Blood Revision PDF

 Blood Revision EMBRYOLOGY Fetal erythropoiesis occurs in Yolk sac (3-8 weeks) Liver (6 weeks-birth) Spleen (10-28weeks) Bone marrow (18 weeks to adult) Types of hemoglobin (more details in page 4) Fetal globins : alpha globin - gamma globin Adult A1 : alpha globin - beta globin Adult A2 : alp...

 Blood Revision EMBRYOLOGY Fetal erythropoiesis occurs in Yolk sac (3-8 weeks) Liver (6 weeks-birth) Spleen (10-28weeks) Bone marrow (18 weeks to adult) Types of hemoglobin (more details in page 4) Fetal globins : alpha globin - gamma globin Adult A1 : alpha globin - beta globin Adult A2 : alpha globin - delta globin Physilogy Properties of blood 5 Liters in women & 5.5 liters in men Blood represents about 8% of total body weight Blood = 55% fluid part + 45% cellular part Specific gravity - For whole Blood 1060 - For Plasma 1030 - For blood cells 1090 Viscosity Viscosity of the whole blood is 5 times that of the water while viscosity of plasma is 2 times that of water Hemopoeisis itis the formation of new blood cells Stem cells differentiate into * Proerythroblast ----> Rbcs *Myeloblast ----> Granulocytes *Monoblast ----> Monocytes, *Lymphoblast ----> lymphocyte *Megakaryoblast ----> Megakaryocytes ----> Platelets N.B. GROWTH of different stem cells are controlled by special proteins called Growth inducers e.g. Interleukin-3 In adults at the age of 20 :- Red bone marrow is converted into inactive yellow B.M. EXCEPT IN Base of skull/ sternum, Ribs & vertebrae / Pelvic bone / head of long bones as femur & humerus In red B.M., 25% of cells belong to red blood cell series & 75% belong to white blood cells series. Red blood cells = Red blood Corpuscles =Erythrocytes Non-nucleated flat biconcave disc shaped cells ----> Biconcavity provides a larger surface area for diffusion of o2 & co2 across membrane than spherical shape. Average 5 million/mm3 , 5-6 million/mm3 in men & 4-5 million/mm3 in women, & but is less in children than in adult but is higher in newly born infants. Life span of Rbcs in the circulation is average 120 days Structure of Rbcs It is a plasma membrane enclosed sac full of hemoglobin with no nucleus , organelles or ribosomes. Plasma proteins Volume: 55% of blood volume 5% of body weight 3.5 liter in adult 70 Kg Color: yellow Specific gravity: 1030 PH: 7.4 Viscosity: 2 times that of water Colloid osmotic pressure= 25 mmHg Types : [fomsu 2023 - fomsu 2022] [‫ مهم‬function ‫]ال‬ 1-Albumin:is the most abundant plasma protein (Osmotic pressure regulation) 2-Globulins:alpha1&2,beta1&2 and gamma globulins (defense carrier) 3-Fibrinogen (blood viscosity and clotting) 4-Prothrombin:is the least abundant plasma protein (blood clotting) The albumin /globulin ratio-->measure of liver and kidney function (Asked about albumin/globulin function in FOMSU 2023) Normally it is about 1.2-1.6 A-It is decreased in B-1)liver diseases due to decrease synthesis of albumin 2)Kidney failure due to loss of albumin in urine 3)Infection due to increase gamma globulin B-It is increased when globulin fraction is decreased (congenital agammaglobulinemia- AIDS- Immunosuppressive drug) Hypoproteinemia it is marked decrease in plasma proteins less than 7.4 gm% Causes: 1- prolonged starvation 2-malabsorbtion syndrome 3-liver disease (cirrhosis) 4-kidney disease (nephrosis) 5-congenital afibrinogenaemia Effects : 1-Decrease albumin causes decrease in osmotic pressure &increases capillary permeability leading to generalized edema 2-Decrease globulins causes inadequate defense mechanism (frequent infections) 3-Decrease fibrinogen leads to bleeding tendency N.B.Serum= plasma-clotting factors Normal levels of hemoglobin -Infant at birth 20 gm/dl (due to relative intrauterine hypoxia) -Children (3-12 years) 11-14 gm/dl -Adult male 15-17 gm/dl (15 g/dl) -Adult female 12-15 gm/dl (14 g/dl) Types of hemoglobin 1- Adult Hb (HbA): 97% of Hb in normal adult persons contains 2 alpha chains (each is consisted of 141 amino acids) & 2 beta chains (146 amino acids) 2- HbA2 : 2.5% of Hb in normal adult persons Contains 2 alpha chains & 2 delta chains (146 amino acids) which differs from β chain in the terminal 10 amino acids 3-Fetal Hb (HbF) : This type of Hb is present in the RBCs of the fetus & it is normally replaced by HbA soon after birth (2-3 months) It contains 2 alpha chains& 2 gamma chains (146 amino acids) Its oxygen carrying capacity is greater than that of HbA (higher affinity to oxygen) 4-Glycosylated Hb : Normally, there are small amounts of glycosylated Hb (HbA1c) which has a glucose molecule attached to each β chain The quantity of HbA1c increases in poorly controlled diabetes mellitus and it decreases with insulin treatment Abnormalities in Hemoglobin production Sickle cell anemia Cause: Mutation of the gene coding for β chain in which glutamic at position 6 has been replaced by Valine. (Inherited autosomal disease) Effect :Abnormal HbS formed which is less soluble and aggregated forming fibers (long crystals) that deform RBCs into sickle shape. Hemoglobin c anemia Hemoglobin varient that has lysine substituted for glutamate at 6th position in β globin chain. (FOMSU 2021) Patients have mild chronic hemolytic anemia Thalassemia Hereditary disorder in which Hb polypeptide chains are normal in structure but produced in decreased amounts. Alpha thalassemia (reduced in Alpha chains ) Silent carrier of alpha thalassemia:1 gene is defect , no manifestations. alpha thalassemia trait :2 genes are defective ,mild anemia. thalassemia major: 3 genes are defective ,moderate to severe anemia. Homozygous alpha thalassemia : 4 genes are defective , die intra-uterine or shortly after birth (hydrops fetalis) Beta thalassemia (reduced in beta chains ) Beta thalassemia minor: 1 gene is defective. Beta thalassemia major: both genes are defective. N.B. The fetus appear normal at birth because HbF is formed at a normal rate , manifestations of hemolytic anemia appear later after birth ) Hemostasis and Blood coagulation Endothelium injury and Exposed collagen are the trigger for hemostasis Steps of Hemostasis. 1- Local vasoconstriction: to narrow vessel lumen enough to stop bleeding from very small vessels. Causes of vasoconstriction: a. Local myogenic contraction due to direct trauma. b. Nervous reflexes initiated by the pain from the traumatized vessel. c. Local humoral factors liberated from platelets such as ADP, serotonin and thromboxane A2 2-Formation of Platelet Plug :-enough to stop the bleeding from small blood vessels. a- Platelet adhesion: the injured endothelium attracts the von willibrand factor which is plasma protein secreted by endothelial cells & acts as a bridge This factor in turn will attract and adhere to the circulating platelets. b- Platelet aggregation :-After their adhesion, the platelets release its contents (e.g. ADP, thromboxane A2, etc) which will activate more platelets to aggregate and adhere to the formed plug until the injured vessel becomes closed. 3-Formation of Blood clot the blood clot is needed to close the large injuries. It is formed of meshwork of fibrin threads entrapping blood cells and platelets. Blood coagulation occurs around the original platelet plug when the plasma protein fibrinogen is converted to fibrin molecules. The coagulation factors are classified into 3 groups: 1- Fibrinogen group: includes factor 1 (fibrinogen), V, VIII and XIII.  They are activated by thrombin. 2- Prothrombin group: includes factor II (Prothrombin), VII, IX and X.  All need vitamin K for their synthesis in the liver 3- Contact group: includes factors XI and XII.  They are activated by contact to electro-negatively charged surface A- Intrinsic pathway of coagulation: This pathway occurs both in vivo and in vitro. 1- It is initiated by conversion of inactive factor XII to active factor XIIa. This activation occurs when blood is exposed to the collagen fibres present beneath the blood vessel endothelium. The activation is catalyzed by the circulating proteins, highmolecular weight (HMW) kininogen and plasma kallikrein. NB: Factor XII can be activated in vitro by exposing the blood to electro-negatively charged wettable surfaces as glass, 2- Active factor XII then activates factor XI, and active XI activates factor IX. 3- Factor VIII is activated when it is separated from von Willebrand factor by the proteolytic action of thrombin. 4- Activated factor IX forms a complex with active factor VIII. 5- The complex of IXa, Villa, phospholipids (PL) of aggregated platelets and Ca++ activates factor X. 6- Active factor X, in the presence of PL, Ca++ and active factor V, converts prothrombin to thrombin. 