Anemia of Bone Marrow Failure (Chapter 19).pdf

06/09/2023 JAN HENRI G. CARPIZO, RMT ANEMIA OF BONE MARROW FAILURE  06/09/2023 JAN HENRI G. CARPIZO, RMT Pathophysiology BM failure is the reduction or cessation of blood cell production affecting one or more cell lines. Pancytopenia is a common pict...

06/09/2023 JAN HENRI G. CARPIZO, RMT ANEMIA OF BONE MARROW FAILURE  06/09/2023 JAN HENRI G. CARPIZO, RMT Pathophysiology BM failure is the reduction or cessation of blood cell production affecting one or more cell lines. Pancytopenia is a common picture in bone marrow failure. The mechanisms of bone marrow failure are as follows: Destruction of hematopoietic stem cells due to injury by drugs, chemicals, radiation, etc. Premature senescence and apoptosis of HSCs due to mutations Ineffective hematopoiesis due to stem cell mutations or B12/Folate deficiency Disruption of the bone marrow microenvironment Decreased production of hematopoietic growth factors or related hormones Loss of normal hematopoietic tissue due to infiltration of marrow space by abnormal cells  06/09/2023 JAN HENRI G. CARPIZO, RMT Aplastic anemia The earliest case description of aplastic anemia was by Dr. Paul Ehrlich in 1888. He described a young woman who died following an abrupt illness that manifested as severe anemia, bleeding, hyperpyrexia, and a markedly hypocellular bone marrow. Aplastic anemia is the one of the most common syndromes resulting in bone marrow failure through a damage or defective stem cells. It may be acquired or inherited. A greater part of aplastic anemia are acquired (80-85%). The characteristic features of aplastic anemia include pancytopenia, reticulocytopenia, BM hypocellularity, and depletion of HSCs.  06/09/2023 JAN HENRI G. CARPIZO, RMT Acquired Aplastic anemia Most acquired aplastic anemia are idiopathic in origin (70% of acquired) 10-15% are secondary. Both types have similar clinical and laboratory findings. Aplastic anemia occurs at any age, with the highest frequency at 15-25 years of age. Etiology Mostly, the cause is unknown Secondary aplastic anemia is frequently associated with exposure to certain drugs, chemical, radiation, or infectious agents Bone marrow suppression could be of predictable type or of idiosyncratic reaction.  06/09/2023 JAN HENRI G. CARPIZO, RMT Acquired Aplastic anemia Common causes of predictable, dose-dependent BM suppression are radiation, cytotoxic drugs, and benzene. Most drugs that cause aplastic anemia produce the idiosyncratic type. Here’s a list of some of the common drugs assoc. with aplastic anemia: Antiarthritics Penicillamine Antibiotics Chloramphenicol, sulfonamides Anticonvulsants Carbamazepine, hydantoins, Phenacemide Antidepressants Phenothiazine Antidiabetic agents Chlorpropamide, tolbutamide, carbutamide NSAIDS Aspirin, fenbufen, ibuprofen, naproxen, phenylbutazone Antiprotozoals Chloroquine, quinacrine Antithyroidals Methimazole, methylthiouracil  06/09/2023 JAN HENRI G. CARPIZO, RMT Acquired Aplastic anemia It may occasionally caused by complication of infection with certain viruses, such as EBV, HIV, Hepatitis B virus and Parvovirus B19. Some cases of aplastic anemia were found during pregnancy, but further studies are still needed to support the claims.  06/09/2023 JAN HENRI G. CARPIZO, RMT Acquired Aplastic anemia Pathophysiology The qualitative and quantitative deficiency in hematopoietic stem cells is the main mechanism by which acquired aplastic anemia happens. There is decreased CD34 expression in HSCs during aplastic anemia, with subsequent increase in Fas receptors, which facilitates apoptosis. Most of the agents that cause aplastic anemia work by directly damaging the stem cells Decrease in HSCs may also be induced by immune processes, since elevated CD8 lymphocytes are frequently encountered in cases of aplastic anemia  06/09/2023 JAN HENRI G. CARPIZO, RMT Acquired Aplastic anemia Approximately one-third of patients with acquired aplastic anemia have shortened telomeres. This has been associated with shortened lifespan of HSCs as they undergo premature apoptosis. 