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HIV-Associated Thrombotic Microangiopathy

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

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HIV-Associated Thrombotic Microangiopathy

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

  2. 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

  3. Idiopathic TTP • Pentad of symptoms • MAHA • Thrombocytopenia • Renal failure • Fever • Neurologic symptoms

  4. 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

  5. Idiopathic TTP • Pentad of symptoms • 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

  6. HIV-AssociatedThrombotic 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

  7. HIV-AssociatedThrombotic 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

  8. 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

  9. 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

  10. 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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