Hematological manifestations of hiv
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1. HIV can cause a variety of hematological manifestations including anemia, leukopenia, thrombocytopenia, and coagulation disorders due to bone marrow infiltration and effects on hematopoietic progenitor cells. 2. The bone marrow in HIV/AIDS commonly shows hypercellularity, dysplasia of the erythroid and myeloid lineages, plasmacytosis, and lymphoid aggregates. Opportunistic infections also frequently involve the bone marrow. 3. HIV is associated with increased risk of aggressive B-cell lymphomas such as diffuse large B-cell lymphoma. Lymphomas in HIV often involve extranodal sites and the bone marrow.
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Hematological manifestations of hiv
- 1. HEMATOLOGICAL MANIFESTATIONS OF HIV-AIDS Maj Shilpi Singh Guide: Col Sonia Badwal
- 2. • A 48-year-old woman • Presentation – severe epistaxis. – hematologic profile • marked thrombocytopenia (3 x 109/L) • hemoglobin 11.6 g/dL, • leukocyte count 5.2 x 109/L • unremarkable blood film except for rare platelets. – tested positive for HIV • CD4 count was low (20/mm3). – tentative diagnosis HIV–immune thrombocytopenic purpura (ITP) – treated with • antiretroviral medications, • IVIG,
- 3. – No improvement. – After 6 weeks bone marrow examination done. • The aspirate was dry. – core biopsy • hypercellular marrow with heavy infiltrate of Mycobacterium avium intracellulare infection – started on 4-drug antituberculosis treatment, – 2 weeks later her platelet count was 30 x 109/L. – platelet count steadily rose to 150 x 109/L by day 20 and was maintained thereafter
- 4. CASE 2 AFMC NOV 2008 26 yr old lady presented with Fever , Low backache and significant weight loss with past history of cervical Lymphadenitis & exposure to ATT( 2006) . Spleen palpable 03cm below LCM ,firm, non tender • Hb - 10.3gm/dl • TLC - 7600 / cumm • DLC - P 68L24 M03 E 05 • Platelets - 2.3 x 106 / μL • PBS - Microcytic hypochromic picture • ESR (wg) - 18mm fall in 1st hr
- 5. • Spinal Abnormality, kyphosis and gibbus abnormalities present • Put on ATT again at Kolhapur • Presented to us in Nov 2008 with severe pancytopenia requiring multiple transfusions • BM asp BM biopsy suggestive of anaemia of critically ill and showed florid gelatinous degeneration • Thus tested for HIV and found to be positive
- 7. What is AIDS • an HIV infection • any of the disorders in clinical category B or C of HIV infection. – Serious opportunistic infections – cancers, such as Kaposi's sarcoma and non-Hodgkin lymphoma, to which defective cell-mediated immunity predisposes – Neurologic dysfunction • or a CD4+ T lymphocyte count of < 200/μL. CDC disease staging system (most recently revised in 1993)
- 8. Contents • Hematological Manifestations. • BM Manifestations. • HIV associated lymphomas.
- 9. Hematological Manifestations • Cytopenias – Anaemia – Neutropenia – Thrombocytopenia • Thrombotic thrombocytopenic purpura. • Coagulopathies and coagulation disorders
- 10. Anaemia • Most common. • Throughout the course of illness. • ART can cause improvement in Hb levels. • Increased risk of disease progression. • Shorter survival. • Decreased quality of life.
- 11. Etiopathogenesis • HIV induced effect on bone marrow. – Ineffective erythropoesis. – Infection of progenitor cells. – Negative effect on EPO. • Nutritional deficiency. – Fe, B12, Folate. • Infiltration of BM- infections or tumors. • Medications.
- 12. Etiopathogenesis (contd) • Hemolytic anaemia. – Intrinsic red cell defect – Extrinsic red cell defect DCT positive • Both warm and cold AIHA. • Increased risk of thromboembolism. • Thrombocytopenia and fragmented cells in PBS. • Bleeding. – GI bleeding due to CMV, NHLs and kaposi.
