Functions of Blood
Blood performs a number of functions dealing with:
Substance distribution Regulation of blood levels of particular substances Body protection
Viscosity (thickness) - 4 - 5 (where water = 1) The pH of blood is 7.357.45; x = 7.4 Osmolarity = 300 mOsm or 0.3 Osm
This value reflects the concentration of solutes in the plasma
Salinity = 0.85%
Reflects the concentration of NaCl in the blood
Temperature is 38C, slightly higher than normal body temperature Blood accounts for approximately 8% of body weight
Composition of Blood
Blood is the bodys only fluid tissue (a connective tissue) 2 major components
Liquid = plasma (55%) Formed elements (45%)
Erythrocytes, or red blood cells (RBCs) Leukocytes, or white blood cells (WBCs) Platelets - fragments of megakaryocytes in marrow
Plasma (55% of whole blood) Buffy coat: leukocyctes and platelets (<1% of whole blood)
Erythrocytes (45% of whole blood)
Formed elements
1 Withdraw blood
2 Centrifuge
Hematocrit
Males: 47% 5% Females: 42% 5%
Blood Plasma
Blood plasma components:
Water = 90-92% Proteins = 6-8%
Albumins; maintain osmotic pressure of the blood Globulins
Alpha and beta globulins are used for transport purposes Gamma globulins are the immunoglobulins (IgG, IgA, etc)
Organic nutrients glucose, carbohydrates, amino acids Electrolytes sodium, potassium, calcium, chloride, bicarbonate Nonprotein nitrogenous substances lactic acid, urea, creatinine Respiratory gases oxygen and carbon dioxide
Plasma Protein
Plasma : Albumin, Globulin, Fibrinogenro. Serum ; Albumin, Globulin Electrophoretic separated plasma/serum protein.
Formed Elements
Formed elements comprise 45% of blood Erythrocytes, leukocytes, and platelets make up the formed elements
Only WBCs are complete cells RBCs have no nuclei or organelles, and platelets are just cell fragments
Most formed elements survive in the bloodstream for only a few days Most blood cells do not divide but are renewed by cells in bone marrow
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Figure 17.9
RBC
RBC is the most abundant cell in our body Erythrocyte is the simplest cell in our body The highest specific rate of glucose utilization of any cell in the body (10 g/kg tissue/day : 2,5 for the whole body) It has no sub-cellular organelle Without nucleus its cannot divided, degraded after 120 days Without mitochondria cannot produce energy (the lowest rates of ATP synthesis of any cell in the body) without endoplasmic reticulum can not synthesis protein and lipid without lysosome can not produce digestive enzyme
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Hemoglobin
Hb is the oxygen carrier of RBC to bring O2 from the lung to the extra pulmonary tissues (reversible) Mb, is found in muscle tissues, where it store oxygen and use in exercise Its consist of Heme and globin Heme consist of Iron and protophorpyrine Oxygenation: Hb + O2 Hb O2 Oxidation: Fe++ of Hb Oxidi into Fe+++
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Heme group
Heme is the oxygen binding site of Hb and Mb (myoglobin) Heme contain protoporphyrin IX with ferrous iron chelated in the centre. Protoporphyrin contain 4 mol of pyrole rings, held together by methin (-CH=} bridge, decorated with methyl (-CH3), finyl (-CH=CH2), and propionate (-CH2-CH2COO-) side chain.
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Heme (cont-)
The porphyries ring system contain conjugated double bonds. These are responsible for the color of our blood (affected by the oxygenation state) Oxygenated Hb is red, and deoxy-Hb is blue. Therefore Oxygen deficiency or hypoxia can be recognized as a blue discolorization of the lips and other mucus membrane this is called cyanosis.
