SM_213a: Thrombotic Microangiopathies

Question 1

The triad of thrombotic microangiopathies includes _____, _____, and _____

Answer 1

The triad of thrombotic microangiopathies includes microangiopathic hemolytic anemia, thrombocytopenia, and organ injury

Question 2

Describe thrombotic microangiopathies

Answer 2

Thrombotic microangiopathies

• Triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ injury
• Thrombi in capillaries and arterioles
• Glomerular microvasculature is particularly susceptible

Question 3

Three main groups of thrombotic microangiopathies are ____, ____, and ____

Answer 3

Three main groups of thrombotic microangiopathies are thrombotic thrombocytopenia purpura, hemolytic-uremic syndrome, and other TMAs (VEGF-VEGF receptor signaling)

Question 4

Describe the pathogenesis of thrombotic thrombocytopenia purpura

Answer 4

Thrombotic thrombocytopenia purpura

1. Endothelial cells are damaged
2. Endothelial cells release vWF
3. Low levels of ADAMTS 13 so vWF not chopped up
4. Large multimers of vWF trap platelets and cause a clot

Question 5

Thrombotic thrombocytopenia purpura results from a deficiency of _____, which causes _____

Answer 5

Thrombotic thrombocytopenia purpura results from a deficiency of ADAMTS 13, which causes large multimers of vWF to remain, trap platelets, and cause clots

Question 6

Pentad of thrombotic thrombocytopenia purpura includes _____, _____, _____, _____, and _____

Answer 6

Pentad of thrombotic thrombocytopenia purpura includes microangiopathic hemolytic anemia, low platelets, fever, neurologic involvement, and renal involvement

Question 7

Hemolytic uremic syndrome involves _____ and _____

Answer 7

Hemolytic uremic syndrome involves destruction of RBCs and kidney injury

Question 8

Typical hemolytic uremic syndrome is caused by ____ toxin from ____

Answer 8

Typical hemolytic uremic syndrome is caused by shiga toxin from E. coil O157:H7

Question 9

In typical hemolytic uremic syndrome, shiga toxin _____, binds ____, and causes ____

Answer 9

In typical hemolytic uremic syndrome, shiga toxin enters systemic circulation, binds Gb3 on glomerular endothelial cells, and causes platelet clots

Question 10

Atypical hemolytic uremic syndrome results from _____

Answer 10

Atypical hemolytic uremic syndrome results from abnormalities in complement regulation

(low C3 is helpful but may not be present)

Question 11

_____ hemolytic uremic syndrome has a worse outcome than _____ hemolytic uremic syndrome

Answer 11

Atypical hemolytic uremic syndrome has a worse outcome than typical hemolytic uremic syndrome

Question 12

____ hits are required for a patient to develop a thrombotic microangiopathy

Answer 12

Two hits are required for a patient to develop a thrombotic microangiopathy

Question 13

____ is particularly susceptible to thrombotic injury

Answer 13

Glomerulus is particularly susceptible to thrombotic injury

Question 15

____ is the most potent growth factor for proliferation of endothelial cells

Answer 15

VEGF is the most potent growth factor for proliferation of endothelial cells

Question 16

____ of VEGF is critical for glomerular development

Answer 16

Dose of VEGF is critical for glomerular development

Question 17

VEGF blockers cause ____, ____, and ____

Answer 17

VEGF blockers cause proteinuria, nephrotic syndrome, and hypertension

Question 18

VEGF inhibitors cause _____ and _____ by _____

Answer 18

VEGF inhibitors cause proteinuria and glomerular injury (thrombotic microangiopathy) by local reduction of VEGF (on target effect)

Question 19

Describe the proof of principle studies for VEGF and thrombotic microangiopathies

Answer 19

Proof of principle studies for VEGF and thrombotic microangiopathies

• 100% of mice with VEGF deletion develop glomerular injury characteristic of thrombotic microangiopathy
• VEGF produced by podocytes is required by glomerular endothelium in a filtering glomerulus
• Thrombotic microangiopathy observed in patients on VEGF inhibitors: on target effect resulting from local reduction of VEGF

Question 20

Describe what happens with regards to VEGF in preeclampsia

Answer 20

What happens with regards to VEGF in preeclampsia

1. VEGF secreted into bloodstream
2. VEGF decoy binds VEGF and prevents VEGF from acting on endothelial cells
3. Endothelial dysfunction

Question 21

Describe dangerous agents previously used to treat thrombotic microangiopathies

Answer 21

Dangerous agents previously used to treat thrombotic microangiopathies

• Anti-VEGF agents (bevacizumab, VEGF trap, TKIs such as sunitinib)
• sFLT1 (endogenous anti-VEGF molecule) - preeclampsia

Question 22

Describe treatment of thrombotic microangiopathies

Answer 22

Treatment of thrombotic microangiopathies

• ADAMTS 13: caplacizumab (anti-vWF Ig factor that disrupts interaction between vWF and platelets), recombinant ADAMTS13
• aHUS-complement: complement inhibitors such as eculizamab (C5 inhibitor)
• Anti-VEGF agents: drug holiday
• Preeclampsia: delivery of baby, removal of sFLT1 via extracorporeal column