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TTP and ITPALEJANDRA FUENTES M D JULY 16TH 2018 Quick Thrombocytopenia Review DIC activation of coagulation cascade by acute inflammatory state e g sepsis .trauma thrombus formation consumption of coagulation factors and platelets bleeding Tx treat underlying illness transfuse factors FFP or platelets as needed TTP acquired ADAMTS13 deficiency multiple etiologies Von Willebrandaccumulation platelet activation consumption with thrombus formation . Tx plasmapheresis replace ADAMTS13 steroids HIT activation of platelets by heparin induced antibodies thrombus formation platelet consumption Platelets fall by 50 AFTER 5 days of heparin exposure RARE Dx heparin antibody assay then serotonin release assay Tx avoid heparin give argatroban . ITP autoimmune destruction of platelets If isolated thrombocypenia 30k Hep C and HIV normal no infection no schistocytes Tx Steroids TTP and DIC are associated with microangiopathic hemolytic anemia 63 yom with pmh of CVA CAD s p NSTEMI and CABG 2015 on Plavix alcohol and.cannabis abuse who presented to LSU ED complaining of AMS aphasia dysphagia and gait difficulty for several hours Five days prior he started experiencing low gradefever and cough Stroke alert was called ED and CT head showed no acute stroke T 39 5C HR 115 other VS stable Hgb 6 4 Hct 19 5 WBC 13 9K Plt 37K.Haptoglobin 30 LDH 980 T bili 1 8D dimer 624 Fibrinogen 495 PT INR normal aPTT normal LFTs and BMP otherwise normal Peripheral smear 3 schistocytes 15 Blood Cx 1 4 CoN Staph UA Urine cx negative CXR clear . 40 yo AA female presents with weakness and epigastric pain for severalweeks and diarrhea and vomiting for 4 days Hct 25 Plt 10KPeripheral smear schistocytesLDH 722 T bili 2 5.BMP normal How should this case be managed George J NEJM 2006 354 1927 1935 TTP Brief history 1924 First case described by Moschcowitz 1955 first case of HUS.described Otherwise these diseases remained mysterious until 1982 unusually large multimers of vWF found to accumulate inplasma of patients with TTP 1985 typical HUS linked toenterohemorrhagic E coli 1991 Rock et al proved that plasma exchange improved mortality to. 10 20 formerly 90 1998 TTP pathophysiology linked to ADAMTS 13 deficiency thoughnot 100 association George J NEJM 2006 354 1927 1935 Annual incidence 4 11 cases per million people Etiologies . Mostly idiopathic 38 higher incidence in females obese African Americans Autoimmune 13 Drug associated 13 quinine ticlopidine clopidogrel cyclosporine Pregnancy induced 5 HSCT 3 5 . HIV among others Survival with plasma exchange 78 83 including patients with renal failure No evidence of benefit with plasma exchange George J Blood 2010 116 4060 4069 Pathophysiology. ADAMTS 13 protein cleaveslarge vWF multimers ADAMTS 13 deficiency abnormally large vWF multimersaccumulate in plasma reacting.with platelets and inducing theiradhesion aggregation disseminated platelet thromb platelet consumption thrombocytopenia and.microangiopathic hemolyticanemia MAHA Moake J NEJM 2002 347 589 600 Conditions that mimic and must consider HELLP pre eclampsia. Autoimmune with alternate mechanism eg SLE nephritis acutescleroderma APLA Evan s syndrome vasculitis Systemic infection can cause thrombocytopenia and MAHA without DIC High fevers make it less likely to be TTP Systemic malignancy most notably breast and gastric adenocarcinoma . Malignant hypertensionGeorge J Blood 2010 116 4060 69Scully et al BJH 2012 158 323 35 Presentation Full Classic Pentad thrombocytopenia MAHA neurologic and renal abnormalities fever .described in 1966 before plasma exchange was available occurs only in 5 of patients Neurological abnormalities 66 includes minor sx like confusion 31 and major sx likestroke seizure coma 35 Renal failure 23 Fever 23 high fever 38 9 C however is rare and often suggests alternate infectious. GI symptoms vague pain n v d 69 presumably from intestinal ischemia Weakness Fatigue 63 Cough 9 Dyspnea 