HEMATOLOGY - hakeem-sy.com · Anemia of chronic diseases 12 Thrombocytopenia 46 Normocytic...

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1 HEMATOLOGY Dear colleague, Here is my attempt to collect the "important" information about the hematological disorders we have covered. Even though I did my best to extract these information from the sources below and to re-arrange them in an easy-to-understand method, the original textbooks remain as the pure reference for students to get their knowledge from. I wish you all the best in your life and thereafter,,, And don't forget to pray for me Regards, Done by: Ahmed Alsolami [email protected] 2008 Sources: Essential Hematology (A.V. Hoffbrand) Robbins Basic Pathology Davidson's Principles & Practice of Medicine Hematology at a Glance Danish Textbook of Medicine (Chapter of Blood Disorders) Ahmed Alsolami <[email protected]>

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  • 1

    HEMATOLOGY

    Dear colleague,

    Here is my attempt to collect the "important" information about the hematological disorders we have covered. Even though I did my best to extract these information from the sources below and to re-arrange them in an easy-to-understand method, the original textbooks remain as the pure reference for students to get their knowledge from.

    I wish you all the best in your life and thereafter,,,

    And don't forget to pray for me

    Regards,

    Done by:

    Ahmed Alsolami

    [email protected] U

    2008

    USources:

    Essential Hematology (A.V. Hoffbrand)

    Robbins Basic Pathology

    Davidson's Principles & Practice of Medicine

    Hematology at a Glance

    Danish Textbook of Medicine (Chapter of Blood Disorders)

    Ahmed Alsolami

    mailto:[email protected]

  • 2

    Index

    Hemopoiesis diagram 3 Non-Hodgkin's lymphoma 35

    White blood cells 4 Myelodysplasia 37

    Benign disorders of white cells 5 Myeloproliferative disorders 38

    Types of anemias-scheme 8 Polycythemia rubra vera 39

    Symptoms & Signs of Anemia 9 Essential thrombocythemia 40

    Microcytic Hypochromic anemia 10 Myelofibrosis 41

    Iron deficiency anemia 10 Multiple myeloma 43

    Sideroblastic anemia 10 Bleeding disorders 44

    Lead poisoning 11 Vascular bleeding disorders 45

    Anemia of chronic diseases 12 Thrombocytopenia 46

    Normocytic Normochromic Anemia 13 Platelet dysfunction 49

    Aplastic anemia 13 Coagulation disorders 49

    Macrocytic Anemia 15

    Megaloblastic anemia 15

    Hemolytic Anemia 18

    Hereditary spherocytosis 20

    Thalassemia 21

    Sickle cell anemia 23

    G6PD deficiency 24

    Autoimmune hemolytic anemia 25

    Alloimmune hemolytic anemias 26

    Non-immune hemolytic anemias 27

    Leukemia 29

    Acute leukemias 30

    Acute lymphoblastic leukemia 30

    Acute myeloid leukemia 31

    Chronic myeloid leukemia 32

    Chronic lymphoblastic leukemia 33

    Lymphomas 34

    Hodgkin's lymphoma 34

    Ahmed Alsolami

  • 3

    Diagrammatic representation of the bone marrow pluripotent stem cell and the cell lines that arise from it

    Ahmed Alsolami

  • 4

    White blood cells

    Function of white cells:

    Their primary function is to protect the body against infections. The white blood cells (leucocytes) may be divided into two broad groups:

    1. Phagocytes (neutrophils, esinophils, basophils & monocytes) they ingest and destroy pathogens and cell debris.

    2. Immunocytes (lymphocytes, their precursor cells & plasma cells) responsible for both the humoral and cellular specific immunity.

    Phagocytes:

    • Neutrophils (polymorphs): They are the most numerous peripheral blood leucocyte.

    • Esinophils: They are particularly important in the response to parasitic and allergic diseases.

    • Basophils: They are the least numerous peripheral blood leucocyte. They play an important part in immediate hypersensitivity reactions. In the tissues they become mast cells.

    • Monocytes: In tissues they become macrophages.

    Immunocytes:

    • B-lymphocytes: They mediate humoral or antibody-mediated immunity

    • T-lymphocytes: They mediate cell-mediated immunity

    • Plasma cells: These are mature B-lymphocytes after their activation and release of membrane-bound immunoglobulins. They have a specific memory for certain pathogens.

    Ahmed Alsolami

  • 5

    Benign disorders of white cells

    Neutrophilia: increase in circulating neutrophils above the normal level. It can be caused by:

    1. Bacterial infections (especially pyogenic bacteria)

    2. Inflammation & tissue necrosis, e.g. vasculitis, MI, trauma

    3. Metabolic disorders, e.g. uremia, acidosis, gout, eclampsia, DKA

    4. Neoplasms of all types, e.g. carcinoma, lymphoma, melanoma

    5. Acute hemorrhage or hemolysis

    6. Drugs, e.g. corticosteroid therapy, tetracycline, lithium

    7. Chronic myeloid leukemia & myeloproliferative disorders

    8. Pregnancy

    Esinophilia: increase in circulating esinophils above the normal level. It can be caused by:

    1. Allergic diseases, e.g. asthma, hay fever, urticaria, food allergy

    2. Parasitic diseases

    3. Skin diseases, e.g. psoriasis, drug rash

    4. Drug sensitivity

    5. Connective tissue disease

    6. Hematological malignancy, e.g. Hodgkin's lymphoma

    7. Idiopathic hyperesinophilia

    8. Esinophilic leukemia

    Basophilia: increase in circulating neutrophils above the normal level. It is uncommon but occurs in myeloproliferative disorders.

    Monocytosis: increase in circulating monocytes above the normal level. It can be caused by:

    1. Chronic bacterial & protozoal infections

    2. Connective tissue disease, e.g. SLE, RA, temporal arteritis

    3. Chronic neutropenia

    4. Myelodysplasia

    5. Hodgkin's disease, acute myeloid leukemia & other malignancies

    Ahmed Alsolami

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    Neutropenia: decrease in circulating neutrophils below the normal level. It can be caused by:

    1. Decreased production:

    • General bone marrow failure, e.g. Aplastic anemia, megaloblastic anemia, myelodysplasia, acute leukemia, chemotherapy, replacement by tumour

    • Specific failure of neutrophil production:

    i. Congenital, e.g. Kostman's syndrome

    ii. Cyclical

    iii. Drug-induced, e.g. sulfonamides, chlorpromazine, diuretics, clozaril, neomercazole, gold

    2. Increased destruction:

    • General, e.g. hypersplenism

    • Specific, e.g. autoimmune-alone or in association with connective tissue disorder as RA (Felty's syndrome)

    Lymphocytosis: increase in circulating lymphocytes above the normal level. It can be caused by:

    1. Infections:

    • Acute: infectious mononucleosis, rubella, pertussis, mumps, infectious hepatitis, CMV, HIV, herpes simplex or zoster

    • Chronic: TB, toxoplasmosis, brucellosis, syphilis

    2. Acute lymphoblastic leukemia

    3. Chronic lymphoid leukemias

    4. Non-Hodgkin's lymphoma

    5. Thyrotoxicosis

    Lymphopenia: decrease in circulating neutrophils below the normal level. It can be caused by:

    1. Bone marrow failure

    2. Corticosteroid and other immunosuppressive therapy

    3. Hodgkin's lymphoma

    4. Widespread irradiation

    Ahmed Alsolami

  • 7

    Defects of phagocytic cell function:

    1. Defects in adhesion:

    Leukocyte adhesion deficiency type 1 (LAD1):

    There is defective synthesis of leukocyte integrins impaired adhesion, spreading, phagocytosis and generation of an oxidative burst.

