BLOOD PHYSIOLOPGY

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Blood

Functions of Blood

• Deliver O2
• Remove metabolic wastes
• Maintain temperature, pH, and fluid volume
• Protection from blood loss- platelets
• Prevent infection- antibodies and WBC
• Transport hormones

Blood Composition

• Hematocrit: % of erythrocytes volume to the total blood volume.

• Normal hematocrit values in healthy males is 47% ± 5% and in females it is 42% ± 5%
• Normal pH between 7.35 and 7.45
• Approximately 8% of body weight
• Average volume in healthy adult males is 5-6 L, but 4-5 L in healthy adult females
• 90% Water
• Proteins 8% w/v
• Albumin (60 %):
• Produced by the liver

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• Maintain osmotic pressure
• Transport hormones and enzymes
• Proteins 8% w/v
• Globulins (36%) :
• Alpha and Beta Globulins: produced by the liver, transport lipids, metals and fat soluble vitamins
• Gamma Globulins: Antibodies released by plasma cells in response to immune response – Fibrinogens (4%):
• Produced by the liver, form fibrin fibers of blood clots
• Gas
• Electrolytes:
• Na+, K+, Ca2+, Mg2+, Cl-, SO4-, HCO3
• Maintain plasma osmotic pressure and pH
• Organic Nutrients – Carbohydrates
• Amino Acids
• Lipids
• Vitamins
• Hormones: Steroid and thyroid hormones are carried by plasma proteins
• Metabolic waste
• CO2, urea, uric acid, creatinin, ammonium salts

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Formed Elements of the Blood - 45%

• Erythrocytes (red blood cells)

• Leukocytes (white blood cells)
• Platelets (thrombocytes)

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Erythrocytes

• Diameter :7.5 m
• Morphology: biconcave discs—flattened discs with depressed centers
• Anucleate and have essentially no organelles
• Contain 97% hemoglobin
• Contain antioxidant enzymes that rid the body of harmful oxygen
radicals
• Function- transport respiratory gases
• Hemoglobin- quaternary structure, 2 chains and 2 chains
• Lack mitochondria, because they generate ATP by anaerobic
mechanisms, therefore they do not consume any of the oxygen
they carry
• An RBC contains 280 million hemoglobin molecules
• Life span 100-120 days and then are destroyed in spleen
• (RBC graveyard)
• Erythrocytes count
• Men: 4.7–6.1 million cells/ microliter
• Women: 4.2- 5.4 million cells/ microliter
• Erythrocytes are the major factor contributing to blood viscosity.

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• When the number of Erythrocytes increases beyond the normal range, blood becomes more viscous and flows
more slowly.
• When the number of Erythrocytes drops below the lower end of the range, the blood thins and flows more
rapidly

Hemoglobin

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• Normal values for hemoglobin are 13–18 g/100 ml in adult males, and 12–16 g/100 ml in adult females
• Hemoglobin is made up of the red heme pigment bound to the protein globin.
• Globin consists of four polypeptide chains: two alpha (α) and two beta (β)—each binding a ring-like heme
• Each heme group bears an atom of iron in its center
• Hemoglobin
• A hemoglobin molecule can transport four molecules of oxygen because each iron atom can combine
reversibly with one molecule of oxygen
• A single RBC contains about 250 million hemoglobin molecules, so each RBC can carry about 1 billion
molecules of oxygen
• Why Hemoglobin does not exist free in the plasma?
• To protect hemoglobin from breaking into fragments that would leak out of the bloodstream (through porous
capillary walls)
• To prevent hemoglobin from making blood more viscous and raising osmotic pressure
• Hematopoiesis
• Hematopoiesis (hemopoiesis): blood cell formation
• Occurs in red bone marrow of axial skeleton, girdles and proximal epiphyses of humerus and femur
• On average, the marrow turns out an 29.5 ml of new blood containing 100 billion new cells every day
• Hemocytoblasts (hematopoietic stem cells)
• Give rise to all formed elements
• Hormones and growth factors push the cell toward a specific pathway of blood cell development