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Heme Iron
The most important part of the heme group is its iron. Ionized iron can form coordinate bonds with the unpaired electron of oxygen or nitrogen atom. In heme, the iron is bounds to nitrogen of 4 pyrole rings Both in Hb and Mb, the iron forms a fifth bond with a nitrogen atom in a histidine side chain of apoprotein . This histidine is called proximal histidine. A sixth coordinate bond can be form with mol O2
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Iron can exist in ferrous (Fe++) and ferric state (Fe+++). Ferric state is the oxidized form because it can be formed from ferrous iron by a removal of electron. The heme iron of Hb and Mb is always in ferrous state. Even during oxygen binding, it is not oxidized to the ferric form. It becomes oxygenated but not oxidized
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RBC
RBCs circulate about 120 days before they scavenged by phagocytic cells in the spleen and other tissue. RBCs have no nucleus there fore unable to divide and synthesized proteins. Also lack of mitochondria they do not consume any of the oxygen they transport. They cover their energy needs by anaerobic metabolism of glucose to lactic acid
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RBC-Hb
RBCs are bagsfilled with Hb with concentration not less than 33%, dissolved in cytoplasm. Blood cells concentration of whole blood = hematocrit. Patient with an abnormally low Hb concentration are said to have anemia.
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Structure of Hemoglobin
Figure 17.4
SYNTHESIS HEMOGLOBIN
Its start from pro-erythroblast stadium and a bit of reticulocyte stadium Retikulocyte leaving bone marrow to blood stream hemoglobin Suksinil-KoA (Krebs cycle) bind glysin pyrole. 4 pyrole condense to formed protoforfirin IX Protoforfirin IX + Fe++ heme Heme + globin Hemoglobin
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Heme + long polypeptida (globin, synthesizes in ribosome) hemoglobin chain (MW 16.000) 4 hemoglobin chain connect together to formed hemoglobin
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Chain variation of Hb sub-unit depend on aa array in polypeptide. Chain type : , , gamma dan delta Adult Hb : hemoglobin A (MW 64.458) consisit of 2 and 2 chain combination. 4 atoms of iron Hb, @ connect to 1 molekul O2
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Chain abnormalities
Would changes physical properties Hb. E.g : cycle cell anemia. aa valine replace by glutamate in each of beta chain, if it is shine by O2 low grade formed long crystal 15 mikrometer in erythrocyte, destroyed erythrocyte membrane.
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Sintesis Hemoglobin
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MetHb
Is non funcional oxidized form of Hb The heme iron of Hb bind molecular oxygen only in the ferrous state (Fe++). Its oxidation to the Ferric forms result in met-Hb which is useless as an oxygen transporter. Normally less than 1% of total Hb is in the form of Met-Hb, but oxidizing chemicals (aniline dyes, aromatic nitrous compounds, inorganic and organic nitrous compound) cause excessive met-Hb formation.
Defense mechanism
1. 2. Fortunately the RBCs can defend itself against excessive met-Hb formation e.g Erythrocyte reducing substances (ascorbic acid and glutathion). The binding of heme to the apoprotein, creates a protective environment for the iron. Heme hemin + hydroxyl ion hematin. Met-Hb reductase reduce met-Hb back to Hb using NADH as a reductant. Deficiency of this enzyme Congenital methemoglobinemia. Met-Hbemia is treated with methylene blue which reducing Fe+++ Fe++
3.
CO cont Carbon monoxide binding is reversible: in normally breathing patient with CO poisoning, O2 gradually displaces CO , leading to slow recovery in several hours. The interaction between CO and O2 at the heme iron competitive antagonism CO concentration of only 1/200th of the O2, is sufficient to convert half of oxy-Hb to CO-Hb. Hyperbaric oxygen is the treatment of choice.
BPG
BPG concentration in RBC increases during hypoxic condition, including lung disease, severe anemia, and adaptation to high altitude. This increase affect oxygenations in the lung capillaries, but enhances the unloading of oxygen in the tissue.
Iron metabolism
Iron exist in 3 formed: functional iron ( Hb, mioglobin & some enzymes), store iron (feritin & hemosiderin) & transport iron (transferin) Total iron : 40 50 mg Fe/kg BW
65% Hb 15 30% stored as feritin (liver) 4% mioglobin 1% heme 0,1% bind to protein transferin in blood plasma.