    Leukocyte adhesion deficiency type 2 (LAD2):

    There is defective synthesis of a selectin receptor impaired adhesion to activated endothelium.

    2. Defects in microbicidal activity:

    Chronic granulomatous disease:

    Deficiency of one component of the NADPH oxidase pathway responsible for generating superoxide impaired activation of oxygen-dependent killing mechanism after engulfment of bacteria as it supposed to occur.

    3. Defects in phagolysosome formation:

    Chediac-Higashi syndrome:

    Disordered intracellular trafficking of organelles impaired lysosomal degranulation into phagosomes.

    Leukomoid reaction:

    Severe or chronic infections, severe hemolysis or metastatic cancer excessive increase of leucocytes & accompanied by the presence of immature cells e.g. myeloblasts and myelocytes.

    BUT, to differentiate between the leukomoid reaction & chronic myeloid leukemia which shows the same leucocytosis picture:

    • Leukomoid reaction ↑ Neutrophil alkaline phosphatase (NAP) score

    • Chronic myeloid leukemia ↓NAP score

    Ahmed Alsolami

  • 8

    Types of Anemia

    Microcytic Hypochromic

    D/D :

    • Iron deficiency • Thalassemia • Sideroblastic • Chronic diseases

    Normocytic Normochromic

    D/D :

    • Many hemolytic anemias • Acute blood loss • Aplastic anemia • Myelofibrosis • Bone marrow failure (post-

    chemotherapy, infiltration by carcinoma)

    • Endocrine disorders • Chronic diseases

    Megaloblastic

    D/D :

    • Vit.B12 deficiency • Folate deficiency

    Physiologic

    D/D :

    • Pregnancy • New born

    Pathologic

    D/D :

    • Alcohol • Liver disease • Hypothyroidism • Myelodysplasia • Aplastic anemia • Multiple myeloma • Reticulocytosis

    Non-Megaloblastic

    Macrocytic

    Ahmed Alsolami

  • 9

    Symptoms & Signs of Anemia

    Symptoms:

    • Exertional dyspnea

    • Fatigue

    • Palpitation

    • Headache

    • Angina (in older patients)

    • Intermittent claudication (in older patients)

    • Visual disturbances (in severe anemia)

    Signs:

    • General :

    o Pallor

    o Tachycardia

    o Bounding pulse

    o Signs of heart failure (in older patients)

    • Specific :

    o Koilonychia Iron deficiency anemia

    o Jaundice Hemolytic or Megaloblastic anemia

    o Leg ulcer Sickle cell anemia or spherocytosis

    o Bone deformities Thalassemia major or other severe congenital hemolytic anemias

    Excess infections

    Spontaneous bruising

    suggest

    Neutropenia and Thrombocytopenia

    Possibly due to

    Bone Marrow Failure

    Ahmed Alsolami

  • 10

    Microcytic Hypochromic Anemia

    Iron deficiency anemia :

    Causes:

    • Chronic blood loss (GI bleeding, Menorrhagia) most common

    • ↑demand (infancy, adolescence, pregnancy, lactation)

    • ↓absorption (celiac disease, gastrectomy, atrophic gastritis)

    • Poor intake

    Clinical features:

    • General symptoms and signs of anemia (see page9)

    • Manifestation of iron deficiency :

    o Brittle hair and nails

    o Atrophy of the tongue papillae

    o Angular stomatitis

    o Plummer Vinson syndrome (Iron def. anemia + Dysphagia)

    Laboratory findings :

    See the table on page12

    Sideroblastic Anemia

    Defect in the enzyme ALA synthase ineffective utilization of iron to form haem iron accumulate in erythroblasts in the bone marrow formation of a ring of iron granules around the nucleus Ring Sideroblasts.

    when 15% or more of the erythroblasts are ring sideroblasts in the bone marrow Sideroblastic anemia is diagnosed.

    Ahmed Alsolami

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    Causes :

    • Hereditary: (X-Linked ) occur independently without any other disease.

    • Primary: (one subtype of Myelodysplasia).

    • Secondary: sideroblastic anemia may also occur with :

    o Malignant diseases of the marrow (e.g. Myelofibrosis, myeloid leukemia, myeloma)

    o Drugs: antituberculous e.g. isoniazide

    o Alcohol

    o Lead poisoning

    o Benign conditions (e.g. hemolytic anemia, Megaloblastic anemia, malabsorption, rheumatoid arthritis)

    Manifestation :

    • Signs & symptoms of anemia (see page9)

    • Manifestation of the secondary causes if found.

    Laboratory findings :

    See the table on page12

    Lead Poisoning

    Lead poisoning causes anemia which is either

    It does so by inhibiting both haem & globin synthesis at several points.

    Characteristic features of lead poisoning :

    o Ring sidroblasts in bone marrow

    o Basophilic Stippling in the RBCs (deep-blue dots in the cytoplasm under staining) because lead interferes with the enzyme responsible for RNA degradation, causing its accumulation in the cytoplasm, which under staining gives this appearance.

    Hemolytic (predominant)

    Hypochromic

    Ahmed Alsolami

  • 12

    Anemia of chronic diseases

    Pathogenesis: it occurs in relation to:

    • Decreased release of iron from macrophages (due to Hepcidin release by the liver in response to inflammation inhibition of iron release from macrophages as well as iron absorption)

    • Inadequate erythropoietin response to anemia (due to the effect of cytokines such as IL-1, TNF on erythropoiesis)

    • Reduced red cell lifespan.

    Causes :

    • Chronic inflammatory diseases:

    o Infections (e.g. pulmonary abscess, TB, pneumonia, osteomyelitis, bacterial endocarditis).

    o Non-infectious (e.g. SLE, RA, sarcoidosis, Crohn's disease).

    • Malignant diseases (e.g. carcinoma, lymphoma, sarcoma).

    Laboratory diagnosis of hypochromic anemia.

    Iron deficiency

    Chronic diseases

    Thalassemia trait (α or β)

    Sidroblastic

    MCV & MCH ↓ Normal or

    mild ↓ ↓

    ↓ in congenital type, but MCV

    often ↑ in acquired type

    Serum iron ↓ ↓ Normal ↑

    TIBC ↑ ↓ Normal Normal

    Serum ferritin ↓ Normal/↑ Normal ↑

    Bone marrow iron stores

    Absent Present Present Present

    Erythroblast iron Absent Absent Present Ring forms

    Hemoglobin electrophoresis

    Normal Normal ↑ Hb A2 in β

    form Normal

    Ahmed Alsolami

  • 13

    Normocytic Normochromic Anemia

    Causes :

    • Many hemolytic anemias

    • Acute blood loss

    • Aplastic anemia

    • Myelofibrosis

    • Bone marrow failure (post-chemotherapy, infiltration by carcinoma, myeloma).

    • Endocrine disorders (Hypopituitarism, hypothyroidism, hypoaldosteronism).

    • Chronic diseases

    Aplastic anemia

    It is a disorder characterized by the Usuppression of multipotent myeloid stem cells (that have the capacity to differentiate into RBCs, WBCs or platelets).

    Causes :

    • Primary :

    o Congenital (Fanconi and Non-Fanconi types)

    o Idiopathic acquired (autoimmune)

    • Secondary (direct damage to the hemopoietic marrow) :

    o Chemicals (benzene, insecticides)

    o Drugs (busulfan, cyclophosphamide, chloramphenicol)

    o Ionizing radiation

    o Viruses (EBV, viral hepatitis)

    o Paroxysmal nocturnal hemoglobinuria (PNH)

    Aplastic anemia usually presents with symptoms and signs of pancytopenia.

