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 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

6. 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 …
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-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

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: S
Brecher, ME et al. Is it HIV TTP or HIV-Associated Thombotic Microangiopathy. Journal of Clinical Apheresis. 23:
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:
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:
George, JN. Causes of Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome in adults. UpToDate
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:

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