Guest Lecture: April 2014: Haematological manifestations of hiv
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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
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