Blood Disorders I PDF

BLOOD DISORDERS Dr. J. Savory Université d’Ottawa | University of Ottawa Disclosure You may only access and use this PowerPoint presentation for educational purposes. You may not post this presentation or the associa...

BLOOD DISORDERS Dr. J. Savory Université d’Ottawa | University of Ottawa Disclosure You may only access and use this PowerPoint presentation for educational purposes. You may not post this presentation or the associated videos online or distribute it without the permission of the author. uottawa.ca  Pre-lecture Review (Self learning) The relevant chapter in the Marieb & Hoehn Anatomy and Physiology text relating to this topic:  Chapter 17 - Blood Your ANP1105 lecture note on Blood would also be helpful Slides with this symbol will be discussed VERY briefly during the lecture because the information on these slides would have been covered in your ANP courses and it will be assumed that you have taken the time to review the information on your own if you need a refresher  Objectives Chapter 13: Alterations in Oxygen Transport 1. Review the composition and functions of blood, as well as the process of hematopoiesis. 2. Describe the hematologic tests and the significance of the measurements. 3. Define anemia, give the clinical manifestations and explain the compensatory mechanisms. 4. Explain the classification of anemias based on i) general causes and ii) RBC indices. 4.1. Amenias of Deficient RBC Production: 4.1.1. Aplastic anemia: explain the main causes and clinical manifestations of aplastic anemia and explain how chronic disease can lead to anemias. 4.1.2. Megaloblastic anemia: explain why deficiency of cobalamin (vitamin B12) or folate leads to macrocytic anemia; compare the causes and describe clinical manifestations and diagnostic tests for these deficiencies. 4.1.3. Iron-deficiency anemia: review iron homeostasis and describe the causes and clinical manifestations of iron- deficiency anemia; list diagnostic tests and discuss nutritional strategies for prevention and treatment of iron deficiency anemia 4.2. Hemolytic anemias 4.2.1 Explain the clinical manifestation; compare the differences between i) intrinsic causes (generally hereditary) and extrinsic causes (generally acquired); ii) extravascular hemolysis and intravascular hemolysis. 4.2.2. Describe the major causes of acquired hemolytic anemias 4.2.3 Thalassemia: explain the causes, pathophysiology and different forms; describe clinical manifestations, treatment and complications of thalassemia. 4.2.3. Describe the pathophysiology, clinical manifestations and treatment of the sickle cell disease, hereditary spherocytosis and Glucose-6-Phosphate Dehydrogenase Deficiency 4.2.4 Describe the major causes of acquired hemolytic anemias. 4.2.4. Hemolytic Disease of the Newborn: explain the causes & pathophysiology; describe clinical manifestations, treatment and complications 5. Polycythemia 5.1. Define polycythemia and explain the differences between the three types of polycythemias. 5.2. Describe the clinical manifestations, pathophysiology, complications and treatment of polycythemia vera.  Objectives cont. Chapter 14: Alterations in Hemostasis and Blood Coagulation 6. Briefly review the stages of hemostasis and compare the information obtained from INR (international normalized ratio) and PTT (partial thromboplastin time) tests. 7. Hemostasis: Platelet disorders 7.1 Define thrombocytopenia, discuss the possible causes, pathophysiology and clinical manifestations 7.2 Define thrombocytosis and describe the conditions and factors that can induce thrombosis, with specific examples of disorder associated with each case. 7.3 Define qualitative platelet disorder, discuss possible causes, clinical manifestations, diagnosis and treatment options 8. Hemostasis: Coagulation disorders: 8.1. Describe the causes, pathophysiology, clinical manifestations and treatment of von Willebrand disease and hemophilia. 8.2. Describe the role of vitamin K in coagulation; list the sources of vitamin K and discuss the causes and consequences of vitamin K deficiency 8.3. Discuss causes, pathophysiology and consequences of thrombosis. List known treatment options for undesirable blood clots 8.4. Explain the pathophysiology, clinical manifestations and typical laboratory findings of disseminated intravascular coagulation. 