Diseases of RBC & Bleeding Disorders II PDF

PATHOLOGY | TRANS # 5B LE Diseases of RBC & Bleeding Disorders II DR. ARACELI P. JACOBA| (10/04/2024) | Version 1...

PATHOLOGY | TRANS # 5B LE Diseases of RBC & Bleeding Disorders II DR. ARACELI P. JACOBA| (10/04/2024) | Version 1 02 OUTLINE I. Anemia due to decreased IV. Evaluation of Anemia by production RBC Indices A. Megaloblastic Anemia V. Polycythemia B. Pernicious Anemia A. Polycythemia Vera C. Iron deficiency anemia VI. Bleeding Disorders D. Anemia of Chronic A. Vessel Wall Abnormality Disease B. Abnormal Platelet Number II. Hypochromic Microcytic C. Abnormalities in Platelet Anemia Function A. Iron Deficiency Anemia D. Abnormalities of Clotting B. Thalassemia Factors Figure 1. Normal vs. Megaloblastic hematopoiesis [Lecturer’s PPT] C. Anemia of Chronic VII. References Disease VIII. Formative quiz Cytoplasm maturation III.Anemia of Marrow Failure → Matures normally from blue to pink in both normal and A. Aplastic Anemia megaloblastic B. Myelophthisic Anemia Nuclear maturation C. Anemia due to Chronic Renal Failure → The nucleus remains large and immature throughout the D. Anemia due to Diffuse development in the case of megaloblastic maturation Liver Disease Orthochromatic Normoblast E. Anemia due to Neoplasia → The 4th cell with a pink cytoplasm in both series. F. Anemia due to → Orthochromatic normoblast: pyknotic dense small Hypothyroid Disease nucleus Must Lecturer Book Previous Youtube ▪ Megaloblastic anemia: remains large with a coarse ❗️ Know 💬 📖 📋 Trans 🔺 Video ❗ chromatin Nucleocytoplasmic dissociation → Normal cytoplasmic maturation with an immature SUMMARY OF ABBREVIATIONS nucleus in megaloblastic anemia dTMP Deoxythymidine monophosphate TIBC Total iron binding capacity Table 1. Normal vs. Megaloblastic hematopoiesis [2026 trans] PBS Peripheral Blood Smear Cell Normal Megaloblastic IDA Iron deficiency anemia parameter RDW Red Cell Distribution Width Cytoplasm Matures normally from blue to pink in normal and megaloblastic hematopoiesis LEARNING OBJECTIVES Nucleus Size decreases Remains large ✔ To understand the different types of anemia, its causes, throughout the and immature symptomatology, laboratory diagnosis based on RBC development throughout alterations and prognosis the development ✔ To understand hemolysis Orthochromic Pyknotic, dense, Remains large ✔ To understand bleeding disorders normoblast small nucleus with a coarse chromatin 📋→akaI.Nutritional ANEMIA DUE TO DECREASED PRODUCTION Anemias of Diminished Erythropoiesis Deficiencies Central pallor Present Absent VITAMIN B12 METABOLISM ▪ Decrease in substances necessary for red cell production ▪ Most important and most common ▪ B12, B9 (Folic Acid), and Iron deficiency → Chronic inflammation or Renal Failure → Bone Marrow Failure ▪ Aplastic Anemia, Primary Hematopoietic Neoplasms → Infiltrative disorders replacing the marrow ▪ Metastatic cancer, Disseminated Granulomatous Disease ❗ Caused A. MEGALOBLASTIC ANEMIA by B12 and folic acid deficiency 📋 →AlltheImportant for DNA synthesis during nuclear maturation. cells remain large in megaloblastic anemia, including mature erythrocyte which loses its central pallor when Figure 2. Vitamin B12 (Cobalamin) Metabolism [Oh et al., 2022] seen on the peripheral smear. Metabolism starts in the stomach where pepsin cleaves B12 from the binding protein in food and attaches it to a transport protein haptocorrin. LE 2 TG 1 | R. Punla, P. Quanico, D. Quebral, M. Quimson, TE | M. Reyes, P. Roces AVPAA | P. Pinlac PAGE 1 of 13 TRANS 5 H.Quintero VPAA | D. Patajo PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD → Saliva: produces transport protein haptocorrin MEDICAL CONDITIONS ASSOCIATED WITH FOLIC ▪ Transport protein prevents B12 degradation in the gut ACID DEFICIENCY → Stomach (metabolism) Dialysis and hemolysis ▪ Pepsin cleaves B12 from the binding protein and → There are chronic hemolytic conditions that start as attaches it to a transport protein haptocorrin. normochromic normocytic but later become macrocytic ▪ Production of intrinsic factor by the parietal cells when the folic acid deficiencies start to appear → Duodenum Cancer patients on methotrexate can also develop folic ▪ Haptocorrin-B12 complex is cleaved by the acid deficiency pancreatic proteases and releases the B12 from haptocorrin and attaches it to intrinsic factor. VITAMIN B12 DEFICIENCY → Ileum (absorption) Derived from animal products; vegetarians are at risk ▪ B12-intrinsic factor complex is absorbed. Liver stores large amounts of Vitamin B12. It will take B12 PATHWAYS several months before symptoms appear after complete absence of vitamin B12 in the diet Abnormalities of the ileum leading to malabsorption → Chronic intestinal lesions such as inflammation or ileitis, lymphoma, and malabsorption syndrome will decrease B12 absorption Surgical removal of either the stomach (produces IF) or resection of the ileum Fish tapeworm (Diphyllobothrium latum) competes with B12 absorption LABORATORY DIAGNOSIS OF MEGALOBLASTIC ANEMIA Same laboratory abnormalities are present whether it’s B12 or folic acid deficiency Figure 3. Pathways requiring B12 and Folic Acid. (a) dTMP Synthesis; (b) Propionate metabolism