Haematological Complications of HIV

Dr Jessica Opie
Haematopathologist
Division of Haematology, UCT and GSH NHLS
April 2013
• Haematological manifestations of HIV are common
• Occur at all stages of infection
• Often first clinical manifestation of HIV
• Commonest abnormalities are cytopenias esp
anaemia of chronic disease
Basic approach to cytopenias

• Blood cell production problem (ie bone marrow)

OR

• Increased peripheral destruction/loss of blood cells

 HIV and Haemopoeitic cells
• HIV infects CD4+ cells: cytotoxic
• Evidence of infection and dysfunction of T cells,
monocytes, endothelial cells
• which indirectly influences survival & growth of
haemopoeitic progenitors/stem cells
• Progenitor populations in BM themselves generally
intact (some controversy)
• CD34 +ve stem cells are mainly indirectly effected by
HIV
Commonest morphological changes in the
peripheral blood and BM is HIV related dysplasia

• Dysplastic changes in haemopoeitic precursors

• Not pre-leukaemic or clonal as in MDS
• Associated with more advanced disease
• Typically iron stores increased in the marrow, but iron in
sideroblasts reduced in keeping with iron malutilisation
• Cytokine related
• Improve with HAART
Normal Bone Marrow Normal Bone Marrow
Aspirate (BMA) Trephine (BMT)
Bone Marrow (BM): HIV Dysplasia
 Opportunistic Infections eg MTB, MAC and
histoplasmosis
• Cause anaemia/cytopenias by BM infiltration and granuloma
formation
• BMA cultures recommended for culture and sensitivities
• BM Trephine Biopsy (with special stains) provides morphological
evidence of infection
• Diagnosis can be made less invasively by blood culture /serology.
• BM more likely to be useful in patients with low CD4 counts.
 MTB in the Bone Marrow

Granuloma with multinucleate giant cell High power magnification: ZN stain +ve
 Common HIV associated malignancies

• Non Hodgkin Lymphoma (aggressive)

• Burkitts
• Diffuse Large B cell Lymphoma (↑rate dissemination)
• Plasmablastic lymphoma
• Lymphoma arising out of HHV8 associated Castlemans Disease
• Hodgkin Lymphoma
• Myeloma
• Kaposi’s Sarcoma
 Burkitt lymphoma/leukaemia

• Most aggressive tumour known

• “Lymphoma” in nodes/mass only
• “Leukaemia” Disseminated in blood and BM
• Characterised by translocations of c-MYC gene on
Chromosome 8 leading to uncontrolled cell proliferation
• Cytogenetics/FISH typically t(8;14) +ve
Why so much lymphoma in HIV??
• Postulated mechanisms:
• Chronic antigen stimulation
• Cytokine dysregulation
• EBV and HHV8 co-infection
• EBV identified in up to 40% of HIV-related lymphoma
• No reduction in HIV related lymphomas since ART
 Hodgkin Lymphoma in the bone marrow

BM Infiltrations often present with cytopenias/pancytopenia

Blood smear: “Leucoerythroblastic”
NB: retic count/RPI less helpful in anaemia of HIV
Anaemia in HIV
 Found in 63% - 95% (depending on study), ↑ incidence with
advancing stage1
 Anaemia of chronic disease commonest
 Normochromic normocytic, ↓ reticulocyte count
 Macrophages/monocytes infected by HIV→ cytokine dysregulation
• Erythropoietin Levels often low with a blunted response to low Hb.
• Levels of cytokines correlate with the viral load and the severity of the
cytopenias.
• HAART beneficial to BM function
 Drug induced
 Haematinic deficiencies
 Opportunistic infection
 Pure Red Cell Aplasia (parvovirus B19)
Drug Induced Cytopenias in HIV
 ARV Drugs:
 AZT notorious:
 Severe anaemia. Macrocytic. Not prevented by B12/folate
 Bactrim : megaloblastic anaemia, leucopenia and ↓
platelets
 Anti TB Drugs: INH, Rifabutin (RIF): anaemia,
neutropenia, thrombocytopenia. Aplastic anaemia RARE
The effect of Drugs in HIV
Management of anaemia in HIV
• Treat the underlying cause - HAART most NB
• Blood transfusion not advised 2.
• Iron overload (HIV progression, impaired macrophage
function)
• Transfusion-associated immunosuppression (cytokines)
• Transfusion-associated infections (eg CMV, Hepatitis B/C)
 Parvovirus B19
• Small single stranded DNA virus
• Can cause severe chronic anaemia in AIDS patients
• Usually acquired via respiratory tract
• Invades erythroid progenitor cells, replicates and
lyses infected cell.
• Causes Pure Red Cell Aplasia: low retic count
• Characteristic Bone Marrow features (see next slide)
• Diagnostic test of choice: Parvovirus B19 PCR (not
serology or BMB!)
• Rx: HAART+/- intravenous immunoglobulin
 Bone Marrow Aspirate: Parvovirus

