-
Hemostasis
- Hemorrhage + Clotting
- Balance between the two
-
Four components of the Hemostasis System
- Vasculature (blood vessels)
- Thrombocytes (Platelets)
- Plasma coagulation proteins
- Fibrinolytic system (Inhibits/removes clots)
-
Basic Hemostasis sequence after a cut:
- Vasoconstriction: Blood vessels diameter decreases
- Formation of platelet plug at damaged site
- Platelet--Plasma protein--vasculature
- Fibrin clot formation
- Clot removal: fibrinolysis
-
Arteries
- Vessels transporting oxygenated blood away from the heart.
- High BP: 100-120 mm/hg
-
Veins
- Vessels transporting de-oxygenated blood back to the heart
- Veins are thinner and weaker than arteries
- Low BP: 60-80 mm/Hg
-
Capillaries
- middle ground between arteries and veins
- oxygen delivered to the cells
- Very thin, only a single cell layer thick
-
Tunica intima
- Innermost
- Single endothelial cell layer in contact with blood
- Underneath lies collagen
-
Tunica Media
Middle layer of smooth muscle and elastic tissue
-
Tunica adventia
- Outer layer
- Connective tissue nerve endings, and the vas vasorm (layers of tissue on outside)
-
Functions of the endothelial lining
- If intact, then inert with blood components
- If traumatized then physiologically active
- First: Responder to injury (vasoconstriction)
- Synthesis and stores active chemicals
- Prostacyclins: inhibit platelet aggregation and adhesion)
- Plasminogen activators: Clot dissolution
- Von Willebrand Factor: platelet adhesion protein
- Collagen activates plasma coagulation proteins: Factor 7
-
Hemostasis related substances f/endothelium:
- Collagen: Binds to platelet membrane GP Ib/IIa
- vWF: Binds to platelet membrane GP Ib/IIa
- PG12: Prostacyclin inhibits plt. aggregation
- Tissue factor: Liproprotein activates plasma coagulation protein
- Thrombomodulin: Protein C cofactor (inhibits fibrin formation)
- TPA: starts fibrinolysis
-
Disruption of endothelium activates all 4 components
- Vasculature: Short term vasoconstriction closes small blood vessels and limits blood loss.
- Platelets: Aggregation and adhesion form small clumps at injured site
- Plasma proteins: proteins begin formation of an insoluble protein "glue" fibrin clot
- Fibrinolysis: proteins begin the process of limiting formation, eventual removal of clot.
- Endoreplication: Cell division without cytoplasmic division (nucleus divides, cytoplasm does not)
-
Platelet structure
Glycocalyx
Fluffy outer coat, regulates shape platelet adhesion and aggregation
-
Open Canalicular system
- Sponge like
- Porous network system that permeates the platelet
- Releases the cytoplasmic granule contents to the outside.
-
Microfilaments and microtubules (cytoskeleton)
Structural proteins
-
Platelet Granules
Alpha granules (most abundant)
vWF (platelet adhesion), fibronectin, thrombospondin (platelet aggregation), platelet fibrinogen, Platelet factor 4
-
Dense Granules
- ADP
- Serotonin (vasoconstriction)
-
Platelet Kinetics
- Life span 8-10 days
- 1 megakarocyte produces 1-2000 platelets. Matures in 5 days
- 2/3 platelets circulate in blood
- 1/3 platelets sequestered in spleen
- Old platelets phagocytized by the RE system (mainly spleen)
-
Platelet function in hemostasis
- Endothelium is damaged, platelets will being to interact with exposed sub-endothelium tissues.
- Platelets are activated by exposure to the sub-endothelium, they lose their disk shapes to form pseudopods that extend and attach to exposed collagen
-
Platelets "tie up" to collagen and other platelets with proteins that bind with different glycoprotein receptors.
-
-
-
-
-
Fibrinogen
(aggregation)
Plasma and Platelets
-
Glycoprotein receptors
GP IIb/IIIa
Attaches to other platelets with Fibrinogen
-
GP Ib
Attaches to collagen with vWF
-
Adhesion
Platelets "stick" to the surfaces of damaged blood vessels
-
Aggregation
- Platelets sticking to each other at the damaged vessel
- Promoted by: Collagen, Thrombin, Serotonin, TXA2
- Inhibited by: Aspirin, Some prostaglandins
-
Aspirin
- Impairs the synthesis of thromboxane (TXA2), stimulates platelet granule release.
- Platelet aggregation is impaired for the entire life span of the platelet.
- Commonly prescribed to inhibit vascular occlusions (clots) in patients at risk for coronary occlusions
- Effect on platelet's take place within 5-15 minutes after ingestion.
-
Plavix
- Inhibits platelet GP IIb/IIIa
- When people die from hemostasis disorders, they usually die from excessive clotting
-
Quantitaive and Qualitative Platelet Tests
- A normal platelet count does not necessarily imply normal function.
- Excessive bruising or bleeding with a normal platelet count suggests a qualitative platelet disorder.
-
Thrombocytopenic patients can be transfused with platelets
-
Blood (plasma) coagulation proteins
- Synthesized in liver
- "Cascading-domino" sequence of chemical interactions between the proteins, tissue substances and calcium leads to the formation of an insoluble protein-the fibrin clot at the site of the injured blood vessel.
- The fibrin clot seals off the damaged blood vessel and limits blood loss.
- Other proteins in the fibrinolytic system limit fibrin formation and eventually its dissolution.
