Case Based Presentation Dr. Jai Khullar Department of Internal Medicine BLK Super Speciality Hospital New Delhi

Mr. XY, 33 year old married, Hindu male, resident of New Delhi, accountant by profession having a desk job.

Initially our patient was admitted and thoroughly investigated at a Govt. hospital in Delhi, where he had presented with complaints of high grade fever with chills, itching all over body, poor oral intake, weight loss and pain abdomen on and off for 1-2 months. The only remarkable positive investigations during initial workup were raised ESR, CRP, S. IgE and AEC. Whole body PET scan done on 18/03/2016 showed mildly FDG avid and non FDG avid bilateral cervical, bilateral axillary, abdominal and bilateral inguinal lymphnodes with mildly FDG avid heopatosplenomegaly, likely infective / inflammatory. He was started on four drug ATT empirically on 21/03/16.

Following unsatisfactory response, he presented to BLK 2 weeks later and during the course of admission he was found to have Brucella antigen (IgG) positivity. Bone marrow aspiration and biopsy showed significant eosinophilia with mild prominent of histiocytes. He also underwent an excisional inguinal lymph node biopsy which suggested reactive eosinophilic reaction and sinus histiocytosis. He was discharged on treatment for Brucellosis and oral steroids, and responded well.

During follow up in OPD, after an initial good symptomatic response for 15 days, he reported B/L diminution of vision, and became febrile yet again. He was found to have severe thrombocytopenia. Ophthalmology opinion was taken and patient was diagnosed to have retinal haemorrhages, in view of which he was readmitted. He was found to have severe thrombocytopenia with a normal coagulogram and raised LDH with renal azotemia. Peripheral blood smear showed fragmented RBCs. He was diagnosed as a case of acquired Thrombotic Thrombocytopenic Purpura and taken up immediately for Plasma exchange under guidance with Hematology and Transfusion Medicine teams.

SCHISTOCYTES/ FRAGMENTED RBCs MYELOCYTES Peripheral smear showing microangiopathic hemolytic features with numerous RBC fragments (helmet cells/schistocytes). Marked thrombocytopenia is evident. Inset: Peripheral smear showing RBC fragmentation consistent with a microangiopathic hemolytic process. SCHISTOCYTES/ FRAGMENTED RBCs

He was initially given five cycles of plasma exchange to which he responded well (Platelet counts increased and LDH levels decreased). He developed fever with neutrophilic leukocytosis for which he was treated on lines of CRBSI and his central line removed. White cell counts normalized and he became afebrile, however platelet count began to fall again along with rise in Serum LDH. He was given further 4 cycles of Plasma exchange i/v/o relapsed TTP, however response was poor this time and in consultation with Hematology team he was started on Rituximab. Patient responded well and is relapse free since his last Rituximab dose which was given on 12/07/16.

26/5 27/5 29/5 30/5 31/5 HB 10.5 10.9 7.5 7.9 6.8 TLC 7.2 22.1 8.8 9.6 Platelets 25 30 33 40 68 Urea 84.9 124.6 Creatinine 2.63 4.20 LDH 2150 1816 1309

Review of Literature Pts with neuro abnormalities that are dominant are considered by some to represent idiopathic or “classical” TTP, where as when acute renal failure is dominant and neuro abnormalities are minimal or absent, it is considered by some to represent HUS. However, many patients present with severe neuro abnormalities and acute renal failure and can be classifies as TTP-HUS.

Definitions and Diagnosis The Classic Pentad of TTP Microangiopathic hemolytic anemia Thrombocytopenia Renal insufficiency or abnormalities Neurologic abnormalities that can be fluctuating Fever Most common symptoms at presentation are nonspecific and include abdominal pain, nausea, vomiting and weakness.

DDx of thrombocytopenia and microangiopathic haemolytic anaemia

Acquired TTP The acquired form accounts for >99% of the adolescent and adult cases. Pathophysiology von Willebrand factor, a glycoprotein secreted from vascular endothelial cells in very large polymeric forms, supports platelet adhesion and aggregation at sites of vessel injury. ADAMTS13, a metalloprotease in plasma, cleaves von Willebrand factor when it is conformationally unfolded by shear stress. By cleaving vWF before it is fully activated by shear stress, ADAMTS13 prevents vWF-mediated platelet aggregation.

Autoimmune TTP is due to anti - ADAMTS - 13 antibodies that inhibit the proteolytic activity of ADAMTS - 13 and/or bind the protease to accelerate its clearance from plasma through opsonization and/or other yet unclear mechanisms.

Presentation

Clinical Course In approximately two - thirds of cases, TTP occurs only once (acute sporadic TTP). In the remaining one - third of patients, the disease tends to recur after periods of remission of the acute episode. Recurrence, has a spectrum of presentations ranging from a single relapse to several episodes developing with variable frequency and less severe clinical manifestations.

Plasma therapy Plasma exchange may help by removing anti - ADAMTS - 13 autoantibodies, the most frequent mechanism of acute sporadic TTP. It also helps to replace the deficient protease, infusion alone being probably sufficient in congenitally deficient cases with no associated autoantibody. Treatment with plasma should be initiated as soon as the clinical diagnosis is suspected .

Further treatments in acquired TTP Corticosteroids Recommendation Intravenous daily methylprednisolone (e.g. 1 g/d for three consecutive days – adult dose) or high dose oral prednisolone (e.g. 1 mg/kg/d) should be considered .

Rituximab Recommendation 1 Rituximab Recommendation 1 .In acute idiopathic TTP with neurological/cardiac pathology, which are associated with a high mortality, rituximab should be considered on admission, in conjunction with PEX and steroids . 2. Patients with refractory or relapsing immune-mediated TTP should be offered rituximab .

Supportive therapy Recommendation 1 Supportive therapy Recommendation 1. Red cell transfusion should be administered according to clinical need especially if there is cardiac involvement . 2. Folate supplementation is required during active haemolysis. 3. Platelet transfusions are contra-indicated in TTP unless there is life-threatening haemorrhage. 4. Thromboprophylaxis with LMWH and low dose Aspirin is recommended once platelet count has reached >50 x 109/l .

Relapse Recommendation 1 Relapse Recommendation 1. Increased PEX and/or rituximab therapy are the agents of choice in relapsing disease . 2. Patients should be counselled about symptoms, signs and risk of relapse before discharge. In patients with a documented reduction of ADAMTS 13 activity to <5%, elective therapy with rituximab can be considered.

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