8.5. Describe the most common tests for bleeding disorders  Introduction Hematocrit: Composition of blood in the Mature ProgenitorsCommitted precursors Stem Cells Maturation of Human Blood cells Two groups of disorders: Anemia a deficit of red cells Polycythemia as an excess of red cells  ERYTHROCYTE INDICES Standard lab TEST DESCRIPTION values M: 4.2 - 5.4 X 106/mL RBC count # RBC/mL of blood F: 3.6 - 5.0 X 106/mL % of total blood volume F: 37 - 47% Hematocrit occupied by RBCs M: 40 - 50% F: 12 - 15g / dL (100 mL) Hemoglobin (Hb) # g Hb/L of blood M:14 - 16.5g / dL (100 mL) Mean corpuscular volume (size) of the 85-100 fL / RBC volume (MCV): average RBC Mean corpuscular Red cell mass 27 - 34 pg/cell hemoglobin (MCH) Mean corpuscular hemoglobin [Hb] (g) per 10 ml of RBCs 31 - 35 g/dL concentration (MCHC) % of immature RBC 1 – 1.5 % of total RBC  Anemia  a reduction in the total number of erythrocytes or a decrease in the quality or quantity of hemoglobin. Relative anemia - normal total red cell mass with disturbances in regulation of plasma volume Absolute anemia - actual decrease in numbers of red cells Commonly results from:  blood loss (acute or chronic) https://assets.aboutkidshealth.ca/akhassets/ Anemia_MED_ILL_EN.png?RenditionID=19  impaired RBC production  increased RBC destruction  a combination of the three factors  General Effects of Anemia Reduction in oxygen-carrying capacity tissue hypoxia Compensatory mechanism to: 1. increase blood flow – increased HR, CO, circulatory rate, and flow to vital organs 2. restore tissue oxygenation – increase in 2,3-DPG in erythrocytes and decreased oxygen affinity of hemoglobin in tissues – increase in erythropoietin activity Physiological adaptations is influenced by: – the severity of the anemia – the competency of the pulmonary and cardiac systems – the oxygen requirements of the individual, which are dependent on physical and metabolic activity – the duration of the anemia – the underlying disease or condition – the presence and severity of coexisting disease  General Effects of Anemia Mild anemia – Usually no clinical symptoms – Elderly with cardiovascular, pulmonary disease may have symptoms Mild to moderate anemia – Fatigue, generalized weakness, and loss of stamina, followed by tachycardia and exertional dyspnea Moderate to severe anemia – Orthostatic and generalized hypotension, vasoconstriction, pallor – Tachypnea, dyspnea – Tachycardia, transient murmurs, angina pectoris, heart failure – Intermittent claudication, night cramps in muscles – Headache, lightheadedness and faintness – Tinnitus, roaring in the ears Hemolytic anemias are accompanied by jaundice due to levels of bilirubin Aplastic anemia: petechia & purpura due to  platelet function tiological Classification of Anem Etiology - underlying cause 1. Decreased RBC Production – Inherited genetic defects leading to stem cell depletion (e.g. Fanconi anemia) – Infection of RBC progenitor in the bone marrow (e.g. parvovirus B19 infection) – Immune mediated injury of progenitor in the bone marrow (e.g. aplastic anemia) – Primary hematopoietic neoplasm malignancies affecting precursor cells (e.g. acute leukemia, myeloproliferative disorders) – Space occupying marrow lesions (e.g. metastatic neoplasia) – Nutritional Deficiencies: – Deficiencies affection DNA synthesis (e.g. B12 and folate) – Deficiencies affecting hemoglobin synthesis (e.g. iron deficiency) – Inflammation mediated Fe sequestration (e.g. sequestration of Fe in macrophages in anemia of chronic diseases) – Erythropoietin deficiency (e.g. renal failure) – Unknown mechanisms (e.g. endocrine or liver disorders) tiological Classification of Anem 2. Increased RBC destruction – Inherited genetic defects (RBC membrane disorders, enzyme deficiencies (G6P), Hb deficiencies (thalassemia, SCD) – Acquire genetic defects – Antibody medicated sequestration (e.g. transfusion reaction, hemolytic disease of the newborn) – Mechanical trauma (e.g. defective valves, DIC) – RBC infections (e.g. malaria) – Toxic or chemical injury (e.g. snake venom or led poisoning) – Membrane lipid abnormalities (e.g. sever lipid disease) – Sequestration Hypersplenism 3. Blood Loss – Acute or sudden (e.g. accident) – Chronic or gradual (e.g. GI lesions or gynecological disturbances) orphological Classification of Anem 1. According to the mean corpuscular volume (MCV) of RBC High Macrocytic MCV Normal Normocyti c Variations in Size of Erythrocytes (From Rodak BF, Carr JH. Clinical hematology atlas. 