HIV-Associated Thrombotic Microangiopathy Jack Kuritzky, PGY-2 UNC Internal Medicine April 16, 2010

Thrombotic Microangiopathy Generic term for microvascular thrombosis from vascular diseases characterized pathologically by fibrinous clot TTP/HUS Malignant HTN Eclampsia/Preeclampsia DIC Connective Tissue Disease

Idiopathic TTP Pentad of symptoms MAHA Thrombocytopenia Renal failure Fever Neurologic symptoms

MAHA and TTP MAHA is not unique to TTP/HUS… Malignant HTN DIC APLAS Rheumatologic conditions (SLE or scleroderma) Pre-eclampsia/eclampsia HELLP syndrome Mechanical trauma (artificial heart valves) HIV Hematopoietic progrenitor cell transplants Myelodysplasia Erythroleukemia TTP is a diagnosis that requires exclusion of more plausible etiologies

Idiopathic TTP Pentad of symptoms Pathophysiology MAHA, thrombocytopenia, renal failure, fever, neurologic symptoms Pathophysiology ADAMTS13 (von Willebrand metalloprotease) deficiency often due to an inhibitor Normal ADAMTS13 cleaves Unusually Large VWf (ULVWf) into VWf Presence of ULVWf leads to platelet aggregation, clumping, and ultimately microthrombi Treatment with plasma exchange rests in its ability to remove ADAMTS13 inhibitor and replenish the ADAMTS13 protein

HIV-Associated Thrombotic Microangiopathy “TTP” was more commonly diagnosed in HIV patients during the pre-HAART era Associated with advanced disease and low CD4 counts Often found in conjunction with opportunistic infections In a study of 350 consecutive admission to Hopkins inpatient HIV service 1996-1997… 24% of patients had schistocytes 7% had TTP-like syndrome w/anemia, thrombocytopenia, schistocytosis and renal dysfunction/neurologic disease Associated with very high-mortality rates (70-100% at 3 months) Once HAART became more commonplace, the incidence has decreased Most studies document <1% incidence

HIV-Associated Thrombotic Microangiopathy ADAMTS13 Levels (almost) Normal Limited to case series Inhibitor typically not present Correlate with severity of HIV/AIDS Lower CD4 and High viral load = normal ADAMTS13 and no inhibitor As a result, HIV-Associated Thrombotic Microangiopathy does not respond as well to Plasma Exchange Do not need to remove inhibitor Do not need to replenish ADAMTS13 Several case series and case reports document improvement with HAART Improvement typically seen within one week

HIV-Associated TMA: Pathogenesis Debated, studies ongoing, likely multifactorial Infection of hematopoietic cells – explains thrombocytopenia Affect maturation and differentiation of megakaryocytes Leads to deposition of immune complexes on platelets and thus accelerated clearance Endothelial cells infected Leads to increased release of VWf, which has been observed clinically in several patients with HIV-Associated Thrombotic Microangiopathy This may overwhelm available ADAMTS13  increased ULVWf  increased platelet clumping and aggregation

HIV-Associated Thrombotic Microangiopathy Summary Similar to TTP clinically, but has (more) normal ADAMTS13 levels Associated with lower CD4 counts and higher viral loads Responds to HAART better than plasma exchange UNC Laboratory Medicine has contributed significantly to the research in this field

REFERENCES Becker, S, et al. HIV-Associated Thrombotic Microangiopathy in the Era of Highly Active Antiretroviral Therapy: An Observational Study. Clinical Infectious Diseases. 39: S267-275. 2004. Brecher, ME et al. Is it HIV TTP or HIV-Associated Thombotic Microangiopathy. Journal of Clinical Apheresis. 23:186-190. 2008. Egan, JA et al. Frequency and Significance of Schistocytes in TTP/HUS Patients at the Discontinuation of Plasma Exchange Therapy. Journal of Clinical Apheresis. 19: 165-167. 2004. Gervasoni, C et al. Thrombotic Microangiopathy in Patients with Acquired Immunodeficiency Syndromes Before and During the Era of Introudction of Highly Active Antiretroviral Therapy. Clinical Infectious Diseases. 35:1534-1540. 2002. George, JN. Causes of Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults. UpToDate. 2010. Park, YA et al. ADAMTS13 Activity Levels in Patients with Human Immunodeficiency Virus-Associated Thrombotic Microangiopathy and Profound CD4 Deficiency. Journal of Clinical Apheresis. 24:32-36. 2009.

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