7- Thrombin then catalyzes the conversion of soluble fibrinogen polymer to insoluble fibrin monomer threads. Fibrin threads will be arranged spontaneously into a loose mesh. 8- Fibrin stabilizing factor (XIII) of platelets converts the loose fibrin threads into tight strands. Factor XIII is activated by thrombin in presence of Ca++ ions. 9- The net result of this process is formation of clot that closes and adheres to the injured vessel wall. B- The Extrinsic System for Blood Coagulation The Extrinsic system occurs only in vivo. 1- Tissue trauma either vascular or extravascular will release thromboplastin (tissue phospholipid TPL) which activates factor VII (Fig 16) 2- TPL and factor VIIa activate factor IX and X. 3- Active factor X, in presence of PL, Ca++ and active factor V, converts prothrombin to thrombin 4- Thrombin then catalyzes the conversion of soluble fibrinogen polymer to insoluble fibrin monomer threads which will be arranged spontaneously into a loose mesh. 5- Fibrin stabilizing factor (XIII) of platelets converts the loose fibrin threads into tight strands. Factor XIII is activated by thrombin in presence of Ca++ ions. 6- The net result is formation of clot that closes and adheres to the injured vessel wall Ca+ (in the ionized state) is required for promotion of all reactions in the intrinsic and extrinsic pathways (except the 2 steps in intrinsic pathway). Role of thrombin 1- Conversion of fibrinogen to fibrin 2- Activates factor 13 fibrin stabilizing factor 3- Activate factor 5, 8 so stimulate its own formation (positive feedback) Interaction beween 2 pathways 1- Both works simultaneously but extrinsic is more rapid 2- extrinsic pathway stimulates intrinsic pathway by:- A- Small amount of thrombin that is released by extrinsic pathway activate factor V & VIII (5,8) B – Activated factor VII (7) share in activation of factor IX. (9) Natural anti-clotting Mechanisms A-Mechanisms related to endothelium: 1- Smoothness of the endothelium:-Negative charged surface that repel clotting factors and platelets 2- Secretion of prostacycline (prostaglandin I2) & Nitric oxide by the healthy endothelium which inhibits the aggregation of platelets. B-Mechanisms related to blood: 1- Rapid blood flow. why? -Remove the activated factors to the liver to Be inactivated -Prevent platelet aggregation 2- Presence of heparin (anticoagulant) which is secreted from mast cells and basophils. 3- Presence of antithrombin III (heparin cofactor I) -It needs heparin. -Heparin antithrombin Complex causes inactivation of factors II,IX, X, XI,XII (2,9,10,11,12) 4- Presence of protein C and protein S (natural anticoagulants). C-Fibrinolysis It is done by the action of plasmin enzyme (fibrinolysin) which is present in its inactive form (plasminogen=Profibrinolysin) and is activated by 1-Thrombin 2- tPA (tissue plasminogen activator) 3- uPA(Urokinase plasminogen activator) This plasmin breaks (degrades) the fibrin into Fibrinogen degradation products (FDP). List Anticoagulant drugs, mechanism of action of each Disorders of Hemostasis 1- Intravascular clotting (thrombosis): Causes: Venous stasis [as in prolonged recumbancy (e.g. bed ridden)]. Roughness of endothelium [e.g. atherosclerosis]. Complications of Septicemia or Excessive tissue damage This problem may lead to formation of: i- Thrombus: clot fixed to a blood vessel wall. ii- Embolus: clot moving freely in the circulation. Both of thrombus and embolus will ↓ the blood supply to the supplied area → ischemia. 2-Bleeding 1- Defect in wall Causes 1- Vitamin C deficiency 2- Senility 3-Bacterial toxin 2- Defect in platelets Purpura: It is a small punctuate hemorrhages under the skin. It is due to: a- Thrombocytopenia (↓ platelet count to less than 50,000). b- Thrombasthenia (abnormal function of platelets). 3-Defect in clotting factors 1- Liver diseases:- decreased synthesis of clotting factors Except 2-Vitamin K deficiency: ↓ formation of clotting Factors. [Prothrombin, VII, IX, X]. {1972} 3- Congenital deficiency of one of clotting factors -Hemophilia: it is a disease characterized by bleeding tendency. It is a disease of males (sex linked recessive). There are 3 types of hemophilia: a- Hemophilia A (classic hemophilia) (85%): it is due to factor VIII deficiency. b- Hemophilia B (Christmas hemophilia) (10%): it is due to factor IX deficiency. c- Hemophilia C (5%): it is due to factor XI deficiency. -Parahemophilia:- it is due to factor V deficiency -Afibrinogemia -Hypoprothrombinemia Blood transfusion It is the Process of Transferring whole blood or products of blood (e.g. Rbcs, Platelets, clotting factors) From one person into Circulatory system of another. Indications of Blood Transfusion 1- Hemorrhage 2- Bleeding attacks 3-Severe anemia 4-Patients with Hemophilia or Sickle cell anemia 5- In erythroplastosis Fetalis storage of Blood - ADD Acid citrate (to prevent its clotting) & Glucose (as a nutrient to Rbcs) - Kept at 4 C in blood banks and not Freezed, otherwise Rbcs will be destroyed. Blood shouldn’t be used after 5 weeks. Complications “Dangers of Blood transfusion” I- Immediate 1-Hemolytic reactions e.g. pain, Jaundice & acute renal shutdown 2-Volume overload especially in cardiac diseased patient 3-Hyperkalemia in stored blood due to its release from old hemolysed Rbcs -----> ventricular fibrillation & Sudden death 4-Citrate intoxication in massive transfusion----> decrease ionized Ca++&Acidosis 5-Bacterial Contamination due to prolonged storage at room temperature > 4 hours due to Growth of bacteria especially cold- growing gram –ve bacilli causing -------> shock & Fever. N.B. complication of blood transfusion that make acute injury in lung. Answer: acute respiratory distress syndrome within 6hs [fomsu 2022] II- Delayed Transmission of diseases e.g. AIDS, HEPATITIS, Malaria &Syphilis  ‫تجميعة لرقام الفسيولوجي‬ Blood 5 L in women----> 4-5 million/mm3 RBCs 5.5 L in men -----> 5-6 million/mm3 RBCs Blood---> 45% cellular part ( 4% platlets/WBCs-41% red blood cells) ---> 50% fluid part (plasma) Specific gravity---> 1090 blood cells - 1060 whole blood - 1030 plasma Vicosity ----> blood 5 times - plasma 2 times In red bone marrow 75%---> WBCs - 25% ---> red blood cells Diameter of RBCs---> 7.5 um RBCs----> 60% water - 34% hemoglobin - 6% organic and inoraginc 20 gm/dl infant HB level 11-14 gm/dl children(3-12) HB level 15-17 gm/dl male 12-15 gm/dl women Plasma---> 55% blood volume -----> 5% body weight 3.5 liter in adult 25mmHg colloid osmotic pressure 80% of osmotic pressure by albumin Buffer abillity of blood ---> 15% plasma ptn - 85% hemoglobin Albumin/globulin ration ------> 1.2-1.6 HbA = 97% HBA2 = 2.5% Microbology Human Immunodeficiency Viruses & AIDs Retroviruses are enveloped, single stranded (+) RNA viruses that replicate through a DNA intermediate using reverse transcriptase. The most important members that affect humans: Human Immunodeficiency viruses (HIV). Human T-cell lymphotropic viruses (HTLV). The structure of human immunodeficiency virus HIV has a characteristic dense, cone-shaped nucleocapsid composed of the core protein p24 which harbors two identical copies of single stranded positive RNA HIV encodes 3 structural genes and 6 regulatory genes. Structural genes: 1. Group Specific Antigen (Gag): p24, p7, p17 2. Envelope (Env): gp 120, gp 41 gp120 binds to CD4 on CD4+ T lymphocytes and cells of the monocyte/macrophage lineage and coreceptors (CCR5 and CXCR4) (asked about coreceptors in fomsu 2022) gp41 mediate fusion between the cellular and viral membranes. 3. Polymerase (Pol): Reverse transcriptase, integrase, protease Pathogenesis of HIV infection and viral tropism: The gp120 protein on virus binds specifically to CD4 receptor on host cell with high affinity. Gp41 causes fusion of the virus to the cell membrane. After fusion virus particle enters cell. Uncoating of the virus occurs. Reverse transcriptase produces viral DNA from RNA. Becomes a provirus which integrates into host DNA. Mode of transmission [body fluids-mother to baby-IV drugs-sex] Stages of HIV and clinical impact (1)Acute HIV infection (2) Clinical latency, (3) AIDS (acquired immunodeficiency syndrome). Acute HIV Infection Stage: Within 2-4 weeks after HIV infection, manypeople develop flu-like symptoms and it’s the body’s natural response to the HIV infection. large amounts of virus are being produced in your body. The virus uses CD4 cells to replicate and destroys them in the process. your CD4 cells can fall rapidly. Eventually your immune response (induced CD8 T cells and antibodies) will begin to bring the level of virus in your body back down At this point, your CD4 count begins to increase During the acute HIV infection stage, you are at high risk of transmitting HIV to your sexual or drug using partners because the levels of HIV in your blood stream are very high. Clinical Latency Stage patients experience no symptoms, or only mild ones. the HIV virus continues to reproduce at very low levels, although it is still active. People in this symptom-free stage are still able to transmit HIV to others, even if they are on ART, although ART greatly reduces the risk of transmission. If you are not on ART,your viral load will begin to rise and your CD4 count will begin to decline. AIDS you become vulnerable to opportunistic infections and cancers as lymphomas and Kaposi sarcoma. You are considered to have progressed to AIDS If: The number of your CD4 cells falls below (200 cells/mm3), You develop one or more opportunistic illnesses, regardless of your CD4 count. Without treatment, people who progress to AIDS typically survive about 3 years. Once you have a dangerous opportunistic illness, life-expectancy without treatment falls to about 1 year. Opportunistic infections associated with AIDS Bacterial--->TB-strept pneumonia parasitic--->pneumocystis carinii Viral--->herpes(herpes simplex-cytomegalovirus-varicellazoster virus) Fungal--->candida-cryptococcus Antiretroviral drugs (‫)تحديدات دكتورة المايكرو‬ Nucleoside reverse transcriptase inhibitors (NRTI):interfere with synthesis of proviral DNA eg:lamivudine , zidovoudine Non reverse transcriptase inhibitors: eg: rilpivirine-nevirapine-efavirenz Protease inhibitors: interfere wit cleavage of proviral poly ptns during budding resulting in generation of non infectious viral particles eg:retonavir (most potent antiretroviral drugs) -post attachments inhibitors (fusion): eg: fuseom -integrase inhibitors: eg: raltegravir -antiretroviral therapy (ART) (two NRTIs + an NNRTI or a PI) Ex: lamivudine ex: nerirapine ex; ritonavir Zidovudine efavironz N.B: confirmatory test for HIV is westernbolt test (fomsu 2022) Immune mediated hemolysis (many questions in 2023) Mechanism of immune mediated hemolysis 1-The intravascular destruction of RBC by complement lysis, which is initiated by antibodies that are often, but not exclusively, of IgM class. 