Cardio/Renal - Physiology: Hemostasis, Platelet Plug, Clotting Cascade

What is the first thing that happens when you injure a blood vessel?

immediate response to loss of pressure at injury site cause constriction of vascular smooth muscle-this causes constriction to decrease blood loss and retraction of the damaged area into the surrounding tissue to protect from exposure to foreign materials

the vascular spasm that occurs immediately after injury to a blood vessel is caused by what mechanisms specifically?

- local myogenic spasm

- sympathetic nervous system

- local chemical factors released from damaged tissue and platelets (e.g. thromboxane A2, kinins and serotonin)-all powerful vasoconstrictors

- blood loss into a tissue can increase local tissue pressure (turgor), slowing blood loss

thrombocytes (platelets) are cellular fragments derived from...

megakaryocytes in the bone marrow

under normal conditions, what is the role of platelets?

they playa. critical role in the maintenance of the endothelial lining of blood vessels, rapidly repairing small breaks

Describe adhesion, the first step in platelet plug formation.

- a break in the vessel wall exposes collagen fibers in the basement membrane of the endothelium and underlying connective tissue

- the positively charged amino acids in collagen (lysine,hydroxylysine) attract nearby platelets which adhere to the cut surfaces (which are negative)

- the adhesion is dependent upon a glycoprotein complex present on the platelet surface, GpIb/Ix/V, and upon von willebrand factor (vWF), a protein secreted by endothelial cells and platelets

- von willebrand factor (vWF) binds to a site on the Ib subunit of the GpIb/Ix/V, and also to exposed collagen fibers linking platelets to site of injury

T or F: von willebrand factor (vWF) only binds to either platelets or exposed collagen fibers

FALSE

von willebrand factor (vWF) binds to a site on the Ib subunit of the GpIb/Ix/V, and also to exposed collagen fibers linking platelets to site of injury

adhesion of platelets is dependent upon what 2 things?

- GpIb/Ix/V, a glycoprotein complex present on the platelet surface

- von willebrand factor (vWF), a protein secreted by endothelial cells and platelets

platelets are positive or negatively charged?

negative

Describe platelet activation and aggregation, the second step in platelet plug formation.

adhesion of platelets induces their activation which involves 4 steps:

1. morphological changes - adherent platelets swell and extend processes that make contact with their neighbors

2. platelet release of thromboxane A2 and serotonin - vasoconstrictors that decrease blood flow and ADP which causes additional platelets to attach to the site

3. expression of the GpIIb/IIIa complex on the platelet surface binds with fibrinogen to cross-link platelets together to form a platelet plug over the injury site

4. secretion of other substances by platelets including growth factors, platelet factors (PF3) needed for plasmas coagulation, calcium, kinins, etc.

GpIIb/IIIa is expressed on the surface of what cells?

activated platelets

How do we limit the platelet response to the site of injury?

undamaged endothelial cells adjacent to the injury site secrete two potent inhibitors of platelet adhesion, activation and aggregation into the local circulation:

- prostacyclin

- nitric oxide (NO)

what are the two potent inhibitors of platelet adhesion, activation and aggregation into the local circulation?

- prostacyclin

- nitric oxide (NO)

primary hemostasis is defined as:

formation of the platelet plug

T or F: platelets have contractile capabilities

TRUE

- platelets contain actin and myosin in amount comparable to skeletal muscle

T or F: platelets have significantly less actin and myosin than skeletal muscle

FALSE

- platelets contain actin and myosin in amount comparable to skeletal muscle

Is the platelet plug alone enough to stop blood loss in small injuries?

YES

what role do actin and myosin play in platelets?

these proteins may play a role in shape changes during platelet activation and in cot retraction

what is petechiae?

multiple small hemorrhages under the skin as a result of lack of platelets

initiation of coagulation occurs by...

formation of prothrombin activator complex

when is coagulation triggered?

when blood comes into contact with collagen from a damaged vessel or other fluids resulting from tissue trauma

what are the two pathways that can be involved in the formation of a clot?

intrinsic and extrinsic

contrast initiation of the intrinsic and extrinsic pathways

intrinsic: coagulation begins within the bloodstream

extrinsic: coagulation begins with trauma to tissue outside the vessel

What is unque to the intrinsic pathway?

tissue factor activating factor 7

how is the extrinsic pathway intiiated?

traumatized tissue releases a complex of several factors called tissue factor or tissue thromboplastin

What happens after the release of tissue factor?

tissue factor further complexes with factor VII and, in the presence of calcium ions, acts enzymatically on factor X to form activated factor X

factor VII acts on factor X in the presence of what?

calcium ions (factor IV)

what factor is calcium?

factor IV

What happens after factor X is activated?

Xa (activated factor X) forms prothrombin activator

- Xa combines with tissue or platelet phospholipids as well as factor V to form the complex called prothrombin activator

What is included in the complex prothrombin activator? (3)

- Factor Xa

- tissue of platelet phospholipids

- Factor V

what activates the intrinsic pathway?

blood trauma or contact with collagen

what happens in the first step of the intrinsic pathway after activation by blood trauma or contact with collagen?

a) activation of factor XII and

b) release of platelet phospholipids (containing platelet factor 3)

What happens after activation of factor XII?

XIIa will enzymatically activate Factor XI -> which needs kininogen and is accelerated by prekallikrein

What happens after activation of Factor XI?

XIa enzymatically activates Factor IX -> IXa

What is the fate of Factor IX after activation by Factor XIa?

Factor IXa + Factor VIIIa + platelet phospholipids and factor 3 activate Factor X to Factor Xa

What does Factor Xa join with after activation?

Factor Xa + Factor V + platelet or tissue phospholipids form the complex called prothrombin activator

what does prothrombin activator do upon activation?

cleaves prothrombin to form thrombin

What does Thrombin activate?

- fibrinogen to fibrin

- Factor XIII to XIIIa

fibrin and XIIIa combine to form what?

fibrin mesh

How does thrombin activate fibrinogen?

thrombin splits two small fibrinopeptides from the center of the fibrinogen. molecule to form a fibrinogen monomer (Factor Ia)

What happens to fibrinogen monomers?

the monomers spontaneously polymerize into long fibrin polymer threads (protofibrils) held loosely together by hydrogen and hydrophobic bonds

What factor XIIIa? what is its role?

fibrin stabilizing factor

- it catalyzes the formation of covalent bonds between the monomers and between adjacent fibrin chains to form branched fibers

All factors are proteins except:

calcium (factor IV)

PF3 (a phospholipid)

both intrinsic and extrinsic pathways share which steps?

the last 4 (come together at Factor 10)

the coagulation cascade is an example of...

biological amplification

shortly after formation what happens to a clot?

it begins to shrink

- most of the entrapped fluid (serum) oozes out of the clot (serum is plasma without clotting factors)

retraction results at least in part from what?

contraction of platelet actomyosin

what is the final step of hemostasis?

dissolution of the clot

dissolution of the clot happens gradually as...

new fibroblasts migrate to the injury site and begin the repair process

fibrinolysis requires activation of what?

the plasma protein plasminogen into plasmin.

This occurs when the clot itself induces the release of plasminogen activator

What are 3 ways in which coagulation is prevented in healthy vessels?

• normally blood flow is non-turbulent and flows over the negatively charged endothelial cell layer.

• since most plasma proteins are themselves negatively charged, they are repelled from contact with vessels walls.

• a number of anticoagulants circulate in normal plasma or are expressed on the endothelial surface