5th edition. St. Louis: Elsevier; 2017) Low Microcytic 2. According the Mean Corpuscular Hb Concentration Low (MCH) Hypochromic MCHC Normal Normochrom https://medschool.co/images/detail/bloodfilmhypochromia.gif ic Classification of Anemia ANEMIA RELATED TO DECREASED RBC PRODUCTION Aplastic anemia Anemia of Chronic Renal Failure Vitamin B12 or folate (B9) deficiency Iron deficiency anemia (IDA) 1.APLASTIC ANEMIA Stem cell disorder characterized by reduction of hematopoietic tissue, fatty marrow replacement, and pancytopenia (low RBC, WBC, and platelets) rare but is the most common form of normocytic, normochromic anemia caused by toxic, radiant, or immunologic injury to the bone marrow stem cells diagnosed with bone marrow biopsy disease of the young (15-25) or old (>60) 1. Acquired - Primary 75% of all cases / autoimmune disease direct against hematopoietic stem cells - Secondary Acquired (15%) Exposure to high doses of radiation, chemical (dose dependent) & toxins – Chemotherapy & radiation bone marrow suppression 2. Familial (Genetic alterations) Fanconi anemia: pancytopenia due to defects in DNA repair 1.APLASTIC ANEMIA Clinical Manifestations:  Onset may be insidious or sudden; can occur at any age  Initial symptoms: weakness, fatigue, lethargy, pallor, dyspnea, palpitations, ons of transient murmurs, and tachycardia of anemia (↓RBC)  Increase susceptibility to infection, fevers, chills (neutropenia)  Petechial, ecchymoses, bleeding from nose gum, vagina, GI tract (↓ platelets) Patient history LAB FINDINGS CBC / Reticulocyte ~ 0/ (What about RBC indices?) Bone marrow biopsy – Hypocellular marrow replaced by fat – Absence of progenitor cells The common pathology of the bone marrow replaced by fat. (A) Low power. (B) High power From Kumar V, Abbas A, Aster J. Robbins & Cotran pathologic basis of disease, 10th edition. Philadelphia: Elsevier; 2021.) TREATMENT  Depends on cause & severity  Manage symptoms: blood transfusion of PRBC (anemia) platelets (bleeding)  Bone marrow transplant from compatible donor (80 - 85% curative rate)  When no suitable donor available – immunosuppression therapy. What is the risk?  2. Anemia of Chronic Kidney Failure Failure of the renal endocrine function leading to impaired EPO production Clinical Manifestations Depends on the severity of renal failure but may include any of the manifestations described earlier LAB FINDINGS  What would you predict for RBC Georges Nakhoul, and James F. Simon CCJM 2016;83:613-624 indices? WBC? Platelets? Treatment  EPO therapy 3. Anemia related to Vitamin B12 (cobalamin) or folate (B9) deficiency B12 and folate are coenzymes required for nuclear maturation and DNA synthesis Their absence: Disruption in DNA synthesis of blast cells produces megaloblasts (macrocytic) abnormally large erythroid precursors (megaloblasts) in the marrow that mature into large erythrocytes (macrocytes) the granulocytes are hypersegmented; and the numbers of red cells, white cells, and platelets are decreased. 3. Anemia related to Vitamin B12 (cobalamin) or folate (B9) deficiency Causes of B12 deficiency Damage/atrophy parietal cells in the stomach Re-sectioning of stomach or small intestine Chronic malabsorption in severe Crohn’s disease, AIDS Eg Pernicious anemia autoimmune disease - antibodies against parietal cells and IF Neurological lesions of unknow origin nerve damage degeneration of spinal cord white matter abnormal FA metabolism in peripheral nerve Folate deficiency dietary deficiencies (poor or fad diet), alcoholism, cirrhosis, pregnancy, or infancy, malabsorption 3. Anemia related to Vitamin B12 (cobalamin) or folate (B9) deficiency Clinical Manifestations pernicious anemia – Megaloblastic madness (paranoia, delusions, hallucinations, cognitive dysfunction) – symmetric paresthesia of the feet and hands with proprioception disturbances folate deficiency – blunted affect in general demeanor with evidence of depression, sleep deprivation, and irritability. – Irritability, memory impairment, perversions of smell, taste & vision; depression; disruption of sleep, personality changes Both pedal edema, dyspnea, tachycardia, heart congestion, glossitis, weight loss LAB FINDINGS RBC: MCV, MCH, but normal MCHC Bone marrow: megaloblastic dysplasia – macrocytosis & hyper segmented neutrophils WBCs & Platelets numbers -?? 