2-The extravascular destruction by immune cells, which recognize IgG and complement bound to RBC. Primarily in the spleen and liver and is effected by macrophages. The Fc-receptor is critical in binding RBC coated with IgG. Also, the 2 complement proteins C3b and iC3b are recognized by macrophages and facilitate RBC binding. Immune-mediated destruction or alteration of a red blood cell (RBC). Three mechanisms can lead to the RBC’s destruction or alteration: (i) An RBC is engulfed by a macrophage and lysed intracellularly (phagocytosis). (ii) An RBC is partially phagocytized (fragmentation), but the altered RBC (spherocytes) escapes the immune attack by the macrophage and remains circulating. (iii) An RBC is attacked by a macrophage and lysed extracellularly by ADCC, (antibody-dependent cell mediated cytotoxicity). in which the macrophage secretes toxic substances lytic for the attached RBC. Immune mediated hemolysis is a type II hypersensitivity reaction: Alloimmune hemolysis Autoimmune hemolysis:classified into two groups; Warm reactive antibodies, which react at 37°C. Cold reactive antibodies, which only react below 30°C. Alloimmune hemolysis Example: blood transfusion reaction. ABO and RH incompatibility = alloimmune hemolysis (fomsu 2023) Transfusion of ABO-incompatible blood results in complement-mediated cytotoxic reactions. RBCs will be lysed intravascularly (IgM antibodies) by the destructive action of complement on their membranes. RH incompatibility reaction (hemolytic disease of new born) seen in infants born of mothers with Rh-incompatible blood groups. Ttt: exchange transfusion Prevention: Anti-D injections RH incompatibility cause erythroblastosis fetalis (fomsu 2022) The Coombs test The Coombs test checks the blood to see if it contains certain antibodies. There are two types: The direct Coombs checks for antibodies that are attached to the surface of RBCs. used to detect Rh antibodies The indirect Coombs test checks for unattached antibodies that are floating in the bloodstream. Notes from fomsu 2023 The type of hemolytic anemia in pregnant & fetus incompatibility is Alloimmune hemolytic anemia The test that detects the Ab is …. a. Coombs test Type 2 hypersensitivity in ….. Compatible blood groups transfusion Cold agglutinins Cold agglutinins are autoantibodies that react with antigens on the RBC membrane at cold temperatures. The reaction is reversible These cold-reacting antibodies belong to the IgM class. Polyclonal cold agglutinins can be produced secondary to certain infections, most notably Mycoplasma pneumonia and infectious mononucleosis associated with B- or plasma cell-lymphoproliferative disorders including B-cell chronic lymphocytic leukemia,…. The areas of the body most affected are those having greatest exposure to the cold, most notably the fingers, toes, earlobes, and nose. The direct antiglobulin (Coombs) test is used to determine whether RBC-binding antibody (IgG) or complement (C3) is present on RBC membranes. Generally, IgG is present in warm antibody hemolytic anemia. Autoantibodies in cold agglutinin disease are usually IgM. In cold agglutinin disease, C3 (C3b and C3d) is present, but IgG is not. Free antibodies in plasma are identified with the indirect antiglobulin [indirect Coombs] test. (fomsu 2022) N.B. cold agglutination: reversibble - increase C3 - mediated by IgM - areas most affected are fingers, toes, earlobes, and nose (fomsu 2023) Diagnosis and treatment of immune mediated hemolysis Diagnosis: detection of circulating antibody against RBCs Treatment: Anti-inflammatory immunosuppressive drugs Corticosteroids are the treatment of choice in idiopathic warm antibody AIHA. Transfusion-transmitted Infections The hepatitis B virus (HBV) HBV is of the family of hepadnaviruses, its genome consists of partially double-stranded DNA. The virus particle, called Dane particle (virion), consists of an outer lipid envelope and an icosahedral nucleocapsid core (‫)شكل هندسي بعشرين وجه‬composed of protein. The nucleocapsid encloses the viral DNA and a DNA polymerase.The outer envelope contains embedded proteins which are involved in viral binding of, and entry into, susceptible cells , These particles are not infectious and are composed of the lipid and protein that forms part of the surface of the virion, which is called the surface antigen (HBsAg), and is produced in excess during the life cycle of the virus. Modes of Transmission Parenterally via blood, saliva, menstrual and vaginal discharges, semen and breast milk. Infected blood and blood products. Sexual contact. Prenatally from mother to child. Pathogenesis and clinical picture: The incubation period of hepatitis B is 6 to 24 weeks, The hepatic cell damage resulting from a cellular (Cytotoxic T cells) and humoral immune response directed against the virus antigens on the surface of the infected hepatocytes.. 90% of neonates and 10% of adults become chronic carriers. The following forms are differentiated : Chronic persistent hepatitis without viral replication. Chronic active hepatitis with viral replication and a progressive course. A chronic infection can result in development of cirrhosis or hepatocellular carcinoma of the liver. Laboratory Diagnosis Elevated liver enzymes as serum alanine aminotransferase (ALT). Hepatitis B virus markers Serological tests are used for the diagnosis of acute and chronic hepatitis B infection. HBsAg - used as a general marker of infection. HBsAb - used to document recovery and/or immunity to HBV infection. anti-HBc IgM - marker of acute infection. anti-HBcIgG - past or chronic infection. HBeAg - indicates active replication of virus and indicate high infectivity. Anti-Hbe - virus no longer replicating. However, the patient can still be positive for HBsAg which is made by integrated HBV. HBV-DNA - indicates active replication of virus, Used mainly for monitoring response to therapy. The “window period” refers to that period in infection when neither hepatitis B surface antigen (HBsAg) nor its antibody (HBsAb) can be detected in the serum of the patient.... Serologic tests conducted during the window period will be positive for HBcAb and HBeAb. Treatment: Alpha Interferon and Nucleoside analogue as Lamivudine Preventionand control Vaccination: Vaccine can be given to those health care workers. It is also given routinely to neonates as universal vaccination in many countries. The vaccine is given in 3 doses at 0,1 and 6 months by intramuscular injection. Hepatitis B Immunoglobulin: HBIG may be used to protect persons who are exposed to hepatitis B. It may also be given to neonatesnwhose mothers are HBsAg and HBeAg positive. Other measures: screening of blood donors, blood and body fluid precautions Notes for HBV (FOMSU 2022) -HBV---> chronic infection result in development of liver crirrhosis or hepatocellular carcinoma -Window period---->HBsAG and HBsAB----> not found,can be detected by HBcAB and HBeAB -HBsAG is used for screening test of hepatitis B Hepatitis D It is defective and cannot produce infection unless the cell is also infected with HBV. A naked strand of RNA that enters the cell. Infection is either a Coinfection where the patient acquires both viruses at the same time or Superinfection ( on top of a chronic HBV infection where it may lead to an acute exacerbation. Diagnosis by detection of anti-HDV antibodies. Prevention and control: through control of HBV infection. Hepatitis C virus (HCV) HCV is a member of flavivirus family. HCV genome is a single stranded positive-sense RNA Transmission The transfusion of unscreened blood and blood products. The reuse or inadequate sterilization of medical equipment. HCV can also be transmitted sexually and can be passed from an infected mother to her baby Hepatitis C is not spread through breast milk, food, water or sharing food or drinks with an infected person. Clinical Manifestations: Resembles HBV I.P.: 2 to 24 weeks and 80% of acute infections are asymptomatic Persistent carrier state 80% of patients patients have chronic liver damage associated with cirrhosis or hepatocellular carcinoma Diagnosis : Elevated liver transaminases Screening for anti-HCV antibodies by ELISA or RIBA.