    Ahmed Alsolami

  • 14

    Manifestations of aplastic anemia (pancytopenia) :

    • ↓RBCs symptoms of anemia (see page9)

    • ↓WBCs Impaired immunity infections (mouth & throat)

    • ↓Platelets Bleeding tendency (bruising, bleeding gums, epistaxis, menorrhagia).

    Other causes of pancytopenia :

    • Decreased bone marrow function:

    o Aplasia

    o Acute leukemia, myelodysplasia, myelofibrosis, myeloma

    o Infiltration with lymphoma, solid tumors, TB

    o Megaloblastic anemia

    o Paroxysmal nocturnal hemoglobinuria (PNH)

    • Increased peripheral destruction :

    o Hypersplenism

    Laboratory findings :

    • Normochromic anemia, but either normocytic or macrocytic.

    • Extreme↓in reticulocyte count.

    • ↓WBCs (Leucopenia) especially granulocytes.

    • ↓Platelets (Thrombocytopenia).

    • Bone marrow shows hypoplasia, with loss of hemopoietic tissue and replacement by fat which comprises over 75% of the marrow.

    Ahmed Alsolami

  • 15

    Macrocytic Anemia

    Macrocytic anemia is subdivided into Megaloblastic and Non-megaloblastic based on Uthe appearance of the developing erythroblasts in the bone marrow

    Megaloblastic anemia :

    • Vit.B12 or Folate deficiency ↓DNA synthesis slow erythroblast maturation cell division is decreased but cytoplasmic maturation progresses large cell with ↓DNA mass ( ↑ RNA/DNA ratio) which is called "Megaloblast" these cells are destroyed in bone marrow the bone marrow becomes hypercellular to compensate for the destruction, but the RBC production is still severely reduced " Ineffective Erythropoiesis".

    • WBC & platelet production are also affected Pancytopenia.

    Causes of Vit.B12 deficiency :

    • Nutritional : Vegetarian diet

    • Malabsorption :

    o Gastric causes :

    Pernicious anemia

    Congenital lack or abnormality of Intrinsic Factor

    Total or partial gastrectomy

    o Intestinal causes :

    Ileal resection or Crohn's disease

    Chronic tropical sprue

    Bacterial overgrowth

    Fish tapeworm

    Ahmed Alsolami

  • 16

    Causes of folate deficiency :

    • Nutritional

    • Malabsorption :

    o Tropical sprue, gluten-induced enteropathy

    • Excess utilization :

    o Physiological :

    Pregnancy, lactation, Prematurity

    o Pathological :

    Hematological diseases (e.g. hemolytic anemias, myelofibrosis)

    Malignant diseases (e.g. carcinoma, lymphoma, myeloma)

    Inflammatory diseases (e.g. Crohn's disease, TB, RA)

    • Excess urinary folate loss :

    o Active liver disease

    o Congestive heart failure

    • Drugs :

    o Antifolate drugs (e.g. phenytoin, methotrexate, trimethoprim)

    o Anticonvulsants, Sulfasalazine

    Manifestation of Megaloblastic anemia :

    • Gradually progressive symptoms and signs of anemia (see page9)

    • RBC destruction Mild jaundice.

    • Epithelial abnormality Glossitis, angular stomatitis, mild symptoms of malabsorption and loss of weight.

    • Neuropathy : the patient feels tingling in the feet, difficulty in walking and loss of proprioception. (only with Vit.B12 deficiency)

    • Neural tube defect : deficiency of Vit.B12 or Folate in the mother predisposes to neural tube defect in the fetus (anencephaly, spina bifida, encephalocoele).

    • Purpura due to thrombocytopenia is less frequent.

    Ahmed Alsolami

  • 17

    Laboratory findings:

    • CBC :

    o ↑MCV

    o ↓reticulocyte count

    o WBC & platelet are moderately ↓

    o Neutrophils show hypersegmented nuclei

    • Bone marrow is hypercellular and the erythroblast are enlarged "Megaloblasts".

    • ↑serum unconjugated bilirubin and lactate dehydrogenase (LDH), due to RBC breakdown.

    • In VitB12 deficiency ↓serum Vit.B12

    • In Folate deficiency ↓folate in serum and RBC.

    • Vit.B12 absorption test. (Schilling test).

    Non-Megaloblastic anemia:

    Refer to the diagram on page8 to see the causes.

    Ahmed Alsolami

  • 18

    Hemolytic anemia

    Laboratory findings in hemolytic anemia:

    • Features of increased RBC breakdown:

    o ↑serum unconjugated bilirubin

    o ↑urobilinogen

    o ↑stercobilinogen

    o ↑ uric acid & lactate dehydrogenase LDH

    o ↓serum haptoglobin, because it binds to the released hemoglobin and the complex is removed by the reticuloendothelial system.

    o Hemoglobinuria

    o Hemosiderinuria

    • Features of increased RBC production:

    o Reticulocytosis

    o Bone marrow erythroid hyperplasia

    o Bone deformity due to marrow overexpansion

    These findings can be found in any hemolytic anemia but they vary from one disease to another. Thus, prominent features of each hemolytic disease will be mentioned correspondingly.

    Intravascular and Extravascular Hemolysis:

    • Intravascular Hemolysis is due to:

    o Mismatched blood transfusion

    o G6PD deficiency

    o Microangiopathy

    o Some autoimmune hemolytic anemias

    o PNH

    o March hemoglobinuria

    o Some drug-induced or infection-induced (e.g. Falciparum Malaria)

    Ahmed Alsolami

  • 19

    • Extravascular Hemolysis is due to:

    Abnormal RBCs trapped in the reticuloendothelial system destroyed by macrophages

    Classification of hemolytic anemias:

    Hereditary Acquired

    Membrane defect:

    spherocytosis, elliptocytosis

    Metabolism defect:

    G6PD deficiency, pyruvate kinase deficiency

    Hemoglobin defect:

    sickle cell anemia, thalassemia

    Immune:

    Autoimmune:

    worm Ab type, cold Ab type

    Alloimmune:

    hemolytic transfusion reaction

    hemolytic disease of newborn

    bone marrow transplantation

    Drug induced

    Non-immune:

    Chemical/physical:

    microangiopathy, burns, prosthetic valves, drugs, industrial/domestic substances

    Infectious:

    malaria, clostridia

    Secondary:

    liver or renal disease

    March hemoglobinuria

    Hypersplenism

    Paroxysmal nocturnal hemoglobinuria (PNH)

    Ahmed Alsolami

  • 20

    Inherited Hemolytic anemias

    Hereditary spherocytosis (autosomal dominant):

    Abnormal RBC membrane spherical shape & less deformable destroyed in spleen

    Manifestations:

    • Fluctuating jaundice

    • Splenomegaly

    • Pigment gallstone: due to increased release of bilirubin from RBC breakdown

    • Aplastic crisis: if infection with Parvovirus has occurred switch off the hematopoiesis in bone marrow

    • Megaloblastic crisis: due to folate deficiency as a result of increased hemolysis

    Laboratory findings:

    • CBC:

    o Spherocytosis

    o ↑reticulocyte count

    • ↑serum bilirubin

    • Osmotic fragility test

    Ahmed Alsolami

  • 21

    Thalassemia

    Beta Thalassemia major:

    Normally, α and β chains bind to form the normal adult hemoglobin (A type).

