Haematological manifestations of HIV by Dr Senani Williams (FRCPath, MD), Consultant Haematologist, Faculty of Medicine, University of Kelaniya, Sri Lanka
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
3.
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
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.
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
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.
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