- 13. Lab investigations • PBS- – Macrocytosis due to AZT. – Normocytic due to HIV infection. – Schistocytes . • Fe indices- – Low serum Fe and transferrin and high serum ferritin. – BM Fe increased
- 14. Lab investigations (contd) • Positive DAT- – 20-43% of hospitalised patients of AIDS. – Cold agglutinins in 22%. • B12 levels low. • Folate levels are normal. • EPO levels are- – Low due to post-translational events. – High in patients with zidovudine associated anaemia.
- 15. Leukopenia • Lymphopenia and neutropenia commonly. • Impaired granulopoesis. • Neutropenia due to drugs- – Pentamidine, gancyclovir, zidovudine. • Autoimmune distruction. • PBS – – hypopigmentation, shift to left, pseudo-pelger huet and other dysplastic changes. • Neutrophil function abnormalities.
- 16. Thrombocytopenia • <100,000/mm3. • 3-8% of HIV positive and 30-45% of AIDS. • Neither a prognostic indicator nor a sign for progression. • Any stage of disease. • Rarely significant bleeding problem. • Responds to ART.
- 17. Etiopathogenesis • Platelet destruction in early course. • Reduced production in later course. • Causes- – Chronic ITP-megakaryocytic . • Elevated platelet associated antibodies. GpIIIa • Cross reactivity between anti-HIV and platelet antigens. – Impaired thrombopoesis- • Depressed marrow platelet production. • Low MPV and dyspoetic – Drug induced
- 18. TTP • Pentad of fever, neurological deficit, thrombocytopenia, oliguria and microangiopathy. • PBS-schistocytes, reticulocytosis. • Indirect hyperbilirubinaemia, raised LDH. • Precipitated by-infection, drugs, pregnancy etc. • More in era before HAART.
- 19. Etiopathogenesis • Absence of vWF cleaving protease activity. • In HIV the cause is IgG autoantibody against the enzyme. • Common coexistence of AIDS defining illnesses. • CD4+<250/mm3. • TTP should always be in the list.
- 20. Coagulation Disorders • HIV is a prothrombotic condition. • Low CD4+ count and protease inhibitors are the culprits. • Coexistent-APLA, LA, Protein C and S deficiency, malignancies, autoimmune disorders. • Endothelial damage due to tumor cells.
- 21. Other coagulation protein abnormalities • Heparin cofactor II deficiency. • AT deficiency is reported in HIV patients- – Malnutrition – Protein loosing nephropathy. • Prevalance – LA=53-70% – anti-cardiolipin antibodies=46-90%. • Infections like Hep C, syphilis, PCP cause production of antibodies.
- 22. Role of protease inhibitors • Abnormalities of glucose metabolism and serum lipids. • Disturbances of fibrinolysis.
- 24. Bone Marrow • Cytological features – M/E ratio 2-5:1 – Hypercellular, – normocellular or hypocellular – Erythroid dysplasia – Erythroid hypoplasia • MAC infection,
- 25. Bone Marrow • Myeloid dysplasia – Left-shifted, – hyposegmented, – maturation arrest at metamyelocyte stage • Megakaryocytes – Adequate to increased – Dysplastic – hyposegmented, – Micro megakaryocytes denuded nuclei.
- 26. Bone Marrow • Plasmacytosis • Lymphoid aggregates/infiltrates • Histiocytes • “Loose granulomas” (aggregates of plasma cells, lymphocytes, histiocytes) • Erythrophagocytosis
- 27. Bone Marrow • Increased eosinophils • Iron adequate to increased (reticulo- endothelial cell distribution) • Marrow Increased reticulin • Matrix Necrosis • Serous atrophy
- 28. Etiopathogenesis • Infection of MSCs with HIV- – Abrogates growth – Hematopoetic supportive function. • Defective progenitor growth- – Secondary to suppressor T-cell. – Inversely proportional to T4 to T8 ratio. • CD34 progenitor cell – infected with HIV.