    In β thalassemia decreased synthesis of β chain the excess α chains precipitate in erythroblasts and in mature RBC causing severe ineffective erythropoiesis and abnormalities to RBC membrane destroyed in the reticuloendothelial system

    The production of gamma γ chains helps to decrease the excess α chain aggregation.

    α chains bind to the available β chains “normally”, but the remaining of α bind to either :

    Delta (δ) chain Hb A2 type

    Gamma(γ) chain Hb F type

    Type Hb A (α+ β) Hb A2 (α+ δ) Hb F (α+ γ)

    Thalassemia major

    0% 4-10% 90-96%

    Clinical features:

    • The anemia becomes apparent at 3-6 months after birth when the switch from γ to β chain should take place.

    • Splenomegaly and hepatomegaly as a result of excessive RBC destruction, extramedullary hemopoiesis and later because of iron overload.

    • Infections

    • Bone marrow overexpansion bossing of head, prominent malar eminence

    • Multiple blood transfusion iron overload hemochromatosis heart failure (major cause of death), liver cirrhosis and endocrinopathies (growth retardation, delayed puberty, DM, hypothyroidism and hypoparathyroidism)

    Laboratory findings:

    • CBC: o Severe microcytic hypochromic anemia o Increased reticulocytes o Basophilic stippling: blue dots with staining due to hemoglobin

    aggregations. • Plasma electrophoresis: to detect the type of hemoglobin.

    Ahmed Alsolami

  • 22

    Beta Thalassemia trait (minor):

    Usually symptomless.

    Type Hb A (α+ β) Hb A2 (α+ δ) Hb F (α+ γ)

    Thalassemia minor

    80-95% 4-8% 1-5%

    Laboratory findings:

    • CBC:

    o Microcytic hypochromic picture

    o Increased RBC count

    o Mild anemia due to slight Hb decrease

    • Plasma electrophoresis: to detect the type of hemoglobin.

    Alpha Thalassemia: There are 4 genes encoding for α chain synthesis:

    • If 1 gene is missing α thalassemia trait asymptomatic

    • If 2 genes are missing α thalassemia trait (also) microcytic picture with no anemia.

    • If 3 genes are missing Hb H disease moderate anemia and splenomegaly

    • If 4 genes are missing α thalassemia major can’t carry oxygen Hydrops Fetalis (the baby die very shortly after birth and look pale, edematous with enlarged liver and spleen)

    Laboratory findings:

    • CBC: o microcytic picture.

    • Plasma electrophoresis: to detect the type of hemoglobin.

    Ahmed Alsolami

  • 23

    Sickle cell anemia:

    The homozygous disease USubstitution of valine for glutamic acid in the 6th position in the β chain of hemoglobinU abnormal Hb S sickle shaped of RBC, leading to the following consequences:

    1. The RBCs become rigid and destroyed in the spleen anemia symptoms and signs of anemia

    2. these cells have abnormal charge on the surface increased adherence to vessel wall vaso-occlusive crisis ( Uprecipitated by hypoxia, acidosis, dehydration or infectionU) organ infarction + low grade fever. It occurs in the following organs:

    • Bone Infants: “hand-foot syndrome” causing painful swelling. Adults: aseptic necrosis of head of femur, back or chest pain due to bone involvement

    • Kidney papillary necrosis tubular concentration defect and gross hematuria. More common in sickle cell trait

    • Mesentery acute abdominal pain . • Lungs

    o increased pulmonary hypertension heart failure o pulmonary infarction chest pain .

    • CNS sinus thrombosis stroke . • Liver hepatomegaly . • Spleen early in life: there is splenomegaly, and repeated attacks

    of occlusion infarction with acute pain. Late: spleen is shrunken and fibrotic due to infarctions “Autosplenectomy”.

    • Retina retinopathy and blindness • Leg non-healing ulcer around the ankle, due to vascular stasis

    and local ischemia • Penis “Priapism”, a state of persistent painful eriction

    3. Aplastic crisis: if infection with Parvovirus has occurred switch off

    the hematopoiesis in bone marrow

    4. long term problems: fatigue, infections, pigment stones, bossing of the head and prominent malar eminence (due to marrow overexpansion).

    Laboratory findings:

    • CBC: o Sickle sells and target cells o ↓ Hb

    • Hb electrophoresis No Hb A is detected !! and Hb F is variable .

    Ahmed Alsolami

  • 24

    Sickle cell trait: This is a benign condition with no anemia and normal appearance of RBC on blood film.

    Hematuria is the most common symptom, due to minor infarcts causing papillary necrosis.

    The Hb S varies from 25-45% of the total hemoglobin.

    G6PD deficiency (X-Linked inheritance):

    ↓G6PD enzyme ↓ formation of reduced glutathione (Hexose monophosphate shunt) Decreased ability to handle oxidative stresses

    1. Causing damage to the RBC membrane intravascular hemolysis and hemoglobinuria; it occurs in crises but there is no chronic state of hemolysis and no splenomegaly.

    2. Hb denaturation by oxidative stress Hb precipitate Heinz bodies removed by spleen “Bite cells” on blood film during a crisis.

    Oxidative stress occurs with:

    • Infections • Drugs (dapsone, primaquine, quinine, sulphonamides) • Beans (so called: Favism) • Chronic hemolysis may only occur in severe deficiency.

    Manifestations:

    Acute symptoms and signs of anemia; it is self limiting because the new reticulocyte are made with near normal enzyme levels.

    Laboratory findings:

    • Between crises, blood count is normal. The enzyme deficiency is detected by direct enzyme assay on RBC.

    • During a crisis, the blood film shows contracted and fragmented cells “bite cells”.

    • Direct enzyme assay during a crisis may give “false” normal level due to the higher enzyme level in the newly formed reticulocytes.

    • Direct enzyme assay after the acute phase reveals the low G6PD level.

    Ahmed Alsolami

  • 25

    Acquired hemolytic anemia

    A) Immune mediated hemolytic anemia

    Autoimmune hemolytic anemia

    Warm autoimmune hemolytic anemia

    In warm environment auto Ab (usually IgG alone or with complement) attach to RBC and destroy them.

    There is a chronic minor hemolysis in normal body temperature.

    Causes:

    • Idiopathic

    • Autoimmune diseases

    • Lymphomas

    • Chronic myeloid leukemia

    • Carcinoma

    • Drugs (methyldopa)

    Laboratory findings:

    • Evidence of hemolysis (Lab. Findings of hemolysis).

    • +ve Coombs’ test with IgG and complements

    • Autoimmune thrombocytopenia

    Cold autoimmune hemolytic anemia

    In cold environment auto Ab attach to RBC and destroy them. IgM is the main immunoglobulin involved.

    Ahmed Alsolami

  • 26

    Causes:

    • Idiopathic

    • Lymphomas

    • Paroxysmal cold hemoglobinuria

    • Infections (mycoplasma pneumoniae, infectious mononucleosis)

    Laboratory findings:

    • Evidence of hemolysis (Lab. Findings of hemolysis).

    • +ve Coombs’ test with complements only

    • Monoclonal IgM Ab

    Alloimmune hemolytic anemias:

    Complications of blood transfusions: • Hemolytic transfusion reaction: may be immediate or delayed.

    Immediate life-threatening reactions associated with massive intravascular hemolysis are usually due to ABO incompatibility. The clinical features of a major hemolytic transfusion reaction include urticaria, pain in the lumbar region, flushing, headache, precordial pain, shortness of breath, vomiting, rigours, pyrexia and a fall in blood pressure which may cause shock acute renal failure).

