Blood Homeostasis Coagulation Flashcards
Blood Composition
ALL
Formed Elements (45%)
Platelets (4.8%) [250-400 thousand]
RBCs (95.1%) [4.2-5.8 million]
WBCs (0.1%)…[5-9 thousand]
* Neutrophils (50-70%)
* Eosinophils (2-4%)
* Basophils (<1%)
* Monocytes (2-8%)
* Lymphocytes (20-30%)
Plasma (55%) aka fluid matrix
Electrolytes
Water (92%)
Wastes
Nutrients / Vitamins / Hormones
Gases (N2 , O2 , CO2)
Proteins (7%)
* Albumins (60%)
* Globulins (35%)
* Fibrinogen (4%)
Blood Composition
Plasma Only
Plasma (55%) aka fluid matrix
Electrolytes
Water (92%)
Wastes
Nutrients / Vitamins / Hormones
Gases (N2 , O2 , CO2)
Proteins (7%)
* Albumins (60%)
* Globulins (35%)
* Fibrinogen (4%)
Blood Composition
Formed Elements Only
Formed Elements (45%)
Platelets (4.8%) [250-400 thousand]
RBCs (95.1%) [4.2-5.8 million]
WBCs (0.1%)…[5-9 thousand]
* Neutrophils (50-70%)
* Eosinophils (2-4%)
* Basophils (<1%)
* Monocytes (2-8%)
* Lymphocytes (20-30%)
The Red Blood Cell
Importance in Structure
Biconcave disks- Malleability is imperative!
A-nucleate
Cytoplasmic Enzymes:
* Metabolize Glucose
* Form small amts of ATP
* Pliability of Cell Membrane
* Transportation of ions
* Ferrous Form of Fe
* Prevents oxidation of proteins
Contains Hemoglobin Molecules
* Hemoglobin must remain in RBC to function properly
* Ability to concentrate 34gram of Hgb per 100mL of cell fluid
* Metabolic limit of the cell
* Size of the cell
Red Blood Cell Size
Biconcave Disk
Width: 7.2-8.4um
Height (inner): 0.45-1.16um
Height (outer): 2.31-2.85um
RBC Production
During Gestation: Yoke Sac -> Liver -> Spleen/Lymph -> Bone Marrow
Up until 5 years: Bone Marrow of ALL bones
Slowing become fatty and leave the Tibia & Femur to do the work
After 20 years: Membranous Bones ( Vertebra, Sternum, Ribs, Ilia)
Genesis of Blood Cells
Erythropoietin = differentiator
* PHSC –> PHSC
* PHSC –> LSC –> Lymphocyte (B or T)
* PHSC –> CFU-S –> CFU-GM –> Granulocytes (Neutrophils, Eosinophils, Basophils) or Monocytes –> Macrocytes
* PHSC –> CFU-S –> CFU-M –> Megakaryocytes –> Platelets
* PHSC –> CFU-S –> CFU-B –> CFU-E –> Erythrocytes
PHSC = Pluripotent Hematopoietic Stem Cell
LSC = Lymphoid Stem Cell
CFU = Colony Forming Unit
CFU-S = CFU Spleen
CFU-GM = CFU Granulocutes, monocytes
CFU-M = CFU Megakaryocytes
CFU-B = CFU Blast
CFU-E= CFU Erythrocytes
Stages of RBC Differentiation
ALL
1st generation (Basophilic)
- Little Hgb
2nd/3rd generation (Polychromatophil/Orthochromatic)
- Hbg fill cell (34%)
- Nucleus condenses and is absorbed/extruded
- ER is reabsorbed
4th generation (Reticulocyte)
- Basophilic material, GA, Mitochondria
- Diapedesis into blood capillaries from bone marrow
- If there are large numbers, there is a problem - RBC not maturing enough to carry on RBC function
1st generation RBC Differentiation
(Basophilic)
- Little Hgb
2nd/3rd generation of RBC Differentiation
(Polychromatophil/Orthochromatic)
- Hbg fill cell (34%)
- Nucleus condenses and is absorbed/extruded
- ER is reabsorbed
4th generation of RBC Differentiation
(Reticulocyte)
- Basophilic material, GA, Mitochondria
- Diapedesis into blood capillaries from bone marrow
- If there are large numbers, there is a problem - RBC not maturing enough to carry on RBC function
Role of Erythropoietin
Tissue oxygenation is the most esential regulator of RBC production!
Anything to decrease oxygenation will stimulate erythropoietin for RBC production b/c we need more oxygenation.
