1. DR AHMED SHAFI C.P MBBS.MD.(PATH). EX.PGI.CHANDIGARH PROFESSOR OF PATHOLOGY KMC. ANJARAKANDY

2. INTRODUCTION Among the renal parenchymal diseases, thrombotic microangiopathy(TMA), is one of the four important vascular lesions capable of causing acute renal failure. The other three are :- 1. Hypertensive renal disease 2. Renal artery occlusion. 3. Renal vasculitis.

3. DISEASES ASSOSIATED WITH TMA Hemolytic Uremic Syndrome. Thrombotic Thrombocytopenic Purpura Malignant hypertension Autoimmune disease(SLE, progressive sclerosis) Primary Antiphospholipid Antibody Syndrome Pregnancy Venoms, toxins and stings Radiation Nephritis and certain malignancies

4. TERMINOLOGY

5. HISTORICAL PERSPECTIVE Eli Moschcowitz reported the first detailed report of idiopathic TTP in 1924. The patient was a 16 year old girl with fever, severe anemia, leukocytosis, petichiae and hemi paresis. Her renal function was not impaired, but the urine contained albumin, hyaline casts and granular casts. She became comatose and died two weeks after her first symptoms. At autopsy hyaline thrombi found in terminal arterioles and capillaries particularly of the heart and kidney. For many years patients with similar findings were described having moschcowitz disease.

6. In 1955, the term hemolytic uremic syndrome (HUS) was proposed for thrombotic microangiopathy occurring in children and associated with acute anuric renal failure, which is uncommon in TTP. Childhood HUS often was preceded by a diarrheal illness and unlike TTP in adults, the prognosis was favourable. The majority of patients survived and recovered normal renal function only with supportive care. In 1966, a review of 272 published cases defined the major clinical features of TTP. Most patients were females between the ages of 10 and 39 years. Mortality exceeded 90%. The average hospital stay was only 14 days before death. However, dramatic recoveries occurred in some cases following spleenectomy.

7. This grim prognosis was recorded before the recognition that blood or plasma in fusions improved the outcome of TTP. A few reports including one from moschcowitz in 1925 had suggested that blood transfusion some times induced dramatic responses. However, interest in transfusion therapy increased after 1976, when whole blood exchange transfusions reportedly induced prompt remissions in 8 of 14 patients. Similar responses were described after plasma pheresis with plasma replacement.

8. THROMBOTIC MICROANGIOPATHY Thrombotic microangiopathy (TM) refers to a combination of microangiopathic hemolytic anemia, thrombocytopenia and microvascular thrombosis, regardless of cause or specific tissue involvement. Various kinds of microangiopathy differ with regard pathogenesis and prognosis but can be difficult to distinguish because their clinical features overlap.

9. IDIOPATHIC THROMBOTIC THROMBOCYTOPENIC PURPURA TTP is a form of thrombotic microangiopathy in which tissue injury can affect any organ but often results in neurologic damage and fever. Renal involvement is common but oliguric renal failure is not. TTP is associated with microangiopathic hemolytic anemia, thrombocytopenia and microvascular thrombosis that results in variable injury to the central nervous system, kidney and other organs. Most case of TTP are caused by autoantibodies to ADAMTS13, a metalloprotease that cleaves von Willibrand Factor (vWF) and thereby inhibits vWF –dependant platelet aggregation.

10. TTP occurs in patients without other medical conditions that sometimes cause thrombotic microangiopathy, metastatic cancer, systemic infection, solid organ or hemopoetic stem cell transplantation, radiation exposure, chemotherapy or various other causes of disseminated intravascular coagulation (DIC). Congenital TTP, Upshaw-Schulman syndrome, refers to TTP caused by inherited deficiency of ADAMTS13.

11. ETIOLOGY AND PATHOGENESIS Unregulated vWF-dependant platelet thrombosis appears to be the mechanism underlying congenital TTP and most instances of idiopathic TTP. Large vWF multimers mediate platelet addition at sites of vascular injury by binding to connective tissue and glycoprotein (Gp)1b on the platelet surface. vWF multimers bind to collagen through domain A3 and to platelet Gp 1b and through domain A1. When platelet binds to vWF under conditions of high fluid shear stress, the vWF multimers is stretched and the Tyr-1605-met-1606 bond within domain A2 become accessible to metalloprotease ADAMTS13, which cleaves it and may release any adherent platelets. ADAMTS13 deficiency prevents this feedback inhibition and leads to microvascular platelet thrombosis.

12. CLINICAL FEATURES OF TTP The onset of idiopathic TTP can be dramatically acute or insidious. Approximately one third of patients have symptoms of hemolytic anemia. Thrombocytopenia typically causes petechiae or purpura. Systemic microvascular thrombosis can affect any organ and the consequences are variable. Renal involvement is common but acute renal failure occurs in fewer than 10% of cases. Neurologic findings may include headache, visual disturbances, vertigo, personality change, confusion, lethargy, syncope, seizures, aphasia, hemiperisis and other focal motor or sensory deficit.

13. Almost all patients have normal values for plasma fibrinogen, prothrombin time (PT) and activated partial thromboplastin time (aPTT) reflecting a minor role of blood coagulation in TTP. Severe congenital ADAMTS13 deficiency (<5%) is characteristic of congenital TTP. Severe acquired ADAMTS13 deficiency appears to be specific for idiopathic TTP. Assays for ADAMTS13 activity usually are performed on citrated plasma, anticoagulation with EDTA irreversibly inactivates the enzyme.