    • Other reactions:

    o Febrile reactions; due to HLA Abs.

    o Non-hemolytic allergic reactions (febrile or non-febrile); due to hypersensitivity to donor plasma proteins. If severe anaphylactic shock.

    o Circulatory overload.

    o Transmission of infections.

    o Transfusion related acute lung injury; caused by positive transfer of leucoagglutins donor plasma causing endothelial and epithelial injury.

    o Post-transfusion purpura; caused by Abs in the recipient (who was previously transfused or pregnant) against a platelet-specific antigen.

    o Iron overload, in repeated transfusions over many years.

    Ahmed Alsolami

  • 27

    B) Non-immune hemolytic anemias

    Paroxysmal Nocturnal Hemoglobinuria (PNH):

    Acquired, clonal disorder of marrow stem cells in which the RBCs become vulnerable to lysis by complements. Hemosiderinuria is a constant feature and can give rise to iron deficiency which may exacerbate the anemia.

    Platelets and white cells may also be affected thrombosis of large veins including portal, mesenteric and hepatic veins.

    Red cell fragmentation syndromes:

    These arise through Uphysical damageU to red cells as follows:

    • Abnormal surfaces:

    o Prosthetic heart valves.

    o Arterial grafts.

    • Arteriovanous malformations.

    • Microangiopathic hemolytic anemia:

    o Disseminated intravascular coagulation DIC (see page 44)

    o Thrombotic thrombocytopenic purpura TTP (see page 41)

    o Hemolytic uremic syndrome HUS.

    o Vasculitis.

    o Malignant diseases

    March hemoglobinuria:

    Caused by damage to red cells between the small bones of the feet, usually during prolonged marching or running . The blood film doesn't show fragments.

    Ahmed Alsolami

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    Infections: can cause hemolysis in a variety of ways such as:

    o ↑oxidative stress precipitate acute hemolytic crisis in G6PD deficiency

    o Cause widespread endothelial injury by toxins, or increased synthesis and release of thromboplastic substances microangiopathic hemolytic anemia as in DIC (see page44)

    o Malarial direct intravascular hemolysis, or by extravascular destruction of parasitized RBCs

    Chemical and physical agents: these conditions cause acute hemolysis:

    o Certain drugs e.g. dapson & salazopyrin in high doses

    o The high copper levels in Wilson's disease

    o Poisons e.g. lead & arsine

    o Severe burns

    Ahmed Alsolami

  • 29

    Leukemia The leukemias are a group of disorders characterized by the Uaccumulation of malignant white cells in the bone marrow and bloodU. These abnormal cells cause symptoms because of:

    o Bone marrow failure (i.e. anemia, neutropenia, thrombocytopenia)

    o Infiltration of organs (e.g. liver, spleen, lymph nodes, meninges, brain, skin or testes).

    Types:

    • Acute

    o Acute lymphoblastic leukemia (ALL) , B-cell or T-cell specific.

    o Acute myeloid leukemia (AML)

    • Chronic

    o Chronic lymphoblastic leukemia (CLL) , B-cell or T-cell specific.

    o Chronic myeloid leukemia (CML)

    Risk Factors:

    As in most diseases it is the combination of genetic background and environmental influence that determines the risk of developing a malignancy.

    • Inherited factors:

    o the risk is greatly increased in some genetic diseases e.g. Down's syndrome, Klinefelter's syndrome, Fanconi's anemia, Bloom's syndrome.

    o There is a weak familial tendency in some disease e.g. AML, B-cell CLL, Hodgkin's and non-Hodgkin's lymphomas.

    • Environmental factors:

    o Chemicals e.g. Benzene o Drugs e.g. Alkylating agents o Radiation

    • Infection:

    o Viruses e.g. Epstein-Barr virus EBV, HIV, Human herpes virus 8 (HHV-8)

    o Bacteria e.g. Helicobacter Pylori o Protozoa e.g. Malaria

    Ahmed Alsolami

  • 30

    Acute Leukemias

    Pathogenesis: Genetic damage that results in

    • An increased rate of proliferation

    • Reduced apoptosis

    • Block in cellular differentiation

    These events together cause accumulation of blast cells, resulting in

    o Bone marrow failure o Organ infiltration

    The diagnosis of acute leukemia requires more than 20% of blast cells in the blood or bone marrow.

    Acute lymphoblastic leukemia (ALL):

    Most common in Children (highest at 3-7 years)

    Pathogenesis:

    A proportion of cases are intiated by genetic mutations that occur during development in utero, with a secondary event possibly precipitated by abnormal response of the immune system to infection in childhood.

    Clinical features:

    • Bone marrow failure: o Anemia (pallor, lethargy and dyspnea) o Neutropenia (fever, malaise, feature of mouth, throat, skin,

    respiratory infections) o Thrombocytopenia (spontaneous bruises, purpura, bleeding

    gums and menorrhagia) • Organ infiltration (Tender bones, lymphadenopathy, moderate

    splenomegaly, hepatomegaly and gum hypertrophy)

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    Laboratory findings:

    • CBC: o Pancytopenia o circulating blast cells

    • Bone marrow: o Hypercellular with >20% leukemic blasts

    • Biochemistry: o ↑ serum uric acid o ↑ serum calcium o ↑ serum lactate dehydrogenase LDH

    • Radiography: o Mediastinal mass (enlarged thymus or Mediastinal lymph nodes

    characteristic of T-ALL) • Immunological TdT surface marker

    Acute myeloid leukemia (AML):

    Most common in Adults

    Pathogenesis:

    The pathogenesis of AML includes number of translocations and mutations which dysregulate cell division.

    Clinical features:

    Resemble those of ALL.

    Laboratory findings:

    The general hematological and biochemical findings are similar to those seen in ALL.

    To differentiate between AML & ALL :

    AML The Auer rod, an esinophilic needle-like inclusions in cytoplasm of blast cells, it is pathognomic of AML.

    ALL TdT surface marker on blast cells in characteristic of ALL

    Ahmed Alsolami

  • 32

    Chronic myeloid leukemia (CML):

    It is a myeloproliferative stem cell disorder resulting in proliferation of all hematopoietic lineages, but Umanifesting predominantly in the granulocytic series (esinophil, neutrophil and basophil).

    Pathogenesis:

    95% of the patients have a chromosome abnormality known as UPhiladelphia (Ph) chromosomeU. It is a translocation of genetic material between chromosome 9 & 22. Thus, there is an increased rate of myeloid cell production Uwith normal cellular differentiation and bone marrow function.

    Clinical features:

    • Symptoms related to hypermetabolism (e.g. weight loss, lassitude, anorexia or night sweats)

    • Splenomegaly is almost always present and is frequently massive

    • Features of anemia may include pallor, dyspnea and tachycardia

    • Symptoms due to platelet dysfunction such as bruising, epistaxis, menorrhagia or hemorrhage

    • Gout or renal impairment caused by hyperuricemia

    • Rare symptoms include visual disturbances and priapism

    Laboratory findings:

    • CBC:

    o ↑↑ WBC

    o A complete spectrum of myeloid cells is seen in the peripheral blood, with increased circulating basophils.

    o Normocytic, normochromic anemia is usual

    o Platelet count may be increased

    o ↓↓ Neutrophil alkaline phosphatase (NAP) score

    • Bone marrow is hypercellular with predominance of granulocytic precursors

    • Cytogenic analysis Ph chromosome

    • ↑↑Serum uric acid

    Ahmed Alsolami

  • 33

    Chronic lymphocytic leukemia (CLL):

    CLL is a clonal malignancy of B-lymphocytes (rarle T-lymphocytes). And it is Uthe most common variety od leukemia.