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Transferin bind tightly to membrane receptor erythroblast cell of bone marrow. Transferin-Fe, pass the erythroblast by endositosis, iron to mitochondria Low transferin impaired transport of Fe to eritroblas severe hipochromic anemia Fe excreted 1 mg/day trough feces. Menstrual woman lost about 2 mg/day, lactating 1 mg/day
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In the intestine apotrasferin + free Fe transferin receptor membrane intestine epitheel cell by pinositosis. Iron absorbtion depend on body required for Fe: Mechanism of iron absorbtion regulation: Dietary regulator, stores regulator & erythropoetic regulator
Dietary regulator : kind of diet Stores regulator : iron body store Erythropoetic regulator : the rate of erytropoesis
Absorbtion
Fe, absorbed in brush border of epithel vili small intestine, specially duodenum & upper part of jejunum Divided to 3 phase : luminal, mukosal & corporeal
Luminal : in gaster and ready to absorbed in doeodenum. Mucosal : absorption in small intestine. Corporeal : transport Fe in sirculation, utilisation by cell. And sore of Fe
Iron absorption depend on : Fe diet, Iron from plan (non heme) absorb 1-7% Heme iron (meat, fish absorp 25-30%), with high bioavailility and easier to absorb.
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To increase non heme iron absorpion need trigger factor such as ascorbic acid (lemon,grape, guava, papaya and green vegetable). Inhibite by tannat (tea), coffe and cereal (phitate).
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Fe deficiency
Deficient of Fe Fe deficiency anemia Caused by : bleeding, worm investation (ankylostomum duodenale ), intake Fe reduce, Fe absorption block etc Hypochromic microcytic anemia.
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Erythrocyte degradation
Ery enzymes NADPH Function of NADPH : - maintain membrane fragility. - maintain ion transport through membrane - maintain Fe of Hb cell in the form of Fe++ - Protect oxidation of protein in Ery.
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Hemoglobin Degradation
Ery cell lysis/fagocyte by macrophage heme and globin. Heme ring open free iron transport to the blood by transferin biliverdin reduction bilirubin plasma. Bilirubin + albumin, reabsorb to the the liver conjugated to glucoronic acid (biliirubin glucoronate 80% and bil sulfate 10% and with another substance 10%.
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Bil secreted to bile canaliculi (active transport) intestine. of conjugated bil. urobilinogen (easier to solute in water. Some reabsorbs by mucosa to the blood. Excretion to by liver and renal. Urobilinogen urine oxidized by air urobilin On feses urobilinogen stercobilin.
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GENERAL DIAGNOSTIC
A. History and physical examination 1. Chronicity of the problem Ethnic, racial background Family history Medical conditions New medication
2. - Jaundice - Splenomegaly
B. Laboratory
1. reticulocyte index respon BM 2. LDH, unconjugated bilirubin, or absent of haptoglobin 3. RBC morphology abnormal ( important clue underlying diseases ) 4. Blood smear rarely pathognomonic
Enzymatic defect
G6PD - X linked - >> Africa - self limited hemolysis by stress, infection or drug - intrinsic & extrinsic defect - extravasculer & intravasculer hemolysis Pyrovat kinase - autosomal recessive disorder - chronic hemolysis
Hemoglobin defect
Thalasemias - quantitative defect - globin chain imbalance ( / ) Sickle cell ds - qualitative defect - amino acid substitution stability Hb
HS
- abnormalities RBC structural protein (Spectrin,Ankyrin,Band) mediate vertical interactions - clinical presentation : a. Jaundice b. Formation of pigment gallstones c. Mild to moderate splenomegaly d. Leg ulcer - Laboratory - peripheral blood smear spherocytes - anemia polychromasia - osmotic fragility test - Treatment - severe anemia splenectomy
HE
- abnormalities RBC Structural protein (Spectrin) mediate horisontal interactions - clinical presentation : a. Jaundice b. Formation of pigment gallstones c. Mild to moderate splenomegaly d. Leg ulcer - Laboratory - peripheral blood smear elliptocytosis - anemia - osmotic fragility normal or abnormal - Treatment - severe anemia splenectomy
Spherocytosis
Elliptocytosis
G6PD Deficiency
X linked inheritance Pathophysiology : - acute hemolysis RBC is exposed to oxidant stress, infection, drugs (page 53) - Glutathion stores oxidative damage to RBC component - Heinzs bodies (+) Hemolysis extravasculer commonly Hemolysis intravasculer severe