pathway [Lecturer’s PPT] PERIPHERAL BLOOD SMEAR Production of Deoxythymidine monophosphate (dTMP) Peripheral Smear: abnormalities may not be limited to red → Thymidine precursor: one of the four nucleic acids in cells DNA → Folic acid enters the pathway through tetrahydrofolic ❗ Megaloblastic Anemia Macrocytic “hyperchromic” RBC → Large red cells compared to small lymphocytes, without acid (THF) → B12 enters the pathway as methionine synthase coenzyme ❗ central pallor Leukopenia with hypersegmented neutrophils or “macropolys”(more than the normal 3-4 lobes) A deficiency of either folic acid or B12 → increase in homocysteine → increase CVD risk including stroke and myocardial infarction 📋 → Decreased number of platelets Large nucleated RBC in PBS “megaloblasts” ▪ Normoblasts with immature nuclei may be present Propionate metabolism pathway requires only B12 → B12 acts as methylmalonyl-CoA mutase enzyme RBC Indices - ↑MCV, High Normal MCHC → In the absence of B12 Retic Count - Decreased or Normal ▪ Methylmalonic acid is increased → In hemolytic anemia, reticulocyte count is always ▪ Results in neurologic abnormalities in B12 deficiency elevated but in nutritional forms of anemia, the which is not present in folic acid deficiency reticulocyte count is either normal or decreased. → It increases only up the administration of treatment. CAUSES OF MEGALOBLASTIC ANEMIA ▪ Striking reticulocytosis - seen at least 5 days after Table 2. B12 vs Folic Acid (B9) Deficiency treatment, corresponding to the time needed to B12 Deficiency Folic Acid Deficiency stimulate the normoblasts until maturity. Vegetarian diet Alcoholics Impaired absorption Increased requirement → Malabsorption, ileitis, → Pregnancy, infancy, gastrectomy, thyrotoxicosis, intestinal resection, hemolysis lymphoma Folic acid antagonists Fish tapeworm → Methotrexate Increased losses → Dialysis FOLIC ACID DEFICIENCY 📋 Folic acid is derived from vegetables but it is easily destroyed by heating or cooking. Common people at risk: → Alcoholics: alcohol causes disordered folate Figure 4. Peripheral smear with megaloblastic anemia metabolism in the liver showing variability of cell size, presence of red blood cells → Pregnancy, Infancy and Thyrotoxicosis due to with no central pallor, and presence of hypersegmented increase requirement neutrophils.[Lecturer’s PPT] PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 2 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD Figure 5. Hypersegmented neutrophils (L) and Megaloblasts with N:C dissociation (R) [Lecturer’s PPT] BONE MARROW Figure 7. Demyelination of dorsal & lateral tracts [Lecturer’s PPT] Megaloblasts with nucleocytoplasmic dissociation. → Cytoplasm: mature and assumes almost the same 📋 Typical morphological change in B12 deficiency is seen in the spinal cord with demyelination (seen as loss of color as the mature red blood cell. → Nucleus: remains immature and has large coarse stains) and loss of axons in these specific areas of the chromatin. ▪ The normal maturity of the nuclei as it develops 📋 cord. Subacute combined degeneration → Locations are limited to the dorsal (ascending sensory should be dense, darkly stained, small nuclei at this stage when the cytoplasm has already turned pink. tracts) and lateral (descending motor tracts) → Symptoms: sensory and motor problems such as numbness, muscle weakness, sensory ataxia, severe paresthesia and spastic paraparesis Table 3. Summary of Laboratory Diagnosis for Megaloblastic anemia. Laboratory Observed results Tests PBS Large nucleated RBCs → Macrocytic Hyperchromic Leukopenia with hypersegmented neutrophils Decreased number of platelets Bone Bone marrow hyperplasia Marrow Megaloblasts with nucleocytoplasmic Figure 6. Megaloblastic erythropoiesis [Lecturer’s PPT] dissociation Bone marrow hyperplasia RBC ↑ MCV, High Normal MCHC → Hypercellular: The bone marrow is hypercellular but Indices ↓ Hemoglobin (Hg) and Hematocrit (Hct) RBCs are defective and die prior to being released into Decreased or Normal reticulocyte count the peripheral blood hence the anemia despite Others ↓ serum B12 hypercellular marrow ↑ Homocysteine → Erythroid:Myeloid ratio 1:1 ↑ Methylmalonic acid ▪ Equal volume of erythroid and myeloid precursors in contrast to the normal E:M ratio of 1:4 (one erythroid for every 4 or 5 myeloid precursor) ❗ Type B. PERNICIOUS ANEMIA of megaloblastic anemia caused by autoimmune destruction of the parietal cell of the gastric mucosa → “Megaloblasts” ▪ All stages of erythroid development are large with → Leading to loss of intrinsic factor and ultimately B12 nucleus: cytoplasm asynchronism or dissociation deficiency OTHERS PATHOLOGY OF PERNICIOUS ANEMIA Decreased serum Vitamin B12 Autoantibody to IF (70%) → This test is not routinely done due to the cost → Type I blocks attachment of B12 to intrinsic factor Increased homocysteine and methylmalonic acid → Type II blocks B12-IF complex to ileal receptor → Increased Homocysteine in Vit B12 and folic acid Autoantibody to gastric parietal cells (90%) deficiency → Directed against the parietal cells → Increased Methylmalonic acid in Vit B12 deficiency → Leads to decline in the number of parietal cells and intrinsic