06/09/2023 JAN HENRI G. CARPIZO, RMT  06/09/2023 JAN HENRI G. CARPIZO, RMT Clinical findings Symptoms vary in acquired aplastic anemia. It may range from very mild to extremely severe anemia. Pallor, fatigue and weakness are common features Pancytopenia contributes to most symptomatology. Bleeding is frequently encountered due to thrombocytopenia. Fever and bacterial infections may follow because of prolonged neutropenia Note: Splenomegaly and hepatomegaly are absent 06/09/2023 JAN HENRI G. CARPIZO, RMT 06/09/2023 JAN HENRI G. CARPIZO, RMT Bone marrow in Aplastic anemia  06/09/2023 JAN HENRI G. CARPIZO, RMT Laboratory findings CBC: Blood smear: Pancytopenia Toxic granulation of neutrophils MCV = increased or normal No blasts Retics = decreased Macrocytic to normocytic RBCs Iron studies: Bone marrow examination: Serum iron = increased Fat cells prominent Transferrin saturation = increased No blasts Severe hypocellularity  06/09/2023 JAN HENRI G. CARPIZO, RMT Treatment and prognosis The offending agent must be identified and removed Blood component transfusion may be done to reach safe blood levels Bone marrow transplantation is the treatment of choice for patients with severe aplastic anemia under 40 years of age. For patients not under this criteria, antithymocyte globulin and cyclosporine could be the treatment of choice. Antibiotics should be administered to alleviate neutropenia  06/09/2023 JAN HENRI G. CARPIZO, RMT Inherited Aplastic anemia Manifestations of inherited aplastic anemia appear during childhood and may have physical malformations Fanconi anemia Manifestations: skeletal abnormalities, skin pigmentations, short stature, and abnormalities in eyes, kidneys and genitals They have increased risk of developing tumors 06/09/2023 JAN HENRI G. CARPIZO, RMT Characteristic Thumb malformation in Fanconi Anemia  06/09/2023 JAN HENRI G. CARPIZO, RMT Inherited Aplastic anemia Genetics and pathophysiology FA is caused by biallelic mutations or deletions in one of 13 genes Mostly autosomal recessive, except for FANCB, which is X-linked recessive Cells are highly susceptible to chromosome breakage, have accelerated telomere shortening and apoptosis, hypersensitivity to oxidants, and cytokine dysregulation  06/09/2023 JAN HENRI G. CARPIZO, RMT Inherited Aplastic anemia Laboratory findings Similar to acquired aplastic anemia Elevated HbF and Alpha-Fetoprotein Addition of DNA-cross linking agent (eg, diepoxybutane, mitomycin C) to cultured lymphocytes causes a characteristic chromosome breakage and is diagnostic for FA. Treatment Supportive treatment includes transfusion and administration of cytokines. Bone marrow transplantation  06/09/2023 JAN HENRI G. CARPIZO, RMT Inherited Aplastic anemia Dyskeratosis Congenita Rare; only 600 cases have been reported Characterized by mucocutaneous abnormalities, bone marrow failure, pulmonary fibrosis and pancytopenia. There is abnormal skin pigmentation, dystrophic nails, and oral leukoplakia. 06/09/2023 JAN HENRI G. CARPIZO, RMT  06/09/2023 JAN HENRI G. CARPIZO, RMT Inherited Aplastic anemia Genetics and pathophysiology An X-linked gene is inherited which produces the protein DKC1 or Dyskerin. This protein interacts with TERC (the RNA component of telomeres) which causes telomere shortage, eventually signaling low cell survival and early apoptosis Laboratory findings: Pancytopenia and Macrocytosis HbF may be elevated Very short telomeres especially on WBCs  06/09/2023 JAN HENRI G. CARPIZO, RMT Inherited Aplastic anemia Treatment and Prognosis Almost 60-70% of patients die due to bone marrow failure. Some die due to pulmonary complications. The median survival is 42 years. Treatment: Bone marrow transplantation, although not full effective since pulmonary conditions are not improved Androgen therapy may be used, but it does not halt the progression of bone marrow failure.  