Katelyn Fong 20 1
Haemostasis & Blood Clotting Mechanism
Haemostasis Introduction = Maintenance of blood volume [stoppage
of bleeding to prevent blood loss] Normal hemostatic response to
vascular damage involves platelets, endothelial cells and
coagulation factors Blood clotting: a positive feedback process
Involved when a vessel is severe/ ruptured: Small blood vessels
(arterioles, capillaries, venules): Hemostatic mechanisms Medium to
large arteries bleeding: CANNOT control Vein bleeding: Raise body
part above heart level pressure Stop bleeding Accumulation of blood
in tissues pressure Eliminate pressure gradient needed for
continued blood loss Haematoma = accumulation of blood in tissues
due to bleeding from any vessel Usually when blood vessels bleed
Changes in local vasodilator & constrictor substances released
by endothelial cells & blood cells Vessel contricts flow rate
of blood & glue the opposed endothelial surfaces of the vessel
together When blood is taken out from the body, it forms a gel
called clot and finally separates from the liquid serum 4 Steps to
blood formation:(1) Vascular constriction(2) Formation of a
temporary platelet plug (primary phase)(3) Formation of a blood
clot due to blood coagulation (secondary phase)(4) Clot retraction
& fibrinolysis (Growth of fibrous tissue into blood clot to
close the hole in vessel permanently)
Vascular Constriction After a blood vessel has been ruptured,
the vessel walls smooth muscle will contract due to:: Local
myogenic contraction of blood vessels initiated by the direct
damage to the vascular wall Can last for a long time: During this
period, formation of platelet plug & blood clotting can occur
Local autacoid factors from injured tissues & blood platelets
E.g. thromboxane A, ADP, tissue factor, prostacyclin &
endothelins, peptide hormones Stimulates: Smooth muscle contraction
& promotes vascular spasms Division of endothelial cells,
smooth muscle cells & fibroblasts to accelerate repair process
Nervous reflexes initiated by pain/sensory nerve impulses from that
area Sympathetic nerves send messages Smooth muscles in the wall
contract Vessel walls smooth muscle contracts
Reduce blood flow to ruptured vessel Reduce blood loss Permanent
closure by constriction & contact stickiness only occur in the
smallest vessels Stoppage of bleeding in other vessels requires:
Platelet plug formation Blood clotting
Formation of a Temporary Platelet Plug (/Primary Hemostatic
Plug) Platelets (Thrombocytes): Disc shaped cells: 2-4 m in
diameter Formed in bone marrow from megakaryocytes Do not have
nuclei & cannot reproduce Cellular characteristics:
Actin/myosin molecules: allow contraction Endoplasmic reticulum,
Golgi apparatus, mitochondria, etc. Factors (growth factor,
fibrin-stabilizing factor): help repair damaged vascular walls
Glycoproteins on surface: aids adherence to injured areas of vessel
walls by providing receptors for agents activating platelets
Phospholipid membrane: Provide a catalytic surface for blood
clotting and yield arachidonic acid for synthesis of prostaglandins
Release clotting factors Main functions [Extremely important for
closing tiny ruptures in very small blood vessels that occur
thousands of times daily]: Closure of leak by formation of
temporary patch Release of chemical mediators to regulate blood
clotting Contraction of blood clot Mechanism of the platelet plug:
Occurs in the first minute or so following injury Injury to vessel
disrupts endothelium & expose underlying connective-tissue
collagen fibres Platelets come into contact with the damaged vessel
surface The platelets are activated & immediately change their
own characteristics drastically: Swell Assume irregular forms with
numerous pseudopods protruding from their surfaces To increase
surface area Become sticky glycoproteins on membrane (GPIb, GPIIb,
GPIa, etc.) adhere to von Willebrand factor (a plasma protein
secreted by endothelial cells & platelets that leaks into the
traumatized tissue from plasma) Secrete large quantities of ADP
& thromboxane A2 These (also secreted by other ruptured cells)
act on the nearby platelets to activate them Stickiness of these
