HIV-Associated HIV-Associated Thrombotic Thrombotic

MicroangiopathyMicroangiopathyJack Kuritzky, PGY-2Jack Kuritzky, PGY-2

UNC Internal MedicineUNC Internal Medicine

April 16, 2010April 16, 2010

Thrombotic Thrombotic MicroangiopathyMicroangiopathy

Generic term for microvascular Generic term for microvascular thrombosis from vascular diseases thrombosis from vascular diseases characterized pathologically by characterized pathologically by fibrinous clotfibrinous clot TTP/HUSTTP/HUS Malignant HTNMalignant HTN Eclampsia/PreeclampsiaEclampsia/Preeclampsia DICDIC Connective Tissue DiseaseConnective Tissue Disease

Idiopathic TTPIdiopathic TTP

Pentad of symptomsPentad of symptoms MAHAMAHA ThrombocytopeniaThrombocytopenia Renal failureRenal failure FeverFever Neurologic symptomsNeurologic symptoms

MAHA and TTPMAHA and TTP MAHA is not unique to TTP/HUS…MAHA is not unique to TTP/HUS…

Malignant HTNMalignant HTN DICDIC APLASAPLAS Rheumatologic conditions (SLE or scleroderma)Rheumatologic conditions (SLE or scleroderma) Pre-eclampsia/eclampsiaPre-eclampsia/eclampsia HELLP syndromeHELLP syndrome Mechanical trauma (artificial heart valves)Mechanical trauma (artificial heart valves) HIVHIV Hematopoietic progrenitor cell transplantsHematopoietic progrenitor cell transplants MyelodysplasiaMyelodysplasia ErythroleukemiaErythroleukemia

TTP is a diagnosis that requires exclusion of more TTP is a diagnosis that requires exclusion of more plausible etiologiesplausible etiologies

Idiopathic TTPIdiopathic TTP Pentad of symptomsPentad of symptoms

MAHA, thrombocytopenia, renal failure, fever, MAHA, thrombocytopenia, renal failure, fever, neurologic symptomsneurologic symptoms

PathophysiologyPathophysiology ADAMTS13 (von Willebrand metalloprotease) ADAMTS13 (von Willebrand metalloprotease)

deficiency often due to an inhibitordeficiency often due to an inhibitor Normal ADAMTS13 cleaves Unusually Large Normal ADAMTS13 cleaves Unusually Large

VWf (ULVWf) into VWfVWf (ULVWf) into VWf Presence of ULVWf leads to platelet Presence of ULVWf leads to platelet

aggregation, clumping, and ultimately aggregation, clumping, and ultimately microthrombimicrothrombi

Treatment with plasma exchange rests in Treatment with plasma exchange rests in its ability to remove ADAMTS13 inhibitor its ability to remove ADAMTS13 inhibitor and replenish the ADAMTS13 proteinand replenish the ADAMTS13 protein

HIV-AssociatedHIV-AssociatedThrombotic Thrombotic

MicroangiopathyMicroangiopathy ““TTP” was more commonly diagnosed in HIV TTP” was more commonly diagnosed in HIV

patients during the pre-HAART erapatients during the pre-HAART era Associated with advanced disease and low CD4 Associated with advanced disease and low CD4

countscounts Often found in conjunction with opportunistic Often found in conjunction with opportunistic

infectionsinfections In a study of 350 consecutive admission to Hopkins In a study of 350 consecutive admission to Hopkins

inpatient HIV service 1996-1997…inpatient HIV service 1996-1997… 24% of patients had schistocytes24% of patients had schistocytes 7% had TTP-like syndrome w/anemia, thrombocytopenia, 7% had TTP-like syndrome w/anemia, thrombocytopenia,

schistocytosis and renal dysfunction/neurologic diseaseschistocytosis and renal dysfunction/neurologic disease Associated with very high-mortality rates (70-100% Associated with very high-mortality rates (70-100%

at 3 months)at 3 months) Once HAART became more commonplace, the Once HAART became more commonplace, the

incidence has decreasedincidence has decreased Most studies document <1% incidenceMost studies document <1% incidence

HIV-AssociatedHIV-AssociatedThrombotic MicroangiopathyThrombotic Microangiopathy ADAMTS13 Levels (almost) NormalADAMTS13 Levels (almost) Normal

Limited to case seriesLimited to case series Inhibitor typically not presentInhibitor typically not present Correlate with severity of HIV/AIDSCorrelate with severity of HIV/AIDS

Lower CD4 and High viral load = normal ADAMTS13 Lower CD4 and High viral load = normal ADAMTS13 and no inhibitorand no inhibitor