- 29. Etiopathogenesis • HIV infection of Monocyte/Macrophage- – Exaggerated TNF, IL-1 and TGF-b – Development of immunodeficiency. – HIV-1 dementia. • HIV infection of microvascular endothelial cells- – Poor response to IL-1a. – Impaired release of IL-6 and G-CSF
- 30. Dyserythropoesis • Most common, includes- – Changes in erythroblasts – • Lobulations • Binucleation and fragmentation- • Basophilic stippling in later stages. • Florid megaloblastic changes • Unrelated to B12, folate and drugs. – Erythroid hypoplasia- • In AIDS, ARC, Ziduvudine and MAC infection. • PRCA secondary to parvovirus B19.
- 31. Dyserythropoesis
- 32. Dysmegakaryopoesis • Can be with or without thrombocytopenia. • Dysplastic changes- – Micromegs with denuded nuclei – Hyposegmented megs – Fragmented nuclei – Clustering of megs. • Dysplastic changes and presence of HIV RNA in megs
- 34. Cellularity • BM is difficult to aspirate. – Focal or diffuse increase in reticulin • Normo to hypercellular. – Myeloid dysplasia – Ineffective erythropoesis • M:E ratio of 2-7:1 – Myeloid hyperplasis – Erythroid hypoplasia.
- 35. Plasma cell abnormalities • Increase seen in 31-85% people. • Due to- – Physiological response to antigenic stimulation. – Dysregulated B-cell proliferation. – Seen in all stages. • Morphology – Dysplasia, large bi or tri nucleate – In clusters
- 36. Plasma cell abnormalities • Russel bodies, multiple globules. • Myeloma is clearly reported in AIDS. • Monoclonal spikes on serum electrophoresis. • Marrow plasmacytosis • Atypical forms. • Without demonstration of clonality. • Paraproteinemia activity against HIV gag & pol Vigrous immune response to HIV.
- 37. Lymphoid aggregates • 10-50% of patients of AIDS-ARC. • Small, round, well circumscribed- small lymphocytes. • Large poorly defined mixed with histiocytes. • Atypical, cleaved lymphocytes-paratrabecular
- 39. Lymphoma • 80% peripheral, 20% arise in CNS. • Aggressive B-cell lymphoma. • PCNSL • Primary effusion Lymphoma. • Plasmblastic multicentric Castleman disease. • Hodgkin Lymphoma.
- 40. Why HIV- Associated • Sharp decline post HAART • Similar geographic distribution • Same risk group individuals • Not responding to chemo as other lymphomas • More extranodal spread , BM commonest
- 41. HIV –associated lymphomas • Co-infection with HIV and KSHV/HHV-8 • Liquid phase • No masses or adenopathy • Fever, night sweats, weight loss and hepatosplenomegaly.
- 42. Aggressive B-cell lymphomas • DLBCL • B-cell immunoblastic lymphomas • Small non-cleaved lymphoma – Burkitt – Burkitt-like.
- 43. Plasmablastic lymphoma • Cells resemble B-immunoblasts • Immunphenotypically plasma cells • Highest incidence in HIV-patients • Mass in oral cavity, extranodal sites • Diffuse and cohesive proliferation • EBV associated • CD 38,138 positive-CD 45,20 negative.
- 45. PCNSL • CD4< 50. • Also large cell lymphomas • EBV associated • Lack c-myc translocation • Responds well to HAART.
- 46. HIV associated HD • HD not a part of CDC definition • More aggressive, extranodal, BM involvment • Less mediastinal adenopathy • Mixed cellularity or LDHL • CD4< 300/dl
- 47. Lymphoma
- 48. ROLE OF FLCs • Circulating Serum Free Light Chains As Predictive Markers of AIDS-Related Lymphoma • The κ and λ FLCs were both significantly higher in patients and strongly predicted NHL in a dose-response manner up to 2 to 5 years before diagnosis/selection • © 2010 by American Society of Clinical Oncology
- 49. Miscellaneous • Increased histiocytes- – Showing hemophagocytosis. – Non-caseating granulomas. – Loose granulomas. – Triggered by HIV itself. • Increased number of histiocytes→hemophagocytic syndrome→severe pancytopenia.