* Low blood volume, anemia, low hemoglobin, poor blood flow, pulmonary disease
Kidneys and liver release erythropoietin
Hypoxia= inducible factor-I
Non-renal sensors can stimulate hormone release not just renal tissue hypoxia
Dec. tissue oxygenation –> erythropoietin —> hematopoietic stem cells –> proerythroblasts –> RBCs –> tissue oxygenation
Hematinics
Vitamins
B12 (cyanocobalamin)
Folate
Ascorbic acid (Vit. C)
Vitamin E
B6 (pyridoxine)
Thiamine
Riboflavin
B5 (pantothenic acid)
Metals
Iron
Manganese
Cobalt
Essential Amino Acids
Formation of hemoglobin
I. 2 succinyl-CoA + 2 glycine –> pyrrole
II. 4 pyrrole –> protoporphyrin IX
III. protoporphyrin IX + Fe++ –> heme
IV. heme + polypeptide –> hemoglobin chain (alpha or beta)
V. 2 alpha chains + 2 beta chains –> hemoglobin A
Hemoglobin Structure
Heme (mitochondria) molecules combine with Globin (ribosomes)
Tetramer!
Hgb A – most common- 2 alpha; 2 beta chains
4 iron molecules/Hgb
4 oxygen molecules (O2)/Hgb
250 million Hgb molecules/Erythrocyte!!!
When it’s not a tetramer…
It’s a dimer (only 2 chains in hemoglobin – different shape!)
Result of Hemolysis
Filtered by the kidneys – not good!
Stroma can clog the glomerulus –not good!
Stroma can clog small capillary beds – lungs, heart, brain- not good!
Reduced Hgb time in Circulation – not good!
Shifts OxyHgb Curve to the Left- not good!
Decreased O2 binding – not good!
“Free” Hgb scavenges NO = Vasoconstriction – not good!
Stroma = dimers
Tetramere = 4 globulin chains
Iron and Heme
Determines the ability of Hgb to hold on to O2
4-5g in the body - 65% in Hgb
Ferritin is stored iron
Hemosiderin is backup storage
Transferrin is a binder to transport iron
RBC and metabolic waste
Picture slide :(
In the RBC…
Carbonic anydrase = enzyme in rxn below
CO2 + H2O —> H2CO3 (carbonic acid)
H2CO3 –> HCO3- + H+ –> Hb
Rxn also goes in reverse
Hb –> H+ + HCO3- –> H2CO3
H2CO3 –> CO2 + H2O (in presence of carbonic anhydrase)
RXN = reaction
“Fun” Facts
How CO2 and O2 are transported
CO2 is transported…
* Bicarbonate Ions (70%)
* Hemoglobin (23%)
* Dissolved in Plasma (7%)
O2 is transported….
* Hemoglobin (98%)
* Dissolved in Plasma (2%)
Oxygen Carrying Capacity
(1.34 x Hgb x SpO2) + (0.003 x PaO2)
Example:
Hgb = 12, SpO2% = 95%, PaO2 = 96mmHg
(1.34 x Hgb x SpO2) + (0.003 x PaO2) = ??
(1.34 x 12 x 0.95) + (0.003 x 96) = 15.56mL of O2/100mL blood OR 15.56mL of O2/dL <—-deciliter!!!
1.34 b/c 1g of Hgb can maximally bind to 1.34mL of O2
Henry’s Law = (0.003 x PaO2)
ABO Blood System “Chart”
Agglutinogens and Agglutinins
Type A
* A agglutinogens (RBC surface proteins)
* B agglutinin (plasma antibodies)
* Can donate to A and AB
* May receive from A and O
* May not receive from B or AB b/c the B agglutinogens on the RBC surface of B and AB blood (donor) will bind with (agglutinate) the B agglutinin in the blood of a Type A person (receiver).
Type B
* B agglutinogens (RBC surface proteins)
* A agglutinin (plasma antibodies)
* Can donate to B and AB
* May receive from B and O
* May not receive from A or AB b/c the A agglutinogens on the RBC surface of A and AB blood (donor) will bind with (agglutinate) the A agglutinin in the blood of a Type B person (receiver).