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Erythropoiesis: formation of red blood cells

Reticulocytes are released into the bloodstream

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• Erythropoiesis: red blood cell production
• A hematopoietic stem cell descendant called a myeloid stem cell transforms into a proerythroblast
• Proerythroblasts develop into basophilic erythroblasts
• Reticulocytes are released into the bloodstream
• Hemoglobin is synthesized and iron accumulates as the basophilic erythroblast transforms into a
polychromatic erythroblast and then an orthochromatic erythroblast
• Reticulocytes (account for 1–2% of all erythrocytes) are formed after ejection all of the organelles and the
nuclei
• Reticulocytes fully mature to erythrocytes within two days of release as their ribosomes are degraded by
intracellular enzymes
• Reticulocytes are released into the bloodstream
• Regulation of Erythropoiesis
• Too few RBCs leads to tissue hypoxia
• Too many RBCs increases blood viscosity
• Balance between RBC production and destruction depends on
• Hormonal controls: Erythropoietin (EPO)
• Adequate supplies of iron, amino acids, and B vitamins

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Hormonal Control of Erythropoiesis

• Erythropoietin (EPO)
• Direct stimulus for erythropoiesis
• Released by the kidneys in response to hypoxia Hormonal Control of Erythropoiesis

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Causes of hypoxia

• Hemorrhage or increased RBC destruction reduces RBC numbers

• Insufficient hemoglobin per RBC (e.g., iron deficiency)
• Reduced availability of O2 (e.g., high altitudes) or during pneumonia
• Hormonal Control of Erythropoiesis
• Effects of EPO
• More rapid maturation of committed bone marrow cells
• Increased circulating reticulocyte count in 1–2 days after erythropoietin levels rise in the blood
• hypoxia does not activate the bone marrow directly.
• Instead it stimulates the kidneys to provide EPO
• Testosterone also enhances EPO production, resulting in higher RBC counts in males
• Dr. Naim Kittana, PhD
• Imbalance of EPO
• Kidneys of renal dialysis patients fail to produce enough EPO to support normal erythropoiesis.
• Consequently, their RBC counts becomes less than half those of healthy individuals.
• Treatment: Genetically engineered (recombinant) EPO is frequently administered

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 Dietary Requirements
• Iron is essential for hemoglobin synthesis.
• Iron is available from the diet, and it is absorbed by the intestinal cells.
• Approximately 65% of the body’s iron supply (about 4000 mg) is in hemoglobin
• Free iron ions (Fe2+, Fe3+) are toxic, so iron is stored inside cells as protein-iron complexes such as ferritin
and hemosiderin
• In blood, iron is transported loosely bound to a transport protein called transferrin
• Developing erythrocytes take up iron as needed to form hemoglobin
• Small amounts of iron are lost each day in feces, urine, and perspiration.
• The average daily loss of iron is 1.7 mg in women and 0.9 mg in men.
• In women, the menstrual flow accounts for the additional losses.
• Vitamin B12 and folic acid are necessary for normal DNA synthesis.
• Even slight deficits endanger rapidly dividing cell populations, such as developing erythrocytes.

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• Fate and Destruction of Erythrocytes

• Life span of RBC ranges from 100 to 120 days

• Erythrocytes become “old” as they lose their flexibility, become increasingly rigid and fragile, and their
hemoglobin begins to degenerate.
• They are trapped and fragmented by the spleen “red blood cell graveyard.”
• Macrophages engulf and destroy dying erythrocytes.
• The heme is seperated from globin.
• Its core of iron is salvaged, bound to protein (as ferritin or hemosiderin), and stored for reuse.
• Most of this degraded pigment leaves the body in feces, as a brown pigment called stercobilin.
• Some of urobilinogen (coloreless) is reabsorbed from the intestine, and converted into urobilin (yellow color)
that is excreted by the kidneys.
• The protein (globin) part of hemoglobin is metabolized or broken down to amino acids, which are released to
the circulation.