(Fomsu2022) N.B. confirmatory test for HCV is RIBA (FOMSU 2023) Treatment: Pegylated interferon:encourages the immune system to attack virus Ribavirin: stops the virus reproducing Sofosbuvir (Sovaldi) and other new drugs Prevention of HCV infection : There is no vaccine for hepatitis C, prevention depends on reducing the risk of exposure to the virus Injection drug use is the most common way now people get hepatitis C. Avoid injecting drugs to reduce your risk. Avoid sharing personal care items that might have blood on them Consider the risks if you are thinking about tattooing, body piercing, or acupuncture (proper sterilization of the instruments). Consider safe sex, use latex condoms correctly to prevent the spread of sexually transmitted diseases, including hepatitis C Human T-cell lymphotropic viruses (HTLVs) The human T-lymphotropic virus, or human T-cell leukemia- lymphoma virus (HTLV) family of retroviruses cause adult T-cell leukemia/lymphoma and a demyelinating disease called HTLV-1 associated tropical spastic paraparesis The reverse transcriptase transform viral RNA into DNA copy which is integrated into the cellular genome leading to cell transformation. Transmission: can be transmitted sexually, by blood transfusion or sharing needles when using drugs and via breast feeding. Parvovirus B19 (B19V) Parvovirus B19 most commonly causes a mild rash illness that affects children. Adults can get infected with parvovirus B19 too. symptoms include painful or swollen joints (polyarthropathy syndrome), which is more common in adults, and severe anemia The main target cells (Tropism) are erythroid progenitor cells in the bone marrow. The virus requires the P blood antigen receptor to enter the cell. leads to the suppression of erythrogenesis seen during infection. Transmission Through respiratory secretions, such as saliva, sputum, or nasal mucus. Through blood or blood products. A pregnant woman can pass the virus to her baby. Immunodeficinicy diseases Immunodeficiency can be : Primary (born with it) Innate: phagocytes, complement, NK cells Acquired : B cells, T cells, Combined Secondary immunodeficiency may be Transient or Permanent Primary Immunodeficiency I. Defects of Innate Immunity 1. Phagocyte Cell defects: Migration Leucocyte adhesion deficiency (LAD): LAD-1 LAD-2 Leucocyte adhesion deficiency-1 (LAD-1): defect in CD18 (integrin) Its ligand is ICAM-1 present on endothelium Leucocyte adhesion deficiency-2 (LAD-2): Deficient production of (CD15s), It is a ligand for selectins on endothelium Result of LAD defects: Defective adherence to endothelial surfaces →↑ susceptibility to bacterial infections, no pus formation. Engulfment Rarely alone Intracellular Killing Chronic granulomatous disease: X-linked defect in NADPH oxidase system Or G-6-P dehydrogenase and myeloperoxidase deficiency → no O radicals → ↓ Killing → chronic bacterial infections and recruitment of more phagocytes → lesions resembling granulomas Macrophages and neutrophils affected N.B. In certain immunodeficiencies, lymph nodes are enlarged in chronic granulomatous disease (fomsu 2022) Chediak –Higashi syndrome: Autosomal recessive Defective fusion of phagosomes and lysosomes in neutrophils, macrophages and dendritic cells →↓ killing of phagocytosed microbes→↑susceptibility to bacterial infections Associated with defective granule function in natural killer cells lead to increasing viral and malignant tumors (3. NK Cell Deficiency), defects in T cells Associated with albinism --->Fomsu 2022 2.Complement Deficiencies A. Early Components : (classical) (C1,C2,C4) ↓ elimination of immune complex fromed by humoral immune response → accumulation → damage → lupus-like disease B. Early Components: (alternative) ↓stability of C3bBb convertase on microbial surfaces →↑pyogenic infections C. C3: Severe susceptibility to infection → fatal early in life Immune-complex-related disease in both classical and alternative D. Terminal Components: (C5-C9) not significant, since opsonization seems to be enough The main clinical manifestation is invasive meningococcal disease Disseminated gonococcal infections may also occur E. Regulatory Proteins ↓C1 inhibitor →↑activation by classical pathway → C2a (vasoactive) → accumulation of fluid → swelling of epiglottis → suffocation → death (Hereditary angioedema) A. Defects in Lymphocyte May affect: B cells T cells Both: Severe combined Immunodeficiency (SCID)Severe combined immunodeficiency (SCID) X-linked Defect in T& B cells first few months of life Failure to thrive Continuous diarrhea Infections with all pathogen B Cell Immunodeficiencies X-linked agammaglobulinemia: (Bruton’s agammaglobulinaemia) Defect in B cell tyrosine-kinase → needed for maturation of B cells Result: ↓ B cell numbers ↓ in all serum Ig isotypes Otitis, bronchitis, pneumonia, and other chronic infections Infections with extracellular bacteria B. Defects in Lymphocyte Activation and Effector Function 1. X-linked hyper-IgM Syndrome: Defect: Deficiency of CD40L on activated T cells which results in an inability to switch from making IgM to IgG High serum of IgM without other isotypes, normal B and T cell numbers infection with extra cellular bacteria Ttt: gamma globulin replacement - Antibiotics when indicated Selective IgA deficiency Defect: IgA deficiency is related to the inability of IgA expressing B cells to undergo to the plasma-cell stage Increase infections of the respiratory and genitourinary tracts, the primary sites of IgA secretion. Allergy Normal level of IgG and IgM ----> Fomsu 2023 Ttt: Antibiotics when indicated but no gamma globulin replacement Transient Hypogammaglobulinaemia of infancy at 5-6 months when maternal IgG decreased and infants start synthesizing their own IgG. Sometimes, the infants fail to synthesize IgG at this time resulting in prolonged period of THI. Such infants have recurrent infections and poor response to vaccine taken at that age. T cell immunodeficincies Di goerge syndrome (3th and 4th pharyngeal arch) :congenital absence Or incomplete development of thymus , increase infection with intracellular pathogens , malignant tumore , no reactions to skin tests (delayed hypersensitivity) , no reaction in GVHD Lymphocye Abnormalities associated with Systemic Genetic Diseases Wiskott-Aldrich syndrome: X-linked Defect in protein of cytoskeleton of hematopoietic cells (WASp) Absence → Abnormal maturation and migration of leukocytes and platelets lead to  bleeding tendency  Immunodeficiency  Eczema Ataxia-telangiectasia: -abnormal DNA repair during lymphocyte maturation , leads to Immunodeficiency Abnormal gait Vascular malformations Secondary Immunodeficiency Causes: malnutrition - HIV - extreme age - malignancy - drugs Malnutrition is the most common cause in developing countries Deficiency of Mg and Zn →decrease Th1 ( cell-mediated immunity ). Aging: T-cells production in thymus keep decreasing with aging HIV: Different opportunistic infections occur after HIV has caused different levels of immunodeficiency Relation between type of Infection and Deficiency B cell deficiency → pyogenic infections T cell deficiency: viral infections, intracellular infections,tumours Innate: pyogenic and other varied results N.B. in T-cell invastigation --> DTH test for candidan test In cytotoxic T lymphocyte assay: target cells are labeled with radioactive sodium chromate Organ is less functional with aging--->thymus gland (Fomsu 2022) Management of Immunodeficient Patient Specific (according to defect): SCID and other severe deficiencies → transplantation of thymus or bone marrow (FOMSU-2023) Antibody deficiencies → transfer of Ig Cytokines:  IFN-γ  IL-2 Replacement gene therapy Viral hemorrhagic fever (ARBOVIRUSES &ROBOVIRUSES) Arboviruses: transmitted by blood sucking arthropods,replicate in insect (without obvious disease) , enveloped RNA viruses. Roboviruses: not transmitted by arthropods but are maintained within the rodent reservoir which transmit infection directly to humans without participation of arthropods , Humans are frequently an accidental host fever & bleeding tendencies caused by several families of viruses Filoviruses: Ebola V and Marburg V Flaviviruses: -Yellow fever V –West Nile V – Dengue Fever V Bunya viruses: Rift Valley fever virus (RVV) Hanta and Hantavirus. Arenavirus: Lassa Fever V Pathogenesis of VHF Infection with VHF viruses occur by exposure of mucous membranes or breaks in the skin to infectious virus After introduction, macrophages and dendritic cells are early targets of infection and spread to local lymph nodes → promoting viremia and systemic dissemination. The virus become localized in liver, spleen and kidney Infection of different organs promotes the pathologic processes liver damage may depress production of clotting factors, which may result in hemorrhage. Infection of macrophages also results in uncontrolled production of cytokines, This not only promotes vascular leakage and hypotension but can also activate coagulation pathways that may ultimately lead to disseminated intravascular coagulation. Human arboviruses infections 1. ENCEPHALITIS 2. YELLOW FEVER 3. DENGUE FEVER 4. RIFT VALLEY FEVER 5. SANDFLY FEVER 1. ENCEPHALITS In Egypt, two viruses exist: West Nile virus and Sindbis virus. Infection is acquired from the bite of infected mosquito. 2. YELLOW FEVER Yellow fever is an acute haemorrhagic disease caused by yellow fever virus which is a member of Flaviviridae family These are enveloped viruses containing single-stranded RNA. The virus enters through the bite of an infected mosquito, multiplies in local lymph nodes → the blood → liver, spleen, kidneys and bone marrow. high fever, jaundice, albuminuria, bleeding from nose, gum, haematemesis and melena. Jungle yellow fever:is primarily a disease of monkeys. the disease is transmitted from monkey to monkey by Aedes africanus mosquito , Man is infected accidentally during his work in forests (wood cutters, road builders) and carries the infection to urban areas. Urban yellow fever: involves man to man transmission by Aedes egypti which breeds in stagnant water near houses. Prevention & Control The use of insecticides to kill adult mosquitoes and the elimination of their breeding sites. Yellow fever vaccine: It is a live attenuated virus grown in chick embryo. known as 17D Vaccine ,single injection subcutaneously, persists for 10y 3. DENGUE FEVER The virus is a member of the Flaviviridae family with no cross immunity with yellow fever virus. Monkey is the main reservoir and main vector is Aedes egypti mosquito. (asked about vector in FOMSU-2023) Clinical features Prodromal symptoms begins 4–7 days after an infective mosquito bite. The onset of fever may be sudden or there may be prodromal symptoms of malaise, chills, and headache. Pains soon develop, especially in the back, joints, muscles, and eyeballs. Myalgia and deep bone pain (breakbone fever) are characteristic. A rash may appear on the third or fourth day and last for 1–5 days. Lymph nodes are frequently enlarged. 