Thrombotic microangiopathy (TMA) is characterized by arteriolar and capillary lesions leading to microangiopathic hemolytic anemia, thrombocytopenia, and organ injury due to platelet-rich thrombi. The condition can be hereditary or acquired, affecting various age groups and organs, with multiple classifications evolving over time, including atypical HUS and TTP. Early diagnosis and prompt management, such as plasmapheresis and potential new treatments, are critical for patient survival and mitigating organ damage.

1. Thrombotic microangiopathy
K.Sampath Kumar.MD,DM,FRCP
Meenakshi Mission Hospital
Madurai

2. Definition
• Lesion of arterioles and capillaries with wall
thickening , intraluminal platelet thrombosis
and partial or complete obstruction of vessel
lumina.

3. Beginning of the story
• 1924
• Moschcowitz treats a 16 yr old girl
• Purpura, Pallor, hemiparesis
• Dies of cardiac failure
• Autopsy- Hyaline thrombi in microcirculation
incl. Kidneys
• ? TTP [ ADAMSTS13 Def.]
• More people studied it than suffered from it !

4. 3 Defining features
• 1. Microangiopathic hemolytic anemia
• 2.Thrombocytopenia
• 3.Organ injury due to microcirculatory
obstruction by platelet rich thrombi

5. One underlying fact

6. Peripheral smear in TMA

7. Renal Biopsy- Extensive glomerular
capillary thrombi

8. Renal Biopsy-Arterial thrombi, intimal
proliferation and thick capillary BM

9. Fibrin deposits in the glomerular
capillary wall and arterial wall

10. EM – Endoth. Lifted by fluffy lucent
material on BM

11. Similarities stop
Extraordinary diversity begins !
• New born / Elderly
• Hereditary / Acquired
• Asymptomatic / Lethal
• Renal/CNS/GI/Skin/Pancreas
• Acute/recurring/chronic
• Amenable / Treatment resistant

12. Working Classification of TMA
Terms such as Atypical HUS, Idiopathic HUS are being replaced

13. TMA +
• Pregnancy related – PET,HELLP
• Malignant HT
• Auto immune- SLE,SS,APLA
• Transplant – HSC,SOT

15. TTP [ ADAMTS 13 defect ]
• ADAMTS13 is secreted from Liver
• Gene on chr.9q34
• Cleaves vWf multimers of vasc. Endoth
• If deficient – vWf are uncut and large
• Platelet thrombi in small vv. with high
shear states
Hereditary [Upshaw Schulman]
Homozy, compd het.of
ADAMTS 13
Acquired
Auto antibody inh.ADAMTS13
Females

16. TTP – Clinical,Lab
• Recurrent MAHA
• Thrombocytopenia
• Neurologic signs
• Level < 10%
• AutoAntibody +/-
• Mutation
• Renal involvement is mild- 25 %
ADAMTS13

17. TTP- Management
Long term – Since ADAMST13 Protects against atheroma
Hypertension, cognitive impairment seen in such patients .

18. Shiga Toxin HUS
E.Coli O157:H7Children ,
O104:H4 adult
Sporadic / Epidemic
Shigella dys 1
Developing Countries
Endemic
Meat
Vegetable
Milk
H to H

21. 50% Dialysis
70% Blood transf.
25% Neuro.manif
CKD 25%
ESRD/DEATH 12%
Stx- HUS

22. Lab investigations

23. Management of Stx HUS
• Aggressive hydration with isotonic fluids
• Antibiotics – Warning ! [E.Coli. Infection]
• May increase Stx release
• Quinolones,TMP- Induce of Stx gene transcr.
• However , In Shigellosis – Early antibiotics
indicated
• Stx binder SYNSORB was not effective
• PEX or P.Infusion – Effective along with
Dialysis

25. Pneumococcal HUS
• 5-15%
• N acetyl neuraminidase induced cell wall damage
• Exposure of T antigen in platelets, RBCs and
glomeruli
• Severe AKI/ Pyothorax/Meningitis
• Vancomycin, ceftriaxone
• Plasma infusion ? Role
• PEX

26. Complement factors and TMA
[C-TMA]

27. Tick over
hydrolysis

28. Genetic forms of C-TMA

30. Genetics of C-TMA
Missing Links
• Family members carrying same heterozygous
mutations are normal [ ? Modifier genes]
• SNP in CFH,CD46
• Copy No. variations in CFH1,3 Genes
• Fusion genes of CFHR and CFH due to
homologous recombination
• Normal plasma C3,C4,CFH,CFB,CFI does not
exclude C-HUS

31. Treatment of C-HUS
Tops the Forbe’s List of Costliest Drugs !

32. Renal transplant in C-HUS

34. Drugs and TMA

35. 2 rare causes of TMA
• Vit. B12 metabolic
defect
• Infants
• Methyl malonic aciduria
• Renal failure,HT.
• Vit B12,Folic
acid,Betaine effective
• Thrombomodulin
mutations
• Membrane bound gp.
• Activates protein C
• Interface between
coagulation and
complement systems
• PEX ineffective
• CKD common

36. Predilection for organ inv.
• TTP – Extensive microvasc. Thrombi . But CKD
rare.
• HUS – Renal involvement common since injury
to renal endothelial cells, mesangial cells and
podocytes occur.
• Stx HUS rarely produces CKD since it is one
time injury
• C-HUS is a recurring theme leading to CKD

37. Concluding remarks
• TMA develops in a wide range of clinical
situations
• High degree of suspicion is required for its
diagnosis.
• Prompt PEX,PI – Life saving
• Tests to diagnose C-HUS should become
widely available .
• Newer molecules offer hope to patients