind?

Answer 14

Gb3 receptor on glomerular endothelial cells

-> platelet thrombus formation

Question 15

What causes Atypical HUS (aHUS)?

Answer 15

Abnormalities in complement regulation + trigger

(Example: Factor H deficiency)

• Patient cannot activate complement
  
  • Due to a mutation in any regulatory protein
• Patients may have low C3

Question 16

Why is the kidney at increasd risk of damage to the vascular endothelium?

Answer 16

• Fenestrations
• High capillary pressure
• Continuous exposure to toxins and complement activation
• GBM is pro-thrombotic
  
  • If it is exposed -> thrombus formation

Question 17

Which TMA is associated with mutations in complement regulatory proteins?

Answer 17

Atypical HUS

Question 18

What is the pentad associated with TTP?

Answer 18

• Hemolytic andemia
• Thrombocytopenia
• Neurologic symptoms
• Kidney injury
• Fever

Question 19

What are the adverse effects associated with anti-VEGF agents?

Answer 19

• Proteinuria
• Nephrotic syndrome
• Severe hypertension
• Kidney failure (bloodless glomeruli)

Question 20

Which cells produce VEGF?

Answer 20

Podocytes

Question 21

Why does HUS preferentially affect the pediatric population?

Answer 21

Children may have more Gb3 receptors on glomerular endothelial cells for shiga toxin to bind to

• > Increaed binding of shiga toxin
• > Increaed platelet thrombus formation

Question 22

What is the initial event in all forms of TMA?

Answer 22

Damage to the vascular endothelium

• > Thrombus formation
• > Shear stress in the microvascular with thrombi (-> Shistocytes)
• > Thrombocytopenia

Glomerular microvascular is particularly susceptible to injury

Question 23

What is the triad that characterizes thrombotic microangiopathies (TMAs)?

Answer 23

• Microangiopathic hemolytic anemia
• Thrombocytopenia
• Organ injury (Due to small clots that form in microvasculature)

Question 24

What is the role of VEGF in the glomerulus?

Answer 24

VEGF stimulates endothelial cell proliferation

-> Vasculogenesis and angiogenesis

Also stimulates podocyte growth

A VEGF knockout will not have any glomeruli