Notes Sheet – Blood Clotting
12.25 – Overview of Hemostasis
Hemostasis is the stoppage of bleeding; hemostatic mechanisms are most effective in
dealing with injuries in small vessels (arterioles, capillaries, and venules)
 Hematoma: accumulation of blood in the tissues as a result from any vessel type
bleeding; may increase interstitial pressure enough to eliminate pressure
gradient required for continued blood loss
Immediate reaction of damaged blood vessel: CONSTRICT!
 Next comes formation of platelet plug and blood clotting
12.26 – Formation of a Platelet Plug
Injury exposes underlying connective tissue collagen fibers to platelets, which adhere
through an intermediary called von Willebrand factor
 Von Willebrand factor: binds to exposed collagen, changing their conformation,
enabling them to bind platelets
Platelet activation occurs when collagen-bound platelets release paracrine factors
(ADP, serotonin, etc.) that act on surrounding platelets to change their metabolism,
shape, and surface proteins
 Platelet aggregation: new platelets bind to the old ones creating a platelet plug
 Activation/aggregation can also be stimulated by thromboxane A2, which is
rapidly synthesized because of platelet adhesion
 Fibrinogen forms bridges between aggregating platelets
 CONTRACTION of platelets is caused by their high amount of actin and myosin,
causing compression and strengthening of the plug
During this process, vascular smooth muscle is stimulated to contract, decreasing
blood flow to the area (mediated by thromboxane A2)
 Prostacyclin: inhibitor of platelet aggregation released by endothelium; released
along with nitric oxide, a vasodilator, to prevent needless clot formation
12.27 – Blood Coagulation: Clot Formation
Blood coagulation (AKA clotting) is the transformation of blood into a clot or
thrombus (consisting primarily of fibrin); initiated when injury to a vessel occurs
 Clotting cascade is maintained by activation of factors (AKA plasma proteins)
o Each factor is activated by splitting a small peptide fragment off the
inactive protein, exposing the active site of the enzyme
o Active factors then catalyze the generation of the next enzyme in the
sequence
 Prothrombin  thrombin: very important step of the blood clotting cascade!
o Thrombin catalyzes split of polypeptides from fibrinogen, causing
remnants to bind to each other and form fibrin
o Chemical linking between fibrin catalyzed by factor XIIIa (activation of
factor XIII catalyzed by thrombin as well)

Thrombin is very important! Catalyzes both formation AND stabilization of fibrin
mesh network
o Also exerts positive feedback effect on its own formation; activates
several proteins in cascade
o Thrombin activates platelets to display plasma membrane receptors that
bind several clotting factors and permit reactions to take place on their
surface
o Platelet factor: cofactor in steps mediated by bound clotting factors
Calcium is required at various steps as well!
Two clotting pathways:
 Intrinsic pathway: all
components come from within the
blood
 Extrinsic pathway: requires
elements from outside the blood to
function
They work separately but also interact at
several points (linked via thrombin)
Steps of the intrinsic pathway:
1. XII  XIIa; occurs when exposed
to collagen fibers
2. XI  XIa via factor XIIa
3. IX  IXa via factor Xia
4. X  Xa via factor IXa or factor
VIIIa (part of extrinsic pathway)
Steps of the extrinsic pathway:
1. VII  VIIa via tissue factor (found
in subendothelial cells, exposed
when cells are damaged)
2. X  Xa via tissue factor & VIIa
complex
3. IX  IXa via tissue factor & VIIa
complex
4. IXa can activate even more factor
X via intrinsic pathway
the pathways merge at factor Xa, which catalyzes conversion of prothrombin 
thrombin; thrombin then…
 Catalyzes formation of fibrin
 Activates factors XI and VIII
 Activates factor V, with Va serving as cofactor for Xa
The extrinsic pathway is the usual way of initiating clotting; it typically initiates
thrombin generation, but amount is too small, so intrinsic pathway is generated via
activation of factors V, VIII, and XI (as well as platelets)

Without factor XII, we would most likely be fine, because thrombin generation
through extrinsic pathway would catalyze activation of factor XI, activating the
intrinsic pathway.
The liver indirectly contributes to clotting as it is the site for production of many clotting
factors
 Synthesizes bile salts which are necessary for vitamin K absorption, which is
necessary to produce clotting factors
12.28 – Anticlotting Systems
We need a way to turn off the blood clotting system! We already talked about
prostacyclin and nitric oxide
Factors that Oppose Clot Formation:
 Tissue factor pathway inhibitor: inhibits ability of VIIa complexes to generate
factor Xa
 Thrombomodulin: when bound with thrombin, it eliminates thrombin’s clotproducing effects; thrombin binds protein C, which then inactivates factors VIIIa
and Va
 Antithrombin III: inactivates thrombin and several other clotting factors; greatly
enhanced when it binds to heparin
The Fibrinolytic System:
Principal effector of clot removal
 Plasminogen: once activated, it becomes plasmin, which functions to digest
fibrin, and thus the clot itself
 Tissue plasminogen activator: binds with plasminogen to fibrin during clotting
to become part of the clot; tPA is VERY WEAK in the absence of fibrin!
o Fibrin becomes important in regulating its own destruction
From Kostek’s Sheet for Quiz:
Platelet (Plt) – initiates the entire process of clotting through the formation of a platelet
plug
 Activated when paracrine/autocrine factors released from collagen-bound
platelets change shape, metabolism, and thus platelet function
Thrombin (T) – very important component of the clotting cascade!
 Catalyzes formation of fibrin mesh network via cleavage of polypeptides from
fibrinogen


Catalyzes stabilization of fibrin mesh network via activation of factor XIII
Positive feedback on its own formation via activation of several cascade
components
 Activates platelets to display plasma membrane receptors that bind several
clotting factors, allowing reactions to take place there
 Links the extrinsic/intrinsic pathways
Pro-Thrombin (PT) – precursor to thrombin
Pro-Thrombin Activator (PTA) – functions in catalyzing prothrombin into thrombin
Fibrinogen (Fg) – forms bridges between aggregating platelets
Fibrin (F) – MAIN component of the clot! Makes up most of the meshwork
Fibrin Stabilizing Factor (FSF) – activated by thrombin; gets caught in the fibrin web
and creates a stronger chemical cross link between the fibrin fibers
Tissue Factor (TF) – released into the bloodstream to help activate factor 7; very
important for extrinsic pathway
Von Willebrand Factor (vWF) - binds to exposed collagen, changing their
conformation, enabling them to bind platelets
Thromboxane A2 (TA2) – rapidly synthesized due to platelet aggregation; released to
further stimulate aggregation; also causes vasoconstriction on arteriole smooth muscle
to reduce amount of blood going through capillary
Tissue Plasminogen Activator (tPA) – regulates clot destruction; incorporated into the
clot with plasminogen, becomes activated once fibrin begins to be dissolved, activating
plasminogen into plasmin
Plasminogen (Pg) – inactive form of plasmin; incorporated into the clot with tPA to
later serve a role in clot destruction
Plasmin (P) – binds to and digests fibrin to eliminate clots once they are no longer
needed