Date post: | 16-Jul-2015 |
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Health & Medicine |
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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