4. RIFT VALLEY FEVER member of Bunyaviridae family , Mosquito-borne disease affects primarily sheep & goats also cattle, buffalos and camels. Transmission: Humans acquire infection by: - Bite of infected mosquito - Contact with infected blood or animal tissues - Ingestion of contaminated raw animal milk 5. SANDFLY FEVER belongs to the Bunyaviridae family. The causative virus is distributed in countries bordering the Mediterranean sea, where the sandfly Phlebotomus papatasii exists. ROBOVIRUSES (Rodent Borne Viruses) not transmitted by arthropods , Rodents are the main reservoir of the virus and transmit infection to man directly. The common clinical features are fever, petechial haemorrhage or purpura, bleeding from the gastrointestinal, genitourinary tracts and nose, shock and death. Hantavirus genus (Bunyaviridae family) 1. Hantaan virus: It causes haemorrhagic fever with renal failure. The reservoir of infection is rat. 2. Hanta virus: The reservoir of infection is rodents, which excrete the virus in urine and stools. Man is infected by inhalation of dust contaminated with these excreta. No Man to man transmission. FILOVIRIDAE Marburg & Ebola Viruses They cause African haemorrhagic fever. Man to man transmission occurs with high mortality rate. The virus is extremely virulent and hospital staff members are highly susceptible through close contact with patients, their blood or excreta. N.B. Virus transmited through blood and body fluids : marburg (fomsu-2022) ARENAVIRIDAE Lassa fever virus : Family Arenaviridae they have a granular or sandy surface , Infection occurs by water-contaminated by urine and saliva of infected rats which are the reservoir of infection. Man to man transmission occurs Junin & Machupo viruses They cause haemorrhagic fever Infections occur among workers in maize and wheat fields who are exposed to the reservoir (rodents). Hypersensitivity Inappropriate immune responses to certain antigens causing tissue damage. Depends on: 1)nature of allergen 2) route of sensitization, 3)state of the individual and/or the genetic potential Types: 1.Type I (immediate or anaphylactic reaction): IgE-mediated 2.Type II (cytotoxic or cytolytic): IgG or IgM-mediated 3.Type III (immune complex mediated): IgG or IgM-mediated 4.Type IV (delayed hypersensitivity reaction): T cell-mediated Type I (Immediate or Anaphylactic hypersensitivity) Immediate hypersensitivity Anaphylactic IgE mediated Example (clinical syndrome) : Tissue damage o Systemic form : acute anaphylaxis like antibiotic & insect bite o Local form : atopic diseases like extrinsic asthma – allergic rhinits – conjunctivitis – atopic dermatitis – food allergy Physioglogical role : antiparasitic immunity Mechanism: 1. Allergen stimulates IgE production 2. IgE bind to FC receptor on mast cell and basophils 3. Releasing mediators (histamine, leucotrines , chemotactic factors) 4. ⬆ vascular permeability + contraction of smooth muscles N.B. normal antibody titers in response to vaccines is IgM (FOMSU-2023) Hypersenstiviy type II Ab dependent cytotoxicity (attack specific tissue not systemic) Ab dependent : IgM + IgG Example (clinical syndrome) : -Alloimmune hemolysis:incompatible Blood transfusion or Rh incompatibility (FOMSU-2022-2023) - Early transplant rejection - Autoimmune diseases : AI hemolytic anemia ------> (FOMSU-2022) AI thrombocytopenic purpura (bleeding) Acute rheumatic fever (Myocarditis) Goodpasture syndrome (Nephritis) Graves’ disease (hyperthyroidism) (FOMSU-2023) Myasthenia gravies Mechanism: The reaction time is minutes to hours. It is primarily mediated by antibodies of IgM or IgG class and complement. Phagocytes and NK cells may also play a role (ADCC) (Antibody dependent cell-mediated cytotoxicity) 1. Antibodies on target cell + complement (small amounts) →damage of these cells (tissue cell or circulating RBCs) 2. ADCC: Antibodies coated target cell → attacked by NK cells and phagocytes 3. Ag-Ab complex on the cells interact with phagocytic cells by immune adherence → phagocytosis enhanced by C3b opsonisation Hypersenstiviy type III Immune complex mediated Mainly Ab dependent: IgG Example (clinical syndrome) : Arthus reaction : repeated SC injection (insulin – rabies vaccine) -> local vasculitis and necrosis -----> (FOMSU-2023) Serum sickness : injection of foreign serum -> local vasculitis and arthritis (Abs against Anit-venom antibodies ) Others Autoimmune disease: o Systemic lupus erythematosus o Rheumatoid arthritis o Multiple sclerosis  Farmer’s lung develops after inhalation of dust or mold spores drug reactions : allergies to antibiotics (penicillin and sulfonamides) infectious diseases o Malaria & trypanosomisasis (antiparasitic ) oMeningitis o Hepatitis oGlomeruloonephritis oPoststreptococcal oMononucleosis Mechanism: 1. Ag + Ab mainly IgG → stimulate complement (large amounts rapidly consuming) → inflammatory effect (local & systemic) through membrane attack complex (cytotoxicity = cell lysis) 2. Activation of complement: Chemotactic mediators (influx of neutrophils) & anaphylatoxins (C5a) → Massive inflammation 3. Aggregation of platelets → more inflammation and the formation of microthrombi that block capillaries → Tissue death and hemorrhage (local vasculitis & necrosis) Hypersenstiviy type IV Delayed hypersensitivity Mediated by: T-cell & MQ (not Ab hypersensitivity ) Example (clinical syndrome) : Tuberculin skin test -----> (FOMSU-2023) Granuloma formation (TB) Contact dermatitis (skin-chemicals) -----> (FOMSU-2023) Chronic graft rejection (type of transplant rejection) Insulin dependent DM Mechanism: (TH1) cells secrete cytokines which recruit and activate : 1. monocytes and macrophages → cause bulk of the damage 2. activate cytotoxic T cells that cause direct damage The response starts hours or days after contact with Ag. PARASYTOLOGY Malaria First cause of death in protozoal diseases. 2nd cause of death from anaemia. According to the pattern of fever Malaria is classified into : Benign tertian: P. ovale Benign tertian: P. vivax --> most common Quartan: P. Malarie Subtertian or malignant: P.flaciparum Morphology 1- Ring form (early trophozoite) 2- Developing trophozoite (actively growing-brown in color) 3- Immature schizonts (chromatin granules-seen In severe infections) 4- Mature schizonts (merozoites) 5- Microgematocytes (in p.Falciparum:roundish , crescent-shaped) 6- Macrogematocytes: (round to oval) except p.falciparum--->crescent Mode of infection 1- Biting of vector 2-blood transfusion 3-congenital Infective stage: sporozoites diagnostic: merozoites Life cycle of plasmodium sp. Inside vector (sporogony) Pre-erythrocytic (exoerythrocytic)--->asexual multiplication Erythrocytic stage (inside RBCs) 1- Erythrocytic schizont (8-32 merozoites) 2- Schizont rupture to release(merozoites-pigments-toxins) 3- Micro/macro gametes formed---> patients are infective to mosquito vector Clinical picture 1- FAHM 2-hepatosplenomegaly 3-jaundice 4- anemia (p.v-p.o: invade reticulocytes , p.m:old RBCs , p.f:any age) 5- malarial paroxysm ( cold - hot - sweating stages ) Complications of malaria (p.v , p.o , p.m : are relatively benign) Chronic p.m cause nephrotic syndrome due to immune complex deposition -------> (FOMSU-2023) p.f : (malignant - usually severe and fetal ): (ischemia, cytoadherence , Sequestration ----> congestion , occlusion , rupture of capillaries) Complications related to cytoadherence 1- Cerebral malaria ----> coma , death 2- Dysenteric malaria ----> GIT bleeding 3- Pulmonary edema 4- ARF: Acute tubular necrosis caused by renal anoxia 5- Algid malaria(shock):circulatory collapse-hypothermia-hypotention 6- Speticemia malaria (multiorgan failure) 7-hypoglycaemia 8-.hyperreactive splenomegaly 9-.black water fever ---> complication of P.falciparum (FOMSU-2022) Microscopic exmaination in diagnosis (gold standard in malaria) Treatment: (choroquine - artemisinin) (choroquine): first day: 600mg orally followed by 300mg/6 hours 2nd/3rd day : 300mg daily Choloroquine resistant ----> artemisin + mefloquine Radical treatment (for P.v & Po hypnozoites)-->prevent relapse Primaquine----> 15mg/day for 14 days Don’t use with G6PD and pregnant women Chemoprophylaxis for travellers in endemic area One week before travelling , During and for 4 weeks after leaving endemic area. Chloroquine :300mg/week. Resistant areas: all Africa :mefloquine weekly. In long stay (Pv&Po): Primaquine. Babesiosis Tick born disease caused by Babesia microti& Babesia divergens. DH/vector: Tick IH: man Infective: sporozoites RH: wild animals - rodents - cattles -No exoerythrocytic cycle -multiplying by budding forming trophozoites then merozoites -mode of infection: bite - congenital - blood transfusion Microscopic examination: maltase cross - no pigment or stipping - no change in size of RBCs Early treatment (Quinine sulphate-clindamycin) (10 days) FILARIA 1- Wucheraria bancrofti Cause c/p : Tropical pulmonary eosinophilia - Classical lymphatic filariasis DH: Man IH: mosquito (culex in egypt) Mode of