Haematological manifestations of HIV by Dr Senani Williams (FRCPath, MD), Consultant Haematologist, Faculty of Medicine, University of Kelaniya, Sri Lanka

1. Haematological Manifestations
of HIV
Dr Senani Williams
FRCPath, MD
Consultant Haematologist
Faculty of Medicine
University of Kelaniya

2. HIV
• First recognized more than 30 years ago,
• Within 2 decades, more than 50 million people
infected
• 20 million have died.
• Worldwide, two -thirds of the 36 million known
carriers of HIV live in sub- Saharan Africa.
• Hematologic Manifestations of HIV Infection
increasingly recognized

4. Thrombocytopenia
• Thrombocytopenia was first associated with AIDS before the
discovery of the HIV.
• Prior to the use of HAART, HIV-associated thrombocytopenia
identified in approximately 5% to 30% of patients infected with HIV-
1.
• The incidence and severity is associated with the stage of disease
• 1.7% among patients with HIV infection, but not clinical or
immunologic AIDS,
• 3.1% among persons with immunologic AIDS (CD4 lymphocytes <
200/µL)
• 8.7% in patients with clinical AIDS.
• Severe thrombocytopenia (platelet count 50x109 /L) associated with
• - clinical AIDS.
• - CD4 lymphocyte count of < 200/µL.
• - age > 45 years.
• - Intravenous drug use.
• - Lymphoma and/or anemia.

5. Causes of Thrombocytopenia
Primary HIV related
PHAT
Secondary Thrombocytopenia
• Major cause of thrombocytopenia
• Similar to ITP
• Except Splenomegaly
• Platelet counts higher in HIV
• Mild thrombocytopenia resolves
without therapy.
• Underlying opportunistic infections
• Malignancy,
• Co-morbid conditions resulting in
hypersplenism

6. Aetiology of Thrombocytopenia
• Marrow - normal or numbers of megakaryocytes
• 50 %  platelet survival
• 50 %  in platelet production.
•  recovery of infused platelets
•  marrow megakaryocyte progenitors
•  endogenous TPO
•  TPO receptor number

7. Aetiology of Thrombocytopenia
• Doubling of splenic platelet sequestration,
• Ineffective delivery of viable platelets
• Reduced platelet survival due to antiplatelet antibodies
• Platelet-associated IgG cross reacts with the platelet
glycoprotein complex (GP)IIb/IIIa and the HIV envelope
glycoproteins GP160/12015.
• IgM antii diotype antibodies against platelet anti-
GPIIIa
• Molecular mimicry between HIV proteins and platelet
GPIIb/IIIa

8. Pathogenesis of thrombocytopenia
• Macrophages in the RES major mediators of
platelet destruction
• HIV transcripts directly infect megakaryocytes
•  in platelet production.
•  apoptosis of megakaryocytes
• A spontaneous remission rate of almost 20 %
in patients with PHAT.

9. Treatment of Thrombocytopenia
• Zidovudine (AZT) mainstay of therapy of PHAT
• HAART improves PHAT
• Reduces complications of HIV infection
• Opportunistic infections and Kaposi's sarcoma.
• IVIG
• WinRho
• Prednisolone
• Interferon alfa
• Vincristine
• Splenectomy
• Splenic irradiation
• Thrombopoietic growth factors

10. Infections causing Thrombocytopenia
• Bacterial - Bartonellosis, Bacteremia/sepsis,
Ehrlichiosis
• Parasitic - Toxoplasma, Babesia,
• Mycobacterial - Disseminated tuberculosis,
Disseminated mycobacterium avium-complex
• Viral - Cytomegalovirus, HIV, Rubella
• Fungal - Histoplasmosis, Coccidioidomycosis, Other
disseminated fungal infections
• Malignancy - Kaposi's sarcoma, Metastatic
adenocarcinomas, Hodgkin's lymphoma

11. Therapy related Thrombocytopenia
• Trimetrexate Ketoconazole,
• Ganciclovir, Pyrimethamine,
• Trimethoprim-sulfamethoxazole, Foscarnet,
• Flucytosine, Cidofovir,
• Acyclovir, Pentamidine,
• Pyrazinamide, Interferon
• Rifampin Heparin
• Chemotherapeutic agents, Rifabutin,
• Valganciclovir

12. Other causes
• Secondary hypersplenism
• Chronic viral / other causes of
hepatitis/cirrhosis
• Thrombotic thrombocytopenic purpura
• Disseminated intravascular coagulation
• Patients with HIV infection higher frequency
of HIT

13. Platelet Function and HIV
• Platelet aggregation is induced by
• Adrenaline,
• Thrombin receptor-activating peptide (TRAP),
• ADP and
• Collagen.
• Platelet aggregation was decreased in response
to TRAP, ADP and collagen
• Aggregation increased in response to adrenaline.