4. Iron Deficiency Anemia (IDA)  is the most common micronutrient deficiency worldwide  results in the unavailability of iron for hemoglobin synthesis Causes:  Dietary deficiency (low intake)  diminished absorption (e.g., from chronic disease)  physiologic increase in requirements (e.g., during pregnancy)  excessive iron loss (e.g., from acute or chronic hemorrhage)  chronic renal failure, hemodialysis  idiopathic iron loss.  ID more common in women than men 4. Iron Deficiency Anemia (IDA) Clinical Manifestations 1. No signs or symptoms 2. Features of the underlying disorder responsible for the development of iron deficiency 3. General sign of anemia 4. IDA specific symptoms Pallor of the skin, mucous membranes & palmar creases (palmar creases become as pale as the surrounding skin) Koilonychia -the nails are concave, ridged, and brittle. Glossitis -tongue has bald, fissured appearance caused by loss of papillae and flattening. Pica (craving of non-food substances e.g. dirt, ice, cardboard) predisposes a person to infection can precipitate heart failure and has been associated with restless leg syndrome in the elderly 4. Iron Deficiency Anemia (IDA) LAB FINDINGS  RBC: hypochromic, microcytic  WBC count normal, platelet count may vary (depending on deficiency cause) Iron Binding Studies  serum ferritin level is decreased; serum iron level is decreased, total iron- binding capacity (TIBC) is increased, and tissue iron stores are decreased. Treatment  Oral iron therapy using iron salts  iron sulfate is most commonly used for 3-6 months Adults: 100 – 200 mg; children 3-6 mg/kg of body weight of liquid preparation  If oral therapy fails intravenous ferric gluconate determine reason Treat underlying cause  Anemia Related to Inherited Disorders of the Erythrocytes Inherited genetic defects causing anemia include:  abnormalities of hemoglobin synthesis causing slow production (thalassemia)  increased RBC hemolysis and destruction (sickle cell disease)  structural abnormalities (spherocytosis)  inherited enzyme deficiencies (glucose-6-phosphate dehydrogenase [G6PD] deficiency) Anemia results from hemolysis (hemolytic anemia)  premature accelerated destruction of erythrocytes, either episodically or continuously Hemolytic anemias are accompanied by jaundice due to levels of bilirubin Hemolytic anemias may be either  congenital (hereditary spherocytosis, thalassemia, SCD)  Acquired (immunogenic - erythrocyte destruction caused by autoantibodies against erythrocyte antigens  CLASSIFICATION 1. Whether the cause of hemolysis is intrinsic or extrinsic Intrinsic causes: usually hereditary; include defects of RBC membranes & hemoglobinopathies (eg thalassemia, sickle cell disease, hereditary spherocytosis) Extrinsic causes: acquired; cause by agents external to the RBCs such as drugs, toxins, antibodies, physical trauma & mechanical factors (eg prosthetic heart valves & severe burns) 2. Location of hemolysis: within or outside the vascular compartment Intravascular hemolysis: less common; due to complement fixation in transfusion reaction/ mechanical injuries or toxic factors o Characterized by hemoglobinemia, hemoglobinuria, jaundice & hemosiderinuria Extravascular hemolysis: RBCs become deformed & unable to traverse capillaries / abnormal RBCs sequestered & phagocytized by macrophages in the spleen 1. Thalassemia  associated with mutant genes that suppress the rate of globin chain synthesis  classified by the polypeptide chain(s) with deficient synthesis (α-thalassemia or β- thalassemia)  all forms involve an imbalance rate of production of the globin protein of HbA  Heterozygotes have thalassemia minor and exhibit mild signs of anemia  Homozygotes: thalassemia major - a severe form of the anemia Pathophysiology of β- thalassemia 1. Thalassemia Clinical Manifestations Thalassemia minor (silent carriers) mild to moderate anemia Thalassemia major: – Bone deformities (intramedullary & extramedullary bone marrow expansion) – hepatomegaly / splenomegaly – Cardiac