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Formation & Destruction of RBCs

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Blood Cell Production

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• Erythrocyte Disorders
• Anemia
• It is a condition in which the blood’s oxygen-carrying capacity is too low to support normal metabolism.
• It is a sign of some disorder rather than a disease in itself.
• Anemic individuals are fatigued, often pale, short of breath, and chilled
• The causes of anemia can be divided into three groups:
• Blood loss
• Not enough red blood cells produced
• or too many of them destroyed

• Blood loss (Hemorrhagic anemia)

• Acute hemorrhagic anemia: blood loss is rapid Persistent blood loss: due to hemorrhoids, an undiagnosed
bleeding ulcer or malignancies

• Iron-deficiency anemia
• Cause:
• A secondary result of hemorrhagic anemia
• Inadequate intake of iron-containing foods and impaired iron absorption.
• Erythrocytes produced, called microcytes, are small and pale because they cannot synthesize their normal
complement of hemoglobin

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• Pernicious anemia

• Autoimmune disease most often affects the elderly.

• The immune system destroys cells in the stomach mucosa that produce a substance called intrinsic factor
• (important for vitamin B12 absorption) by intestinal cells.
• Without vitamin B12, the developing erythrocytes grow but cannot divide, and large, pale cells called
macrocytes result (megaloblastic anemia).
• Treatment involves regular intramuscular injections of vitamin B12 or as sublingual tablets
• Lack of vitamin B12 in the diet also leads to anemia.

• Renal anemia
• Frequently accompanies renal disease because damaged or diseased kidneys cannot produce enough EPO. It
can be treated with synthetic EPO.

• Aplastic anemia
• Results from destruction or inhibition of the red marrow by certain drugs and chemicals, ionizing radiation, or
viruses.
• In most cases, though, the cause is unknown.
• Because marrow destruction impairs formation of all formed elements, anemia is just one of its signs

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• Aplastic anemia
• Defects in blood clotting and immunity are also present. Blood transfusions provide a temporal treatment until
stem cells harvested from a donor’s blood, bone marrow, or umbilical cord blood can be transplanted.

• Hemolytic anemias
• Erythrocytes rupture, or lyse, prematurely and with high rate
• Common causes:
• Hemoglobin abnormalities: thalassemia and sickle-cell anemia
• Transfusion of mismatched blood
• Certain bacterial and parasitic infections

• Thalassemias
• Occur in people of Mediterranean ancestry
• One of the globin chains is absent or faulty, and the erythrocytes are thin, delicate, and deficient in hemoglobin
• Severity of the diseased varies according to the associated mutation

• Sickle-cell anemia

• Caused by the abnormal hemoglobin, hemoglobin S (HbS)

• Results from a change in just one of the 146 amino acids in a beta chain of the globin molecule!

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• This alteration causes the beta chains to link together under low-oxygen conditions, forming stiff rods so that
hemoglobin S becomes spiky and sharp

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Genetics of Sickle Cell Anemia

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• This, causes the red blood cells to become crescent shaped when they unload oxygen molecules or when the
oxygen content of the blood is lower than normal, as during vigorous exercise and other activities that increase
metabolic rate.
• The stiff, deformed erythrocytes rupture easily and tend to occlude small blood vessels
• This causes organ ischemia, leaving the victims gasping for air and in extreme pain

• Polycythemia
• Abnormal excess of erythrocytes that increases blood viscosity
• Risk of stroke and heart failure due to high hematocrit and high blood viscosity
• Types:
• Polycythemia vera
• Secondary polycythemia

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• The hematocrit may be as high as 80% and blood volume may double, causing the vascular system to become
engorged with blood and severely impairing circulation