Type AB
* AB agglutinogens (RBC surface proteins)
* NO agglutinin (plasma antibodies)
* Can donate to AB
* May receive from A, B, AB and O (universal receiver) b/c there are no agglutinins
Type O
* NO agglutinogens (RBC surface proteins)
* A and B agglutinin (plasma antibodies)
* Can donate to A, B, AB and O (universal donor) b/c it is a blood ninja with no agglutinin
* May receive from O
* May not receive from A, B or AB b/c the A and B agglutinogens on the RBC surface of A, B and AB blood (donor) will bind with (agglutinate) the A and B agglutinin in the blood of a Type O person (receiver).
Antigen = Agglutinogen - physical structure on RBC surface which causes an antibody rxn
Antibody = Agglutinin - protein produced in response to and counteracting a specific antigen
Agglutination = clumping of particles together when an antigen-antibody rxn occurs when an antigen is mixed with its corresponding antibody
Antibodies
AKA Agglutinins
Plasma Antibodies
Almost completely absent at birth
Titers peak between 8-10 years old
Gamma Globulins (IgG & IgM)
Transfusion Rxn’s
ppt text: Antibodies of recipient attack the antigens of the donor blood
Agglutination followed by delayed hemolysis d/t need for higher titers and IgM antibodies (hemolysins)
Brian’s text: after the initial agglutination in response to the newly administer donor blood, hemolysis is delayed, b/c the body needs both IgM antibodies specifically AND a higher titer of them, aka hemolysins. I think b/c IgM antibodies have 10 binding sides due their shape they produce a stronger transfusion rxn
Rh Blood Types
Difference between ABO system & Rh system?
6 type of Rh factors (aka antigens)
C, D*, E, c, d, e
(everyone has 1 of each antigen)
If D, Rh +; is no D, Rh-
Erythroblastosis Fetalis
Mom = Pam (Rh-); Dad = Jim (Rh+); Baby 1 = Cece (Rh+); Baby 2 = Phillip (Rh+).
1st pregnancy: Pam has uncomplicated pregnancy with Cece but develops Anti-Rh antibodies
2nd pregnancy: Pam’s anti-Rh agglutinins (antibodies) attacks Phillips Rh+ antigens (agglutinogens)….
Erythroblastosis Fetalis = Hemolysis/Agglutination -> Excess Bilirubin
Occured on 2nd exposure
Prevention: @ 28 weeks Alice gets treated with anti D antibody immunoglobulins (Rhogam).
Hemolysis Concerns
400 ml of blood hemolyzed per day to cause jaundice in people with healthy livers
Most Severe Complication of Hemolysis:
Renal Shutdown
AA rxns release vasoactive toxins- decreasing GF
Circulatory Shock
Free Hgb “Dimers” clogs glomerulus
Oxygen-hemoglobin Dissociation Curve
O2 extraction from Hgb to the tissues
Sigmoid Curve
Partial pressure of oxygen (mmHg) on x-axis & Oxyhaemoglubin (% saturation) SpO2 on y-axis
Left Shift: (Increased affinity)
Haldane Effect
* Decreased temp
* Dec. 2,3-DPG
* Dec. H+
* CO
Right Shift: (Decreased affinity)
Bohr Effect
* Increased temp
* Inc. 2,3-DPG
* Inc. H+
104 = partial pressure of O2 in alveoli (lungs)
40 = partial pressure after unloading in the capillaries / start of venous circulation
80 = partial pressure plateau on graph
Hemostatsis
ALL
- Vascular Constriction (Spasm)
- Platelet Plug Formation
- Blood Clot (Coagulation)
- Fibrous Tissue
Hemostasis
Vascular Constriction (Spasm)
Local Myogenic Spasm/Constriction
Autacoid factors from injured tissues & platelets
Nervous Reflexes
Thromboxane A2 (humoral factor) is released from platelets – causes vasoconstriction
Begins within minutes of injury and last up to 2 hours
Reduces Flow of Blood
Hemostasis
Platelet Plug Formation
Cell membranes coated with glycoproteins (coat hangers) enable platelets to be “snagged” by roughened edges of the endothelium
Picture: Release of chemicals ADP, thromboxane A2, Ca2+, platelet factors shown at location of platelet plug
SWELL, SECRETE, STICK, STACK!!!!
* Platelet begin to swell with fluid
* Pseudopod protections, contractile forces release substances making the platelets sticky
* Secrete ADP & Thromboxane A2: activates nearby platelets
* Addition platelets adhere to the others (stacking) causing the formation of a platelet plug.