-
Activated Factor IIa
Thrombin
-
Inactivated Factor II
Prothrombin
-
Coagulation proteins can be measured
- Individually (factor assays test, fibrinogen)
- Collectively (PT and PTT tests)
-
Group I Fibrinogen
1,5,8,13
- Consumed during clotting (absent in serum)
- Factors 5 and 8 extremely liable
- Increased in inflammation, pregancy, and oral contraceptives
-
Group II
Prothrombin Group
2,7,9, 10
- Not consumed during clotting (except 2)
- Requires Vitamin K for synthesis
-
Group III
Contact Group
(11, 12, PK, HMWK)
- PK=Fletcher
- HMWK=Fitzgerald
- Not consumed during clotting
- Stable storage
-
Factor I
Fibrinogen
- Soluble plasma protein precursor to fibrin
- Fibrinogen--Fibrin clot
-
Factor II
Prothrombin
- Stable precursor of thrombin
- Prothrombin---Thrombin
-
Factor IIa
Thrombin
- Active form of prothrombin
- Thrombin converts fibrinogen--fibrin
- Promotes platelet aggregation
-
Thromboplastin
Any tissue (non-plasma) phospholipid substance (cell membrane guts)
-
Ionized Calcium
- Electrolyte
- Only ionized Ca is active in hemostasis
-
Factor V
Proaccelerin
- Very liable (1/2 life=16 hours)
- Consumed during clotting
-
Factor VIII
Anti-Hemophiliac Factor
- 2 Complex components
- High Molecular Weight: vWF, VIII RCo (Platelet aggregation), VIII Ag (Antigenic site)
- Low Molecular Weight: VIII C (Procoagulant), VIII Ag (Antigenic Site)
-
-
Factor IX
Plasma Thromboplastin Component
-
-
Factor XI
Plasma Thromboplastin Antecedent
-
-
Factor XIII
Fibrin Stabilizing Factor
-
Mechanisms of the coagulation proteins
Goal=Fibrin clot
-
Three pathways
Extrinsic Pathways
Activated by contact with tissue phospholipids following endothelial damage.
-
Intrinsic pathway
Activated by contact with negatively charged solid surfaces (collagen, glass)
-
Common pathway
Represents the merging of the extrinsic and intrinsic pathway
-
Fibrin Formation
Fibrinogen--(thrombin)---Fibrin Monomers--- Fibrin
-
Proteolysis
Thrombin splits fibrinogen into smaller parts
-
Polymerization
Monomers polymerize using (weak) hydrogen bonds
-
Stabilization
Factor 13 promotes stronger covalent bonding between monomers forming a strong fibrin polymer
-
Platelets trapped in the fibrin extend pseudopods to fibrin strands and pull the strands together--clot retracts and becomes stronger
-
Fibrinolysis
(Limitation and dissolution of the Fibrin clot)
- Plasminogen----Plasmin
- Plasminogen activators can include such substances as endothelial cell enzymes, bacterial products.
- Plasmin, enzyme that breaks fibrin and fibrinogen into small pieces.
- Pieces are fibrin degradation products (X, Y, D,E)
-
FDP
- Inhibit platelet aggregation, fibrin, fibrin polymerization.
- Plasminogen activators can be used to treat AMI's pulmonary emboli and other vascular occlusion.
-
FDP testing
- Special tube in kit.
- Serum specimen
- Fibrinolytic activity of plasmin--fibrinogen and fibrin into small fragments
- DIC, DVT, PE have presence of FDPs
- Latex particles coated with anti-fibrinogen.
- No agglutination in either tube: < 10 ug/ml
- Agglutination in 1:5: 10-20 ug/ml
- Test doesn't differentiate between Primary and Secondary because it uses an anti-fibrinogen antibody that reacts with FDPs and fibrinogen.
-
Normal Mechanisms against thrombosis
normal blood flows limits the concentration of pro-coagulants at the injury site.
-
Natural anticoagulants
AT III
- Most active natural anticoagualnt
- Inhibits thrombin (9,10,11,12)
- Synthesize by liver, platelets, endothelium
-
Protein C
- Inhibits Factor 5,8
- Synthesized by liver (vitamin K dependent)
-
Protein C and S
- Both Natural anticoagulant
- Protein C-Protein S pathway a major system involved in the regulation of blood coagulation and in the protection against thrombotic diseases.
- Congenital or acquired Protein C and Protein S deficiencies, causes recurrent thrombotic diseases, in the absence, in the absence of any obvious underlying cause.
- Factor 5 mutation: results in a prolonged survival of thrombotic activated Factor 5, following stimulation of the coag cascade, and increases the risk of thrombosis.
-
People who keep making too many clots, mutation in 5, didn't respond to Protein C or natural anticoagulation.
-
Therapeutic Anticoagulants
Blood thinner
- PT measures
- Oral anticoagulants
- Effective for long term, self-medication
- Vitamin K antagonists
- Group 2 (2,7,9,19)
- Slow acting (8-12 hour before effects)
- Long acting
-
Wisconsin Alumini Research Foundation
Originally utilized as rat poison after research into the unexplained deaths of cows during 1920s discovered a naturally occuring substance that caused internal bleeding
-
Heparin
- PTT measured
- IV anti-coagulant
- Given in hospital
- Inactivates factors IIa and Xa
- Fast acting
- Short duration (1/2 life=one hour)
- Standard dose acheived when the PTT is 1.5 times the baseline
|
|