Primary Hemostasis

Primary hemostasis is the initial response to vascular injury.

Now, I'm one of those people who learns best with a goal in mind, where small details only make sense if I have an initial idea of where they fit in with the big picture. I need to know the generals before I move to specifics, like looking at something from a distance then zooming in, rather than zooming out from the specifics to the general. I don't know why, but my professor seems to think a one sentence explanation of the general outline and then hours of the specifics moving to the general is good enough. I don't know about the rest of you, but I feel like most human beings can't learn that way, so I'm going to teach this to you the right way.

So with that long-winded explanation out of the way, here's the general outline of this section:

PRIMARY HEMOSTASIS
- Overview of the three stages of Hemostasis
- Blood vessel function for the primary hemostatic plug
- Platelets in Hemostasis
      ~ Production
      ~ Structure
      ~ Formation of a platelet plug
            - Adhesion
            - Shape alteration
            - Aggregation (Primary and Secondary)
            - Secretion

Stages of Hemostasis
1. Primary Hemostasis
    - platelets and the injured vessels interact to form the primary hemostatic plug, which is a clump of platelets
    - it only temporarily stops the bleeding and is very fragile
2. Secondary Hemostasis
    - the fibrin-platelet plug is then formed by a series of interactions involving the coagulation factors (coagulation cascade)
    - the fibrin stabilizes the clot covering the hole in the vessel
3. Fibrinolysis
    - the process of removing the clot once the wound has been healed, involves converting the fibrin to fibrinogen, which is not pictured

(I'd like to apologize for the fuzzy image to your left--I felt the image in my textbook was the best one I've seen and I couldn't find it in a search engine so I was forced to resort to my crappy camera phone) 




Now let's focus on the first stage.

Blood Vessel Functions
1. Damaged vessels
    - Vasoconstriction
          > minimizes the flow to blood to wound and escape of blood from the wound site
          > brings hemostatic components of blood together through the cell wall
          > happens immediately and only lasts for a short while
2. Healthy vessels
    - the surrounding intact endothelial cells secrete a prostaglandin called PGI₂ (prostacyclin), which counteracts the vasoconstriction by causing vasodilation of the arterioles
          > this increases blood flow to the injured site, but not in the sense that it makes the purpose of vasoconstriction pointless
             - by doing this, vasodilation brings fresh supplies of plasma-clotting substances to the site--what point would there be if there were no platelets or fibrin or coagulation proteins available to make the actual clot?
             - this is why the skin around the wound turns RED
3. Endothelial cells
    - Contract
          > this creates gaps btween the endothelial cells and allowes plasma leakage into the tissues, causing sweeling or edema (meaning increased vascular permeability)
          > combined with vasodilation, this is known as the inflammatory response

PLATELETS

Production
    - Platelets are disk-shaped cells produced in the cytoplasm of megakaryocytes in the bone marrow
          > takes 3-5 days
          > normal range is 150,000-45,000/cu mm
          > each megakaryocyte produces ~1,000-3,000 platelets
          > 80% are circulating in the blood, with the rest pooling in the spleen
          > total lifespan is 9-12 days

Structure
    - Three main structural zones
        1. Peripheral
        2. Membranous
        3. Organelle






    - Peripheral Zone
          >  function is adhesion and aggregation, responsible for cell's negative charge
          > Glycocalyx (exterior coat)
             - consists of coagulation factors (I, II, VII, IX, X)
             - Receptors (Glycoproteins Ib/IX, IIb/IIIa)
                    ~ GPIb is the major platelet receptor for VWF (Von Willebrand Factor), has an α and β chain
                            - GPIbα chain is larger and contains the binding sites for VWF, thrombin, and ristocetin
                    ~ GPIIb/IIIa is a complex which is the main receptor for fibrinogen, though the complex can also bind with VWF, thrombospondin, and fibronectin
             - Sol-gel zone
                    ~ Thrombosthenin microfilaments and microtubules (CMT)
          > Membrane
                    ~ Site of serine protease reaction in coagulation
                    ~ Has a number of phospholipids and proteins embedded within it
                            - as such the location of pumps, channels, receptors, enzymes, and structural proteins
                    ~ Responsible for the release of fatty acid derivatives
                            - prostaglandins, thromboxanes, prostacyclins
    - Membranous Zone
         >  function is structure and support
         > OCS (Open Canalicular System)

             - responsible for the secretion of granule contents
             - provides a route for entry and secretion
         > DTS (Dense Tubular System)
             - responsible for the storage of calcium
             - cAMP produced
             - major sit of prostaglandin and thromboxane synthesis

    - Organelle Zone
          >  function is secretion and storage
          > Mitochondria
          > Glycogen particles
             - support metabolic activities
          > Granules dispersed within the cytoplasm, which serve as storage sites for proteins and other substances necessary for platelet function
             1. Dense bodies
                    ~ high Ca+ content
                    ~ contain mediators of platelet function and hemostasis that aren't proteins
                    ~ Serotonin, ATP, ADP (nonmetabolic), Ca+, pyrophosphate
             2. Alpha granules
                    ~ most numerous
                    ~ coagulation cofactors
                            - VWF, fibronectin, HMWK, Factors I and V
                    ~ protease inhibitors
                            - α₂ macroglobulin, α₂ antiplasmin

                    ~ platelet specific proteins
                            - Thrombosphondin, thromboglobulin
             3. Lysosomal granules
                    ~ microbicidal enzymes, acid hydrolases
             4. Peroxisomes 

Formation of a Hemostatic Platelet Plug

    1. Adhesion
          >  Initial stimulus is the exposure of the vessel wall's subendothelial components
          >  adheres to collagen
             - low shear rates, the GPIaIIa and GP6 receptors are used
             - high shear rates, VWF is required to be present
             - VWF binds to platelet surface and collagen while GPIb just binds to the platelet
          >  platelet then swells, releases ADP and ATP, which cause other plateles to change their shape
          >  thromboxane α₂ is then released and cases vasoconstriction of the damaged vessels
    2. Shape alteration/Activation
          >  term viscous metamorphesis applies, change from ovoid disks to spheres with pseudopodia (discoid shape is maintained by the CMT)
          >  only after being stimulated by an agonist will the platelets be able to proceed to the next step of aggregation
             - if the stimuli isn't strong enough, the shape change will reverse
          >  agonists
             - ADP, serotonin, PAF (platelet-activating factor), thromboxane A2, collagen, thrombin, epinenphrine
    3. Aggregation
          >  attachment of platelets to one another
          >  Dense granules will form a white clot and thrombin will form a red clot
          >  Primary
             - platelets adhere loosely to one another, and can be broken apart
          >  Secondary
             - results in irreversible aggregation
             - ADP is needed
          >  if a test is done for platelet aggregation, the sample of choice should be platelet-rich plasma, citrated
    4. Secretion

          >  occurs if secondary aggregation occurs
          >  release of internal storage organelles
          >  agonists cause the formation of thromboxane which then elevates the cytosolic calcium
          >  releases dense and alpha granules as well as lysosomal contents