Haematological Manifestations of HIV

Dr Senani WilliamsFRCPath, MD

Consultant HaematologistFaculty of Medicine

University of Kelaniya

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

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.

Causes of Thrombocytopenia

Primary HIV relatedPHAT

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

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

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

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.

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

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

Therapy related Thrombocytopenia

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

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

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.

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 microparticlesFrom apoptotic CD4 cells

Thrombosis

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.

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.

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

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.

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

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)

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.

Aetiology of Anaemia

• Multifactorial,• Infection, • Malignancy, • Malnutrition • Polypharmacy• Careful evaluation for treatable underlying

illnesses,

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.

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

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.

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.

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

Granulomata in the bone marrow

Leishmania in the Trephine biopsy

Giant pronormoblasts in Parvo B19

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

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

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.

Transfusion associated GVHD

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.

Conclusion

• Haematological complications / manifestations are numerous

• NO pathognomonic feature• High degree of suspicion necessary• Multi disciplinary team approach

Thank you

Jaffna December 2013