SM 213: TMAs

Question 1

What are the 3 key clinical features of thrombotic microangiopathies?

Answer 1

1. Microangiopathic Hemolytic Anemia - fragments of RBCs on smear
2. Thrombocytopenia
3. Organ Injury (capillary clotting, can occur in glomerular microvasculature)

Question 2

Three classifications of TMAs

Answer 2

1. Thrombotic Thrombocytopenic Purpura
2. Hemolytic-Uremic Syndrome
3. Miscellaneous

Question 3

What is the cause of Thrombotic Thrombocytopenic Purpura?

Answer 3

Low Enzyme ADAMTS13 activity (normally cleaves vWF, if low - more clot risk)
Cause: genetic (rare) or acquired (developing auto-antibodies: more common)

Question 4

Typical HUS

presentation, population, mortality, pathophysiology

Answer 4

Presentation: Diarrhea + HUS
Pop: more common in pediatrics; more common cause of HUS
Pathophys: E. coli bacteria releases Shiga-Toxin = enters systemic circulation = binds glom endothelial cells (Gb3) = triggers platelet clotting
Mortality: 12%; 25% have long term renal sequelae
Germany outbreak: bean sprouts, caused by EAEC that acquired shiga-toxin gene

Question 5

Atypical HUS (aHUS)
(features, how it occurs)

Answer 5

NOT Shiga-toxin
Abnormalities in alternate complement pathway causes upregulation and overactivation (due to antibody/mutation against regulatory protein in pathway)
Overactivated MAC causes endothelial damage & clots
2 Hit Hypothesis: need additional trigger and genetic predisposition for disease to manifest

Question 6

Name 2 less common causes of HUS (neither typical nor atypical)

Answer 6

1. Strep pneumoniae - neuraminidase could expose toxin
2. Cobalamin deficiency - vitamin B12 metabolism deficiency
3. DGKE - enzyme mutation presenting in children

Question 7

Key features of HUS on biopsy

Answer 7

1. Bloodless glomeruli (AA clots + closes up glom)

2. ENDOTHELIOSIS (endothelial cell swells and blocks capillary loop)

Question 8

Causes of other TMAs (Miscellaneous)

Answer 8

Drugs
HIV, Cancer
Preeclampsia, anti-VEGF therapies, HELLP, Malignant HTN, anti-phospholipid

Question 9

What is the role of VEGF? How can it lead to TMAs?

Answer 9

VEGF - in embryo, plays role in angiogenesis/vasculogenesis; in adult, only produced by podocyte
Certain VEGF deficiency: causes ENDOTHELIOSIS
VEGF blocker use: anti-tumor by blocking tumor angiogenesis, SE: may cause reduction of VEGF in kidney glomeruli - ENDOTHELIOSIS AND TMA

Question 10

What is the mechanism of TMAs in Pregnancy? What is the disease process called?

Answer 10

Preeclampsia
Placenta does not cause vessel remodeling in utero = low bloodflow = high hypoxia = high sFLT1
sFLT1 acts as VEGF-receptor circulating in blood - lowers free VEGF - causes endothelial dysfunctional - HTN, glom dysfunction, proteinuria, coag abnormalities, brain/liver abnormalities

Question 11

How to treat TMAs for various conditions?

Answer 11

1. ADAMTS13: plasma infusion (if enzyme deficient) or plasma exchange (to clear bad IC), Rituximab - antibody to B lymphocytes (inhibit antibody formation), Caplacizumab - anti-vWF mAb
2. aHUS: Plasma infusion/exchange; Eculizamab (C5 inhibitor - no MAC activation) or other C’ inhibitors
3. due to anti-VEGF agents: stop drug use
4. Preeclampsia: deliver baby (remove sFLT1), use extracorporeal column to remove VEGF decoy