failure – Hypogonadism from excessive intestinal iron absorption. Lab Findings  # of RBC  MCV, MHC, MCHC  reticulocytes  WBC- usually increased  Platelets - normal. Sickle Cell Disease (SCD) most common & most severe form of the hemolytic anemias an inherited, autosomal recessive disorder caused by mutation in the b globin gene leading to abnormal hemoglobin - HbS HbS formed by the replacement of an Glu with Val, in the - chain, secondary to a mutation of a base on the DNA (flipping of A and T) very frequent among Blacks from the sub-Sahara Africa (9- 10% are gene carriers) Sickle Cell Disease (SCD) Clinical Manifestations Chronic hemolytic anemia, recurrent painful episodes, and acute and chronic organ dysfunction particularly of the spleen, bones, brain, kidneys, lungs, skin, and heart are the cardinal features of sickle cell anemia Severe Anemia – Sickled RBC are mechanically weak, have  survival time & are prone to intravascular hemolysis (jaundice) – Chronic hyperbilirubinemia Vessel occlusion – venous thrombosis; arterial emboli – cardiac & renal failure – frequent, often serious, infections – retinopathies (due to micro thrombosis) – pregnancy accidents Pulmonary & cardiovascular complications – chamber enlargement related to significantly increased forward output due to chronic anemia – myocardial infarction from vasoocclusion of the coronary arteries – RV dysfunction may lead to pulmonary hypertension Splenomegaly, hepatomegaly Sickle Cell Disease (SCD) LAB FINDINGS Severe anemia with red cells of different shapes and sizes. RBC: present, and occasionally sickled cells increases serum bilirubin, urobilinogen, and urobilin levels Reticulocyte count: high WBC and Platelets - normal Acute hemolytic crisis : hemoglobinuria, leukocytosis diffuse intravascular coagulation may develop. 3. Hereditary Spherocytosis a disorder of the RBC membrane transmitted as an autosomal, dominant trait Mutations in genes producing RBC membrane proteins involved in transport, attachment & maintain cell structure, RBC flexibility Mutations in RBC membrane proteins result in changes in shape, becoming more spherical instead of a flattened disc shape, and rigid Clinical Manifestations  anemia, jaundice, and splenomegaly anemia is usually mild because of compensation by the erythropoietic bone marrow cells. yellowing of the skin and eyes (jaundice), pale color (pallor) in infants, leg ulcers, bilirubin, gallstones 3. Hereditary Spherocytosis LAB FINDINGS [hemoglobin] within the red cells is increased spherocytes in the peripheral blood smear increased number of reticulocytes Hereditary Spherocytosis – Blood Smear RBC --?? WBC / Platelets ??? https://askhematologist.com/wp-content/uploads/2016/02/ Hereditary-Spherocytosis-HS.jpg Treatment Splenectomy: cures the anemia but doesn't correct the abnormal cell shape Blood transfusions may be required in a crisis Anemia Related to Extrinsic Red Cell Destruction or Loss Hemolytic Disease of the Newborn Hemorrhagic anemia 5. Hemolytic Disease of the Newborn can occur only if antigens on fetal RBC differ from antigens on maternal RBC fetal-maternal ABO incompatibility is the most common cause of HDNB Rh incompatibility is clinically more important because of the severity of the hemolytic disease.  1. Hemolytic Disease of the ClinicalNewborn Manifestations  neonates with mild HDN may appear healthy or slightly pale, with slight enlargement of the liver and spleen Severe disease:  hemolytic anemia (pronounced pallor, splenomegaly, & hepatomegaly extramedullary erythropoiesis, hyperbilirubinemia & jaundice, petechial hemorrhages  heart failure (with pulmonary edema, pleural effusions, ascites, and edema- hydrops fetalis)  diffuse intravascular coagulation are seen in these infants. Many infants die in utero. LAB FINDINGS anemia, an increased number of circulating reticulocytes RBC indices (MCV, MCH, MCHC) ?? leukocytosis is present platelet counts are usually normal, but thrombocytopenia seen in infants with severe disease HEMORRHAGIC ANEMIA Blood loss Due to trauma or secondary to a disease process Rapid or gradual decrease in overall blood volume which impairs oxygen delivery LAB FINDINGS  Normal to low hematocrit and Hb  Reticulocytes ?? What would you predict for the following RBC indices?  MCV  MCH  MCHC