additional platelets causes them to adhere to the original
activated platelets Their contractile proteins contract forcefully
Platelets release granules that contain multiple active factors:
clotting factors & platelet factors (also for platelet
aggregation/repair) Platelet aggregation occurs: successively
increasing number of platelets are activated & attract more
& more additional platelets Platelet plug forms At first a
loose plug, but is usually successful in blocking blood loss at
small vascular opening During the subsequent process of blood
coagulation: fibrinogen forms fibrin bridges between the
aggregating platelets Fibrin threads attach tightly to the
platelets, constructing an unyielding platelet plug
Positive feedback cascade: Platelets stick platelets release
contents more platelets stick Platelet plug Platelet plug wont
spread to undamaged endothelium synthesis of prostacyclin (a
prostaglandin) & nitric oxide from undamaged endothelial cells
are both vasodilator & inhibitor of platelet adhesion,
activation & aggregationThey inhibit platelet aggregation
Formation of Blood Clot Due to Blood Coagulation Blood clotting
= Transformation of blood into a solid gel: clot/ thrombus, with
fibrin as the main component Begins to develop in 1520 seconds
after the trauma if severe; 12 minutes if trauma is minor Within
3-6 minutes the whole broken end of the vessel will be covered by
the clot Occurs locally around the original platelet plug Dominant
hemostatic defense Supports & reinforce the platelet plug &
solidifies blood that remains in the wound channel Clotting factors
play an important role in the reactions: Most of these proteins are
inactive forms of proteolytic enzymes. When converted to the active
forms, their enzymatic actions will cause the successive, cascading
reactions of the clotting process.Clotting
FactorsNameFunctionsSynonyms
IFibrinogenConversion to fibrin
IIProthrombinConversion to thrombin
IIITissue ThromboplastinActivation of factor X Tissue factor
IVCalcium ionCofactor for several reactions
VProaccelerinThrombin formation (not an enzyme) Labile factor
Ac-globulin (Ac-G)
VIIProconvertinFactor X activation Serum prothrombin conversion
accelerator (SPCA) Stable fator
VIIIAntihemophilic globulin [AHG]Factor X activation
Antihemophilic factor (AHF) Antihemophilic factor A
IXPlasma thromboplastin (component) [PTC]Formation of factor
VIII Chirstmas factor Antihemophilic factor B
XStuart factorThrombin formation Stuart-Prower factor
XIPlasma thromboplastin ancedent [PTA) Factor IX activation
Abtihemophilic factor C
XIIHageman factorFactor XI activation
XIIITransglutaminaseCross-linking of fibrin Fibrin-stabilizing
factor
-Prekallikrein Fletcher factor
-High-molecular-weight kininogen [HMWK] Fitzgerald factor
Platelets
Initiation of coagulation: Factors that could initiate the
clotting process Trauma to vascular wall & adjacent tissues
Trauma to the blood Contact of the blood with damaged endothelial
cells, collagen or other tissue elements outside vessel Each case
leads to the formation of prothrombin activator (catalyzes
conversion of prothrombin to thrombin in the presence of sufficient
Ca2+) with the use of blood clotting factors (e.g. Ca2+) Theres
positive feedback: thrombin later produced help increase activity
& production of factor VIII (antihemophilic globulin;
responsible for factor X activation and hence thrombin foramtion)
& V (Proaccelerin; responsible for thrombin formation) Clotting
defects due to too low level of Ca2+: NOT POSSIBLE muscles
paralysis/ cardiac arrhythmias would already cause death 2 pathways
[can occur simultaneously]: Extrinsic & Intrinsic Extrinsic
Pathway Extrinsic: A cellular tissue protein tissue factor outside
blood vessel is needed Begins with (i) traumatized vascular wall or
(ii) damaged extravascular tissues come into contact with blood (1)
Traumatized tissue releases factor III (tissue factor) Factor III
is composed especially of phospholipids from the membranes of the
tissue & a lipoprotein complex that functions mainly as
proteolytic enzyme(2) Factor III & factor VII (proconvertin)
leads to the activation of factor X (Stuart factor) Activation of