• Secondary polycythemias
• Due to high level of EPO secretion
• Detected in smokers and individuals living at high altitude

Aplastic anemia

• Results from destruction or inhibition of the red marrow by certain drugs and chemicals, ionizing radiation, or
viruses.
• In most cases, though, the cause is unknown.
• Because marrow destruction impairs formation of all formed elements, anemia is just one of its signs

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Leukocytes (White Blood Cells)

• On average, there are 4800–10,800 WBCs/μl of blood

• Leukocytes are grouped into two major categories on the basis of structural and chemical characteristics.
• Granulocytes: contain obvious membrane-bound cytoplasmic granules, and
• Agranulocytes: lack obvious granules

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Granulocytes

• Include: neutrophils, eosinophils, and basophils

• They have lobed nuclei
• Functionally, all granulocytes are phagocytes to some degree

Neutrophils

• Also called Polymorphonuclear leukocytes (PMNs)

• Account for 50–70% of the WBC population
• About twice as large as erythrocytes
• Their numbers increase explosively during acute bacterial infections
• Some of their granules contain hydrolytic enzymes, and are regarded as lysosomes.
• Others, especially the smaller granules, contain a potent “brew” of antimicrobial proteins, called defensins that
pierce holes in the membrane of the ingested pathogen.
• They also kill pathogens by respiratory burst (the cells metabolize oxygen to produce potent germ-killer
oxidizing substances such as bleach and hydrogen peroxide.
• Neutrophils are chemically attracted to sites of inflammation and are active phagocytes

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Eosinophils

• Account for 2–4% of all leukocytes

• Their granules are lysosome-like and filled with a unique variety of digestive enzymes.
• They lack enzymes that specifically digest bacteria.
• The most important role is to lead the counterattack against parasitic worms, such as flatworms (tapeworms
and flukes) and roundworms (pinworms and hookworms) that are too large to be phagocytized
• They release the enzymes from their cytoplasmic granules onto the parasite’s surface to digesting it
• Eosinophils have complex roles in many other diseases including allergies and asthma

Basophils

• The rarest white blood cells, accounting for only 0.5–1% of the leukocyte population
• Their cytoplasm contains large, coarse, histaminecontaining granules
• Histamine is an inflammatory chemical that acts as a vasodilator (makes blood vessels dilate) and attracts other
white blood cells to the inflamed site
• Granulated cells similar to basophils, called mast cells, are found in connective tissues. They also release
histamine

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Agranulocytes

• Include lymphocytes and monocytes

• Lack visible cytoplasmic granules

Lymphocytes

• Accounting for 25% of the WBC population

• Few are found in the bloodstream, as they are closely associated with lymphoid tissues (lymph nodes, spleen,
• etc.), where they play a crucial role in immunity.
• T lymphocytes (T cells) function in the immune response by acting directly against virus-infected cells and
tumor cells.
• B lymphocytes (B cells) give rise to plasma cells, which produce antibodies

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Monocytes

• Account for 3–8% of WBCs

• When circulating monocytes leave the bloodstream and enter the tissues, they differentiate into highly mobile
macrophages.
• Macrophages are actively phagocytic, and they are crucial in the body’s defense against viruses, certain
intracellular bacterial parasites, and chronic infections such as tuberculosis

Leukocyte Disorders

Leukemia and infectious mononucleosis: overproduction of abnormal leukocytes

• Leukopenia: is an abnormally low white blood cell count, commonly induced by drugs, particularly
glucocorticoids and anticancer agents.
• a group of cancerous conditions involving overproduction of abnormal white blood cells
• The diseased leukocytes are members of a single clone (descendants of a single cell) that remain unspecialized
and proliferate out of control, impairing normal red bone marrow function.