    Pathogenesis:

    In the disease B-lymphocytes fail to form antibodies therefore increasing number of immuno-incompetent cells accumulateU, causing impairment of immunity, bone marrow failure and organ infiltration.

    Clinical features:

    • Recurrent infections due to hypogammaglobulinemia and cellular immune disfunction.

    • Symmetrical enlargement of cervical, axillary or inguinal lymph nodes.

    • Splenomegaly is common.

    • Features of anemia and thrombocytopenia, possibly caused by autoimmunity.

    Laboratory findings:

    • CBC:

    o ↑↑ WBC, in which 70-99% are lymphocytes.

    o Normocytic, normochromic anemia is present later stages.

    • Bone marrow is infiltrated with lymphocytes

    • ↓↓ serum immunoglobulins

    Ahmed Alsolami

  • 34

    Lymphomas Lymphomas are a group of diseases caused by Umalignant lymphocytes that accumulate in lymphoid tissues.

    Types:

    • Hodgkin's lymphoma

    • Non-Hodgkin's lymphoma

    Hodgkin's lymphoma:

    Hodgkin's lymphoma is caused by malignant lymphocytes that Uaccumulate in lymph nodesU and cause the characteristic lymphadenopathy. UThe histological hallmark of Hodgkin's lymphoma is the presence of Reed-Sternberg (RS) cells, Uwhich are large malignant lymphoid cells of B-cell origin. Occasionally, they may spill over into blood (leukemic phase) or infiltrate extranodal organs.

    Pathogenesis:

    Some studies suggested that the RS cell is often derived from a B-cell with a defect in the immunoglobulin gene that prevents synthesis of full-length immunoglobulin. Epstein-Barr virus genome has been detected in 50% or more of cases in Hodgkin tissue.

    Clinical features:

    • Superficial lymphadenopathy, painless rubbery enlargement of LN, usually the cervical 60-70%, axillary 10-15% or inguinal lymph nodes 6-12% are involvedU. The disease is typically localized initially to a single lymph node region and then spreads to the contiguous lymph nodes.

    • Mediastinal lymph nodes are commonly involved, which can be detected by CT scan only.

    • Constitutional symptoms such as fever, night sweat, weight loss, fatigue, pruritus, anorexia or cachexia.

    Ahmed Alsolami

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    Clinical staging:

    • Stage I involvement of one lymph node area

    • Stage II involvement of 2 or more lymph nodal areas confined to one side of the diaphragm

    • Stage III involvement of lymph nodes above & below the diaphragm

    • Stage IV indicates adiffuse or disseminated disease in the bone marrow, liver and other extranodal sites

    Laboratory findings:

    • CBC:

    o Normochromic, normocytic anemia is most common.

    o Esinophilia or neutrophilia in one-third of patients.

    o ↑Erythrocyte sedimentation rate (ESR).

    o Lymphopenia is evident in the advanced disease.

    • ↑↑Serum LDH

    Ahmed Alsolami

  • 36

    Non-Hodgkin's lymphoma:

    In this disease, there is malignant proliferation of lymphocytes. These cells are B-lymphocytes (in 70%) or T-lymphocytes (in 30%). UThe extranodal involvement is more common than in Hodgkin's lymphoma.

    Clinical features:

    • Superficial ymphadenopathy in one or more peripheral lymph node regions.

    • Oropharyngeal involvement, "Waldeyer's ring" of lymphoid tissue in the oropharynx is frequently involved and cause sore throat or noisy or obstructed breathing.

    • Liver and spleen are often enlarged and involvement of retroperitoneal or mesentric lymph nodes is frequent. The GIT is the most commonly involved extranodal site after bone marrow, and patients may present with acute abdominal symptoms.

    • Constitutional symptoms such as fever, night sweat, and weight loss

    • Anemia, neutropenia and thrombocytopenia may be presenting features in patients with diffuse bone marrow disease. Cytopenia may also be autoimmune in origin.

    Laboratory findings:

    • CBC:

    o Normocytic, normochromic anemia is usual but autoimmune hemolytic anemia may also occur.

    o Neutropenia or thrombocytopenia in advanced disease with marrow involvement.

    o Lymphos cells may be detected in peripheral blood.

    • ↑serum LDH

    • ↑ serum uric acid may occur

    • Lymph node biopsy is the definitive investigation

    • Bone marrow aspiration infiltration by lymphoid tissue.

    • Chest X-ray & abdominal CT scan to see lymph node involvement.

    Ahmed Alsolami

  • 37

    Myelodysplasia (Myelodysplastic Syndromes)

    In this syndrome, the bone marrow is partly or wholly replaced by Ua clone of multipotent stem cells that have a mutation preventing their differentiation into RBCs, WBCs, or platelets. As a result, the bone marrow is usually hypercellular or normocellular but the peripheral blood shows pancytopenia.

    These abnormal stem cells have the tendency to transform into Uacute myeloid leukemia

    Clinical features:

    • Features of bone marrow failure:

    o Anemia (macrocytic non-megaloblastic)

    o Thrombocytopenia (e.g. easy bruising or bleeding)

    o Infections.

    Laboratory findings:

    • CBC:

    o Pancytopenia

    o Macrocytic picture of RBCs

    o ↓ Reticulocyte count

    • Bone marrow studies:

    o Hypercellular with increased number of blast cells.

    o Signs of ineffective erythropoiesis (e.g. ring sideroblasts, multinucleated erythroblasts and iron overload in macrophages of bone marrow)

    o Abnormal morphology of granulocyte precursors and megakaryocytes.

    Ahmed Alsolami

  • 38

    Myeloproliferative disorders This is a group of disorders characterized by abnormal proliferation of marrow stem cells of one or more of the hemopoietic components (erythroid, granulocytic and megakaryocytic cells).

    Three disorders are included in this category:

    1. Polycythemia rubra vera

    2. Essential thrombocythemia

    3. Myelofibrosis

    These disorders are closely related to each other. Indeed, transitional forms occur, and in many patients a transformation from one disorder into another occurs during the course of the disease, because all of the hemopoietic components are derived from a single multipotent stem cell.

    Ahmed Alsolami

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    Polycythemia rubra vera:

    It is associated with excessive proliferation of erythroid, granulocytic and megakaryocytic elements. Although platelets and granulocytes are increased, Uthe most obvious clinical signs and symptoms are related to the absolute increase in RBC mass.

    Clinical features:

    • Features of hyperviscosity (e.g. Headache, dizziness, dyspnea and blurred vision)

    • Features of expanded blood volume (e.g. epistaxis and hypertension)

    • Features of hypermetabolism (e.g. night sweats and fatigue)

    • Pruritus characteristically after a hot bath, and peptic ulcer disease is resulting perhaps from histamine released as a result of increase in basophils.

    • Hemorrhage or thrombosis either arterial or venous are frequent.

    • Splenomegaly in 75% of cases, is due to seeding of the spleen with the neoplastic marrow stem cells.

    • Gout (as a result of raised uric acid production).

    Laboratory findings:

    • CBC:

    o ↑Hb

    o ↑RBC count & hematocrit value

    o ↑WBC count, neutrophilia and basophila are common

    o ↑Platelets

    • Bone marrow studies:

    o Hypercellular with prominent megakaryocytes

    o ↓Iron stores

    • ↓Serum erythropoietin

    • ↑NAP score

    • ↑Uric acid

    • ↑ Serum LDH

    Ahmed Alsolami

  • 40

    Causes of polycythemia:

    • Primary:

    o Polycythemia rubra vera

    o Familial (congenital) polycythemia

    • Secondary:

    o Caused by compensatory erythropoietin increase in:

    High altitudes

    Pulmonary disease and alveolar hypoventilation

    Cardiovascular disease, espicially congenital with cyanosis

    Heavy cigarette smoking

    o Caused by inappropriate erythropoietin increase in:

    Renal disease (e.g. hydronephrosis, cysts, carcinoma)

    Tumours (e.g. uterine leiomyoma, hepatocellular carcinoma, cerebellar hemangioblastoma)

    • Relative:

    o Dehydration

    o Plasma loss as in burns or enteropathy

    *For diagnosing polycythemia rubra vera, other causes of polycythemia should be roled out !!