PK Deficiency
Autosomal recessive disorder Pathophysiology : - In the glycolytic pathway convert phosphoenolpyruvate to pyruvate accumulation of 2-3 dyphosphoglycerate extremely severe hemolytic anemia intense reticulocytosis, splenomegaly Diagnosis measurement of enzyme Treatment : Splenectomy
- Methylene blue - Nalidixic acid - Napthalene (Mothballs) - Niridazole - Nitrofurantoin - Pamaquine - Pentaquine - Phenylhydrazine - Primaquine
Thalassemias
a globin chain imbalace Mutation partially or completely a globin
chain imbalance ratio dan globin chain The most common type : - Beta () - Alpha () - Combination with Hb abnormal (HbE) Clinicaly : - Thalassemia major - Thalassemia intermedia - Thalasemia minor / thalassemia trait Treatment ~ clinicaly
Thalassemia
2 2 = 97 % (Hb A)
2 2 4
2 2 4 (Hb H)
2 2 (Hb F)< 1 %
2 2 4 (Hb Bart`s)
Immune-mediated hemolytic disorder: a. auto immune hemolytic anemias: is a groups of disorder that are the result of antibody or complement binding to specific antigen on the RBC membrane, which leads to RBC life spand. This disorder can be primary (idiophatic) or secondary (underlying disease, drug)
Anti-erythrocyte antibody can be devided into 3 catagories: a. IgG warm auto antibodies bound to RBC but failed to agglutinate RBCs b. Cold agglutinin almost are of the IgM subtype and clump RBC at cold temperature. c. Donat-Landsteiner (IgG) antibodies binds to RBC membrane in the cold and activate hemolytic complement cascade when the RBC warmed to 37C
The nonimmune hemolytic anemias are generally the result of extrinsic factors or effects on otherwise normal RBCs. Many physical, chemical, and infectious causes make up the differential diagnosis for the nonimmune hemolytic anemias.
Fragmentation hemolysis
Fragmentation hemolysis occurs when mechanical trauma or shear stress disrupts the physical integrity of the RBC membrane.
Etiology
a.Damaged microvasculature with the resulting disorder commonly referred to as microangiopathic hemolytic anemia, b.Arteriovenous malformations (e.g., arteriovenous shunts) c.Cardiac abnormalities (e.g., prosthetic heart valves) d.Drugs (e.g., cyclosporine, cancer chemotherapy agents, ticlopidine, clopidogrel, cocaine)
Hypersplenism
Hypersplenism is a functional state of hyperactivity of the spleen, including its cellular sequestration activity. For this reason, hypersplenism can lead to a decrease in the life span of RBCs, leukocytes, and platelets. Splenomegaly is an anatomic term for enlargement of the spleen. All of the activities of the spleen are accentuated in a large spleen; therefore, hypersplenism is often associated with splenomegaly. Anemia in these patients is the result of increased RBC destruction and splenic sequestration. Treatment of hypersplenism a.Therapy is directed at the underlying cause of the splenomegaly or hyper splenism. b.Anemia and pancytopenia are not usually severe; if they are severe, sple nectomy typically leads to improvements in the blood counts.
Causes of Hypersplenism
Vascular congestion Right heart failure Hepatic vein thrombosis (Budd-Chiari syndrome) Cirrhosis Portal vein obstruction Splenic vein thrombosis Infection Bacterial endocarditis Tuberculosis Parasites Viruses Fungi Inflammatory diseases Systemic lupus erythematosus Rheumatoid arthritis Hemolytic anemias Congenital (thalassemias, hereditary spherocytosis) Acquired (autoimmune) Neoplasms Lymphomas Hairy cell leukemia Chronic lymphocytic leukemia Myeloproliferative disorders Storage disorders Caucher disease Mucopolysaccharidoses Benign structural abnormalities Cysts Hamartomas Other Amyloidosis Sarcoidosis
Infection
Direct parasitization (e.g., malaria, babesiosis, bartonellosis) can result from an organism infecting the RBC, which leads to intravascular or extravascular hemolysis, or attaching to the RBC membrane, which leads to RBC destruction. Immune mechanisms, such as Mycoplasma pneumoniae, Epstein-Barr virus (mononucleosis), are discussed earlier in the text (see III.C.2.b.). Induction of hypersplenism can occur as a sequela of some infections (e.g.,malaria, schistosomiasis) by immune-mediated and non-immune-mediated mechanisms. Altered RBC surface topology (e.g., Haemophilus influenzae) caused by interactions between the microorganism and the RBC surface can lead to hemolysis. Release of toxins and enzymes by a microorganism (e.g., Clostridium, Escherichia coli 0192) can cause direct damage to the RBC membrane, which leads to shortened RBC survival.
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