Pathophysiology of Blood System PDF

# Chapter 18: Blood System Pathologies Blood system pathologies can be due to: - Blood volume changes - Physicochemical properties changes - Changes of cells - Changes of hemostasis ## Blood Volume Changes Blood makes up 6-8% of body weight (~5-6L) ~3.5-4L is circulating. Hematocrit in males is 4...

# Chapter 18: Blood System Pathologies Blood system pathologies can be due to: - Blood volume changes - Physicochemical properties changes - Changes of cells - Changes of hemostasis ## Blood Volume Changes Blood makes up 6-8% of body weight (~5-6L) ~3.5-4L is circulating. Hematocrit in males is 44-46%, in females 41-43% ### Hypovolemia - Oligocytemic: Massive hemolysis, Addison-Birmer - Simple: 1 stage blood loss - Polycytemic: Dehydration, shock ### Normovolemia - Oligocytemic: Hemolysis, aplastic, 1-2D after bleeding - Simple: Normal - Polycytemic: RBC infusion ### Hypervolemia - Oligocytemic: ADH↑, Renal failure, Plasma Substitution - Simple: Blood transfusion, exercise - Polycytemic: Hypoxia, Polycythemia vera ## Changes of Physicochemical Properties ### Physicochemical Properties - Specific gravity: 1.05-1.06 - Viscosity: Plasma (1.9-2.6), Blood (3.5-5.4), CO2↑→Viscosity↑ - Osmotic pressure: 7.5-8.1 atm (60% Na), Colloid: 25-30 mmHg - RBC resistance to osmosis: A/V, minimal 0.48-0.44%, maximum 0.32-0.28% - ESR: Women 2-15, men 1-10 - ESR↑: Protein↑, PH↑, ↓cholesterol↑, osmiat, pregnancy, inflammation - ESR↓: Lecithin, bilet, RBCs↑ ## Changes of Cells: RBCs ### Quantitative/Qualitative - **Quantitative**: Cytosis or Penia - **Qualitative:** Regenerative, degenerative, pathological ### Size (MCV) - Normal Size: 6.5 < x < 8 µm - Schistocytes: <2-3 µm - Measured through MCV: 80-98fl ### Shape/Saturation - **Shape**: Anisocytosis, Poikilocytosis, Anisochromia, inclusions - **Saturation**: Cl, MCH, MCHC - Cl: 3Hb/first 3 No of RBC/l - MCH: Hb/RBC, 26-33 pg - MCHC: Hb/HCx100, 30-36% ### Anisocytosis - **Anisocytosis**: Variation in RBC size: - Normal - Macrocyte - Microcyte - Oval macrocyte - RBC according to the color: - Hypochromasia (thalassemia) - Polychromasia (reticulocyte) - Hyperchromasia - **Poikilocytosis**: Variation in shape - Target cell - Teardrop cell - Ovalocyte - Elliptocyte - Acanthocyte - Burr cell - Stomatocyte - Sickle cell - Fragmented RBC - Crenated RBC - Red blood cells inclusions: - Basophilic stippling - Cabot ring - Heinz bodies - Siderocyte - Howell-Jolly body - Hemoglobin C ### Megalocytes - Men: 4-5x10¹²/l, 130-160g/l - Women: 3.7-4.7x10¹²/l, 120-140g/l ## Erythrocytosis ### Absolute Erythrocytosis - **Primary**: Polycythemia vera (vaquez-osler disease) - Normal erythropoietin - **Secondary**: - Sympathetic ↑ - Endocrine↑ - Hypoxia - Tumors - *Erythropoietin↑* ### Relative Erythrocytosis - Plasma loss: Vomiting, diarrhea, burn - Gaisböck Syndrome ## Polycythemia vera - Pathophysiology: JAK2 mutation -> Erythropoiesis↑+WBCs -> Pancytosis - At terminal stage: *Myelofibrosis* -> Pancytopenia - Symptoms: - Limb swelling and red color - BP↑ - Viscosity↑ - Thrombosis - LV hypertrophy - Bleeding - Itch - Splenomegaly - *Myelofibrosis* ## Anemias - Pathogenesis: - Post-hemorrhage - Dyserythropoietic - Hemolytic - *Origin*: Genetic, Acquired - *Regeneration* : Regenerative, hypo-, hyper-, a- - *Color* : Hypochromic, Normochromic, Hyperchromic - *Hematopoiesis* : Normoblastic, Megaloblastic - *Course*: Acute, chronic ## Posthemorrhagic Anemia - Due to trauma, pathology, or permanent (diapedesis) ### Acute - Symptoms: HR↑, Dyspnea, pale skin, BP↓ - Compensation: - Vascular-reflex stage (8-12h): Sympathetic ↑ - Peripheral constriction - Heart↑ - CI normal - Hydremia stage (1-2D): Fluid from plasma - 2-3D proteins from lymph, 4th D from liver - 8-10D normalize - CI normal - Bone marrow stage (4-5D): - Erythropoietin↑ - Aniso + Poikilo - CI↓ ### Chronic - Hyporegenerative, Hb↓ -> Micro, Poikilo, hypochromic ## Dyserythropoietic Anemia - 4 types: - Iron deficiency anemia - B9, B12-deficiency anemia - Hypoplastic anemia - Aplastic anemia ### Iron Metabolism - *DcytB* + Vitamin C, HCl. Pyruvate - If excess Fe: - **Liver: Storage** - *Fe₃⁺* - *Hepcidin* - *Ferroportin* - *Ceruloplasmin* - *Fe₂⁺* - **Spleen: Storage** - *Fe₃⁺* - *Apoferritin* - *Ferritin* - *Fe₂⁺* - *Hemosiderin* - *Transferrin* - *Fe₂⁺* - **Bone marrow: Erythropoiesis** ## Iron-Deficiency Anemia - Auto R - Etiology: - Nutrition - Demand↑ - Malabsorption - Chronic bleeding - Transport: *Atransferrinemia*, acquired hypotransferrinemia - Pathogenesis: - *Fe*↓ -> *Heme*↓ -> *RBCs*↓ + *Cytochromes*↓ -> *Hypoxia* + *ROS*↑ - Symptoms: - Hemato: *Hb*↓, *CI*↓, hyporegen, Micro, neutrophils↑, ferritint, sideroblasts↑, erythroid line↑ - *Blue bone marrow* - Hypoxic: Hemic+Tissue hypoxia - Trophic: *Ros*↑ -> Dry skin, cracks, brittle nails, hair loss, papillae atrophy, atrophic glossitis, angular stomatitis, atrophic gastritis - Sideropenia: Parorexia (pica) - Muscles: Myoglobin↓ -> Weakness, fatigue, myocardial dystrophy, dysphagia ## B9, B12 Deficiency - Etiology: - Nutrition - Demand↑ - Malabsorption: - *Castle factor* - Intestinal diseases - Diphyllobothriasis - Deposition and synthesis issues - Autoimmune: Addison-Biermer - Ig to parietal cells - Ig to block binding - Ig to B12-factor complex - Pathogenesis: DNA synthesis disruption -> Nuclear-cytoplasmic asynchrony -> Megalocytes (one mitotic cycle instead of 3) - Anemia - Hypersegmented giant neutrophils: Pancytopenia - Symptoms: - GI mucosal inflammation and atrophy - Aniso + Poikilo (oval) - *CI*↑ - Inclusions: Jolly, Cabot - *Adосы* -> *Propionic* + *Methylmalonic* acids↑ -> Funicular myelosis - Axresthic anemia (Israel-Wilkinson) ## Hypoplastic and Aplastic Anemia - Such anemias can be acquired: Drugs, chemicals, radiation, infections, autoimmune, endocrine or hereditary - Pathogenesis: - Damaging factors -> DNA damage - Autoimmune: Autoreactive CD8+ -> Kill stem cells - *Telomerase shortening* ### Specific Values - ESR: 30-50 - Fe level: ↑ - *Normal spleen* ## Hereditary Hypoplastic and Aplastic Anemia ### Hypoplastic - Ehrlic anemia ### Aplastic - **Partial** - Diamond-Blackfan - Red cell aplasia - **Total** - Fanconi anemia - Estren-Dameshek ## Hemolytic Anemia - Normo *CI*, regen, erythroblastic - **Types**: - Acquired - Hereditary - **Extravascular/Intravascular**: - Jaundice - Hepatosplenomegaly - Hyperbilirubinemia - Hyper everything ### Acquired/Hereditary - **Acquired**: - Trauma - Immune - Drugs - Toxins - Infections - Membranopathies - **Hereditary**: - Membranopathies - Enzymopathies - Hemoglobinopathies ## Membranopathies - Most important - Can be due to: - Membrane proteins: Spherocytosis, elliptocytosis, ovalocytosis, stomatocytosis - Membrane lipids: Acanthocytosis, LCAT deficit anemia ### Hereditary Spherocytosis (HS, Minkowski-chauffard Syndrome) - *Auto D* - Spectrin+Ankyrin mutation -> Violation of membrane - Loss of parts -> Spheroid shape - Macrophages kill RBCs in spleen every 6-12D ## Enzymopathies - The most important one is 6-6-P DH deficiency: - Favism: X-Rec, triggered by oxidative stress or drugs - *G-6-P DH deficit* -> *NADPH*↓ -> *glutathione*↓ -> *Ros*↑ -> Oxidized *Hb* -> Heinz bodies - *Very damaged cells* -> Intravascular hemolysis, less damaged cells -> Bite cells, extravascular ## Hemoglobinopathies - **Quantitative/Qualitative**: - Quantitative: Sickle cell anemia - Qualitative: Thalassemia ### Sickle Cell Anemia - *Codominance* - Mutation at 6th position of B-globulin: valine instead of glutamate -> *HbS* -> Polymerize - *(HbS is 25x less soluble)* -> Tactoids -> Sickle shape - Symptoms: Extravascular hemolysis + clumping -> Ischemia, pain, angina, cirrhosis, gallstones, osteoporosis ### Thalassemia - *Auto R* - In HbA, there are 2 *α* and 2 *β* chains, each *α* chain is encoded by 2 genes, and each *β* chain is encoded by 1 gene. If *α* genes mutate, *α-Thalassemia* develops, and if *β*, *β-Thalassemia* develops. - In *α-Thalassemia* two types of abnormal Hb develop: - HbH: BBBB, HbBar: rrrr. - They're unstable and accumulate in the center and are under the membrane -> Target cell. - HbH and HbBart have *extreme affinity to O₂* -> Hypoxia. - Results: Extravascular hemolysis, microcytic and hypochromic anemia. ### α-Thalassemia - **Minimal ("silent")** : One gene, no symptoms, 2% HbH - **Minor ("trait")**: 2 genes, might show mild anemia, 5-6% HbH - **Intermedia ("HbH disease")**: 3 genes, moderate-severe, 40% HbH - **Major**: All 4 genes, fatal, 90% HbBart ### β-Thalassemia - **β⁰** (Cooley's disease): homozygous, no *β*, severe - **β⁺**: - Major: homozygous, some *β*, moderate - Minor: heterozygous, "trait", no symptoms - **Cooley's disease**: - Excess *α* -> Rigidity -> Extravascular hemolysis - Ineffective erythropoiesis - Fe absorption↑ -> Hemochromatosis: Liver and heart damage - Bone marrow expansion -> Skeletal deformities ## Acquired Hemolysis - Trauma: - Mechanical vessels - Microangiopathic: DIC, SLE, HTN, TTP, HUS, cancer, marching - Immune: - Isoimmune: Rh, ABO - Autoimmune: SLE, rheumatoid, etc... - Drugs: - Drugs that act like haptens: Penicillins, sulfa, methyldopa -> Rh - Toxins: Endogenous, exogenous, chemical, biological - Infections: Strep, Plasmodium - Membranopathy: Paroxysmal nocturnal hemoglobinuria (Marchiava-Micheli syndrome): - Sporadic mutation of PIGA -> *Glycosylphosphatidylinositol anchors*! - →CD55, CD59! -> Activation of complement at RBCs. - Nocturnal due to *CO₂*↑ at sleep ## Changes of Cells: WBCs - **Quantitative/Qualitative**: - Quantitative: Leukocytosis, leukopenia - Qualitative: Degenerative, regenerative ### Leukocytosis - **Normal:** 4-9x10⁹/l - **Physiological**: Emotion, myogenic, static, alimentary, pregnant, newborns - **Pathological**: - Neutrophilia: >70%, bacteria, purulents, MI, bloodloss, insects, emotion+alimentary - Eosinophilia: >4%, allergies, helminths, endocrine, drugs, collagenoses, hemoblastoses - Basophilia: >1%, type I - Lymphocytosis: >45%, myogenic, veg diet, infections, endocrine, asthma, CLL - Monocytosis:>9%, chronic infections, tumors, inflammatory diseases, splenectomy - **Reactive Leukocytosis**: Happen due to effects of pathogens: Macrophages release *CSF* -> Proliferation↑, IL-1, LPS, TNF-a -> Passage into blood↑ - **Leukemoid reactions**: Leukemia-like (≥30x10⁹/l): - Myeloid (neutrophilic or eosinophilic) - Lymphoid (at mononucleosis) ## Leukopenia - **Acquired**: Physical, chemical, biological - **Hereditary**: Chediak-Higashi syndrome, Kostmann syndrome, lazy leukocyte syndrome ### Pathogenesis - Passage: Damage to stem cells, maturation issues - Staying: Destruction, passage-tissue, elimination↑: Smokers - Redistribution: Transfusion, anaphylaxis - **Agranulocytosis**: Due to agranulopoiesis, immune, ulcerative necrotic tonsillitis - **Lymphocytopenia**: Many diseases - **Monocytopenia**: Severe sepsis ## Qualitative Changes - Degenerative forms: In neutrophils and monocytes - **Vacuolization**: At sepsis, abscess, radiation - **Ridder forms**: Binuclear lymphocytes - **Shadows of Botkin-Gumprecht**: Lymphocytes with destroyed nuclei, at CLL (smudge cells) - **Knyazkov-Döhle bodies**: Oval blue inclusions, at scarlet, measles, sepsis, pneumonia, and burn - **Auer rods**: Dark red sticks - **Hypersegmented neutrophils**: At addison-Biermer - **Immature** -> **Left shift** -> **Nuclear (neutrophilic) index**-> **Right shift** -> **Mature** - **Regenerative**: Poiesis↑: Sepsis-purulent - **Hyperregenerative**: Hyperplasia: Sepsis-purulent - **Degenerative**: Poiesis↓: Severe infections, intoxication - **Regen-Degen**: Formation↑ but impaired maturation ## Hemoblastosis - Hemoblastosis are malignant tumors that originate from hematopoietic cells; it includes leukemias and lymphomas. ## Leukemias - Are tumors that develop in the bone marrow, either acute (from classes I-IV of hematopoietic cells) or chronic (from class V). Classes I-III are undifferentiated. - **Acute leukemias**: Aleukemic or leukopenic, hiatus leucemicus - **Acute undifferentiated leukemia**: Very rare, fatal - **Acute myeloblastic leukemia**: From myeloblasts, in adults - **Acute lymphoblastic leukemia**: From lymphoblasts, in children - **Acute plasmablastic leukemia**: From B cells, Paraproteins ## Chronic Leukemia - Subleukemic or leukemic, no hiatus leucemicus - **Chronic myelocytic leukemia**: *Hyperregenerative*, >50x10⁹/l, in 85-95% there is *Ph'* marker due to Philadelphia chromosome (22nd) - **Idiopathic myelofibrosis**: Myeloid lines hyperplasia + Myelofibrosis, < 50x10⁹/l - **Chronic lymphocytic leukemia**: Mainly from B cells, shows shadows of Botkin - **Erythremia** ## Paraproteinemic Leukemias - Myeloma - Tumor cells produce *IL-1*, *TNF-α*, *β* -> Hyper *Ca*₂⁺. - In 20%, Igs are only *light chains:* Bence-Jones are produced -> Protein in urine+amyloidosis - Waldenström macroglobulinemia - Macromolecular *IgM* (cryoglobulins) are produced, rarely Bence-Jones too. - Shows myelopenia, thrombosis. - Heavy chain disease - Only *α heavy chains* of Igs are produced -> Immunosuppression ## Lymphoma - Are tumors that develop in lymphoid tissue, either *Hodgkin's lymphoma* (Reed-Sternberg cells: *B cells*) or non-Hodgkin's lymphomas. ## Hemostasis Pathologies - *Normal bleeding time* is 2-9 min - *Normal Platelets count* is 150-350x10⁹/l - *Prothrombin time (PT)*, assess extrinsic and common pathways - *Partial thromboplastin time (PTT)*, assess intrinsic and common pathways ### Etiology of Hemorrhages - Damage to the vascular wall - Thrombocytes changes - Coagulopathies ## Damage to Vascular Wall - 4 parameters are normal ### Rendu-osler Syndrome (Hemorrhagic Telangiectasia) - *Auto D*: Vascular CT insufficiency -> Thinning of vessels -> Bleeding (oral+nasal) - Oster-Weber Rendu Syndrome: Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease. Autosomal dominant disorder. Characterized by multiple mucocutaneous telangiectasias. - Clinical picture: - Most common cause of pulmonary arteriovenous malformations. - Telangiectasia: lips, gingiva, tongue, palate, and palpebral conjunctiva. - Recurrent epistaxis (nighttime). - Vascular malformation (lung, liver, GI, and brain) ### Henoch-Schönlein Purpura (IgA Vasculitis) - Vasculitis triggered by infections or toxins -> Ig-Ag complexes containing IgA at vessels -> Purpura, arthritis, and abdominal pain. - Most common systemic vasculitis of childhood. - Self-limited, improves after a few weeks of supportive care. ## Ehler-Danlos Syndrome - Group of 13 diseases caused by hereditary collagen deficit. ## Scurvy - Lack of *Vitamin C* -> *Collagen*↓ -> Weak vessels -> Bleeding ## Changes in Platelets - Can be *thrombocytopenia* or *thrombocytopathies* ### Thrombocytopenia - *Bleeding time*↑, *platelets* ↓ - Due to: - Impaired formation - Destruction: Hypersplenism, ITP, drugs, etc... - Consumption: TTP, HUS, DIC - Redistribution ### Thrombocytopathies - *Bleeding time*↑, *platelets*= - Impaired adhesion: - Von-Willebrand disease: *Auto D*, VWF insufficiency - Bernard-Soulier disease: *Auto R*, GpIb insufficiency - Impaired aggregation: - Glanzmann's thrombasthenia: *Auto R*, GpIb/III deficit - Impaired degranulation ## Coagulopathies - *Bleeding*↑, *platelets*=, *PT* or/and *PTT*↑ - **Hereditary**: - Hemophilias: - A: *Factor VIII*, X-R - B (Christmas disease): *Factor* IX, X-R - C (Rosenthel disease): *Factor* XI, *Auto R* - Afibrinogenemia - **Acquired**: *Vitamin K*!, DIC ## DIC - *Platelets*!, *fibrinogen*!, *PT* and *PTT*↑ - Release of tissue factor (from placenta, AML, sepsis, and adenomas) or severe endothelial damage (SLE, burns, infections) -> Thrombosis in small vessels -> Ischemia + Microangiopathic hemolytic anemia - Depletion of platelets, then activation of *fibrinolysis* -> Bleeding - Pathogenesis of DIC: - Activation of intravascular coagulation - Platelet consumption - Coagulation factors consumption - Fibrinolysis - Endothelial damage - Microvascular thrombosis - Multi-organ ischemia or failure: - Multi-organ dysfunction (MODS) is a serious condition that can occur when multiple organs in the body fail. The kidneys, liver, and brain are most commonly affected. - MODS often develops over time. It is typically the result of infection, sepsis, severe trauma, or major surgery. The mortality rate for MODS is high.