14. DVT
HIV Specific
Infections
AIHA
EC
Endothelial cell Activation
PAI 1 
t PA 
Anticoagulants
AT
 Protein C
 Protein S
 Heparin Co II
 APLS
EC EC
TM  TF vWF 
microparticles
From apoptotic
CD4 cells
Thrombosis

15. Specific HIV – Related Factors
• Concomitant infections - additional risk for
thrombosis.
• CMV associated with pulmonary embolism
and cerebral venous thrombosis
• HIV infection complicated by autoimmune
hemolytic anemia.
• Increased risk of thromboembolic events,
especially during transfusion of blood.

16. DVT Prophylaxis
• Strongly considered for HIV patients with
thrombotic risk factors (surgery, trauma,
stasis, pregnancy, nephrotic syndrome, CMV
infection, acute hospitalization),
• HIV infected patient at higher risk of HIT than
non infected patient.

17. NEUTROPENIA
• Absolute neutrophil count (ANC) of <
1500/microL.
• ANC = WBC (cells/microL) x percent (PMNs +
bands) ÷ 100
• Neutrophilic metamyelocytes and younger
forms are not included
• Risk of infection starts to rise at an ANC below
1000/microL

18. Risk Management of neutropenia
• >1500 - none
• 1000-1500 - No significant risk of infection, fever
managed on outpatient basis
• 500- 1000 - Some risk of infection, fever can be
occasionally managed on an outpatient
basis
• <500 - Significant risk of infection, fever should always
be managed on a patient basis with IV antibiotic;
few clinical signs of infection.
• <200 - Very Significant risk of infection, fever should
always be managed on a patient basis with IV
antibiotic; few or no clinical signs of infection.

19. Aetiology of neutropenia
• Multifactorial
• Therapies used in the management of HIV,
• Associated opportunistic infections,
• Malignancies lead to clinically significant neutropenia,
• Zidovudine ,
• Trimethoprim-sulfamethoxazole,
• Ganciclovir,
• Hydroxyurea
• Chemotherapy for HIV-related malignancies
• HAART appears to be protective against HIV-associated
neutropenia,
• Opportunistic infection or malignancy that infiltrates the bone
marrow

20. Aetiology of Neutropenia
• Disseminated fungi may infiltrate bone marrow.
• Lymphomas produce pancytopenia through diffuse bone
marrow involvement.
• Cytomegalovirus infection directly infects marrow stromal
elements and myeloid cells.
• Anti neutrophil antibodies detected in 1/3rd
• HIV itself is a mediator of abnormal hematopoiesis in all
cell lines.
• Direct infection of hematopoietic precursors
• Aberrations of local cytokine and growth factor signaling,
• Changes in the bone marrow stroma.
•  (G-CSF)

21. ANEMIA
• The most common hematologic abnormality
affecting 60 to 80 % in late stage disease.
• Risk factors for anemia (Hgb<12g/dl) are
• CD4 count <200/microL
• HIV-1 viral load ≥50,000/mL
• Use of AZT in past six months
• Anemia is independently associated with
decreased survival.

22. Aetiology of Anaemia
• Multifactorial,
• Infection,
• Malignancy,
• Malnutrition
• Polypharmacy
• Careful evaluation for treatable underlying
illnesses,

23. Investigation of Anaemia
• FBC with red cell indices
• Reticulocyte count
• Serum bilirubin
• Vitamin B12,
• Red cell folate levels,
• Iron studies,
• Peripheral blood smear and,
• In refractory or unexplained anemia - serum
erythropoietin and bone marrow sampling.