As a result, HIV-Associated Thrombotic As a result, HIV-Associated Thrombotic Microangiopathy does not respond as well Microangiopathy does not respond as well to Plasma Exchangeto Plasma Exchange Do not need to remove inhibitorDo not need to remove inhibitor Do not need to replenish ADAMTS13Do not need to replenish ADAMTS13

Several case series and case reports Several case series and case reports document improvement with HAARTdocument improvement with HAART Improvement typically seen within one weekImprovement typically seen within one week

HIV-Associated TMA: HIV-Associated TMA: PathogenesisPathogenesis

Debated, studies ongoing, likely multifactorialDebated, studies ongoing, likely multifactorial Infection of hematopoietic cells – explains Infection of hematopoietic cells – explains

thrombocytopeniathrombocytopenia Affect maturation and differentiation of Affect maturation and differentiation of

megakaryocytesmegakaryocytes Leads to deposition of immune complexes on Leads to deposition of immune complexes on

platelets and thus accelerated clearanceplatelets and thus accelerated clearance Endothelial cells infectedEndothelial cells infected

Leads to increased release of VWf, which has been Leads to increased release of VWf, which has been observed clinically in several patients with HIV-observed clinically in several patients with HIV-Associated Thrombotic MicroangiopathyAssociated Thrombotic Microangiopathy

This may overwhelm available ADAMTS13 This may overwhelm available ADAMTS13 increased ULVWf increased ULVWf increased platelet clumping and increased platelet clumping and aggregationaggregation

HIV-Associated Thrombotic HIV-Associated Thrombotic MicroangiopathyMicroangiopathy

SummarySummary Similar to TTP clinically, but has (more) Similar to TTP clinically, but has (more)

normal ADAMTS13 levelsnormal ADAMTS13 levels Associated with lower CD4 counts and Associated with lower CD4 counts and

higher viral loadshigher viral loads Responds to HAART better than plasma Responds to HAART better than plasma

exchangeexchange UNC Laboratory Medicine has UNC Laboratory Medicine has

contributed significantly to the contributed significantly to the research in this fieldresearch in this field

REFERENCESREFERENCES- Becker, S, et al. HIV-Associated Thrombotic Microangiopathy in Becker, S, et al. HIV-Associated Thrombotic Microangiopathy in

the Era of Highly Active Antiretroviral Therapy: An Observational the Era of Highly Active Antiretroviral Therapy: An Observational Study. Clinical Infectious Diseases. 39: S267-275. 2004.Study. Clinical Infectious Diseases. 39: S267-275. 2004.

- Brecher, ME et al. Is it HIV TTP or HIV-Associated Thombotic Brecher, ME et al. Is it HIV TTP or HIV-Associated Thombotic Microangiopathy. Journal of Clinical Apheresis. 23:186-190. 2008.Microangiopathy. Journal of Clinical Apheresis. 23:186-190. 2008.

- Egan, JA et al. Frequency and Significance of Schistocytes in Egan, JA et al. Frequency and Significance of Schistocytes in TTP/HUS Patients at the Discontinuation of Plasma Exchange TTP/HUS Patients at the Discontinuation of Plasma Exchange Therapy. Journal of Clinical Apheresis. 19: 165-167. 2004.Therapy. Journal of Clinical Apheresis. 19: 165-167. 2004.

- Gervasoni, C et al. Thrombotic Microangiopathy in Patients with Gervasoni, C et al. Thrombotic Microangiopathy in Patients with Acquired Immunodeficiency Syndromes Before and During the Acquired Immunodeficiency Syndromes Before and During the Era of Introudction of Highly Active Antiretroviral Therapy. Era of Introudction of Highly Active Antiretroviral Therapy. Clinical Infectious Diseases. 35:1534-1540. 2002.Clinical Infectious Diseases. 35:1534-1540. 2002.

- George, JN. Causes of Thrombotic thrombocytopenic purpura-George, JN. Causes of Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults. UpToDate. 2010.hemolytic uremic syndrome in adults. UpToDate. 2010.

- Park, YA et al. ADAMTS13 Activity Levels in Patients with Human Park, YA et al. ADAMTS13 Activity Levels in Patients with Human Immunodeficiency Virus-Associated Thrombotic Microangiopathy Immunodeficiency Virus-Associated Thrombotic Microangiopathy and Profound CD4 Deficiency. Journal of Clinical Apheresis. and Profound CD4 Deficiency. Journal of Clinical Apheresis. 24:32-36. 2009.24:32-36. 2009.

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