Factor X requires calcium ions & lipoprotein complex of Factor
III(3) Activated factor X combines with factor V (proaccelerin)
& phospholipids to form prothrombin activator Within a few
seconds, in the presence of Ca++, prothrombin activator splits
prothrombin to form thrombin, and the clotting process proceeds At
first, the Factor V in the prothrombin activator complex is
inactive, but once clotting begins & thrombin begins to form,
the proteoclytic action of thrombin activates Factor V Factor V
becomes an additional strong accelerator of prothrombin activation
In the final prothrombin activator complex, activated factor X is
the actual protease that causes splitting of prothrombin to form
thrombin, a process thats greatly accelerated by factor V &
platelet phospholipids= positive feedback effect of thrombin
(acting through Factor V) accelerates the entire process once it
begins Intrinsic Pathway Intrinsic: Everything occurs in blood for
this path Begins with (i) trauma to the blood itself or (ii)
exposure of blood to collagen from traumatized vessel wall (1)
Blood trauma causes activation of Factor XII (Hageman factor) &
release of platelet phospholipids Factor XII is activated when it
comes into contact with collagen fibres underlying damaged
endothelium Platelet phospholipid contains the lipidprotein called
platelet factor 3(2) Activated factor XII enzymatically activates
factor XI (antihemophilic factor C) Activation of Factor XI
requires HMWK (high-molecular-weight kininogen) & is
accelerated by prekallikrein(3) Activated factor XI enzymatically
activates factor IX (antihemophilic factor B) (4) Activated factor
IX combines with activated factor VIII (antihemophilic factor A) to
activates factor X (Stuart factor) Activation of Factor X requires
platelet phospholipids & Ca++ Haemophilia (excessive bleeding)
is due to absence of VIII(5) Activated factor X combines with
factor V (proaccelerin) & phospholipids to form prothrombin
activator Same as the last step in the extrinsic pathway
Prothrombin activator initiates within seconds the cleavage of
prothrombin to form thrombin, thereby setting into motion the final
clotting process Extrinsic pathway usually start first to produce
thrombin, but the amount is always too small, so there is positive
feedback from thrombin on the activation of factors V, VIII, XI of
the intrinsic pathway, then there would be enough amount of
thrombin for blood clotting Difference between intrinsic &
extrinsic pathways:PathwayIntrinsicExtrinsic
Initiator Contact of Factor XII & platelets with collagen in
traumatized vascular vessel wall Tissue factor (factor III)
released from traumatized tissues
Speed of completion Slow [1-6 minutes] Fast [15
Seconds](explosive once initiated)
Amplification Enzyme cascade No
Thrombin produced Much Little
3 main steps to coagulation 1. Prothrombin activator is formed
Formed due to complex chemical reaction in response to vessel wall
damage2. Prothrombin activator catalyzes conversion of prothrombin
to thrombin Prothrombin activator in presence of enough Ca2+ can do
the conversion Prothrombin is a plasma protein produced in the
liver3. Thrombin coverts fibrinogen to fibrin Fibrinogen is a
plasma protein produced in the liver Thrombin is a protein enzyme
with proteolytic capabilities Acts on fibrinogen to remove peptides
Forms molecules of fibrin monomers Fibrin monomers can polymerize
to form fibrin fibres Thrombin whilst catalyzing the formation of
fibrin, activates fibrin-stabilizing factor (factor XIII) Enhances
the fibrin meshwork Fibrin fibres adhere to damaged surface of
blood vessels Fibrin enmeshes platelets, blood cells & plasma
to form clot Clot formation normally remains localized at the site
of injury because: Fibrin absorbs thrombin into the clot Stops the
spread of thrombin into blood Inhibit blood clotting in other
places Although theres dispersal of some clotting factors to other
places, their concentrations are too low to bring about clotting
Thrombins functions in blood clotting: Facilitate formation of
loose fibrin Activate factor XIII (stabilization of fibrin mesh)
Activate factor XI Activate factor VIII Activate factor V Further