factor → Leads to gastric atrophy or chronic atrophic gastritis PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 3 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD LABORATORY DIAGNOSIS OF PERNICIOUS ANEMIA PEOPLE WITH POOR ABSORPTION Pernicious anemia can have all the manifestations and Iron is difficult to absorb and has poor bioavailability laboratory findings of B12 deficiency → Usually prescribed with other drugs that promote → Elevated red cell indices, macrocytes, and absorption (e.g. ascorbic acid) hypersegmented neutrophils → Patients are warned to avoid substances that inhibit → These are the same because pernicious anemia is an absorption (e.g. tea or carbonated drinks) ❗ autoimmune-induced Vit B12 deficiency. Evidence of autoimmune disorders present along with megaloblastic changes are: PEOPLE WITH INCREASED IRON DEMAND Pregnant women and children → Achlorhydria: absence of hydrochloric acid in the → Have excessive demand for iron gastric secretions → Should take iron supplements → Atrophic gastritis (biopsy): Increased risk of PEOPLE WITH CHRONIC BLOOD LOSS developing gastric carcinoma Leads to undetected blood loss for a long period of time → (+) Serum antibodies (occult blood) and depleted iron reserves → Atrophic glossitis → Occur in malignancies of the bladder, endometrium, or ▪ Hunter's glossitis colon, where the blood loss can exit the body without ▪ Papillary atrophy of the tongue, characterized by an the patient knowing absence of filiform and fungiform papillae Most common cause of chronic blood loss in the elderly: − Beefy tongue MALIGNANCY → Those with hypochromic microcytic anemia should be worked up for occult bleeding due to possible ❗ malignancy Most common cause of IDA in developed countries Figure 8. Beefy tongue (L) is present in atrophic gastritis and characterized by a shiny glaze due to loss of surface papillae. Normal tongue (R) [Lecturer’s PPT] Figure 10. Colonic cancer with occult bleeding [Lecturer’s PPT] IRON METABOLISM Iron is recirculated in the body in 2 forms: → Functional pool (80%) ▪ Present in the circulation as hemoglobin while a Figure 9. Gastric atrophy (Top) versus Normal Gastric small percentage seen in myoglobin and a few Mucosa (Bottom) [Lecturer’s PPT] enzymes → Storage pool (20%) ❗ Most common C. IRON DEFICIENCY ANEMIA (IDA) nutritional disorder ▪ Seen in the bone marrow or reticuloendothelial system as ferritin or hemosiderin 4 GROUPS OF PEOPLE AT RISK ABSORPTION PEOPLE WITH LOW DIETARY INTAKE OF MEAT Inorganic iron: poor bioavailability = difficult to absorb Elderly Heme iron: better bioavailability = easier to absorb → Have health issues (e.g. hypercholesterolemia) and Promoting substances: Vitamin C avoid meat → Have dentition problems Infants ❗ Inhibitory substances: Tea, carbonates in soft drinks Serum iron levels are controlled by Hepcidin → Micropeptide produced by the liver → Milk is not a good source of iron → Has numerous inhibitory mechanisms that prevent the Marginalized sector elevation of iron in the blood: → Can afford vegetables like malunggay (source of ▪ Inhibits absorption inorganic iron) more than meat ▪ Prevents whatever that has been absorbed by the gut ❗ Teenagers: eat junk food > table food Most common cause of IDA in poor countries epithelium from being released into circulation PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 4 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD ▪ Prevents the release of iron in the macrophages or Table 4. Summary of Laboratory Diagnosis for IDA. storage form to prevent its transfer to erythroid Laboratory precursors Observed results Tests → Infection increases hepcidin production through PBS Hypochromic, microcytic inflammatory mediators (IL-6) Bone Marrow Decreased sideroblasts ▪ Responsible for anemia in chronic inflammation RBC Indices ↓Hemoglobin (Hg) and Hematocrit (Hct) STORAGE ↓ MCV After 120 days, the red cells are destroyed by the spleen ↑ RDW Iron is extracted and stored in the liver or bone marrow as ↓ Decreased serum iron ferritin or hemosiderin ↓ Ferritin ↑ TIBC EXCRETION Normal reticulocyte count Iron cannot be excreted anywhere in the body although minute amounts can be excreted in the gut SIGNS AND SYMPTOMS OF IDA Nonspecific in all cases of anemia (e.g. dizziness, feeling TRANSPORT of weakness, headache) In circulation, they are transported by Transferrin Manifestations more common in IDA: → Free serum iron: toxic to the tissues → Koilonychia: spoon nails ▪ Requires a transport protein all the time → Alopecia → Pica:eating inedible items (e.g. chalk, sand, ice) due to decreased iron levels in the neurons of the brain → Atrophy of tongue and stomach → Plummer Vinson Syndrome ▪ IDA + atrophic glossitis + esophageal webs ❗ Due D. ANEMIA OF CHRONIC DISEASE (ACD) to elevated hepcidin by inflammatory mediators Mechanisms of hepcidin: → Impaired iron absorption → Reduced supply of iron to erythroid progenitor cells despite its abundance in storage → Impaired iron utilization ACD cannot be treated with iron since hepcidin impairs absorption and utilization of iron → Treat underlying condition first before considering iron therapy Chronic diseases that may develop anemia: → Chronic