- 51. Miscellaneous • Pseudogaucher cells-MAC infection. • Marrow eosinophilia is common: 9-61% of AIDS patient. • BM iron stores↑. • Sideroblasts have been described. • Granulomas are also infrequent.
- 53. BM matrix • Increased reticulin or fibrosis. – Focal – diffuse • “Gelatinous Transformation”. • Make aspiration difficult.
- 55. Oppurtunistic infections • Infection • Mycobacterium avium complex • Mycobacterium tuberculosis • Mycobacterium xenopi and kansasi • Histoplasma • Cryptococcus • Toxoplasma • Cytomegalovirus • Leishmania • Pneumocystis carinii • Disseminated cat scratch • Parvovirus B 19
- 56. MAC
- 57. Oppurtunistic infections • Histology or culture is useful. • Undiagnosed fever or constitutional symptoms. • Low CD4+ count. • BM cultures as sensitive as blood. • BM better due special histological staining.
- 60. HAART and BM changes • HAART and immune reconstitution – increased whole blood count. • Increase in LTC-IC. • HAART- – Controlled HIV replication. – Restored stem cell activity.
Editor's Notes
- A 48-year-old woman presented with severe epistaxis. Her hematologic profile showed marked thrombocytopenia (3 x 109/L), hemoglobin 11.6 g/dL, leukocyte count 5.2 x 109/L, and an unremarkable blood film except for rare platelets. She tested positive for HIV and the CD4 count was low (20/mm3). A tentative diagnosis of HIV–immune thrombocytopenic purpura (ITP) was made. She was treated with antiretroviral medications, IVIG, and subsequently with steroids for 4 weeks without improvement. Rituximab was deemed unsafe because of her immunosuppressed status. After 6 weeks of platelet unresponsiveness, a bone marrow examination was performed. The aspirate was dry. The core biopsy showed a hypercellular marrow with a heavy infiltrate of Mycobacterium avium intracellulare infection (ZN stain in figure). She was started on 4-drug antituberculosis treatment, and 2 weeks later her platelet count was 30 x 109/L. The platelet count steadily rose to 150 x 109/L by day 20 and was maintained thereafter
- So the first lesson learnt is there is more to HIV than eye can see.
- Retroviruses are enveloped RNA viruses defined by their mechanism of replication via reverse transcription to produce DNA copies that integrate in the host cell genome.
- CDC A#, B3, C1, C2 and C3 are AIDs classifies AIDS as an HIV infection with CD4 cell count of less than 200 and those with certain HIV related conditions and symptoms. WHO classification is used in resource strained settings and defines AIDS categories on the basis of clinical manifestations. CDC (Central of disease control) CD4 normal 400-1500.
- Philia- affinity
- BM supression through abnormal cytokine production and alteration in BM microenvironment. Can be both reduced intake or absorption. Infections like MAC, PCP, histoplasma, parvovirus. Kaposi sarcoma and NHLs. Zidovudine, septran, ganciclovir, amphotericin B.
- Mechanisms proposed for AIHA include antierythrocyte antibodies, non-specific coating of red cells by Ig, presence of immune complexes and abnormal B cell regulation.
- Direct hiv effect, oppurtunistic inf and neoplasia megalocytes, increased granulation and peroxidase activity phacocytic and intracellular killing of microbes is affected
- HIV INFECTION SHOULD BE SUSPECTED IN PATIENTS PRESENTING WITH UNEXPLAINED THROMBOCYTOPENIA.
- Megakaryocytes bear CD4 receptor. Platelet destruction due to antibodies, infections, sple3nomegaly and fever. Production reduces due to reduced CD34 and megakaryoctic diffrentiation.
- In patients with asymptomatic HIV infection response to therapy is similar to that seen in HIV negative persons, however in those with advanced HIV disease outcome is often dismal.
- Inability to cleave high molecular wt vWF synthesized by endothelial cells. Like pcp, kaposi, cryptococcus and CMV. Of treating physicians as plasmapheresis provides substantial symptomatic relief .
- Ad fuel to the fire.
- Is more prevalent in hiv. It is a specific thrombin inhibitor whose inhibitory activity is enhanced by heparin and deficiency causes recurrent thrombosis.