24. Investigation of Anaemia
• Infections
• Fungi infiltrating bone marrow - Mycobacterium avium
complex, TB, Hisoplasma capsulatum
• Pneumocystis, Cryptococcus and Penicillium - pancytopenia
• Viral infections - suppresses marrow function – CMV, EBV
• Malignancy and lymphoproliferative disorders - Infiltration –
NHL, Burkitt, Kaposi
• Nutritional deficiencies - with advanced immunosuppression,
• Anorexia,
• Medication-associated gastrointestinal disturbances,
• Wasting and
• Malabsorption

25. Investigation of Anaemia
• vitamin B12 deficiency due to malabsorption
• Achlorhydria
• Secondary reduction in intrinsic factor production,
• Alteration in cobalamin transport proteins.
• Folate deficiency due to reductions in dietary intake
and intestinal absorption.
• Abnormal iron metabolism - anemia of chronic disease
•  serum iron
•  total iron binding capacity
• normal or increased ferritin.
• Some have iron deficiency related to gastrointestinal
blood loss.

26. Aetiology of Anaemia
• Hemolysis - Antibody-mediated hemolysis,
• Drug-induced disease in patients with glucose-6-
phosphate dehydrogenase (G6PD) deficiency, Dapsone
and primaquine
• Microangiopathic hemolytic anemia - DIC, TTP, HUS
• Ribavirin therapy for co infection with Hep C is
associated with hemolytic anemia.
• Bone marrow suppression with Zidovudine
Ganciclovir, Valganciclovir, Hydroxyurea, Amphotericin
B, and TMP-SMX.
• HIV-1 subtype C to infect hematopoietic progenitor
cells greater than HIV-1 subtype B.

27. Bone marrow biopsy
• Broad spectrum of biopsy findings
• NO histologic abnormality considered
pathognomonic.
• Normocellular marrow
• Increased plasma cells, histiocytes and marrow
reticular cells
• Megaloblastic changes noted in patients receiving
AZT or with B12 or folic acid deficiencies.
• Giant pronormoblasts in parvovirus B19 disease.
• Advantage of marrow sampling is the rapidity
with which a diagnosis

28. Granulomata in the bone marrow

29. Leishmania in the Trephine biopsy

30. Giant pronormoblasts in Parvo B19

31. Treatment of anemia
• Treatment of the HIV infection
• Correction of all of the reversible causes
• HAART Reduces both the incidence and degree
of anemia
• Risk of anaemia despite HAART seen in
• MCV) <80 fL
• CD4 count <200/microL
• HIV-1 viral load >50,000/mL.
• use of AZT in the past six months .
• CD4 count <100/microL

32. Treatment of Anaemia
• Infectious aetiologies warrant aggressive treatment.
• Uncommon hematologic complications, such as warm AIHA
and TTP respond to standard treatments
• IVIG therapy of choice for patients with PRCA with
parvovirus B19 infection.
• Treatment with vitamin B12, folate, and/or iron in
deficiencies
• When feasible, dose reduction or discontinuation of
implicated medications
• When discontinuation Is not possible, or when secondary
causes are not identified,
• transfusion,
• use of erythropoietic stimulating agents

33. Blood transfusion
• Mainstay for blood loss or severely symptomatic anemia
• Risks of transfusion - reactions,
• Transmissible infection (eg, viral hepatitis, HTLV-I, CMV),
• Development of alloantibodies
• iron overload and its complications with repeated Txs.
• To minimize the risk of CMV transmission –seronegative blood
• When CMV- seronegative blood is not available, WBC filtering
• Viral activation - directly activate HIV replication.
• Factor VIII infusions on HIV progression in hemophiliacs, rapid
 in CD4 counts
•  survival in the patients who had received transfusions.

34. Transfusion associated GVHD

35. Erythropoietin
• Recombinant Human Erythropoietin
• Therapy with rEPO be reserved for patients with serum
erythropoietin <500 IU/L.
• Iron reserves monitored and replenished
• Initial rEPO dose of 100 U/kg subcutaneously three times weekly is
usually
• increases in hematocrit evident after 2/52weeks.
• Dose escalation by 50 U/kg if no response has been noted after 4-
8/52 of therapy;
• further increases are recommended every four to eight weeks until
reaching the targeted hematocrit or the maximal rEPO dose (300
U/kg). Recombinant erythropoietin is generally well tolerated. The
most common side effects encountered are nausea, headache,
hypertension, seizure, and rash or local reactions at the injection
site.

36. Conclusion
• Haematological complications /
manifestations are numerous
• NO pathognomonic feature
• High degree of suspicion necessary
• Multi disciplinary team approach

37. Thank you
Jaffna December 2013