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Leukocyte Disorders

Leukemia and infectious mononucleosis: overproduction of abnormal leukocytes

• Leukopenia: is an abnormally low white blood cell count, commonly induced by drugs, particularly
glucocorticoids and anticancer agents.
• a group of cancerous conditions involving overproduction of abnormal white blood cells
• The diseased leukocytes are members of a single clone (descendants of a single cell) that remain unspecialized
and proliferate out of control, impairing normal red bone marrow function.
• The leukemias are named according to the cell type primarily involved.
• For example, myeloid leukemia involves myeloblast descendants, whereas lymphocytic leukemia involves the
lymphocytes.
• Leukemia is acute (quickly advancing) if it derives from stem cells, and chronic (slowly advancing) if it
involves proliferation of later cell stages.
• The more serious acute forms primarily affect children.
• Chronic leukemia occurs more often in elderly people.
• Without therapy all leukemias are fatal
• Cancerous leukocytes fill the red bone marrow and immature WBCs flood into the bloodstream.
• The other blood cell lines are crowded out, so severe anemia and bleeding problems result
• Other symptoms include fever, weight loss, and bone pain.
• Although tremendous numbers of leukocytes are produced, they are nonfunctional and cannot defend the body
in the usual way.
• The most common causes of death are internal hemorrhage and overwhelming infections.

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Infectious Mononucleosis

• Highly contagious viral disease

• Caused by the Epstein- Barr virus
• Its hallmark is excessive numbers of agranulocytes
• The affected individual complains of being tired and achy, and has a chronic sore throat and a low-grade fever.
• There is no cure, but with rest the condition typically runs its course to recovery in a few weeks.

Platelets

• They are not cells in the strict sense

• they are cytoplasmic fragments of extraordinarily large cells called megakaryocytes
• Their granules contain lots of chemicals that act in the clotting process, (including serotonin, Ca2+, a variety
of enzymes, ADP, and platelet derived growth factor (PDGF)).

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Stem cell Developmental pathway

Hemocyto- Promegakaryocyte
blast Megakaryoblast Megakaryocyte Platelets

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 Hemostasis
Step 1: Vascular spasm
Smooth muscle contracts
causing vasoconstriction
direct injury to vascular smooth muscle, chemicals
released by endothelial cells and platelets, and reflexes
initiated by local pain receptors

Step 2:
• Platelet plug formation
Injury to lining of vessel exposing
collagen fibers, platelets adhere.

• Platelets release chemicals

that make nearby platelets
sticky, platelet plug forms

Step 3: Coagulation
• Fibrin forms a mesh that
traps RBCs & platelets,
forming the clot.

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 Platelets
• As a rule, platelets do not stick to each other or to the smooth endothelial linings of blood vessels.
• Intact endothelial cells release nitric oxide and a prostaglandin called prostacyclin (or PGI2).
• Both chemicals prevent platelet aggregation in undamaged tissue and restrict aggregation to the site of injury.
• However, when the endothelium is damaged and the underlying collagen fibers are exposed, platelets adhere
tenaciously to the collagen fibers.
• A large plasma protein called von Willebrand factor stabilizes bound platelets by forming a bridge between
collagen and platelets.
• Platelets swell, form spiked processes, become stickier, and release chemical messengers including the
following:
• Adenosine diphosphate (ADP)—a potent aggregating agent that causes more platelets to stick to the area and
release their contents
• Serotonin and Thromboxane A2 messengers that enhance vascular spasm and platelet aggregation

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Coagulation (blood clotting)

• Reinforces the platelet plug with fibrin threads that act as a “molecular glue” for the aggregated platelets
• Blood is transformed from a liquid to a gel in a multistep process hat involves a series of substances called
clotting factors (procoagulants)
• Most clotting factors are plasma proteins synthesized by the liver. They are numbered I to XIII according to
the order of their discovery
• Vitamin K (fat-soluble vitamin) is required for synthesizing four of the clotting factors
• In most cases, activation turns clotting factors into enzymes, except factor IV (Ca2+) and I (Fibrinogen)

Two Pathways to Prothrombin Activator

• Coagulation may be initiated by either the intrinsic or the extrinsic pathway

• In the body, the same tissue-damaging events usually trigger both pathways.
• Outside the body (such as in a test tube), only the intrinsic pathway initiates blood clotting.