Block in erythroid maturation, giant pronormoblasts, no maturing

forms, pronormoblasts have cytoplasmic vacuoles and immature
chromatin
Thrombocytopenia in HIV
• Commonest cause is Immune Thrombocytopenic Purpura (ITP)
• Typically starts early in course; can be first manifestation.
Bleeding rare
• Commonly associated with ↑ levels of platelet associated IgG,
IgM and circulating immune complexes
• Mechasnism though to be molecular mimicry:
- Antibody induced by HIV Gp120.
- Cross-reacts with platelet surface glycoprotein (GPIIb/IIIa).
- BUT Antibodies found even in patients who are not
thrombocytopenic
ITP management
• Treatment recommended <301 or bleeding
• ARV’s effective
• Steroids give short term response in 60 – 80%
• ARVs and steroids ↑ platelet production (not
survival)
• Splenectomy in those not responding to ARVs
• Does not appear to accelerate HIV disease.
 HIV Associated TTP
• HIV commonest cause of TTP at GSH
• Clinical Presentation of TTP
• Typical smear features
• Normal coagulation screen
• Intravascular haemolysis due to red cell
shearing
• Marked elevation of LDH
• Ultra large Von Willebrand factor multimers
cause platelet microthrombi
• Typically in young HIV naïve patients
 TTP in HIV

• Treatment
• Emergency: potentially lethal
• Refer to haematologist
• Avoid platelet transfusions
• Commence FFP infusion + steroids
• Plasmapharesis if non responsive
• Monitor LDH, platelet count, smear
• Commence ARVs
 Leucopenia in HIV
• CD4 lymphopenia is hallmark of HIV infection
• Inverted CD4/CD8 ratio
• Neutropenia: common
• Severe <0,5 x 109 associated with ↑ risk serious bacterial
infection
• Due to HIV itself or ARVs
• Monocytopenia: Mono/macrophages infected via CD4
receptors. Cellular dysfunction and abnormal forms seen.
• Isolated leucopenia most likely due to advanced HIV or ARV
therapy. BMB not useful
 PANCYTOPENIA IN HIV
PRODUCTION DEFECT ↑ PERIPHERAL DESTRUCTION
• B12/Folate deficiency • Hypersplenism
• Advanced HIV/AIDS • Immune
• Other viral infection
• Parvovirus B19
• Hep B, EBV, CMV
• Infiltration
• Lymphoma
• Opportunistic infection
• Non-haemopoeitic
• Drug toxicity
• Severe sepsis
• Aplastic anaemia
Thrombosis and HIV
• HIV is prothrombotic with 2-10 fold ↑ incidence of VTE
• Highest risk with advanced disease and coexisting
infections and malignancies.
• ↑ prothrombotic proteins VWF
• ↓natural anticoagulants protein S and protein C
• ↑ Lupus anticoagulant and antiphospholipid antibodies
• VTE risk improved, but not reversed by HAART
• Have high index suspicion and consider prophylactic
anticoagulants
 When/How to perform a BM in an HIV patient??

• Unexplained progressive cytopenias +/- constitutional

symptoms
• Commonest BM diagnoses at GSH: TB and ITP, BUT bone
marrow often not nec for ITP
• BM can give quick morphological diagnosis of TB (but do
cultures – peripheral blood and BM for subtype and
sensitivities)
• A good sample is VITAL
• Recommend bilateral PSIS biopsies of 20mm each
 Summary
• SA has >5,6 million people infected by HIV
• Haematological complications are common and occur at all
stages of infection
• Commonest causes of cytopenias: ACD, ITP, opportunistic
infections and drug side effects
• Common emergencies: Burkitts and TTP.
• BMB has high diagnostic utility in HIV patients with unexplained
cytopenias (cultures NB)
• HIV prothrombotic state
• HAART crucial adjunct to therapy of haematological
complications
 References:
1. Opie, J. Haematological complications of HIV infection SAMJ 2012;
102 (6)
2. Baker K, The Hematologic Complications of HIV infection. ASH
Education Book 2003 p 299
3. Sloand E, Hematologic Complications of HIV Infection. AIDS Reviews
2005;7: 187-96
4. Moses A et al, The Influence of HIV-1 on Hematopoeisis. Blood 1998
(91): 1479-1495
5. Postgraduate Haematology, 5th Edition, Hoffbrand et al 2005 p380-
394