06/09/2023 JAN HENRI G. CARPIZO, RMT Inherited Aplastic anemia Shwachman-Diamond syndrome Also called Shwachman-Bodian syndrome or Shwachman-Diamond-Oski syndrome, is an inherited multisystem disorder characterized by pancreatic insufficiency, cytopenia, skeletal abnormalities, and predisposition to hematologic malignancies. Clinical findings: Cytopenia with decreased pancreatic secretions. Malabsorption Sepsis due to pancytopenia Delayed bone maturation resulting to low stature  06/09/2023 JAN HENRI G. CARPIZO, RMT Inherited Aplastic anemia Genetics and pathophysiology Inheritance of the SBDS gene, which is involved in ribosome metabolism and mitotic spindle stability. The exact etiology is unknown. There are qualitative and quantitative deficiencies in HSCs, dysfunction in the BM stroma, increased apoptosis, and mitotic spindle destabilization in HSCs. Short telomeres are also found. Lab findings Treatment: Neutropenia Anemia or thrombocytopenia, but not all patients -G-CSF Hypocellular BM -Transfusions 72-hour fecal fat testing reveals elevated fats -Pancreatic enzyme replacement Low trypsin levels  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Pure red cell aplasia A rare disorder of erythropoiesis which results in severe decrease in RBC precursors in the bone marrow, but no alterations in other cell line precursors (Selective deficiency). Patients manifest decreased RBC counts with normal WBC and platelet counts. It may be acquired or congenital, and each general form requires different therapeutic approaches  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Acquired Pure Red Cell Aplasia Can be acute or chronic Primary PRCA may be idiopathic or immunologic in nature Secondary PRCA usually follows cancer or exposure to drugs or chemicals IST can be instituted; Cyclosporine is a common agent used. Acquired PRCA in children is also called transient erythroblastopenia of childhood (TEC) and is usually linked with viral infection and immune mechanisms Findings: Normocytic RBCs which are decreased in numbers. No other abnormalities Treatment: RBC Transfusion  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Congenital PRCA: Diamond-Blackfan anemia Occurs in 1 every 143,000 infants The problem is mutation on genes that code for structural ribosome proteins Normal ribosome biogenesis is disrupted in the disease, although, this event still cannot be connected to the overall manifestations. The exact etiology is unknown. The genes are inherited as autosomal dominant  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Clinical findings: Craniofacial dysmorphism Short stature Neck and thumb malformations  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Lab findings: Macrocytic anemia Reticulocytopenia Normal BM cellularity (erythroid hypoplasia only) Treatment: RBC Transfusion Bone marrow transfusion  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Congenital Dyserythropoietic Anemia A group of disorders characterized by refractory anemia, reticulocytopenia, hypercellular bone marrow but with markedly ineffective erythropoiesis, and bone marrow dysplasia of eryhtroblasts. Common features are hemosiderosis resulting from increase need and ineffective erythropoiesis. CDA has been traditionally classified to three categories, CDA I – III, but now has expanded to seven classifications. It is caused by inheriting an autosomal gene. Treatment usually includes splenectomy and iron depletion, although not all types are same in symptomatology and treatment might be on a case-to-case basis.  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Myelophthisic anemia It is the infiltration of abnormal cells into the bone marrow, with subsequent destruction and replacement of the normal cells. Most infiltrating agents are: Tumor cells (mostly from lung, breast and prostate) Leukemic cells Fibroblast Inflammatory cells Granulomas Because of the unhealthy bone marrow microenvironment, most HSCs migrate into the spleen or liver, initiating extramedullary hematopoiesis.  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Findings: Mild to moderate anemia Normocytic erythrocytes, reticulocytopenia TEARDROP CELLS (Dacryocytes) Nucleated RBCs Leukoerythroblastosis Megakaryocyte fragments Treatment: Treat the underlying condition Bone marrow replacement 06/09/2023 JAN HENRI G. CARPIZO, RMT PBS in myelophthisic anemia  06/09/2023 JAN HENRI G. CARPIZO, RMT Other forms of bone marrow failure Anemia of Chronic Kidney disease Unhealthy kidneys cause inadequate production of erythropoietin May also be caused by uremic toxins accumulating in the blood, which inhibits erythropoiesis and shortens RBC lifespan. Consequences of dialysis leads to chronic blood loss and iron deficiency. Findings: Normocytic, normochromic anemia Burr cells are often found in cases of uremia Treatment: Recombinant human erythropoietin or ESAs