microbial infection (e.g. Tuberculosis, Figure 11. Diagram of Iron Metabolism [Lecturer’s PPT] osteomyelitis) LABORATORY DIAGNOSIS OF IDA → Chronic immune disorders (e.g. Rheumatoid Arthritis, ❗ Peripheral Blood Smear regional enteritis) Morphology: Hypochromic, microcytic → Neoplasms (e.g. malignancies of the breast and → Due to defect in hemoglobin lung)iron therapy ▪ Iron causes defect in heme Symptoms of anemia are mild in these conditions and will ▪ Thalassemia causes defect in globin usually be corrected with the treatment of the underlying − Giving iron will cure the patient with IDA but can condition kill a patient with Thalassemia II. HYPOCHROMIC MICROCYTIC ANEMIAS → Normal reticulocyte count Iron studies can help differentiate the various causes of ▪ Seen in all forms of nutritional anemia hypochromic microcytic anemia ▪ Increases only upon start of treatment ❗ Decreased (Reticulocytosis: occurs 3-5 days after start of A. IRON DEFICIENCY ANEMIA treatment) iron, decreased storage (ferritin), elevated Bone marrow: decreased sideroblasts (erythroid TIBC precursors containing iron) → ↑ TIBC due to the increased capacity to bind iron since Iron Indices there will be increased empty spaces in the transport → Most diagnostic test for differentiating IDA from protein Thalassemia ▪ Decreased serum iron and storage form of ferritin ▪ Elevated total iron binding capacity (TIBC) − Measures capacity to bind iron and vacant areas ❗ Opposite B. THALASSEMIA findings with IDA because of elevated iron levels Increased serum iron, increased serum ferritin, of iron in its transport form decreased TIBC − In the absence of iron = more vacant spaces and increased capacity to load/bind more iron ▪ Elevated Red Cell Distribution Width (RDW) − Indicates increased amount of anisocytosis and Space intentionally left blank poikilocytosis in IDA PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 5 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD C. ANEMIA OF CHRONIC DISEASE Low serum iron Increased serum ferritin 📋 Provoke EXTRINSIC CAUSES: ACQUIRED an immune-mediated response producing cytokines or interferon killing the progenitor cells → Storage and transport proteins are all filled up with iron Drugs (idiosyncratic) → Hepcidin which is increased in inflammation does not → Chloramphenicol, carbamazepine, phenytoin) allow the release and transfer of iron from storage to Chemicals circulation. Hence the low volume in circulation despite → Benzene in paints/thinners, alkylating agents in the increased volume in storage. insecticides ▪ Analogy: Think of it as a sick person who cannot Infections provide enzymes or enough ATP needed to transfer → CMV, parvovirus, hepatitis, EBV iron from storage to the circulation because it ▪ Parvovirus attacks the stem cells and poses the requires a lot of metabolic activity and the patient is highest risk for the development of aplastic anemia sick Morphology: Normochromic, normocytic or hypochromic, microcytic or a combination (normochromic, microcytic) Table 5. Laboratory values for anemia of chronic disease, iron deficiency anemia (IDA), and thalassemia. [Lecturer’s PPT] Laboratory Chronic IDA Thalassemia Parameter DIsease Serum Fe ↓ ↓ ↑ Serum ↑ ↓ ↑ Ferritin TIBC ↓ ↑ ↓ Morphology N/N or H/M H/M H/M III. ANEMIAS OF MARROW FAILURE ❗ A. APLASTIC ANEMIA Failure of hematopoiesis in the marrow due to suppression of hematopoietic activity Figure 12. Biopsy of the bone marrow. (a) Normal cellular marrow; amount of fat is 50%. (b) Hypocellular marrow (seen in aplastic → Decrease in all hematopoietic elements based on bone anemia) in which there is more fat. (c) Hypercellular marrow in which ❗ marrow aspirate (e.g. RBC, WBC, platelets) the progenitor cells completely replaced the adipose content of the marrow. [Lecturer’s PPT] Reflected in PBS as pancytopenia → Loss of all blood elements B. MYELOPHTHISIC ANEMIA → This is in contrast to pure red cell aplasia which mainly Space occupying lesions that destroy a significant amount affects erythroid precursors only. of marrow In aplastic anemia, reticulocyte count is decreased This is what we see in metastatic tumors and extensive ❗ despite presence of anemia. A responsive bone marrow will show increased reticulocyte count. tuberculous lesions in bone resulting in replacement of bone marrow elements, marrow distortion, and fibrosis Diagnosis: → If reticulocyte count remains low and pancytopenia is → Bone marrow: presence of space occupying lesions evident in PBS, it will indicate aplastic anemia with marrow distortion and fibrosis (e.g. metastatic Treatment: transplant / immunosuppressive therapy cancer, multiple myeloma) → PBS: pancytopenia, tear - drop shaped RBC (due to Table 6. Summary of Laboratory Diagnosis for Aplastic the difficulty of the red cell in passing through the Anemia [Lecturer’s PPT] fibrous bone marrow) Laboratory Observed Results Parameter PBS Pancytopenia (hypocellular) Bone Marrow ↑ Fat or fibrous content ↓ Hematopoietic cells Hypocellular RBC Indices ↓ RBC, WBC, Hct, Hgb, platelets ↓ Reticulocyte count CAUSES OF APLASTIC ANEMIA INTRINSIC CAUSES: DEFECT OF STEM CELL Hereditary 📋 Fanconi Anemia Gene defect in a protein complex required for DNA repair leading to a reduced proliferative capacity of the stem cell → Accompanied by several congenital anomalies Idiopathic Figure 13. Biopsy of the bone marrow with myelophthisic anemia → Due to stem cell defect showing a tumor. As the tumor enlarges, more and more marrow elements are replaced resulting in pancytopenia [Lecturer’s PPT] PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 6 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD C. ANEMIA DUE TO CHRONIC RENAL FAILURE Due to decreased EPO (erythropoietin) secretion D. ANEMIA DUE TO DIFFUSE LIVER DISEASE Due to decreased production of coagulation factors; deficiency of folic acid; decrease in phospholipid production affecting production of erythroid progenitors 📋 E. ANEMIA DUE TO NEOPLASIA Tumor uses the substances and nutrients for hematopoiesis F. ANEMIA DUE TO HYPOTHYROID DISEASE Due to decreased metabolic activity in the body IV. EVALUATION OF ANEMIA BY RBC INDICES Table 7. Comparison of Types of Anemia by RBC Indices Types of Anemia MCHC MCV MCH IDA/Thalassemia Dec Dec Dec Chr. inflammation N/Dec N/Dec N/Dec Figure 14. JAK - STAT pathway [Lecturer’s PPT] Spherocytosis Slight inc Dec/N variable Figure 14: Pernicious anemia Hi/N Inc Hi/N → Shows the need for growth factors for mitosis. B12 / Folic acid Hi/N Inc Hi/N → Cell division is controlled by growth factors. If you Hemolytic/Aplastic N N N lacerate your skin, epidermal growth factor and vascular Polycythemia N N N growth factor are needed to regenerate skin and blood Conditions with decreased MCHC and MCV (hypochromic, vessels with transforming growth factor to regenerate microcytic anemia) are caused by hemoglobin problems. the fibroblasts. → IDA and thalassemia, anemia of chronic disease → Growth factors serve as cellular control needed to start Conditions with increased MCHC and MCV (hyperchromic, the process of mitosis. macrocytic anemia) are caused by B12 and folic acid → If the cell undergoes mitosis without growth factor, there deficiency or pernicious anemia is loss of control and is the basis for tumoral growth Divergence of MCHC and MCV values (decreased MCV, The growth factor needed to start hematopoiesis is increased MCHC) or absence of central pallor seen in erythropoietin spherocytosis → Erythropoietin has to attach to the surface of the All the rest, particularly the hemolytic forms, fall under receptor, signaling the JAK pathway and stimulating the normochromic, normocytic anemia nucleus to start mitosis and growth In polycythemia vera, a mutation of the JAK pathway V. POLYCYTHEMIA occurs Increase in red cell mass → Even in the absence of erythropoietin, the pathway is Types: continuously stimulated, thus producing an unlimited → Relative polycythemia number of cell → number of myeloid cells is ▪ Decrease in fluid - portion of the blood producing an exceedingly elevated increase in red cell mass; no true increase (e.g. dehydration) SYMPTOMS OF PCV → Absolute polycythemia Related to increased red cell mass, increased total blood ▪ Primary / polycythemia vera volume → abnormality of blood flow, particularly in low ▪ Secondary / increased EPO secretion pressure areas of circulation (venous circulation) veins − Compensatory or physiologic response to become distended decreased oxygen level (e.g. people in high Plethoric, cyanotic from stagnation of blood altitudes) or due to paraneoplastic symptoms in Pruritus, peptic ulcer from increased histamine levels which tumors secrete EPO (e.g. renal cell from basophilia carcinoma, hepatocellular carcinoma) → Pruritus: occurs typical after a bath ▪ The main difference between the two is the EPO Headache, dizziness, hypertension level. In secondary, the EPO level is elevated and in → From decreased oxygen tension polycythemia vera, it is normal or decreased COMPLICATIONS OF PCV A. POLYCYTHEMIA VERA Deep venous thrombosis, MI, stroke Increased marrow production of myeloid progenitors due to → from abnormal blood flow, abnormal platelet function a mutation of tyrosine kinase receptors that affect the JAK Hyperuricemia: high cellular turnover 2 pathway Bleeding: without treatment patients die from bleeding All elevations seen are those from myeloid lineage PROGNOSIS OF PCV → PBS: panmyelosis Regular phlebotomy can extend life → RBC: > 6 million Development of myelofibrosis (20%) in 10yrs → “spent → Platelets: > 500,000 phase” → extramedullary hematopoiesis → WBC: 12,000 - 15,000 Development of AML (2%) → HCT: >60% → No lymphocyte increase Incidence: males, middle aged - elderly PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 7 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD VI. BLEEDING DISORDERS IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP) Table 8. Bleeding Disorders [Lecturer’s PPT] Autoimmune disease producing Ab against platelets Causes of Bleeding Lab Parameter Normal BM with increased megakaryocytes Disorders Affected Acute ITP Blood Vessel All parameters normal → Self-limited disorder in children after viral infection ↓ Platelet number ↓ PLT Count → Develops 2 weeks after viral infection; resolves around ↑ Bleeding Time 6 months Platelet function (adhesion, (N) PLT Count → Treatment: Steroid aggregation, release ↑ Bleeding Time ▪ For severe Acute ITP reaction) Chronic ITP Deficiency in any of clotting ↑ Clotting Time → Seen in adults, especially reproductive females with factors (Factors I-XII) autoimmune disorders or lympho-proliferative disease Deficiency in Extrinsic ↑ Prothrombin Time Platelet transfusion is contraindicated in any form of ITP Factor VII & Common ↑ Clotting Time → Transfused platelets will only be destroyed by Ab, Factors (I, II, V, X) maintaining the low platelet count Biopsy of ITP Deficiency in Intrinsic ↑ aPTT → Increase in the number of megakaryocyte in the bone Factors & Common Factors ↑ Clotting Time marrow, indicating that the bone marrow is responding (I, II, V, X) to the loss in the peripheral smear A. VESSEL WALL ABNORMALITY THROMBOTIC THROMBOCYTOPENIC PURPURA Usually presents as small hemorrhages in skin or mucous (TTP) membranes Characterized by: → Rarely do they present with hemorrhage in the joints, → Microangiopathic hemolytic anemia GIT bleeding, urinary bleeding/what you see in → Fever coagulation problem defects or platelet deficiency → Transient neurologic deficits NON-THROMBOCYTOPENIC PURPURA (ITP) → Renal failure All bleeding parameters: normal → Usually in females in 4th decade of life Causes Morphology → Infection: meningococcemia, measles, infective → Widespread hyaline microthrombi throughout the body endocarditis ▪ Consumes the platelet in peripheral blood ▪ Due to damage to vasculature that results to ▪ Appearance of fragmented cells in smears vasculitis Pathogenesis − Scurvy, Ehlers Danlos → Excessive activation of platelets due to deficiency of ▪ Due to collagen defects that weaken the vessel wall enzyme, ADAMTS 13 or Von Willebrand’s factor that commonly presents as petechial hemorrhages metalloprotease → Drugs: Penicillin, Sulfa ▪ Main function of ADAMTS 13: degrade Von → Henoch Schonlein Purpura Willebrand’s factor ▪ Immune disorder that result to the deposition of ▪ In its absence, there is increased VWF → more circulating immune complexes in the vessels thrombosis throughout the body → Von Willebrand’s factor → Hemorrhagic Telangiectasia ▪ Mediator for platelet adhesion ▪ Weber Osler Rendu Syndrome: autosomal Treatment: plasma exchange as soon as possible dominant condition characterized by dilated tortuous DDx: Hemolytic Urermic Syndrome (HUS) blood vessels with thin walls, affecting the mucous → HUS has more severe renal problem and no neurologic membranes in the nose, mouth, eyes, GI tract defects B. ABNORMAL PLATELET NUMBER HEMOLYTIC UREMIC SYNDROME (HUS) Normal: 150,000 to 400,000 (upper limit: 450,000) Same manifestations as TTP minus the neurologic Decreased platelet number manifestations → 10,000: spontaneous bleeding → Renal manifestation prominent → 10,000 to 30,000: post traumatic bleeding → S/Sx of hemolysis present Blood transfusions are carried out once platelet number Morphology: Widespread hyaline microthrombi falls below 20,000 Pathogenesis: Excessive activation of platelets by bacterial Minor surgeries need at least 50,000 for the procedure to toxin (E. coli that causes gastroenteritis) be carried out → Results to extensive microthrombi formation Major surgeries (e.g. involve microvasculature – brain and eye vessels) need at least 100,000 Bleeding characteristic secondary to decreased platelet → Petechial hemorrhages in skin & mucous membranes → Easy bruisability → GI, genitourinary tract bleed: melena, hematuria, inc Space intentionally left blank menstrual flow Intracranial bleeding → Most common cause of death in adult dengue fever PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 8 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD MORPHOLOGY OF TTP AND HUS MUST KNOW Figure 15. Morphology of TTP and HUS [Lecture PPT] Figure 16. vWF and Glycoproteins for Platelet Functions [Lecture PPT] Gross (A): Microthrombi (black arrows) in very small vWF - mediates adhesion of platelets to endothelium blood vessels in the brain → Loss of vWF → no platelet adhesion to the wall of Histology (B): thrombus occluding a small blood vessel vessel (Von Willebrand’s Disease) in the brain GpIb (black arrow) - receptors to attachment of vWF PBS (C): MAHA with typical fragmented red cells as a → Loss of GpIB → no platelet adhesion (Bernard consequence of traumatic passage through narrowed Soulier Syndrome) 📋 vasculature MNEMONIC: Key Manifestations of TTP & HUS [2026 trans] GpIIb/IIIa (red arrow) - bridging receptors that promote platelet-to-platelet interaction → Loss of GpIIb/IIIa → no aggregation (Glanzmann → FATRN Thrombasthenia) ▪ Fever (TTP: 100% | HUS: depends on etiology) ▪ Anemia (MAHA) D. ABNORMALITIES OF CLOTTING FACTORS ▪ Thrombocytopenia Can cause: ▪ Renal Pathology (HUS>TTP) → Spontaneous bleeding ▪ Neurological symptoms (in TTP) → Prolonged bleeding (ex. after minor laceration, common after dental extraction) C. ABNORMALITIES IN PLATELET FUNCTION → Bleeding in GIT, GUT, serious cavities (hemothorax, INBORN hemoperitoneum) Von Willebrand’s Disease: Deficient vWF → Weight-bearing joints (hemarthrosis) → vWF is located in subendothelium and any injury to Laboratory findings: blood vessel exposes the factor to promote platelet → Normal: platelet count and BT adhesion → Elevated: CT, PT, APTT → Results to loss or defective adhesion ▪ PT: Factors I, II, V, X, VII Bernard Soulier Syndrome: Absence of Glycoprotein Ib ▪ APTT: Intrinsic & Common Factors → Gp1b: needed for platelet attachment to vWF; receptor No petechial hemorrhages in skin and mucosa (unlike in to vWF thrombocytopenia) → Results to defective adhesion Deficient Factors: Glanzmann Thrombasthenia: Absence of Glycoprotein → Hemophilia: Factor VIII IIb/IIIa → Christmas Disease or Hemophilia B: Factor IX → GpIIb/IIIa: needed for platelet attachment to each other → Liver Disease: All factors except Factor VIII → Results to defective aggregation ▪ since liver produces most of the factors ACQUIRED → Vitamin K deficiency: Factors II, VII, IX, X, Proteins C and S Aspirin/NSAIDs ▪ Protein C and S: Vitamin K-dependent cofactors in → Inhibit COX → suppress TXA2 and prostaglandin the inactivation of Factors V and VIII formation (potent platelet aggregators) − Deficiency of Protein C and S → persistent → Aspirin: potent antiplatelet function; prophylaxis for activation of F V and VIII → clot formation coronary thrombosis Uremia: VON WILLEBRAND'S DISEASE → Deficiency of platelet factor III (PF3) Pathogenesis: Deficient vWF → Defects in adhesion and aggregation → vWF is needed for platelet function and F VIII stability S/Sx: Spontaneous bleeding from mucous membrane, excessive bleeding from wounds, menorrhagia, Space intentionally left blank hemarthrosis → Bleeding tendencies are usually mild and go unnoticed until subjected to surgery or trauma PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 9 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD → Bleeding manifestations are a combination of a platelet → PBS: Fragmented red cells resulting to MAHA defect and a coagulation factor problem Laboratory Findings: Qualitative Defects → Acute DIC: all coagulation parameters abnormal → Type I: Mild decrease with mild bleeding ▪ In the case of endotoxic shock or obstetric → Type 3: Severe decrease with severe bleeding complications Quantitative Defects → Chronic DIC: D-dimer, fibrin split production → Type 2: Moderate bleeding ▪ In the case of carcinomatosis or retention of dead Laboratory Findings: fetus → Normal: Platelet count → Elevated: BT, APTT ▪ BT: increased due to platelet adhesion problem ▪ APTT: increased due to F VIII deficiency; may be normal in qualitative vWD → Decreased: Ristocetin aggregation test ▪ Test that determines the presence and integrity of the GpIbα-V-IX complex and vWF interaction DISSEMINATED INTRAVASCULAR COAGULATION (DIC) AKA Consumption Coagulopathy → Consumption of clotting factors and platelets that ends in bleeding An acute, subacute or chronic thrombohemorrhagic disorder occurring as a complication in a variety of Figure 18. DIC in the Kidney and Lung [Lecturer’s PPT] diseases Thrombosis occurs in the small blood vessels → patient must have a critical illness that result to this (microthrombosis), particularly in the kidney and lungs condition where the narrowest vessels are located (Figure 18) → NOT a primary disorder but a complication of various Oliguria, acute renal failure, and pulmonary failure are disorders common observations in DIC Pathogenesis: Pulmonary DIC can present with dyspnea and cyanosis, → Obstetric complications: release of procoagulants leading to circulatory shock from placenta, dead fetus or amniotic fluid Convulsions may also occur when the brain is affected. → Neoplasms Chronic DIC, like in cancer, will present more with → Infections thrombotic episodes, while the rest will present more with ▪ Release of endotoxin that inhibits release of bleeding thrombomodulin or stimulates TNF production (activates F VIII) CLINICAL SYNDROMES ASSOCIATED WITH → Massive tissue injury BLEEDING ▪ Massive trauma e.g. burns, extensive surgery → Waterhouse Friderichsen Syndrome release of tissue factor → Meningococcemia producing adrenal hemorrhage → Overwhelming septicemia due to bacterial infection classically due to Neisseria meningitidis ▪ This bacteria can attack the adrenals leading to massive bilateral adrenal hemorrhage that leads to rapidly developing adrenal insufficiency, shock, and DIC Kasabach Merritt Syndrome → Multiple giant hemangiomas → stasis of blood → thrombi formation → bleeding due to DIC V. REFERENCES Dr. Araceli’s Asynchronous and Synchronous Lectures 2026 Trans Oh, S., Cave, G. and Lu, C. (2021) ‘Vitamin B12 (cobalamin) and micronutrient fortification in food crops using nanoparticle technology’, Frontiers in Plant Science, 12. doi:10.3389/fpls.2021.668819. Figure 17. Pathogenesis of DIC [Lecturer’s PPT] Endothelial injury and tissue destruction → release of tissue factors and platelet activation → thrombosis → clotting factors and platelets consumed, fibrinolysis activated → bleeding → Bleeding is due to consumption of the PLTs and clotting factors from circulation because of the widespread thrombosis & activation of the fibrinolytic system that produces fibrin split products that inhibit clotting and aggravates bleeding Morphology: Multiple microthrombi PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 10 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD VI. FORMATIVE QUIZ Question & Choices Answer & Rationale 1. 8 y/o grade 1 student of Payatas brought to a health ❗️Red cell indices: center because of pallor. Child was noted to have easy Normal MCV: 80-94 fL fatigability during play. No history of previous Normal MCHC: 32-36 gm/dL hospitalization Peripheral smear: large central pallor and small red cell. CBC Hb 9.2 g/dl MCV determine the size of the red cell Hct 30% MCHC determine the color of the red cell WBC 9500 MCV 77 fl Both the MCV and MCHC of the patient are below the normal MCHC 29 range; hence, this is a hypochromic normocytic anemia. Retic count - 0.9% [red cell indices reference from the PPT synch lecture] Give the morphologic type of anemia: B A. Normochromic normocytic B. Hypochromic microcytic C. Macrocytic D. Normochromic microcytic 2. 8 y/o grade 1 student of Payatas brought to a health ❗️Normal retic count: 0.5% to 2.5% center because of pallor. Child was noted to have easy Peripheral blood smear: definitive for iron deficiency anemia fatigability during play. No history of previous hospitalization Iron deficiency vs Thalassemia History: No previous hospitalization CBC Hb 9.2 g/dl In thalassemia, no globin chain → bone marrow tries to make Hct 30% red cells that are abnormal → peripheral blood → hemolysis → WBC 9500 jaundice → inc iron due to hemolysis → have a history of MCV 77 fl hospitalization. MCHC 29 Retic count - 0.9% Iron deficiency anemia → typically, Bone marrow is normal = Give your diagnosis for this patient: retic is normal. Thalassemia → retic count is high due to compensation of Bone marrow to make new red cells. B A. Thalassemia B. Fe deficiency anemia C. Anemia of chronic disease D. Anemia of renal disease PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 11 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD 3. A 6 year old female with history of chronic diarrhea for The CBC findings reveal large red cells (high MCV) and a year was complaining of dizziness and malaise. hyperchromic cells (high MCHC) with normal reticulocyte count. PBS also reveals the presence of a multiple - lobed Hb: 9.6 g/dL neutrophil which points to megaloblastic anemia. Hct: 26% WBC: 7,800 cells While pernicious anemia may be considered, there is no MCV: 102 fL evidence in the case presented of autoimmunity which is the MCHC: 37 underlying pathology of pernicious anemia. Retic count: 1.3% C Give your diagnosis A. Sickle cell anemia B. G6PD deficiency C. Megaloblastic anemia D. Pernicious anemia 4. 24 y/o journalist assigned to Palawan complained of Presence of Hb in the urine (positive for hemoglobinuria) reddish urine after taking prophylactic antimalarial indicates that this is an intravascular type of hemolysis. drugs 2 days ago Jaundice may indicate either intravascular or extravascular. One common cause of intravascular hemorrhage is G6PD PE: slight jaundice, negative for splenomegaly CBC: Hb 8.8 g/dL Hct: 28% Based on the peripheral smear: Presence of BITE CELLS is WBC: 8000 plt cnt: 230,000 characteristic of G6PD MCV 84 fl MCHC: 32 Urinalysis: negative for red cells, Positive for Hb B What is your diagnosis? A. Spherocytosis B. G6PD C. Sickle cell anemia D. PNH 5. A patient is suspected to have Thalassemia. What Coombs test is used to detect abnormal antibodies in laboratory exam would you request to determine immunohemolytic anemia diagnosis? Osmotic fragility test is used for hereditary spherocytosis B Bone biopsy is reserved for anemias due to bone marrow A. Coombs test failure B. Hb electrophoresis Hb electrophoresis is used to detect abnormal hemoglobin C. Osmotic fragility test conditions (HbF, HbA2). D. Bone biopsy PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 12 of 13 PATHOLOGY | LE 1 Diseases of RBC & Bleeding Disorders II | DR. ARACELI P. JACOBA, MD 6. a 34 year old farmer complaining of dizziness. Hb is Normal Hematopoietic elements: Adipose tissue ratio decreased ○ 1:1 Hypocellular marrow (image) ○ Marked significant increase of fat cells ○ There is decreased reticulocyte count since the ratio is a reflection of the activity of bone marrow → anemia D A. Tuberculous infection of bone B. Spherocytosis C. Hypercellular Marrow D. Aplastic Anemia Abnormalities in Platelet Number (must have decreased platelet 7. 2 y/o boy complained of enlarging bluish mass on knee count in CBC) after hitting a plastic stool. Hx shows easy bruisability 1. ITP (Idiopathic thrombocytopenic purpura) on minor trauma. ○ Autoimmune disease producing antibodies against platelets CBC: Hb 12.1 Hct 37 i. Acute ITP - self limited disorder in children following WBC Count 7000 viral infection Platelet Count 160,000 ii. Chronic ITP - seen in adults especially reproductive MCV 84 fl females with autoimmune disorders MCHC 34 D 2. TTP (thrombotic thrombocytopenic purpura) ○ Increased platelet activation because of increased vWF BT - normal CT - elevated causing numerous microthrombi PT - normal APTT - elevated Von Willebrand's Disease - platelet count normal but bleeding Give your DIAGNOSIS: time must be elevated because only platelet adhesion is A. ITP affected B. TTP C. Von Willebrand disease D. Hemophilia PATHOLOGY Diseases of RBC & Bleeding Disorders II PAGE 13 of 13