29 Chest pain 22 .This data is based only on patients with proven ADAMTS 13 deficiency which is not a requirementfor the diagnosis of TTP George J Blood 2010 116 4060 4069 Diagnosis Diagnosis THROMBOCYTOPENIA MAHA without a readily apparent.alternative cause Based on presenting clinical features ADAMTS 13 deficiency confirms butit is not necessary for diagnosis as normal values do not rule it out Need high index of suspicion These less stringent diagnostic criteria came about after the discovery of.plasma exchange therapy and have resulted in a 7 fold increased incidence diagnoses Although it s recognized that it may result in over diagnosing benefits of immediate plasma exchange are thought to outweigh the risks George J Blood 2010 116 4060 4069 chistocytes for MAHA you need TWO or more schistocytes in a microscopic field with a magnification of.eticulocytes seen George J NEJM 2006 354 1927 1935 Tests to Order Consider get before plasmaexchange CBC with peripheral blood smear. LDH T bili haptoglobin reticulocyte count ADAMTS 13 assay activity antigen and inhibitor antibody Coombs Creatinine PT INR aPTT fibrinogen D dimer. Infectious w u blood cx urine cx hepatitis panel HIV stool studies CT MRI brain if neuro involvement CT c a p if concerned for malignancy Auto antibody screen if clinically applicable eg ANA lupus anticoagulant Pregnancy test.Scully et al BJH 2012 158 323 35 TreatmentTTP thrombocytopenia MAHA without alternate clinical cause If TPE notStart daily therapeutic plasma.immediatelyexchange TPE with 1 1 5 plasmaavailable give FFPvolume within 4 8 hrs Alternative etiology.corticosteroids Continue TPE until1mg kg day prednisone or discovered stop TPEPlatelet 150K and LDH1g day Solumedrol depending onseverity No great EBM behind near normal for 2 days .it and benefit may be limited to but maintain CVL untilpatients with true ADAMTS 13 full remission 30 days If no response or relapse consider deficiency after last TPE TPE twice daily Corticosteroids. RituximabGeorge J Blood 2010 116 4060 406Scully et al BJH 2012 158 323 35 Additional treatment PRBC s PRN . Platelets contraindicated UNLESS there s a life threatening bleed poor data however only old case reports systematic reviews did not document a risk If HIV start HAART immediately in conjunction with TPE reportednormalization of ADAMTS 13 as CD4 recovers Folic acid during active hemolysis . Aspirin 81mg and prophylactic LMWH may be given once platelets recover PltGeorge J Blood 2010 116 4060 4069 Combined Therapy Three Targets Current and EmergingEffective response rates and.currently only considered ifrefractory to Rituxan Splenectomy Cyclosporine Cyclophosfomide .vincristine Limited data further studies Velcade proteasomeinhibitor NAC breaks vWF disulfide.bonds and inhibits plateletadhesion Caplacizumab Ig againstvWF inhibiting interactionwith platelet glycoprotein .Not yet tested in humans Peyvandi et al NEJM 2016 374 511 52 Recombinant ADAMTS13Sayani et al Blood 2015 125 3860 7 HERCULES Trial Caplacizumab. Ig against vWF inhibiting interaction with platelet glycoprotein Ib Abstract presented at ASH Dec 2017 145 pts with acquired acute TTP randomized to caplacizumab vs placebo concurrent with PLEX and steroids 1 55x more likely to achieve Plt count normalization . 74 lower risk of TTP related death recurrence or thromboembolic event 38 reduction in time needing plasma exchange 65 reduced time in ICU 31 reducedtime in hospital Currently on fast track FDA designation look out for full approval Scully et al Blood 130 Suppl 1 2017 LBA 1 . Diagnostic difficulties and uncertaintiesNormal ADAMTS 13 does not rule it out though it is associated with slightly different presentationGeorge J Blood 2010 116 4060 4069 Diagnostic difficulties and uncertaintiesA lot of overlap with HUS Correct diagnosis does affect treatment . TTP thrombocytopenia MAHA ADAMTS 13 Could have renal failure Unclear ifcases with normal ADAMTS13 are actually an alternate dx like aHUS