TTP in HIV A New Entity

1. TTP in HIV A New Entity? Kristine Scruggs, MD AM Report 19 November 2008

2. Thrombotic Thrombocytopenic Purpura Clinical syndrome characterized by thrombocytopenia, elevated LDH and evidence of MAHA (e.g. schistocytes on blood smear) without another explanation Pentad: Fever, AMS, Renal failure, Thrombocytopenia, MAHA ADAMTS13 deficiency, inherited or acquired Mortality >90% without emergent treatment

3. DDx when Schistocytes present on Peripheral Smear TTP/HUS DIC Eclampsia/preeclampsia, pregnancy Metastatic Cancer High dose chemotherapy Mechanical injury (e.g. prosthetic valves) Malignant Hypertension Connective Tissue Disease Post-Hematopoietic Stem Cell Transplant HIV Associated TMA

4. ADAMTS13 Plasma metalloprotease, cleaves vWF at peptide bond Tyr1605-Met1606 TTP results from ADAMTS13 gene mutations (hereditary) or anti-ADAMTS13 autoantibody (acquired) vWF not cleaved, results in ultra-large-molecular-weight vWF and unrestricted thrombus growth, causes shear stress and MAHA

5. ADAMTS13 as diagnostic tool? Does not correlate with clinical diagnosis: Vesely et al. studied 48 pts with similar clinical picture of TTP, 16 had severe deficiency and 32 did not Patients with clinical TTP and severe ADAMTS13 deficiency ranged from 33-100%, depending on the study Test takes 24hrs + to obtain Useful as predictor of relapse and to diagnose inherited TTP Not recommended for initial diagnosis or short term prognosis �Plasma exchange with replacement of plasma remains mandatory for all patients with acute TTP irrespective of their ADAMTS13 activity. (Hovinga 2008)�

6. Prospective, randomized trial to compare PLEX vs. Plasma infusion (102 patients) PLEX: 24/51 (47%) response at 9d, 2 deaths 40/51 (78%) response at 6m, 11 deaths Plasma inf: 13/51 (26%) response at 9d, 8 deaths 25/51 (49%) response at 6m, 19 deaths. Treatment of choice for TTP determined to be immediate PLEX, delay associated with treatment failures and adverse outcomes

7. Other Treatments for Refractory or Chronic TTP Immunosuppressive drugs Steroids, usually along with PLEX Cyclosporine Rituximab Splenectomy Other Vincristine, Cyclophosphamide, Azathioprine, IVIG

8. HIV Associated Thrombotic Microangiopathy Pre-HAART Common entity (up to 7% inpatients) Mortality high even with PLEX Usually comorbidities such as opportunistic infections or sepsis present Post-HAART Rare Usually in patients with CD4 counts <100 Unclear response to PLEX Initiation of HAART often results in resolution and prevents relapse

9. Plasma infusion vs. Plasma exchange in HIV patients No trials comparing PLEX v. plasma infusion BJH: HIV � vs. HIV + patients in South Africa, no access to HAART therapy Rx: Prednisone 1mg/kg + FFP 30mL/kg/d If unable to tolerate fluid load or no improvement in 48hrs -> PLEX

10. Case Reports � HIV and TTP 32yo homosexual M p/w pentad, treated initially with plts, RBC and FFP infusion. Dx of TTP and HIV made, PLEX begun and symptoms resolved 2-5d. Plts stabilized 10d. � Jokela et al. 34yo M p/w seizures, ARF (11.4), elev LDH, found to have TTP (�81). Initially treated with FFP + Asa/Dipyr. Transferred for PLEX on D2. Deteriorated, intubated D5. Expired D8. (Serum HIV + �91). � Ucar et al. 30yo M h/o IVDU p/w seizures, fever, LD 5000, ARF, found to have TTP and HIV. Initially IV Solumedrol and FFP. D2 PLEX added. Rapidly improved and extubated. � Ucar et al. Ucar study 5/7 patients with HIV and TTP died 6/7 patients received PLEX Unclear treatment schedule

11. 32yo M w/ previously undiagnosed HIV treated with PLEX. AMS and renal abn improved, but hgb and plts up and down. HAART begun with good response. � Gruszecki et al.