    Essential thrombocythemia:

    It is associated with excessive proliferation of the megakaryocytic element and Uoverproduction of plateletsU.

    Clinical features:

    • Thrombosis of arterial or venous systems.

    • Hemorrhage as a result of platelet dysfunction (acute or chronic).

    • Erythromelalgia, a burning sensation felt in the hands or feet and relieved by aspirin.

    • Splenomegaly in 40% os cases, or even splenic atrophy due to infarctions.

    Ahmed Alsolami

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    Laboratory findings:

    • CBC:

    o ↑Platelet count

    o Platelets are abnormal and large

    • Bone marrow is similar to that in polycythemia rubra vera but with excess of abnormal megakaryocytes.

    Causes of thrombocythemia:

    • Reactive:

    o Hemorrhage, trauma or postoperative

    o Chronic iron deficiency

    o Chronic inflammatory process (rheumatoid arthritis, ulcerative colitis)

    o Malignancy

    o Chronic infections

    o Post-splenectomy

    • Endogenous:

    o Essential thrombocythemia

    o Accompanying polycythemia vera, chronic myeloid leukemia and myelofibrosis.

    *For diagnosing essential thrombocythemia, other causes of increased platelets have to be roled out !!

    Myelofibrosis:

    There is an abnormal proliferation of megakaryocytes and Uoverproduction of platelet-derived growth factor which stimulates fibroblasts resulting in bone marrow fibrosis. Thus, extramedullary hemopoiesis takes place (spleen, liver and lymph nodes). It tends to be disordered and inefficient leading to moderate to severe anemia and thrombocytopenia in addition to splenomegaly and hepatomegaly.

    Ahmed Alsolami

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    Clinical features:

    • Splenomegaly, and related symptoms (e.g. abdominal discomfort, pain or indigestion).

    • Symptoms of anemia due to bone marrow failure.

    • Features of hypermetabolism (loss of weight, anorexia, fever and night sweats).

    • 10-20% of patients this diorder transform into acute myeloid leukemia.

    Laboratory findings:

    • CBC:

    o Anemia

    o ↑WBC & platelets at the time of presentation, but decrease dramatically later on.

    o ULeukoerythrocytosis, is the presence of nucleated RBCs and immature WBCs in peripheral blood.

    o UCharacteristic "tear-drop" shape of RBCs.

    o UPlatelets are giant and defective in function.

    • Bone marrow is difficult to aspirate, but trephine biopsy shows a fibrotic hypercellular bone marrow.

    • ↑NAP score

    • ↑serum LDH, reflecting the increased but ineffective turnover of hemopoietic cells.

    Ahmed Alsolami

  • 43

    Multiple myeloma It is a neoplastic proliferation of plasma cells that accumulate in bone marrow, & secrete a monoclonal immunoglobulin protein in the serum (paraproteins) and urine (Bence Jhons proteins).

    Pathogenesis and Clinical features:

    • Extensive infiltration of bone marrow bone marrow failure anemia and neutropenia

    • These plasma cells stimulate osteoclasts bone resorption bone pain (especially backache), osteoporosis, pathologic fractures, and Hypercalcemia

    • Neutropenia and severe suppression of normal immunoglobulin secretion Recurrent infections

    • Excessive paraprotein production Hyperviscosity syndrome:

    o Visual disturbances

    o Neurologic problems (headache, dizzines, deafness and stupor)

    o Bleeding tendency due to interference with platelet function and coagulating factors.

    • Recurrent infections, hypercalcemia and the toxic effect of Bence Jhons proteins on cells lining the tubules Renal failure in 50% of cases

    • Amyloidosis occurs in 5% of cases with features such as macroglossia, carpal tunnel syndrome and diarrhea.

    Laboratory findings:

    • CBC:

    o Macrocytic non-megaloblastic anemia

    o Neutropenia and thrombocytopenia in advanced cases

    o ↑erythrocyte sedimentation rate (ESR)

    • Serum electrophoresis paraproteins in serum or Bence Jhons proteins in urine

    • Bone marrow show increased count of plasma cells usually > 20%

    • Radiological investigations show skeletal lesions.

    • ↑ serum calcium

    Ahmed Alsolami

  • 44

    Bleeding disorders

    Abnormal bleeding may result from:

    1. Vascular disorders characterized by

    o USpontaneous appearance of petechiae and easy bruising in the skin and mucous membranes, epistaxes, excessive bleeding from minor trauma and menorrhagiaU.

    o Normal platelet count and tests of coagulation (PT,APTT)

    o Normal bleeding time

    2. Platelet deficiency (thrombocytopenia) or dysfunction characterized by

    o Spontaneous appearance of petechiae and easy bruising in the skin and mucous membranes, epistaxes, excessive bleeding from minor trauma and menorrhagia.

    o Normal platelet count and tests of coagulation (PT,APTT)

    o UBleeding time is always prolonged

    3. Defective coagulation characterized by

    o Petechiae and other evidences of bleeding from very minor surface trauma Uare usually absent

    o Massive hemorrhage may follow operative or dental procedures or severe trauma. UHemorrhage into areas of the body subject to trauma such as joints of the lower extremities is characteristic.

    o UPT, APTT or both are prolonged

    o Normal bleeding time

    Ahmed Alsolami

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    Vascular bleeding disorders:

    UThe underlying abnormality is either in the vessels themselves or in the perivascular connective tissue.

    The bleeding is mainly in the skin Petechiae, bruising or both

    The standard screening tests are normal (bleeding time, PT, APTT)

    Inherited vascular disorders:

    o Hereditary hemorrhagic telangiectasia (autosomal dominant):

    Dilated microvascular swellings (small red dots) develop in the skin, mucous membranes and internal organs. And can cause:

    • Recurrent epistaxes

    • Recurrent GIT bleeding iron deficiency anemia

    • Pulmonary & cerebral arteriovenous malformations

    o Connective tissue disorders:

    In the Ehlers-Danlos syndrome there are hereditary collagen abnormalities, resulting in:

    Defective platelet aggregation purpura

    Hyperextensibility of joints

    Hyperelastic friable skin

    Acquired vascular disorders:

    o Simple easy bruising is a common benign disorder in healthy women especially those in the child-bearing age.

    o Senile purpura caused by atrophy of the supporting tissue of cutaneous blood vessels.

    o Purpura associated with infections (bacterial, viral or rickettsial) as a result of vascular damage by the organism or immune complex deposition (e.g. measles, dengue fever or meningococcal septicemia)

    o Scurvy, In vitamin C deficiency Defective collagen Petechiae, bruising and mucosal hemorrhage

    o Long-term steroid therapy or Cushing's syndrome defective vascular supportive tissue Steroid purpura

    Ahmed Alsolami

  • 46

    Thrombocytopenia:

    These are the Ucauses of thrombocytopeniaU, then brief explanations for some causes will follow:

    1. Failure of platelet production:

    o Selective megakaryocyte depression

    Rare congenital defects

    Drugs, chemicals, viral infections

    o Part of general bone marrow failure:

    Cytotoxic drugs

    Radiotherapy

    Aplastic anemia

    Megaloblastic anemia

    Myelodysplasia

    Myelofibrosis

    Leukemia

    Marrow infiltration (e.g. carcinoma, lymphoma)

    Multiple myeloma

    HIV infection

    2. Increased consumption of platelets:

    o Immune

    Autoimmune

    • Idiopathic thrombocytopenic purpura

    • Associated with SLE, CLL or lymphoma

    Infections: HIV, other viruses, malaria

    Drug-induced & heparin

    Post-transfusional purpura

    Feto-maternal alloimmune thrombocytopenia

    o Thrombotic thrombocytopenic purpura

    o Disseminated intravascular coagulation (see page 51)

    Ahmed Alsolami

  • 47

    3. Abnormal distribution of platelet (splenomegaly)

    4. Dilutional loss (massive transfusion of stored blood to bleeding patient)

    • Autoimmune (Idiopathic) thrombocytopenic purpura (ITP):

    It may be divided into Chronic and Acute forms.

    a. Chronic Idiopathic thrombocytopenic purpura:

    UAntibodies against platelets (usually IgG)U premature removal of platelets from the circulation by macrophages of the reticuloendothelial system, especially the spleen.

    It is usually idiopathic but may be associated with SLE, chronic lymphocytic leukemia (CLL), infection with HIV, Hodgkin's lymphoma or autoimmune hemolytic anemia.

    The onset is insidious with petechiae, easy bruising and menorrhagia.

    Laboratory findings:

    o ↓ Platelet count as low as 10-50 × 109/L

    o Normal hemoglobin concentration and WBC count

    o Bone marrow normal or increased number of megakaryocytes

    o Demonstration of specific antiglycoprotein antibodies on the platelet surface

    b. Acute Idiopathic thrombocytopenic purpura:

    In 75% of patients the episode follows vaccination or an infection such as chickenpox or infectious mononucleosis. Most cases are caused by non-specific immune complex attachment.

    Spontaneous remissions are usual but in 10-15% of cases the disease becomes chronic.

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  • 48

    • Post-transfusion purpura:

    It is due to the development of antibodies against platelets in the received blood. It often occurs 10 days after blood transfusion.

    • Thrombotic thrombocytopenic purpura (TTP):

    There is deficiency of the enzyme that breaks down ultra large Von Willebrand factor ULVWF(the most adhesive and reactive form of Von Willebrand factor) ULVWF attach to the endothelial cells adherence of the passing platelets formation of large occlusive thrombi embolising to microvessels downstream organ ischemia

    TTP occurs in 2 forms:

    o Familial: the enzyme that breaks down ULVWF is non-functional due to multiple mutations

    o Acquired: infection, autoimmune, connective tissue disease, drugs, stem cell transplantation or cardiac surgery production of inhibitory IgG autoantibodies block the enzyme action

    Clinical features, "pentad" of TTP:

    o Thrombocytopenia bleeding tendency

    o Microangiopathic hemolytic anemia due to the narrowing of the blood vessels by the thrombi

    o Neurologic abnormalities

    o Renal failure

    o Fever

    • Abnormal distribution of platelet (splenomegaly)

    Thrombocytopenia which occur with splenomegaly is due to "pooling" of more than 90% of the platelets by the spleen.

    Ahmed Alsolami

  • 49

    Platelet dysfunction:

    Hereditary disorders:

    • Thrombasthenia

    • Bernard-Soulier syndrome

    • Storage pool diseases

    Acquired disorders:

    • Antiplatelet drugs (e.g. aspirin, dipyridamole, clopidogrel, abciximab, eptifibatide, tirofiban)

    • Hyperglobulinemia (as in multiple myeloma and Waldenstrom's disease)

    • Myeloproliferative and myelodysplastic disorders

    • Uremia

    • Others (heparin, dextrans, alcohol and radiographic contrast)

    Coagulation disorders:

    Hereditary coagulation disorders

    • Hemophilia A (sex-linked):

    The defect is an absence or low levels of plasma factor VIII due to a mutation in the encoding gene on the X chromosome.

    Clinical features:

    o Excessive bleeding into joints (hemarthrosis), muscles hematomas, mucous membranes and internal organs (brain, kidney, GIT)

    o Operative and post-traumatic hemorrhage are life-threatening

    o Because of the continuous need to blood transfusion, patients may show symptoms and signs of transmitted disease through infected blood such as HIV, hepatitis C or B infection.

    Ahmed Alsolami

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    Laboratory findings:

    o Abnormal activated partial thromboplastin time (APTT)

    o Abnormal factor VIII clotting assay

    o Normal bleeding time and PT tests

    • Factor IX deficiency (sex-linked):

    Also called Christmas disease or hemophilia B, shows identical clinical features to those of hemophilia A.

    The two disorders can only by distinguished by specific coagulation factor assay.

    Laboratory findings:

    o Abnormal APTT

    o Abnormal factor IX clotting assay

    o Normal bleeding time and PT tests

    • Von Willebrand disease (autosomal dominant):

    Von Willebrand factor (VWF) promotes platelet adhesion to damaged endothelium & it is the carrier molecule for factor VIII.

    Gene mutation either reduced level or abnormal function of VWF decreased level of factor VIII and platelet adhesion increased bleeding tendency mostly from mucous membranes and superficial cuts and operative and post-traumatic hemorrhage.

    Laboratory findings:

    o VWF level is usually low

    o Factor VIII level is often low, and factor VIII-VWF binding assay is performed.

    o APTT may be prolonged

    o Platelet count is normal

    Ahmed Alsolami

  • 51

    Acquired coagulation disorders:

    Causes:

    o Deficiency of vitamin K as in:

    Biliary obstruction

    Malabsorption of vitamin K (e.g. tropical sprue, gluten enteropathy)

    Vitamin K-antagonist therapy (e.g. warfarin)

    Hemorrhagic disease of the new born

    o Deficiency of clotting factors due to:

    Liver disease

    Disseminated intravascular coagulation

    o Inhibition of coagulation:

    Specific inhibitors (e.g. antibodies against factor VIII)

    Non-specific inhibitors (e.g. antibodies found in SLE, RA)

    Therapy with heparin, defibrinating agents or thrombolytics

    Massive transfusion syndrome

    • Disseminated intravascular coagulation (DIC):

    Pathogenesis: 2 major mechanisms may trigger DIC:

    1. Release of tissue factor (factor VIIa) or thromboplastic substances into the circulation (e.g. from the placenta in obstetric complications, from leukemic cells, carcinoma and neoplastic cells, from gram-negative and gram-positive sepsis "endotoxins" or "exotoxins") initiation of the intrinsic coagulation pathway.

    2. Widespread injury to endothelial cells (e.g. by deposition of Ag-Ab complexes as in SLE, by temperature extremes as in heat stroke or burns, by gram-negative sepsis "endotoxins") exposure of collagen in the endothelial matrix initiation of the extrinsic coagulation pathway.

    Ahmed Alsolami

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    Clinical features: DIC has 2 consequences:

    o Widespread fibrin deposition within the microcirculation organ ischemia due to vascular occlusion, and microangiopathic hemolytic anemia as RBCs are traumatized while passing through the fibrin strands.

    o Bleeding tendency as platelets and clotting factors are consumed and there is a secondary release of plasminogen activators

    Laboratory findings:

    o ↓ platelet count

    o ↓ fibrinogen concentration

    o PT and APTT are prolonged in the acute syndromes

    o Blood film shows RBC fragmentation as a result of microangiopathic hemolytic anemia

    Ahmed Alsolami