- One should be alert about the possibility of unprovoked thrombosis in patients of HIV infection and possibility of increased lipid levels in patients on protease inhibitors.
- Hiv infection of stromal cells produces inhibitory factors which suppresses clonogenic potential of MSC. There is now ample evidence that CD34 progenitor cells can be infected by HIV
- However these may accentuate it.
- Dyserythropoiesis with megaloblastic changes and nuclear bridging in MDS associated with previous high BZ exposure. Bone marrow aspirate with Wright–Giemsa stain (original magnification 1000×). Reproduced with permission [11].
- Ultrastructural changes are marked balloning and blebbing of peripheral zone…….as seen in myeloproliferative neoplasms……..along with clinical response to patients with Zidovudine are all consistent with the view meg itself is the target for Hiv infection.
- True marrow cellularity is appreciated on trephine biopsy…….even in the setting of peripheral cytopenias in a majority of patients…therefore hypercellularity of the marrow in the face on cytopenias is common in HIV
- By viruses and other antigenic stimulation or may be secondary to.
- In paratrabecular localization it is important to r/o NHL, since lymphoma in AIDS patients is commoner than benign lymphoid aggregates.
- AIDS was first described in 1981 and in 1985 CDC included HIV patients with aggressive B-cell NHL, also as AIDS. Currently The list is not exhaustive and includes
- PEL and PMCD…..spreading along serous membranes.
- Aggressive B-cell lymphomas include………DLBCL is centroblastic /immunoblastic…….Burkitt is classical/BL with plasmacytoid diffrentiation and atypical BL
- Like mucosal membranes, including sinonasal cavity, bone marrow and skin. Plasmablastic lymphomas not associated with HIV are common in lymphnodes. High proliferation index Ki-67 &gt;90%
- Plasmablastic Lymphoma: This aggressive variant of diffuse large B-cell lymphoma usually occurs in the oral cavity of HIV positive patients, monomorphic population of large immunoblastic population with prominent nucleoli….. Starry sky pattern.
- Becoz of no clear demonstration of its increased incidence in conjunction.
- Hodgkin lymphoma infiltration of the bone marrow. A Reed-Sternberg cell is highlighted by the black arrow. Malignant bone marrow infiltrations often present with cytopenias.
- HIV-infected persons have an elevated risk of developing non-Hodgkin&apos;s lymphoma (NHL); this risk remains increased in the era of effective HIV therapy. We evaluated serum immunoglobulin (Ig) proteins as predictors of NHL risk among HIV-infected individuals. DUE TO DYSREGULATED B-CELL FUNCTION
- Aggregates of histiocytes, plasma cells and lymphocytes……...no obvious second infection, HIV itself triggered histiocyte proliferation and phagocytosis.
- Hematophagocytosis accompanying MDS-Eo associated with previous high BZ exposure. Activated histiocytic cells exhibit prominent phagocytosis of degenerating erythroid granulocytic cells typical of an immune-mediated inflammatory process. Bone marrow aspirate with Wright–Giemsa stain (original magnification 1000×). Reproduced with permission [11].
- In …which foamy histiocytes were described on Giemsa stain….. Although peripheral blood eosiniphiliais rarely seen….…indicating a defect in Fe utilization…….but are uncommon.
- Also called serous atrophy.
- Bone marrow biopsies from post-transplant, immunocompromised patients are evaluated for the presence of primary marrow defects (eg. drug induced cytopenias), infiltrative processes (eg. metastatic carcinoma and epstein-barr virus-related post-transplant lymphoproliferative disorder), and opportunistic infections (eg. fungal, viral, mycobacterial). Although the bone marrow biopsy from this patient is insufficient to assess hematopoiesis, numerous loose collections of foamy macrophages were identified. Special stains for acid fast bacilli [inset] revealed the presence of abundant mycobacteria. Given the clinical history and the number of mycobacteria seen, this finding supports the diagnosis of infection with mycobacterium avium complex (MAC).
- cryptococcus
- Long term culture initiating cells…………in experiments .Probably by supressing cytokines which inhibit normal hematopoesis