12. TTP in HIV � Case Series of 18 Patients (Rarick, et al.) 28yo M with AIDS noncompl with AZT, initially rx for PCP recurrence. MS deteriorated, dx with TTP, PLEX initiated and symptoms resolved in 3D. 26yo M with AIDS dx with TTP, initially rx with FFP, changed to PLEX b/c of slow response and severe thrombocytopenia. Prompt response, subsequently placed on AZT, 18mo f/u. 37yo homosexual M with evidence of OI and Kaposi�s sarcoma dx with TTP. Rx with FFP with poor response, attempt to PLEX but pt refused. Eventually refused further inpt treatment, had occasional outpt infusions with poor compliance, expired 1 week after d/c. 18 total patients, 14 treated with plasma exchange -> 12 with CR (1 with stable plts 50-70K, 1 p/w coma and died D16) FFP -> died occluded airway; FFP -> died DOA; Methylprednisolone -> died 18H after admission; FFP, refused PLEX -> died 1wk after d/c

13. ADAMTS13 in HIV-Associated TMA In review of the literature, 16 HIV patients with ADAMTS13 activity measured (Brecher, et al.) 7/16 patients with severe deficiency In those with CD4 counts measured (9), all those with counts <100 had normal ADAMTS13 levels Gunther, et al, measured ADAMTS13 activity in 20 HIV patients with TTP Six (30%) patients had normal levels Fourteen (70%) had severely reduced levels CD4 levels checked in 18/20 patients, normal ADAMTS13 levels correlated with lower CD4 counts (p = 0.049)

14. Proposed mechanisms for findings in HIV-TMA Thrombocytopenia Direct platelet infection with HIV Induction of anti-platelet Ab Elevated vWF Direct infection of endothelial cells with HIV, resulting in release of vWF Decreased ADAMTS13 Release of vWF leads to transient increased clearance of ADAMTS13 Direct infection of endothelial cells causes local thrombin generation and consumption of ADAMTS13 MAHA Endothelial damage results in turbulent flow and thrombus formation, leads to fragmentation of red cells

15. Conclusions TTP is defined as thrombocytopenia with elevated LDH and evidence of MAHA TTP is a hematologic emergency with mortality >90% without emergent treatment Standard of care is plasma exchange In HIV patients with TTP-like syndrome, no RCT has been performed to compare PLEX with another therapy to establish standard of care While HAART therapy appears to be beneficial and even necessary in reversing the process underlying development of this disorder, PLEX should still be initiated as emergent therapy ADAMTS13 levels can not be used to determine probability of response to PLEX therapy or as a diagnostic tool � it is neither sensitive or specific and takes too long to obtain

16. References ME Brecher, et al. Is It HIV TTP or HIV-Associated Thrombotic Microangiopathy? J of Clin Apheresis. 2008. A Doldan-Silvero, et al. ADAMTS13 activity and inhibitor. Am J of Hem. 2008; 811-812. AC Gruszecki, et al. Management of a Patient with HIV Infection-Induced Anemia and Thrombocytopenia Who Presented with TTP. Am J of Hem. 2002. 69: 228-231. K Gunther, et al. ADAMTS13 activity and the presence of acquired inhibitors in HIV-related TTP. Transfusion. 2007; 47: 1710-1716. Jokela, et al. Brief Report: TTP in an HIV-Seropositive Homosexual Man. 1987. JA Kremer Hovinga, SC Meyer. Current management of TTP. Current Opin in Hem. 2008. 15: 445-450. N Novitzky, et al. TTP in patients with retroviral infection is highly responsive to plasma infusion therapy. Br J of Hem. 2005. 128: 373-379. MU Rarick, et al. TTP in Patients with HIV Infection: A Report of Three Cases and Review of the Literature. Am J of Hem. 1992. 40: 103-109. GA Rock, et al. Comparison of plasma exchange with plasma infusion in the treatment of TTP. Canadian Apheresis Study Group. New Engl J of Med. 1991. 325: 393-397. A Ucar, et al. Thrombotic Microangiopathy and Retroviral Infections: A 13-Year Experience. Am J of Hem. 1994. 45: 304-309.