Thrombotic microangiopathy

K.Sampath Kumar.MD,DM,FRCP

Meenakshi Mission Hospital

Madurai

Definition

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

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 !

3 Defining features

• 1. Microangiopathic hemolytic anemia

• 2.Thrombocytopenia

• 3.Organ injury due to microcirculatory obstruction by platelet rich thrombi

One underlying fact

Peripheral smear in TMA

Renal Biopsy- Extensive glomerular capillary thrombi

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

Fibrin deposits in the glomerular capillary wall and arterial wall

EM – Endoth. Lifted by fluffy lucent material on BM

Similarities stop Extraordinary diversity begins !

• New born / Elderly• Hereditary / Acquired• Asymptomatic / Lethal• Renal/CNS/GI/Skin/Pancreas• Acute/recurring/chronic• Amenable / Treatment resistant

Working Classification of TMA

Terms such as Atypical HUS, Idiopathic HUS are being replaced

TMA +

• Pregnancy related – PET,HELLP

• Malignant HT

• Auto immune- SLE,SS,APLA

• Transplant – HSC,SOT

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 statesHereditary [Upshaw Schulman]

Homozy, compd het.of ADAMTS 13

Acquired Auto antibody inh.ADAMTS13

Females

TTP – Clinical,Lab

• Recurrent MAHA• Thrombocytopenia• Neurologic signs• Level < 10%• AutoAntibody +/-• Mutation • Renal involvement is mild- 25 %

ADAMTS13

TTP- Management

Long term – Since ADAMST13 Protects against atheromaHypertension, cognitive impairment seen in such patients .

Shiga Toxin HUS

E.Coli O157:H7Children ,O104:H4 adult

Sporadic / Epidemic

Shigella dys 1Developing Countries

Endemic

MeatVegetable

MilkH to H

50% Dialysis70% Blood transf.25% Neuro.manif

CKD 25%ESRD/DEATH 12%

Stx- HUS

Lab investigations

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

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

Complement factors and TMA[C-TMA]

Tick over hydrolysis

Genetic forms of C-TMA

Genetics of C-TMAMissing 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

Treatment of C-HUS

Tops the Forbe’s List of Costliest Drugs !

Renal transplant in C-HUS

Drugs and TMA

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

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

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