* Platelet plugs are designed for minute day to day perforations, and really are not “clots” per se
* The clot forms when fibrin threads fill in the “gaps” left in the plug…more on this later
* Once the clot forms, it is invaded by fibroblasts, connective tissue is formed, and the clot is dissolved
Platelets
Platelet half-life = 8-12 days
Megakaryocytes Fragments
Eliminated by tissue macrophages primarily in the spleen
No platelets = petechiae
Contain:
Myosin, Actin, Thrombosthenin
Enzymes
Calcium Storage
ATP
Produces Prostaglandins
Produces Fibrin-Stabilizing Factor
Produces Growth Factor- for cell grow- mend vessel wall.
Surface Glycoproteins- repels from normal tissue; adheres to damaged tissue
Phospholipid membrane helps activate clotting process.
Plasma Clotting Factors
ALL
Factor, Name, Function, Pathway
I. Fibrinogen. Converted to fibrin. Common
II. Prothrombin. Enzyme. Common
III. Tissue Thromboplastin. Cofactor. Extrinisc.
IV. Calcium ions (Ca++). Cofactor. All
V. Proaccelerin. Cofactor. Common
VII. Proconvertin. Enzyme. Extrinsic
VIII. Antihemophilic factor. Cofactor. Intrinsic
IX. Plasma thromboplastin component; christmas factor. Enzyme. Intrinsic.
X. Stuart-Prower factor. Enzyme. Common.
XI. Plasma thromboplastin antecedent. Enzyme. Intrinsic.
XII. Hageman factor. Enzyme. Intrinsic.
XIII. Fibrin stabilizing factor. Enzyme. Common.
Prekallikrein = fletcher factor
High Molecular Weight Kininogen = fitzgerald factor
All = intrinsic, extrinsic and common
Extrinisic Pathway
“Due to external factors” or “non-blood factors”
Injured tissue that meets blood
Intrinsic Pathway
“Blood activated factors”
Trauma to blood or exposure of blood to collagen
check out thrombin-positive feedback loop
Final Common Pathway Prothrombin
Prothrombin activator complex is the rate limiting factor in clotting (usually!)
Prothrombin: Plasma Alpha 2 Globulin, 15mg/dL
Continuously formed by the liver…hepatic disease?
Vitamin K is necessary to produce prothrombin
You have less than a 24-hour supply at any given moment
Final Common Pathway Fibrinogen
Fibrinogen is produced in the liver
Very big molecule – does not (should not-capillary leak?) leak into the interstitum
Thrombin is an enzyme which acts on fibrin to cause a fibrin monomer which link to other fibrin monomers
-Plasma globulins and platelets release Fibrin Stabilizing Factor which is also activated by thrombin – Fibrin Cross Linking activation
Clotting Prevention
- Smooth Endothelium
- “Teflon” Coat of the Glycocalyx lining the Endothelium
- Thrombomodulin on the Endothelium binds with Thrombin -> activates Protein C which INACTIVATES Factor V and Factor VIII
- Thrombin gets absorbed in Fibrin Threads (deactivating thrombin)
- Heparin activates AT III which inhibits Thrombin
Lysis of Clots
- After trauma, tissue plasminogen activator activates plasminogen automatically
- Plasminogen is activated to plasmin
- Plasmin digests fibrin threads, Factor V, Factor VIII, prothrombin and Factor XII
- Plasmin is formed constantly, and would degrade clots we need except for alpha 2 antiplasmin
- This factor binds with and inhibits plasmin
- Plasmin is dose dependent: tissue activation causes more plasmin to be formed than inhibitor available
- Plasmin removes millions of tiny clots which we otherwise would not clear
Vasoconstriction
After vascular injury local neurohumoral factors induce a transient vasoconstriction.
Intact endothelium releases NO and prostacyclin to prevent platelet adhesion beyond the injury site
*
Primary Hemostasis
Platelets bind via glycoprotein Ib (GP-Ib) receptors to von Willebrand factor (vWF) on exposed extracellular matrix (ECM) and are activated, undergoing a shape change and granule release. Released adenosine diphosphate (ADP) and thromboxane A2 (TxA2) induce additional platelet aggregation through platelet GpIIb-IIIa receptor binding to fibrinogen and form the primary hemostatic plug.
Secondary Hemostasis
Local activation of the coagulation cascade [involving tissue factor and platelet phospholipids] results in fibrin polymerization, “cementing” the platelets into a definitive secondary hemostatic plug.
Thrombus and Anti-thrombotic events
Counter-regulatory mechanisms, mediated by tissue plasminogen activator (t-PA, a fibrinolytic product) and thrombomodulin, confine the hemostatic process to the site of injury.