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Vascular Expose Vascular
injury collagen
to injury
blood
XII
Expose Tissue
a Factor (TF) )
(Thrombopl
X XI astin
I a
I IX VII V
X a a II
X X X
a

Prothro(I) ThromII )
mbin I bin ( a

Fibrinog Fibr
XII en (I) in

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Platelet Fibrin thread

RBC

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Disorders of Hemostasis

• Thromboembolytic disorders: undesirable clot formation

• Bleeding disorders: abnormalities that prevent normal clot formation

Thromboembolytic Conditions

• Thrombus: clot that develops and persists in an unbroken blood vessel

• May block circulation, leading to tissue death
• Embolus: a thrombus freely floating in the blood stream
• Pulmonary emboli impair the ability of the body to obtain oxygen
• Cerebral emboli can cause strokes
• Prevented by
• Aspirin
• Antiprostaglandin that inhibits thromboxane A2
• Heparin
• Anticoagulant used clinically for pre- and postoperative cardiac care
• Warfarin
• Used for those prone to atrial fibrillation

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Bleeding disorders

• Thrombocytosis- too many platelets due to inflammation, infection or cancer

• Thrombocytopenia- too few platelets
• causes spontaneous bleeding
• due to suppression or destruction of bone marrow (e.g., malignancy, radiation)
• Platelet count <50,000/mm3 is diagnostic
• Treated with transfusion of concentrated platelets

Bleeding disorders

• Impaired liver function

• Inability to synthesize procoagulants
• Causes include vitamin K deficiency, hepatitis, and cirrhosis
• Liver disease can also prevent the liver from producing bile, impairing fat and vitamin K absorption
• Hemophilias include several similar hereditary bleeding disorders
• Symptoms include prolonged bleeding, especially into joint cavities
• Treated with plasma transfusions and injection of missing factors

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Blood types

Blood type is based on the presence of 2 major antigens in RBC membranes-- A and B

Blood type Antigen Antibody

A A Anti-B
B B Anti-A

AB A&B no anti body

O Nil anti-A and anti-B

Antigen- protein on the surface of a RBC membrane

Antibody- proteins made by lymphocytes in plasma which are made in response to the presence of antigens.

They attack foreign antigens, which result in clumping (agglutination)

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 Rh Factor and Pregnancy

RH+ indicates protein

RH- indicates no protein

Rh Factor and Pregnancy

Rh+ mother w/Rh- baby– no

problem

Rh- mother w/Rh+ baby– problem

Rh- mother w/Rh- father– no problem Rh- mother w/Rh- baby-- no

problem

Rho(D) immune globulin (anti-RhD)

IgG anti-D antibodies

Given at the 28th week of pregnancy as IM for pregnant women how are Rho-negative if the father is Rho-positive

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Target fetal RBCs that leak to the maternal blood circulation before the maternal immune system reacts to it

Prevents Rh disease (hemolytic disease of new born) in the subsequent pregnancies

Type AB- universal recipients

Type O- universal donor

Rh factor:

Rh+ 85% dominant in pop

Rh- 15% recessive

Blood Type Clumping Antibody

A antigen A anti-A serum antibody anti-b

B antigen B anti-B serum antibody anti-a

AB antigen A & B anti A & B serum -

O neither A or B no clumping w/ either anti A or B anti-a, anti-b

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Blood test Serum
Anti-A Anti-B
Type AB (contains
agglutinogens A and B;
agglutinates with both
sera)
RBCs

Type A (contains
agglutinogen A;
agglutinates with anti-A)

Type B (contains
agglutinogen B;
agglutinates with anti-B)

Type O (contains no
agglutinogens; does not
agglutinate with either
serum)
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