activate its own production from prothrombin (positive feedback)
Stimulate platelet activation platelets display receptors that bind
clotting factors & platelet factor (a cofactor) Release of
tissue factor (activation of extrinsic pathway) Livers functions in
blood clotting: Site of production of plasma clotting factors
Produce bile salts to help absorption of vitamin K Useful bacteria
in the colon produce vitamin K & it can also be ingested
Essential in the maturation of prothrombin and other coagulation
factors (VII, IX, X, etc.) in the liver Antibiotics can have an
effect on the production of vitamin In the absence of prothrombin,
thrombin cant be made & fibrin fibres cant be formed
Anti-coagulants (limit clotting): Tissue factor pathway inhibitor
Inhibits the tissue factor-activated factor VII complex Protein C
Activated by thrombin & thrombobondulin Inhibit activated
factors VIII & V Antithrombin III Activated by heparin
Deactivates thrombin & several other clotting factors
Clot Retraction = Stabilization of clot by squeezing serum from
the fibrin strands Within a few minutes after a clot is formed, it
begins to contract & express most of the fluid (serum) out
within 20-60 minutes This serum has all its fibrinogen & most
other clotting factors removed Platelets contribute to clot
contraction by activating actin & myosin molecules (contractile
proteins) As clot retracts, edges of broken blood vessel are pulled
together Functions: Further closure of leak Pulls torn edges of the
vessels closer together, reducing residual bleeding &
stabilizing injury size Reduces the size of the damaged area,
making easier for fibrocytes, smooth muscle cells & endothelial
cells to complete repairs Platelet-derived growth factor stimulates
vascular smooth muscle cells to build new vessel wall Stimulated by
VEH, endothelial cells multiply & restore their inner
endothelial lining
Fibrinolysis Plasma proteins contains plasminogen
(profibrinolysin) When a clot is formed, plasminogen is trapped in
the clot Plasminogen (plasmo proenzyme) is activated by plasminogen
activators (secreted by endothelial cells & is activated by
fibrin in a clot) after the clot has stopped bleeding Plasminogen
becomes plasmin (fibrinolysin) Plasmin (a protease) digests fibrin
fibres & other protein coagulants & clotting factors into
soluble fragments (inactive substance like fibrinogen &
prothrombin)
Blood Clotting Disorders that Leads to Abnormal Bleeding
Thrombocytopenia (low platelet count): Failure of platelet
production This may be due to selective megakaryocyte depression
(induced by drugs, chemicals or viral infections) or as part of
general bone marrow failure Increased destruction of platelets
Immune (idiopathic, drug-induced, infections and other causes)
Disseminated intravascular coagulation DIC (undesirable blood
clotting) Abnormal distribution of platelets Dilutional loss
Massive transfusion of stored blood to bleeding patients Platelet
function defects Hereditary disorders eg. Glanzmanns disease when
platelet aggregation fails due to deficiency in some glycoproteins
Acquired disorders Antiplatelet drugs (eg. aspirin) Uraemia (kidney
failure) Hyperglobulinaemia (liver disease) Disorders of
coagulation Hereditary deficiencies of clotting factors Haemophilia
A - factor VIII deficiency Haemophilia B (Christmas disease) -
factor IX deficiency Acquired disorders Vitamin K deficiency
(needed for clotting factors) Liver diseases Over dosage of
anticoagulants Vascular bleeding disorders These disorders are a
heterogeneous group of conditions characterized by easy bruising an
spontaneous bleeding from small vessels the problem rests in the
vessels or their connective tissues Hereditary hemorrhagic
telangiectasia Dilated microvascular swellings develop in the skin
mucous membranes and internal organs Acquired vascular defects Eg.
purpura (purple spots on skin due to internal bleeding of vessels)
associated with infection Vitamin K deficiency Vitamin K is
essential for synthesis of several clotting factors Half of vit K
from gut bacteria, half from diet Long-teraminm antibiotic use
results in vitamin K deficiency and bleeding disorders