infection ; infected female mosquito vector bites man for blood meal Habitat: lympth nodes DS: microfilaria IS: infective filariform larva Clinical picture (I.P: 8-12 months) -Asymptomatic (most of infected people) -Filarial or elephantoid fever (chils at first , then drops gradually) -Lymphangitis -lymphadenitis -lymphadema -Non-pitting (browny edema) -Severe in chronic diseases (more in adults males) (complications):- Elephantitis , lymph varicosites , hydrocele , lymphorrhagic -death of an adult worm lead to severe localized inflammation --------> worm absorbed , abscess formed around them , calcify -demonstration of microfilaria in blood Blood sample ---> (thin/thick/ABC) Conc techniques: Knot’s conc technique,nucleopore filtration (FOMSU) Immunodiagnosis Ag detection by filarial card test (ICT-ELISA) (gold standard) IgG4 antifilarial - antibodies TREATMENT -DEC (diethylcorbamazine) (adult-microfilaria) -Ivermectin (affect microfilaria only) -Filarial lymphangitis: antihistaminic, antipyretic and Abs - no medical treatment for chronic cases with elephantitis Prevention and control Mosquito vector (chemical control + personal prophylaxis). MDA (Mass Drug Administration). (single dose of DEC+Ivermectin) yearly for 4 years Occulut filarrias Clinical picture: Massive eosinophilia 30-80% Hepatosplenomegaly Pulmonary symptoms like dry nocturnal cough, dyspnea, and asthmatic wheezing Arthritis, glomerulonephritis, thrombophlebitis, tenosynovitis. Classical features of lymphatic filariasis are absent  microfilariae aren’t found in blood Tropical pulmonary eosinophilia: Ex: of occult filariosis , infection without demonstarable microfilaria Children and young adults are commonly Impairment lung function (irreversible) Low-grade fever + loss of wieght + lymphadenopathy Chronic bronchitis----> asthma Increased IgE , X-ray: diffuse patchy mottling 2- Brugia malayi (Malayan filaria) Life cycle as W.B with some differences: Vector: mansonla(mainly) + anopheles + aedes RH: monkeys + cats Habitat: lymph nodes and lymph vessels-----> (FOMSU-2023) Clinical picture Often asymptomatic - no invovlment of genitalia - no chyluria Diagnosis , TREATMENT and control As W.B except (more severe allergic reactions) Presence of RH (control more difficult) Ttt: (DEC) is initiated with small dose and daily anti-histamine BIOCHEMISTERY Vitamin K and minerals Notes: 1. Soluble vitamins [A, D, E, and K] dissolve in fat and are stored to be used later. 2. Water-soluble vitamins B.complex and C can move quickly through the body because the body is a watery environment, they are flushed by the kidney. 3. There are 8 B vitamins including B,1 B2, B3, B5, B6, B7, B8, B9, and B12. 4. There are 3 positions of vitamin K and we can find them: a. K1: In green leafy vegetables. b. K2: Synthesized by intestinal bacteria. c. K3: Synthetics must have potent, and water-soluble vitamins. 5. Vitamin K helps in the process of oxidative phosphorylation in the respiratory chain because vitamin K produces Coenzyme Q. 6. vitamin K helps synthesize blood-clotting proteins. 7. vitamin K2 is necessary for osteocalcin which is an activation of special bone protein. 8. you should not take a prolonged oral antibiotic because it kills flora which is a deficiency of vitamin K. 9. The newborn can have a deficiency of vitamin K because breast milk is poor in vitamin K or their intestines are sterile. (FOMSU-2023) 10. Long use of warfarin and dicumarol lead to a deficiency of vitamin K. 11. In liver disease (in Jaundice) bile salts of Vitamin K are not absorbed. 12. If vitamin k deficiency happened that leads to a lack of active clotting factors producing and a Hemorrhagic tendency happened which will increase clotting time and there will be bleeding after any injury however tiny it is which affects the skin and mucous membranes. 13. There are two types of minerals: a. Major minerals, more than 100mg a day (MacroMinerals). b. Trace Minerals, less than 100mg a day (Microminerals). 14. Iron has 3 sources: a. Animals b. Plants c. From Hb catabolism 15. About 5: 10% of the whole amount of iron that we ate is only being absorbed and absorption happens in the proximal part of the Jejunum and Duodenum( upper part of Interstate). 16. The function of Iron is: a. Supports our healthy growth and development. b. Helps deliver oxygen to our bodies c. Helps maintain our energy levels d. Keeps levels of oxygen in our muscles 17. 18. If there is a high percentage of iron, it is hemochromatosis and there are two types of it genetically or secondary reasons for secondary are a. Parental iron therapy. b. Repeated blood transfusion. c. Anemia e.g.:Thalassemia. N.B. high percentage of iron called hemochromatosis (FOMSU) 19. Manifestation of hemochromatosis: a. bronze diabetes. b. Skin: causing bronzed pigmentation. c. Liver: causing liver cirrhosis. d. Pancreas: leading to diabetes Mellitus. 20. We can get copper from meat, liver, and egg, and it is absorbed from the upper small intestine. 21. Copper is important for hematopoiesis and component of enzymes. 22. Copper is essential as a cofactor for lysyl oxidase.23. Wilson's disease is a genetic disease due to a mutation of a gene encoding copper-binding P.type ATPase (ATP7B) and the results are a. Failure of copper excretion via bile b. Failure to synthesize ceruloplasmin. Ttt: penicillamine chelates copper and increase excretion in urine. 24. Excess copper is deposited in: a. Liver: liver cirrhosis. b. Lentiform nucleus: parkinsonism. c. Cornea: Keyser- fleisher ring. d. Kidney: aminoaciduria. e. Hemolytic anemia may develop. 25. Copper remains loosely bound to albumin and it is readily transferred to tissue such as the liver and the Brain. 26. Menkes disease: a. Genetic. b. Affecting Males. c. Fatal early life. d. Due to a defect in the gene of copper binding P.type(ATPase 7A). e. Weak muscle tone (hypotonia). f. Neurodegeneration in the Grey matter of the brain. 27. Zinc is found in Meat, liver, and egg and it is important for: a. Normal growth and development. b. Reproduction and immunity. c. Metabolism Mobilization of Vitamin A. N.B: the cuppor in plasma in form of ceruloplasmin Structure of haemoglobin hemoglobin It is a conjugated protein It is formed of four heme group attached to globin(4 polypeptide chain) Myoglobin Present in cardiac and skeletal muscles. It functions as reservoir for O2. (myoglobin has a greater affinity to O2 than Hb). Myoglobin is 90% xat pO2 20 mmHg. Myoglobin single polypeptide chain to which one heme is attached. Polypeptide chain 153 aa. Heme Tetra pyrrol ring linked by Metheny (CH) bridge Peripheral H is replaced by M, V, P Ferrous iron is centred heme group consists of an organic component called protoporphyrin as well as inorganic component that consists of an iron atom iron atom lies at the centre of the protoporphyrin and is bound to four nitrogen atoms On one side of the protoporphyrin plane the iron is bound to the histidine residue of the protein. This is known as the proximal histidine. This region is stabilized by another histidine residue called the distal histidine of the protein Hemoglobin A the major hemoglobin in adult (98%) Primary structure of globin Tetramer composed of 4 polypeptide chains 2 identical α chains (141 amino acid) 2 identical β chains (146 amino acid) Each polypeptide chain carries one heme So, a hemoglobin molecule can carry up to 4 O2 molecules Secondary Structure of globin : Each polypeptide chain is folded into 8 stretches of α helix designated A to H. 75% of aa in helix and interhelical region designated AB, BC, etc. Tertiary Structure of globin: Globular protein Surface aa are polar making it soluble in water. Interior aa are nonpolar except for 2 histidine (E7, F8) Heme fits in a hydrophobic pocket in the interior of chain to protects the ferrous ion from oxidation. N.B.---->Heme is present in a pocket between: E and F helices (FOMSU) Quaternary structure of Haemoglobin The hemoglobin is composed of two identical dimers (αβ)1(αβ)2. The two polypeptide chains of each dimer are tightly bound by hydrophobic interactions. Strong association between α subunit and β subunit in each dimer. Each dimer is loosely held to the other by weak ionic and hydrogen bonds. a- T (taut) form: deoxy form of Hb The two dimers interact through ionic and hydrogen bonds that constrain the movement of the polypeptide chain. The T form is low O2 affinity form of Hb. b- R (relaxed) form: the binding of O2 to Hb causes rupture of some bonds between the two dimers. So the polypeptide chain have more freedom of movement. The R form is the high O2 affinity form of Hb Attachment of heme to poly peptide chain Heme is present in hydrophobic pocket between E and F helices Heme is attached to its polypeptide chain through the imidazole group of proximal histidine (His F8) The 2nd or distal histidine (His E7), help to stabilize the binding of O2 to ferrous iron and destabilize binding of CO. The oxygen-binding curve because myoglobin consists of a single polypeptide subunit----> 1-myoglobin binds to O2 molecules quickly. 2-myoglobin has a strong affinity for O2. 3-myoglobin does not release O2, until the pO2 drops to a low quantity. makes it a perfect molecule for storing oxygen in muscles hemoglobin: Physiologically, hemoglobin is a perfect oxygen carrier 1-binds oxygen less strongly than myoglobin. 