14. LABORATORY FEATURES OF TTP The symptoms and signs of idiopathic TTP are non specific. The diagnosis depends on laboratory testing to document microangiopathic hemolytic anemia and thrombocytopenia without another cause such as DIC. Half of the patients have platelet count below approximately 20,000/ µL. Hemolysis indicated by an elevated reticulocyte count and serum lactate dehydrogenase (LDH) and decreased serum heptoglobin. Coombs test is always negative

15. PERIPHERAL SMEAR FINDINGS IN TTP The characteristic morphologic feature of TTP is marked increase in schistocytes. Schistocytes are jagged or irregularly shaped fragments of split red cells with two or more sharply pointed projection, sometimes having the appearance of military helmets. Patients with idiopathic TTP often have markedly increased schistocytes; in a study of six patients, schistocytes comprised a mean of 8.3% of all red cells. Spherocytes also may be seen.

16. PERIPHERAL SMEAR IN TMA

17. DIFFERENTIAL DIAGNOSIS OF TTP The diagnosis of TTP should be considered for any patient with microangiopathic hemolytic anemia and thrombocytopenia, without evidence of DIC and without features associated with D+HUS such as prodromal diarrheal illness and acute oliguric or anuric renal failure. These criteria can only be approximate, however because many diseases associated with secondary thrombotic microangiopathy can overlap clinical and laboratory findings. As a consequence making a diagnosis of TTP can be a challenge and wide differential diagnosis must be considered.

18. HEMATOLOGICAL MANIFESTATION OF TMA

19. SPECTRUM OF CLINICAL RENAL MANIFESTATION Renal failure-mild to severe Urine output- normal to oliguria Hematuria Proteinuria-minimal to nephrotic range Blood pressure- normal or mild to severe increase

20. PATHOLOGY OF THROMBOTIC MICROANGIOPATHY Renal cortical necrosis Predominantly glomerular lesions A combination of glomerular and arteriolar Mainly arteriolar/microvascular lesions Arterial lesions Glomerular and arteriolar lesions occurring simultaneously

21. LIGHT MICROSCOPIC LESION OF TMA Glomerular changes Capillary congestion Ischemic collapse Capillary thrombi Capillary wall thickening Subendothelial widening Entrapment of RBC Messangial cellularity, mild Mesangiolysis/rarefaction Mesangial interposition Double contours of capillary walls Capillary micro-aneurysms Arteriolar and arterial changes Mural fibrinoid necrosis and fibrin deposition Luminal thrombosis (platelet and fibrin) Endothelial swelling and detachment Intimal ‘mucoid’, expantion Myointimal proliferation(onion skin pattern)

22. ULTRASTRUCTURAL LESIONS OF TMA Endothelial swelling Capillary thrombi Subendothelial widening with accumalation of granular material and Mesangiolysis with extention to capillary walls Increased activity or degeneration of mesangial cells and capillary wall interposition

23. CONGENITAL TTP Congenital TTP is caused by homozygosity for inactive mutations in the ADAMTS13 gene. The mutations usually impair the synthesis or secretion of ADAMTS13. the clinical findings in congenital TTP are similar to the findings in idiopathic TTP except for age of onset. Most children with congenital ADAMTS13 deficiency have neonatal jaundice and hemolysis but no evidence of ABO blood group or Rh incompatibility. Congenital TTP can be treated with periodic infusions of fresh frozen plasma.

24. TREATMENT OF TTP 1. Plasma exchange – The mainstay of treatment for idiopathic TTP is plasma exchange which removes antibody inhibitors of ADAMTS13 and replenishes the enzyme. 2. Glucocorticoids- Idiopathic TTP often is an autoimmune disease and use of glucocorticoids is logical, although a beneficial effects has not been demonstrated conclusively. 3. Antiplatelet agents-Use of antiplatelet agents in TTP is controversial. Aspirin and dipyridamol often are combined with plasma exchange, but have not been shown conclusively to modify the course of idiopathic TTP

25. HEMOLYTIC UREMIC SYNDROME Hemolytic uremic syndrome (HUS) refers to thrombotic microangiopathy that mainly affects the kidney that usually causes oliguric renal failure Diarrhea-associated or typical HUS is caused by enteric infection with shiga toxin- producing gram-negative bacilli and usually is associated with prodrome of diarrhea. Diarrhea negative or atypical HUS is not associated with diarrhea or shiga toxin producing organisms and occurs in patients without an obvious predisposing condition.

26. HUS AND TMA IN THE INDIAN SUBCONTINENT In 1975, Rahman et al from Bangladesh were the first to report on a large group of patients with GI infection by shigella species who showed marked leukocytosis and erythrocyte fragmentation. A small proportion of these cases exhibited evidence of microangiopathic hemolytic anemia, thrombocytopenia an transient renal failure resembling HUS. At the same time, Raghupathy et al from vellore observed HUS and acute failure(ARF) in 40 patients below 5 years of age in a span of 33 months. This group formed 65% of ARF in children and had a high mortality rate. These authors proposed that S.dysentriae I infection played an important role in the causation of HUS.

27. ETIOPATHOGENESIS OF HUS The syndrome is initiated by the damage of endothelium of glomerular capillaries and renal arterioles. The damage leads to local platelet deposition, intravascular coagulations and ischemic renal cortical necrosis. Clinical manifestations are pallor, purpura, jaundice and oliguria. Laboratory tests reveal anemia. Blood film displace many deformed and fragmented red cells, increased number of reticulocytes and occasional nucleated red cells. Thrombocytopenia and compensatory increase in marrow megakaryocytes are noted. Distinguishing HUS and TTP can be difficult in many cases. Normal cleaving of von Willebrand multimers is impaired in TTP because of congenital absence of multimer cleaving protease.

28. The new approaches to treatment have lead to substantial improvement in the outcome of the disease.

29. THANK YOU