Plasma exchange Typical HUS thrombocytopenia MAHA renal failure diarrhea Associated with Shiga toxin producing E coli causes endothelial damage then TMA . Only needs supportive care in children in adults rare plasma exchange can be considered ifsevere neuro sx otherwise it provides no benefit Atypical HUS thrombocytopenia MAHA renal failure Associated with abnormalities in complement regulation leading to uncontrolled complementactivation endothelial damage and platelet activation TMA . Both in children and adults Can be sporadic or familial mutation Often recurrent Confirm with low C3 genetic testing in patients with severe renal failure especially if normal Plasma exchange and eculizumab anti C5 antibody indefinitely Scully et al Br J Haematol 2014 164 759 6 Apheresis Guidelines.Schwartz et al J Clin Apher 2016 31 149 338 Monitoring after recovery Patients need gradually fewer routine CBC over several months after this theyneed only routine care from their primary physician Platelet count is absolutelynecessary whe symptoms of any illness occur to immediately diagnose a possible.recurrence of TTP Risk of relapse is 41 at 7 5 years if ADAMTS 13 deficient with greatest risk inthe first year after recovery Patients without ADAMTS 13 deficiency rarely relapse Patients with ADAMTS 13 deficiency may be at risk for developing future.autoimmune disorders Minor chronic cognitive abnormalities possible memory concentration fatigue Do not recommend following ADAMTS 13 activity as there is no correlation George J Blood 2010 116 4060 4069 Questions about TTP . Immune Thrombocytopenia ITP Overview Definition and diagnosis of ITP ITP pathophysiology Most recent ASH guidelines for treatment Is high dose dexamethasone better than prednisone . Proposed mechanism of high dose dexamethasone in ITP What is the optimal number of cycles of high dose dexamethasone Other front line therapy trials Conclusions Future considerations Immune Thrombocytopenia. DEFINITION Platelet count of less than 100 x 10 3 L No other unexplained cytopenias Absence of alternate etiologies DIAGNOSIS very simple. History and physical Exclude other etiologies Peripheral smear INR aPTT HIV Hep C H pylori. Antiplatelet antibody testing is not indicatedNeunert C et al ASH 2011 evidence based practice guideline for immune thrombocytopenia Blood ITP PATHOPHYSIOLOGY Complex and incompletely understood mechanism ofincreased platelet destruction due to cellular immune.dysfunction including Antigen presenting cells abnormal processing or presentationof self antigens following an inflammatory insult T cell dysregulation with decreased regulatory T cells T regs anda consequent increased cell mediated immunity cytotoxic and.helper T cells B cell activation humoral immunity with increased levels of anti GPIIbIIIa platelet antibodies Also involves impaired megakaryocyte maturation andproduction McKenzie el al BJH 2013 163 10 23 . McKenzie el al BJH 2013 163 10 23 Most Recent Guidelines for Treatment ofITP ASH 2011 Indicated when platelet count 30 x 10 3 L FIRST LINE Steroids . Longer courses of prednisone 1mg kg PO for 3 weeks thentapered off listed as preferred due to longer duration of responsewhen it was compared to IV high dose methylprednisolone x 3 IVIg or anti D antibody may be used if more rapid responses areneeded or if steroids contraindicated .NEW DATA HAS EMERGED SINCE SECOND LINE THESE MOST RECENT Splenectomy GUIDELINES Thrombopoetin receptor agonists Rituximab .Neunert et al Blood 2011 117 4190 207 HD DXM Improved Outcomes in ITP Wei et al first head to head randomized comparison of high dosedexamethasone 40mg day x 4 days vs prednisone 1mg kg x 28days then taper . Superior initial response rates RR 82 1 vs 67 4 p 0 044 Cheng Y, Wong RS, Soo YO, et al. Initial treatment of immune thrombocytopenic purpura with high-dose dexamethasone. N Engl J Med. 2003; 349: 831-6. Hou Y, Feng Q, Xu M, et al. High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia.