PAST 516 Hematology Week 1 Notes PDF

**PAST 516 Hematology** **Cohort 2026** **Week 1** **Objectives:** - Recognize and appropriately use key terms associated with hematology (B2.02b, B2.03). - Identify the visual morphology of selected blood cells (B2.02c, B2.07d). - Describe the physiology of thrombosis and hemato...

**PAST 516 Hematology** **Cohort 2026** **Week 1** **Objectives:** - Recognize and appropriately use key terms associated with hematology (B2.02b, B2.03). - Identify the visual morphology of selected blood cells (B2.02c, B2.07d). - Describe the physiology of thrombosis and hematopoiesis (B2.02b). - Recognize key history and physical characteristics of anemia (B2.07a, B2.07b). - **Discuss the pathophysiology, clinical presentation, diagnostic evaluation, and available treatments of anemias, including those listed below (B2.02c, B2.02d, B2.03, B2.07a, B2.07b, B2.07c, B2.07e).** - **Iron-deficiency anemia** - **Anemia of chronic disease** - **Vitamin B~12~ deficiency** - **Folic acid deficiency** - **Hemolytic anemias** - **Paroxysmal nocturnal hemoglobinuria** - **Aplastic anemia** - **Differentiate causes of microcytic, macrocytic, and normocytic anemia (B2.07c, B2.07d).** - Develop a broad and targeted differential diagnosis for patients presenting with signs and symptoms of anemia and hemophilia (B2.07c). - Select appropriate laboratory evaluations for patients presenting with signs and symptoms of anemia and hemophilia (B2.07d). - Determine what type of anemia a simulated patient has based on the results of complete blood count and iron studies (B2.02b, B2.02c, B2.05). - Develop a treatment and referral plan for patients with anemia or hemophilia (B2.02d, B2.05, B2.06d, B2.07e, B2.07f). - Educate patients with anemia or hemophilia on the expected course, emergency department precautions, and the management of their disease (B2.04, B2.07f, B2.12a). - **Discuss the pathophysiology, clinical presentation, diagnostic evaluation, and available treatments of hemoglobinopathies, including those listed below (B2.02c, B2.02d, B2.03, B2.07a, B2.07b, B2.07c, B2.07e).** - **Glucose-6-phosphate dehydrogenase deficiency** - **Sickle Cell anemia** - **Thalassemias** - **Hemochromatosis** - **Discuss the pathophysiology, clinical presentation, diagnostic evaluation, and available treatments of bleeding disorders, including those listed below (B2.02c, B2.02d, B2.03, B2.07a, B2.07b, B2.07c, B2.07e).** - **Hemophilia A** - **Hemophilia B** - **Von Willebrand Disease** **Notes:** **Hematology Key Terms** - **Hematopoiesis:** The production by the bone marrow of all cells in the blood. Generally refers to the production of granulocytes, erythrocytes and platelets. - **Stem Cell:** Earliest progenitor cell, dual property of self renewal and lineage commitment (mitosis into another stem cell and a maturing cell) - **Blast:** the most immature cell type in a given lineage (myeloblast, lymphoblast, monoblast). Notably large nuclei. - If you see a bunch of blasts on a smear, this means there is a lot of fresh proliferation - consider acute leukemia - **"Left Shift":** numerous immature cells in blood, suggestive of proliferation - A "left shift" in a patient with numerous neutrophils can suggest that a patient is actively fighting an infection - The "left" refers to the manual differential counting machines that were used to count cells on a slide. The leftmost button of the neutrophil series is reserved for myeloblasts (the least mature cells). - **Complete Blood Count (CBC):** Test of peripheral blood that gives important information regarding the hematologic and other organ systems - Components of a typical CBC include: - - Red blood cell (RBC) count - Hemoglobin - Hematocrit - RBC indices - White blood cell (WBC) count - WBC differential count - Platelet count - Mean platelet volume - **Red Blood Cell (RBC) Count:** \# of red blood cells in volume of blood (Adult normal ranges - Male: 4.7 to 6.1 million cells/µL; Female: 4.2 to 5.4 million cells/µL) - **Hemoglobin (Hgb):** amount of hemoglobin in volume blood (Adult normal ranges - Male: 14-18 g/dL; Female: 12-16 g/dL) - **Hematocrit (Hct):** Ratio of volume of red cells to volume whole blood (Adult normal ranges - Male: 42%-52%; Female: 37%-47%) - **Red Blood Cell (RBC) Count:** \# of red blood cells in volume of blood (Adult normal ranges - Male: 4.7 to 6.1 million cells/µL; Female: 4.2 to 5.4 million cells/µL) - **Hemoglobin (Hgb):** amount of hemoglobin in volume blood (Adult normal ranges - Male: 14-18 g/dL; Female: 12-16 g/dL) - **Hematocrit (Hct):** Ratio of volume of red cells to volume whole blood (Adult normal ranges - Male: 42%-52%; Female: 37%-47%) - **RBC Indices:** - **Mean Corpuscular Volume (MCV):** Average volume of RBC (size) (Adult normal range: 80-100 femtoliter) - **Microcytic:** low MCV - **Macrocytic:** high MCV - **Normocytic:** normal MCV - **Mean Corpuscular Hemoglobin (MCH):** Average amount of Hgb in average red cell (Adult normal range: 27-31 pg) - **Mean Corpuscular Hemoglobin Concentration (MCHC):** Average concentration of Hgb in given volume of red blood cells - **Normochromic:** normal MCHC - **Hypochromic:** low MCHC, iron deficiency anemia - **Hyperchromic:** high MCHC, consider B12/folate deficiency - **Red Cell Distribution Width (RDW):** Variability of red cell size (Adult: variation of 11% - 14.5%). Calculated by dividing the standard deviation of RBC volume by the MCV. A higher number indicates greater variability in the size of red blood cells - **White Blood Cell (WBC) Count:** \# of white blood cells in volume of blood (Adult normal range: 5000 -10,000/µL) - **WBC Differential Count:** - Neutrophils (Adult normal range: 2500-8000/µL or 55%-70%) - Lymphocytes (Adult normal range: 1000-4000/µL or 20%-40%) - Monocytes (Adult normal range: 100-700/µL or 2%-8%) - Eosinophils (Adult normal range: 50-500/µL or 1%-4%) - Basophils (Adult normal range: 25-100/µL or 0.5%-1%) - **Platelet Count:** \# of platelets in volume of blood (Adult normal range: 150,000-400,000/µL) - **Mean Platelet Volume (MPV):** Average size of platelets in volume of blood (Adult normal range: 7.4-10.4 femtoliter) - **Anemia:** RBC, hemoglobin, hematocrit are low. I tell patients "you're short on blood" or something along those lines consistent with my understanding of their medical literacy. - **Polycythemia (erythrocytosis):** RBC, hemoglobin, hematocrit are high. This is common at our altitude and in smokers, (or Lance Armstrong) but may be falsely elevated due to dehydration. - **Leukopenia:** decreased WBC - Neutropenia: low neutrophils - Lymphopenia: low lymphocytes - Monocytopenia: low monocytes - **Leukocytosis:** increased WBC - Neutrophilia: increased neutrophils - Lymphocytosis: increased lymphocytes - Monocytosis: increased monocytes - **Thrombocytopenia:** low platelets - **Thrombocytosis:** increased platelets - **Pancytopenia:** a combination of - neutropenia - anemia - thrombocytopenia - **Aplasia:** bone marrow is not making as many cells as it should - **Dysplasia:** bone marrow is not making cells that function properly (or appear abnormal morphologically) - **Reticulocyte:** immature young RBC indicating the bone marrow's ability to respond to anemia. (Adult normal range: 0.5% - 2% of total \# of RBCs) - Reticulocytes are released into the peripheral blood under stress and typically last about 1 day - Causes of increased reticulocytes: - Acute loss of blood - Recent correction of an erythropoietic nutrient deficiency - Reduced red cell survival (i.e., hemolysis) - **Peripheral Blood Smear:** Microscopic examination of a smear of a patient's blood. Gives information regarding all three hematologic cell lines -- erythrocytes (RBCs), platelets and leukocytes (WBCs) - - **Circulating vs Marginated Neutrophils:** The number of neutrophils seen in a blood specimen is representative of the neutrophils circulating in the blood, this is generally about half of all neutrophils. The other half is "marginated" or attached to endothelium in the process of migrating into tissue. - **Demargination:** neutrophils that are marginated are released from the endothelium to join the circulating pool. This can be mediated by epinephrine. This is why a patients neutrophil count can rise rapidly in response to infection, trauma, seizure, or other insults. - **Red blood cell, erythrocyte:** oxygen-carrying cell - Life cycle of RBC is about 120 days. - Elderly (senescent) RBCs are removed by the spleen by macrophages - Erythropoiesis occurs in the bone marrow under the influence of **[erythropoietin]** which is released from the kidneys - **Platelets, thrombocytes:** major factor in coagulation - lifespan of about 10-12 days - **Neutrophils:** lifespan of about 3-5 hours in blood, constantly migrating into tissues - **Lymphocytes:** lifespan of decades for T cells, migrate back and forth from blood to tissues - B cells produce antibodies - NK cells to be covered later - **Ethylenediaminetetraacetic acid:** EDTA, an anticoagulant present in the "purple top" (it's really lavender) tube that is used to draw blood for a CBC - **Erythropoietin:** released by kidneys in response to hypoxia, stimulates RBC production in marrow - A common "performance enhancing drug" used in endurance sports - **Prothrombin:** aka factor II, activated into thrombin and converts fibrinogen into fibrin to promote clot formation - **Fibrinogen:** the precursor molecule to fibrin which binds to itself in long strands in order to form a matrix for clot formation. - **Plasminogen:** the precursor to plasmin, which breaks down fibrin clot matrix into fibrin degradation products such as D-dimer - **Fibrinolysis:** the action of breaking down the fibrin matrix into fibrin degradation products - **D-dimer:** a fibrin degradation product. When found in the blood can be an indicator that a clot exists **Visual Morphology** - Erythrocytes - Platelets - Differential count ("diff") - Neutrophils - Lymphocytes - Monocytes - Eosinophils - Basophils - In order to find the absolute counts, you multiply the WBC count by the % for each cell type in the diff **Thrombosis** - Think of the clotting cascade as a pyramid scheme. If I recruit 5 friends, and they each recruit 5 friends, and they each recruit 5 friends... - a lot can get done very quickly - in the case of a pyramid scheme, that "a lot" is the person at the top getting really rich - in the case of clot formation, that "a lot" is you not bleeding out from your papercut - Damage to endothelium: collagen is exposed - Circulating Von-Willebrand factor binds to the exposed collagen and unrolls, exposing binding sites for platelets - Platelets bind to the vWF and form a plug - Platelets change shape from a disc to a spiny sphere with pseudopodia - Platelets activate and release enzymes to promote vasoconstriction - Platelets release factor V, VIII, fibrinogen, von Willebrand factor - then the cascade hits - The Common Pathway - The Prothrombin Activator Complex (Xa and Va) uses calcium ions to convert prothrombin to thrombin (II to IIa) - Thrombin (IIa) uses calcium ions to convert fibrinogen to fibrin (I to Ia) - Fibrin naturally forms strands - Thrombin activates Fibrin Stabilization Factor (XIII to XIIIa) - Fibrin stabilization factor (XIIIa) forms the fibrin strands into a fibrin mesh - The Extrinsic Pathway (AKA tissue factor pathway) - Factor VII is abundant circulating in blood - Damaged tissue expresses Tissue Factor (III) - Tissue Factor activates Factor VII (VII to VIIa) - VIIa uses calcium ions to activate Factor X (X to Xa) - Factor VII is also activated by IIa and Xa - The extrinsic pathway is rapid, due to the large volume of Factor VII and the numerous feedback loops built in - The Intrinsic Pathway (AKA contact activation pathway) - Triggered by inflammation, damage to blood cells, damage to endothelial cells, exposed collagen from cell damage - All components are actively circulating in the blood ("Intrinsic") - Factor XII is activated by above triggers (XII to XIIa) - Factor XIIa uses cofactors to activate Factor XI (XI to XIa) - Factor XIa uses calcium ions to activate Factor IX (IX to IXa) - Factor IXa activates Factor VIII (VIII to VIIIa) - Factor IXa and VIIIa combine with platelet cell membrane and use calcium ions to activate Factor X (X to Xa) - Factors XIIa and IXa both contribute more activation to Factor VII - The intrinsic pathway is slower, but makes much more fibrin than the extrinsic - Meanwhile, plasminogen is converted to plasmin by u-PA and t-PA - plasmin breaks down fibrin into fibrin degradation products (FDPs) FIBRINOLYSIS - A notable FDP is D-dimer - What's the deal with factor 6? - Vitamin K is important in the creation of factors II, VII, IX, X in liver - Prothrombin time (PT/inr) is a measure of the extrinsic pathway, sorta - Activated partial thromboplastin time (aPTT) is a measure of the intrinsic pathway, sorta **Hematopoiesis** - Our bone marrow is a conveyer belt of various lines of blood cells. I'm trying to go for a clinically-applicable breakdown of the process here. - Under "normal" conditions, cell maturation takes place in the bone marrow. Cells are released into the bloodstream when they are "ready" to go out and do their cell jobs. - In times of physiologic stress, immature cells from various lines may be released into the bloodstream. - severe anemia: you may see reticulocytes - bacterial infection: "left shift" of the neutrophil line with a number of neutrophilic myelocytes and bands - Various hematologic neoplasias: we'll discuss this in week 3 **Anemia** - Anemia is a decrease in one or more of the major RBC measurements from a CBC - Measured by: - Hemoglobin content (Hgb) (Males: \ - **Sickle Cell Anemia** - An autosomal recessive hemoglobinopathy which manifests as a chronic hemolytic anemia occurring mainly in people of African origin - It is a chronic hemolytic anemia causing a wide array of clinical consequences - A single DNA base change from glutamine to valine in the 6^th^ position of the beta-globin chain of the hemoglobin molecule causes the molecule to be unstable when stressed forming a sickle-shaped RBC - Hemoglobin S is the major hemoglobin on electrophoresis in patients with this disease - Sickled cells cause blockages of small vessels leading to acute vaso-occlusive episodes which are extremely painful - **Signs and Symptoms** - Onset during first year of life as Hemoglobin F is replaced by Hemoglobin S - Infections & folic acid deficiency can cause an aplastic crisis - Vaso-occlusive episodes triggered by infection, dehydration, or hypoxia - Acute vaso-occlusive episodes can cause strokes - Pulmonary hypertension can develop - Jaundice, gallstones (calcium bilirubinate), splenomegaly (young), hepatomegaly, cardiomegaly with hyperdynamic precordium, systolic murmurs, ulcers on the lower tibia which heal poorly - **Laboratory findings** - Chronic hemolytic anemia - Sickle cells on peripheral smear - Reticulocytosis - Howell-Jolly bodies and target cells (signs of hyposplenism) - Elevated indirect bilirubin - Hemoglobin SS seen on electrophoresis - Hemoglobin AS signifies sickle cell trait - **Treatment** - Allogeneic hematopoietic stem cell transplantation performed prior to development of organ damage - Hydroxyurea decreases frequency of painful crises - Folic acid supplementation - Pain management - Blood transfusions (caution due to risk of iron overload) - Hydration - Avoid activities that may precipitate an acute crisis - Oxygen use if hypoxic - **Thalassemia** - Hereditary reduction in the synthesis of globin chains (alpha or beta) - It is a microcytic, hypochromic anemia but with a normal or elevated RBC count as opposed to iron deficiency anemia which is a microcytic hypochromic anemia with a normal to low RBC count - Mentzer Index: Divide MCV by RBC count. If result \13 then iron deficiency, if \< 13 then thalassemia - Hemoglobin electrophoresis - Alpha Thalassemia: No change in the proportions of hemoglobin A, A~2~, and F - Beta Thalassemia: Increased proportions of hemoglobin A~2~, and F compared to hemoglobin A - Alpha-thalassemia due to gene deletions causing decreased alpha-globin chain synthesis - Primarily affects persons of southeast Asia or China ancestry - Beta-thalassemia due to point mutations rather than deletions resulting in reduced or absent beta-globin chain synthesis - Primarily affects persons of Mediterranean (Italian, Greek) ancestry, as well as, those of African ancestry - Clinical picture dependent upon number of alpha- or beta-chains affected - **[Alpha Thalassemia]** - [Hydrops fetalis ] - Loss of all four alpha-globin genes - Severe anemia during fetal development with hydrops fetalis; typically this is incompatible with live birth - Only hemoglobin produced is hemoglobin Barts (Hb Barts; i.e., tetramers of gamma globin) - [Hemoglobin H disease (HbH)] - Loss of three alpha-chain genes - Clinical severity in HbH disease is variable - Some have a mild microcytic anemia and neonatal jaundice; however, others have a severe anemia - Most are not transfusion dependent - Should be given folic acid supplementation and avoid medicinal iron and oxidative drugs - [Alpha thalassemia minor (also called alpha thalassemia trait)] - Loss of two alpha-chain gen - Clinically mild condition characterized by mild anemia, hypochromia, and microcytosis without other clinically obvious manifestations - Hemoglobin electrophoresis is normal so condition is a diagnosis of exclusion - [Alpha thalassemia minima (also called silent carrier)] - Benign carrier state - No anemia is evident - **[Beta Thalassemia]** - [Transfusion-dependent beta thalassemia (beta thalassemia major) ] - Also known as Cooley\'s anemia - No beta globin chain production - Most severe form of beta thalassemia - Profound anemia - Life-long dependency on blood transfusions - Iron chelation needed to prevent iron overload - Without treatment, patients present with pallor, jaundice and dark urine from hemolysis; irritability from anemia; and abdominal swelling from hepatosplenomegaly - High mortality rate if untreated (85% will die by age 5 years old) - Allogenic stem cell transplantation is the treatment of choice - [Non-transfusion-dependent beta thalassemia (beta thalassemia intermedia) ] - Less severe phenotype than beta thalassemia major - Not transfusion dependent during childhood but may require transfusion dependence later in life - May require a splenectomy - Condition complicated by several diseases: - Osteoporosis - Extramedullary hematopoiesis - Hypogonadism - Cholelithiasis - Thrombosis - Pulmonary hypertension - Abnormal liver function - Leg ulcers - Hypothyroidism - Heart failure - Diabetes mellitus - [Beta thalassemia minor (also called beta thalassemia trait) ] - Carrier state - Often asymptomatic - May have a mild anemia - **Hemochromatosis** - Autosomal recessive disease - HFE gene mutation on chromosome 6 (C282Y or H63D) - Mutation leads to increased iron absorption in gut - Decreased hepcidin also results - Hemosiderin (iron) deposits in liver, pancreas, heart, adrenals, testes, pituitary and kidneys - Hepatic and pancreatic insufficiency, heart failure, and hypogonadism may develop - Cirrhosis more likely in patients how have ETOH abuse or steatosis - Clinical Presentation - Usually manifests after 50 y/o (iron screening can diagnosis earlier) - Nonspecific symptoms at first (fatigue, arthralgia) - Later in course patients can develop: - Arthropathy - Hepatomegaly and hepatic dysfunction - Skin pigmentation - Cardiomegaly +/- HF +/- conduction defects - Diabetes mellitus - Erectile dysfunction - Diagnostic Findings - Elevated AST & Alk Phos - Elevated plasma iron with \45% transferrin saturation - Elevated serum ferritin - HFE mutations on genetic testing - Iron overload in liver can be seen on MRI and CT - Liver Biopsy to eval for cirrhosis in appropriate patients - Screening for + FMHx - Treatment - Avoid iron supplements and iron-rich foods (red meat) - Avoid ETOH, vitamin C, and raw shellfish - Phlebotomy is required in all symptomatic patients - Proton Pump Inhibitors decrease frequency of phlebotomy - Chelating agents - Deferoxamine IV or SQ - Deferasirox PO - Deferiprone PO **Hemophilia A and B** - Genetics - Recessive X-linked inherited deficiency of coagulation factors - Hemophilia appears in all ethnic groups, with no apparent racial predilection - Hemophilia A: Deficiency of coagulation factor VIII (approximately 1 in 5000 live male births) - Hemophilia B: Deficiency of coagulation factor IX (approximately 1 in 25,000 live male births) - Females are carriers - Screening indicated for patients with + FMHx or personal history of excessive bleeding - HIV and HCV are often seen in older patients due to blood transfusions prior to screening - Pathophysiology - As we might remember from a short while ago, factors VIII and IX activate factor X - Hemophilia A is a deficiency in factor VIII - Hemophilia B (Christmas disease) is a deficiency in factor IX - my way to remember: "Benign"... B-9 - These deficiencies result in delayed clot formation---if factor X doesn't activate prothrombin to thrombin, thrombin doesn't adequately convert fibrinogen to fibrin, and we don't get those nice strands to solidify the clot and support the platelet plug. - When a clot does finally form, it is weak and easily degraded - May be hereditary or from spontaneous mutation - Clinical manifestations - Neonates - 2% of neonates with hemophilia develop intracranial hemorrhages - 30% with bleeding from circumcision site - Poorly controlled bleeding from umbilical stump - Toddlers / cruising infants and up - Easy bruising - Intramuscular hematomas - Hemarthroses (hallmark for hemophilia, more common in hereditary) - Spontaneous bleeding in joints and soft tissue occurs most often in severe factor VIII deficiency - Mild deficiency of factor VIII rarely has spontaneous bleeding but may have excessive bleeding with trauma or surgery - - Bleeding from minor mouth injuries may continue for hours to days - Iliopsoas hemorrhage is common and may result in severe hypovolemia and shock - Usually a vague complaint of groin or hip pain - Female carriers will sometimes also manifest bleeding disorders due to varying amounts of factor VIII - Lab findings and diagnosis - Reproducibly low factor VIII or IX activity level - Elevated activated partial thromboplastin time (aPTT) (2-3x upper limit in severe hemophilia) - Platelet count & PT/INR are NORMAL - 25-35% of patients with hemophilia may develop an "inhibitor" (factor specific antibody) and may not improve with infusion of factor VIII or IX - Classification - Severe: \