2-Has a lower affinity for O2 than myoglobin 3-Release O2 much more rapidly than myoglobin Conclusion Myoglobin does not bind oxygen cooperatively, which makes il great at storing oxygen in the muscle cells." On the other hand, hemoglobin cooperative behavior makes it a great O2 carrier. It can readily pick up O2 in the lungs and drop it off at the tissue cells. “cooperative binding kinetics” Oxygenation facilitates further oxygenation Deoxygenation facilitates further deoxygenation Bohr Effect The change in oxygen affinity with pH is known as the Bohr effect Decrease PH at tissues help HB release O2 (FOMSU-2023) Therefore, the Bohr effect facilitates transfer of oxygen. Adult hemolobin Hemoglobin A (α2β2) - The most common with a normal amount over 95% Hemoglobin A2 (α2δ2) - in adults, it has a normal range of 1.5-3.5% Hemoglobin F (α2γ2) Major Hb found in the fetus. Totally replaced by Hb A by the age of 6 months after birth. Heme metabolism Heme is the most important porphyrin containing compound. It is primarily synthesized in the liver & the erythrocyte-producing cells of bone marrow (erythroidc ells). Importance of heme · Haemoglobin · Myoglobin · Cytochromes as CP450 · Antioxidant enzymes as Peroxidases and Catalases · Metabolism as in Tryptophan and Pyrrolase · NO synthase enzyme Heme synthesis Fe + protoporphyrin = heme Protoporphyrin ---> 4 pyrrole ring ----> glycine + succinyl coA · Glycine: non- essential amino acid and Succinyl CoA: from Citric acid cycle fuse by condensation not reaction. · The synthesis occurs in Liver and Bone marrow... and it occurs in Mitochondria and Cytosol So, mature RBCs do not synthesize Haemoglobin. Notes · ALA synthase needs Pyridoxal phosphate (Vit. B6) and copper. · ALA dehydratase is a Zn containing enzyme and sensitive to inhibition by lead so as the Ferrochelatase enzyme. · Porphobilinogen is the 1st precursor of pyrroles. · 4 Porphobilinogen (PBG) at first transformed to Hydroxymethylbilane (HMB)... (which is a linear tetra pyrrole) by Uroporphyrinogen 1synthase (PBG deaminase or HMB synthase) Then HMB (under normal conditions) transformed to Uroporphyrinogen 3 by Uroporphyrinogen 3 synthase. · Uroporphyrinogen 3 differs from Coproporphyrinogen 3 that a CO2 is removed from each acetyl group in Uroporphyrinogen 3 … So, Uroporphyrinogen 3 has acetyl and propionyl groups but Coproporphyrinogen 3 has methyl and propionyl groups. · Protoporphyrin 3 and Protoporphyrin 9 are the same · Protoporphyrin 3 has methyl and vinyl groups. Regulation of heme synthesis  ALA synthesis is a rate limiting step in liver and it is regulated there by: · Feedback inhibition by Heme or hematin (which has a ferric iron Fe+3) · Repression by Heme … means stop synthesis of ALA synthase. · Prevent interance of ALA synthase inside the cell · Glucose prevents the ALA synthase... so, it is used in treatment of Porphyrias. · Derepression (induction): Occurs in presence of drugs like barbiturates, insecticides, carcinogens or steroids due to increase utilization of heme for CP450 hydroxylase system. RBCs maturation.  Regulation of heme in Erythroid cells occurs mainly by Uroporphyrinogen synthase and Ferrochelatase N.B. ferro chelatase enzyme Involved in ----------> incorporation of iron into porphyrins III (FOMSU-2023) Porphyrias Metabolic disorder … duo to defect in one or more enzymes required in heme synthesis. Atiology · Either inherited or aquired · Lead poisoning is the most common cause of aquired porphyria. Types · Hepatic · Erythropoietic Notes · Porphyrias inheritance is an Autosomal disease.. and most typed of porphyrias are carried on the Dominant gene except the Congenital Erythropoietic Porphyria as it needs a recessive gene · The congenital Erythropoietic Porphyria is rare... But Porphyria Cutanea Tarda is the most common type. · Photosensitivity occurs only when there is a compound contain 4 pyrrole rings... So, it does not occur with Acute Intermittent Porphyria · Porphyria also cause Anaemia. Treatment v Bed rest v Avoid drugs or chemicals which trigger the disease v High carbohydrate diet or IV infusion of dextrose 10% v Antioxidants v Avoid sun light in case there is photosensitivity v Blood transfusion v Hematin v Gene therapy Fate of haemoglobin …..? Ø Globin: may be reutelized or degraded to the individual amino acids ØHeme: Notes · The products of heme oxygenase reaction are: Biliverdin is a green pigment, Fe+3 and CO. · Biliverdin reductase also called NADPH dependent soluble enzyme. · Bilirubin attached to albumin by a non-covalent bond. · Bilirubin conjugated with 2 molecules of glucuronate supplied by UDP glucuronate catalized by Bilirubin glucuronyl transferase. · The transport of bilirubin diglucuronide is an active process (against concentration gradient) and it is a rate limiting step and easily affected by any impairment in liver function. · Urobilinogen (stercobilinogen) is a colorless compound. · Urobilin is a yellowish compound.. giving the urine its yellowish color. · Stercobilin is a brownish compound.. giving the stool its brownish color. Jaundice: yellowish discoloration of the skin and sclerae duo to increase serum bilirubin.. usually detectable when bilirubin >3mg Types: Serum bilirubin: * Total bilirubin: 0.2- 1.1 mg/dl * Direct bilirubin (without albumin): 0- 0.2 mg/dl * Indirect bilirubin(with albumin): 0.2- 0.9 mg/dl Note: ‫الكلمات االزرق هي الكثر اهميه‬ N.B. the following serum enzyme elevations is most diagnostic in obstructive jaundice----> ALP (alkaline phosphatase) bilirubin UDP glucuronyl transferase is absent from liver in Crigler nagger syndrome type I (FOMSU-2023) Histology of blood-->Mesodermal in origin ・① RBCS (Erthrocyte) Life span: 120 days, Rounded or disc shaped, non-nucleated corpuscles, biconcave discs in slow blood stream the corpuscles temporary adhere to each other to form what is called (rouleaux appearance) Diameter 6-9 MM (7.5Mm) - In males; 5 to 5.5 millions/ mm3, while in females 4.5- 5 millions/ mm3, this is may be due to sex hormones. Abnormal RBCS 1-Spherocytosis-----> deficiency in membrane Permeability "Na" 2-Sickle Cell-----> inherited abnormal Hb "fragile" 3-Poikilocytes 4-Crenation in hypertonic Plasma 5-Swollen in hypotonic Plasma N.B. Variation in the Size of the RBCs : Anisocytes. (FOMSU-2021) the ratio of the volume of packed red cells to the whole valume of blead------> Hematocrit value. (FOMSU-2021) Adaptability of RBCs to It's Function BiConcave surface to increase surface Which gas exchange takes Place Cell membrane highly Plastic, Selective Non Nucleated, No organelles to fill with H.B BLOOD PLATELETS Small rounded non-nucleated bodies (not cells). * Origin; fragments of large cell called megakaryocytes of bone marrow. * Number: 200.000 - 400.000 /mm3. *Life span and fate: About 5 – 14 days *they have no nuclei. Formed of peripheral pale clear part called (hyalomere) and a central granular basophilic part called (granulomere) which is rich in a specific granule. A) Hyalomere (the peripheral area of the blood platelets): Contains bundles of microtubules and microfilaments. They have a contractile function; they can change the shape of platelets during retraction of blood clot. B) Granulomere (central area of the platelet) contains: - Mitochondria, Ribosomes and Glycogen granules. - A or Alpha granules; large granules (300-500nm) and contains fibrinogen, clotting factors as IV, V and VIII (Von Willebrand factor). Also contain Platelet Derived Growth Factors (PDGF) and Thrombospondin (responsible for platelets aggregation). - Delta (or Dense) granules; medium sized granules 250- 300 nm contains serotonin, Ca, ADP and ATP sometimes epinephrine. - Lambda or Lysosomes 150- 200 nm contain hydrolytic enzymes as acid phosphatase and acid mucopolysaccharidase. N.B. platelets play an important role in hemostasis (FOMSU-2023) White blood cells (WBCs) - They are classified into two main groups: A) Granular cells; which includes neutrophil, eosinophil and basophil. B) Non-granular cells; lymphocytes and monocyte. -The total number of leucocytes varies from 4000 to 11.000 / mm3 Monocytes: Monocyte in blood→ macrophage (FOMSU-2022) *Percentage; represent 3 - 8% of WBCs * Diameter; 13 -18 µm. LM:Irregular in shape (have pseudopodia) non-granular pale basophilic cytoplasm, not clear (similar to frosted glass). - The nucleus is eccentric and indented or kidney shaped and appears basophilic. - Monocytes can penetrate through capillaries and venules to enter the C.T they can extend and withdraw their pseudopodia. -The mother of phagocytic cells in peripheral blood (monocytes ). (fomsu2023) Lymphocytes Bone marrow:- Development of erythrocytes:- Development of granular leucocytes:- Development of non granular leucocytes:- Development of platelets:- Platelet formation A. Numerous invaginations of cell membrane extendthrough the cytoplasm dividing the cytoplasm intoareas that will be shed as platelets.Bloed platelats B. Megakaryocytes extend pseudopodia or plateletribbons into the blood sinusoids then, the platelets are separated from the tips of these ribbons. Lymphatic system histology Lymphoid nodule (follicle) · It is the structural and functional unit of the lymphoid tissue Lymphoid follicle Rounded basophilic mass formed of small lymphocytes (mainly B lymphocytes & few T lymphocytes) Thymas dependent zone in LN-->inner cortex (FOMSU-2023) after lymph enters from afferent lymphatic go to sub cortical lymphatic sinuses (FOMSU- 2023) the place to form immunocompetent T-lymphocytes--->thymus. (FOMSU-2023) Lingual tonsil: Def.: They are small collections of lymphatic tissue in theC.T.at the root of tongue· Function of tonsils:. Quick defense mechanism against infective agents taken with food or air through formation of antibodies against these agents.  ‫تجميعة ارقام هستولوجي‬ Life span of RBCS---> 120 days life span of platlets----> 14 days Granulomere-----> alpha granules----> 300-500nm -----> delta or dense granules -----> 250-300nm -----> lamba or lysosome granukes----> 150-200nm White blood cells: all leucocytes varies from--->4000 to 11000 /mm3 Neutrophils-----> 40-70% Lymphocyte-----> 20-40% Monocyte-------> 3-8% Esinophil--------> 2-5% Basophil--------> 0-1% Specific granule of basophils------> 0.5 um Diameter of monocyte-------> 13-18 um PATHOLOGY Diseases of RBCs A) polycythemia/Erythrocytosis: Increase RBCS / Volume of prepheral Blood Causes: Primary: Neoplastis disorder in B.M Leading to: →Viscosity →Thrombosis →splenomegaly Secondary: hypoxia in B.M. → Congenital Heart disease → Chronic Lung disease → Erythropoietin secreting Tumor -----> (FOMSU-2022) N.B. renal carcinoma (erythropoieten secreting tumor)cause polycythemia B) Anemia: decrease RBCs or hemoglobin Leading to decrease oxygen Capacity Classification According to Eittology/Cause 1)Post hemorrhagic 2)Heamolytic anemia: *Hereditary *Acquired 3)Deficiency anemia: *Irion deficiency *Megaloblastic aneamia 4)Anemia due to bone marrow dysfunction: (Aplastic anemia) According to morphology Microcytic, hypochromic MCV 100 Microcytic: -Iron-deficiency -Thalasemia Anemia -Anemia of chronic disease Normocytic: Hemolytic Anemia Macrocytic: -Folate & B12 Deficiency -Alcoholism -Some Drugs Result of Anemia : Anaemia causes lowered oxygen-carrying capacity Symptoms: tiredness, weakness , Pallor, hyperdynamic circulation CNS & Kidneys dysfunction Pathological Effect: 1-Jaundice→B.M.hyperplasia. 2-Enlarged Liver & spleen →Extra medullary hematopeiosis 3-Normo-chromic, Normocytic-Anemia Type of By Anemia : (classification of anemia by B.M Aspiration) A) Anemia due to Blood loss: 1- Acute Post Hemorrhagic 2- chronic Blood Loss → Patho Effect : → Normochromic Anemia → B.M Hyperplasia→Reticlocytosis B) Hemolytic Anemia → RBCs Destruction Causes: → Congenital anemia 1-Hereditary spherocytosis cause: Defect in Erythrocyte membrane→ ↑ permeability for Sodium & H₂O → spherical shape instead of Biconcave 2) Sickle Cell anemia Cause: inherited abnormal HB (HBs)→Sickled Rbcs→decreased flexibility→rupture→Block blood vessels→tissue&organ damage 3) thalassemia:- (α&β) (Minor & Major) -----> (FOMSU-2022) Cause: Defect synthesis of Hb proteins & decreased Capacity of RBC →Acquired anemia Eythroblastosis fetalis:- red blood cells (erythrocytes) of a fetus are destroyed in a maternal immune reaction resulting from a blood group incompatibility between the fetus and its mother. two main causes of erythroblastosis fetalis: Rh incompatibility and ABO incompatibility. PothoChanges: 1-massive hemolysis Still Birth 2-Less hemolysis → Jundince→kernicters→Death in few days →Deficiency Anemia: -Iron Deficiency Anemia -Macrocytic Anaemia A)Iron deficiency anemia: Causes: 1)Chronic hemorrhage. 2)Increased demands as , Pregnancy and lactation 3)Decreased intake of iron as in Anorexia e.g. in pregnancy 4)Defect in absorption as in Partial or total gastrectomy 5)Increased utilization as in lake of vit B6. Pathological features: 1)Microcytic hypochromic anemia 2)Hyperplasia of BM. 3)Atrophic changes in epithelial membranes. 4)Trophic changes in finger nails, dry and spoon shaped. B) Macrocytic Anemia: ------------> (FOMSU-2023-2022-2021) Causes: 1-Nutritional Defeciency in B12, folate 2- deficiency in Intrinsic Factor Causing impaired Albsorption of Vit B12 (perincious Anemia) TYPES: 1)pernicious anemia 2)Anemia of pregnancy 3)Anemia after gastrectomy 4)Anemia in malabsorption syndrome →Anemia Due to B.M. Dysfunctions: A)Aplastic anemia B)Myelophthisic anemia c)Anemia of chronic infection →Causes :- A-Primary→Immune-Mediated B-Secondry :1-Drugs 2-Toxic chemicals 3-Infection 4- radiation - Pathologic changes 1-BM→Fatty tissue 2-Normo-cytic Anemia 3-Granulocytopenia and thrombocytopenia 4-Atrophic spleen Disseminated Intra vascular Coagulation (DIC) Definition: Acquired Bleeding Disorder Cause:Depostion of Clotting factors. Pathogenesis : increase thrombin→ Decrease Physiological Anticoagulation mechanism: Activation of Blood Coagulation → Deposition of fibrin → leading to microvascular thrombi in various organs leading to multi organs dysfunction syndrome. N.B : Consumption of clotting factors and platelets in DIC can result in life-threatening hemorrhage. White blood Cell Disorders - Types of Disorders - A)Non-neoplastic disorders 1-Decreased Leukopenia by: -Toxemia -Septicemia -Toxic drugs -Aplastic anemia -Bone radiation -Hypersplenism Lymphopenia by: -Congenital: immunodeficiency -Diseases: -HIV infection -High doses of corticosteroids 2-Increased Neutrophilic in: -pyogenic organism -tissue necrosis -myocardial infarction -burns Eosinophilia in: -allergic disorder (asthma, dermatitis) -parasitic infection -drug reaction -Hodgkin &non Hodgkin lymphoma -collagen vascular disorder Basophilia in: Rare & acute myeloid leukemia Monocytosis in: -TB,IE, inflammatory bowel disease Lymphocytosis in: Viral infection, T B)Neoplastic (leukemia) Pathophysiology: causes -chemotherapeutic agents -chemical agents -viruses -radiation -immunologic deficiencies Clinical manifestation 1- bone marrow failure causing: -overcrowding by abnormal cells -Anemia, thrombocytopenia, decreased number and function of WBCs , inadequate production of normal marrow elements 3-leukemic cells infiltrate organs causing: -splenomegaly, hepatomegaly and lymphadenopathy -bone pain, meningeal Neoplastic leukemia Myeloid Acute: AML - ↑ in number of granulocytes, myelocytes and myeloblasts. - One fourth of all leukemias. - Abrupt onset : infection, abnormal bleeding. - Uncontrolled proliferation of myeloblasts (hyperplasia of bone marrow and spleen) - Divided into 8 subtypes M0 to M7 - Malignant cells infiltrate blood and bone marrow - 85% of acute leukemias in adults - Characterized by auer bodies -----------> (FOMSU-2023) Chronic: CML - Excessive development of mature neoplastic granulocytes in bone marrow - Move to peripheral blood in massive numbers - Infiltrate liver and spleen - Philadelphia Chromosome genetic abnormality that causes this type is gene 9&22 ---------------> (FOMSU-2023) - All ages affected (median age 5 th and 6th decades). N.B. basophils increase in chronic myeloid leukemia (FOMSU-2022) Lymphoplastic Acute: ALL - Most common type of leukemias in children ------> (FOMSU-2023) - 15% of acute leukemias in adults - Immature lymphocytes infiltrate bone marrow. - Either B or T cells - Signs may appear abruptly fever, bleeding, weakness and fatigue. - CNS manifestations. Chronic: CLL -Production and accumulation of inactive, long-lived mature lymphocytes. - B cells involvement - Lymph node enlargement. - Characterized by smudge cells------> FOMSU lymph node enlargement (small lymphocytic lymphoma) Lymph nodes diseases Types of lymphoma: Hodgkin & non-Hodgkin lymphoma 1- non-Hodgkin lymphoma: A heterogeneous group of B- and T-cell malignancies. 75% of lymphomas 6th major cause of cancer deaths yearly Origin of principally B-cells derivation (>85%). Predominates in the 40-70 years age group N.B. starry sky + mandibular abnormality = burkitt’s NHL (FOMSU) 2- Hodgkin lymphoma: N.B. : cells with mirror image-->FOMSU Hodgkin’s disease (HD) primarily arises within the lymph nodes and involves the extranodal sites secondarily. This group comprises about 8% of all cases of lymphoid neoplasms. The incidence of the disease has bimodal peaks—one in young adults between the age of 15 and 35 years and the other peak after 5th decade of life. The HD is more prevalent in young adult males than females. So, causes of lymph node enlargement are: Acute enlargement (specific & nonspecific): Acute lymphadenitis Chronic enlargement (specific & nonspecific): Specific: Tuberculous lymphadenitis. Sarcoidosis. syphilitic lymphadenitis. toxoplasma AIDS related lymphadenopathy N.B. lymph node enlargement + granuloma= tuberculosis lymph node enlargement + distorted malignant gland from breast = metastatic carcinoma  Pathology of spleen Functions of spleen: Organ of the immune system where B and T cell multiply Sequestration and removal of normal and abnormal blood cells Vasculature of the spleen plays a vital role in regulating portal blood Under pathological conditions, It is the site of extramedullary hematopoiesis Hypersplenism Splenomegaly Splenic infarction Massive splenomegaly: Myeloprolifative syndrome Sickle cell disease Portal hypertension Splenic vein thrombosis Lift shoulder tip pain infarcts cause abscess which requires splenectomy (coagulative necrosis) Spleen tumors Diffuse large B cell lymphoma: Pharma of blood Control of thrombotic disorders Treatment of anaemia Treatment of Haemorrhagic disorder Treatment of Haemorrhagic shock  Pharma notes from 2023 ❖ ADP Blocker -->clopidogrel ❖ Side effect of Ticlopidine -->neutropenia ❖ Drug causes aplastic anemia --> antirheumatic gold. ❖ Neurological B12-->hydroxocobalamin ❖ ttt of hypothrombinemia -->vit k ❖ Which drug prevent post transactional modification of clotting factor -->warfarin. ❖ MOA of protamine sulfate to antidote heparin -->only combined with heparin. ❖ Vitamin K is used to prevent hypothrombinemia of newborn ❖ side effect of tranexamic acid ---->. risk of thrombosis ❖ hydroxocobalamine is used in treatment of the peripheral neuropathy ❖ Tranexmip increase the risk of thrombosis ❖ Tranexamic acid inhibit plasminogen activation ‫تم اهملا‬