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Basics in hemostasis
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Issue number 1 2012
Basics in hemostasis
Hemostasis is a complex process which controls
bleeding within the finely tuned interplay of
procoagulant, anticoagulant, fibrinolytic, and
antifibrinolytic activities. It relies on the combined
activity of endothelial, platelet, and plasma factors,
which are closely regulated to balance the risk of
excess bleeding (hemorrhage) against the risk of
blood clot formation (thrombosis).
Overview of wound repair
Stage
Mechanism
Result
1
Caused by direct injury
to the blood vessel,
release of vasoconstrictor
chemicals by platelets and
the endothelium at the site
of the injury, and reflex
actions indicate kidney
damage or disease.
Damage to the
endothelium exposes
subendothelial proteins
(e.g. collagen) which
attract and tether
platelets at the site of the
damage (adhesion)
Bound and activated
platelets release vasoactive
and chemotactic agents
(e.g. serotonin, adenosine
diphosphate or ADP,
thromboxane A2)
Result of the coagulation
cascade is the production
and cross-linking of fibrin
to form a stable clot
(thrombus) at the site
of injury
A range of factors act
to control the action of
plasmin, which breaks
down fibrin
Various
Limits the flow of blood
to the area of injury to
help prevent blood loss
Vascular spasm
2 Platelet
aggregation:
Primary
hemostasis
3 Initiation of
coagulation
cascade
4 Stabilisation of
primary clot:
Secondary
hemostasis
5
Fibrinolysis
6
Wound healing
Forms a primary plug
made up of loose
platelets
Attracts more platelets
and initiates coagulation
cascade
Seals the damage until
the blood vessel wall can
repair or regrow
Dissolution of the clot
following repair
Restores normal viability of
the vessel and allows normal blood flow to resume
Primary hemostasis
(simplified)
4
3
2
1
Endothelial cell
Red blood cell
Activated platelet
Collagen
Platelet
von Willebrand
factor
Key factors in hemostasis
Factor number
or name
Synonym
Function
Coagulation factors
I
Fibrinogen
Precursor of fibrin
II
Prothrombin
III
Tissue factor
V
Proaccelerin
Labile factor
VII
Proconvertin
VIII
Antihemophilic
factor/globulin
Christmas factor
Precursor of thrombin and main enzyme of
coagulation
Converts fibrinogen to fibrin
Vitamin K dependent
Lipoprotein expressed on the membrane of
certain cells (e.g. fibroblasts, skin epithelial cells)
Binds factor VIIa which initiates the tissue
factor/extrinsic pathway
Activated to factor Va which acts as a
cofactor for the enzyme factor Xa that
cleaves prothrombin to thrombin
Present in granules in platelets
Binds to tissue factor to initiate the tissue
factor/extrinsic pathway
Vitamin K dependent
Activated form (VIIIa) is a cofactor for the
intrinsic activation of factor X
Activated to factor IXa which is the enzyme
responsible for factor X activation
Vitamin K dependent
Activated to factor Xa, the key enzyme in
the final common pathway that activates
prothrombin
Vitamin K dependent
Activated to factor XIa which activates
factor IX
Calcium dependent
Activated to factor XIIa by surface contact,
kallikrein or other factors
Triggers the prothromin time (PT)-based
contact activated/intrinsic pathway
Activated by thrombin
Cross-links and stabilises the fibrin clot
Circulates in a complex with factor XI and
acts as a cofactor
IX
X
Stuart-Prower
factor
XI
Plasma
thromboplastin
antecedent
Hageman factor
XII
XIII
High molecular
weight
kininogen
Prekallikrein
Fibrin stabilising
factor
Fitzgerald,
Flaujeac or
William factor
Fletcher factor
Participates at the beginning of the
contact activated/intrinsic pathway
Regulatory/other factors
von Willebrand
factor
vWF
Thrombinactivated
fibrinolysis
inhibitor (TAFI)
Carboxypeptidase
B2
Tissue factor
pathway
inhibitor (TFPI)
–
Protein C
–
Protein S
–
Thrombomodulin
Antithrombin
–
–
Plasmin
D-dimer
Associated with subendothelial connective
tissue; serves as a bridge between platelet
glycoprotein GPIb/IX and collagen
Inhibits fibrinolysis by inhibiting binding
and activation of plasminogen
Activated to factor XIIa by surface contact,
kallikrein or other factors
Triggers the PTT-based contact activated/
intrinsic pathway
Inhibits the cofactor activities of factors
VIIIa and Va
Vitamin K dependent
Cofactor for protein C
Vitamin K dependent
Endothelial cell binding site for thrombin
which, when bound, activates protein C
Most important coagulation inhibitor;
controls activities of thrombin, and factors
IXa, Xa, XIa and XIIa
Inactive precursor (plasminogen) is
activated by tissue plasminogen activator
and functions to digest fibrin
Fibrin degradation
product
Small protein fragment present in the blood
after a blood clot is degraded by fibrinolysis
The classical coagulation
cascade*
INTRINSIC
Unphysiological surfaces
EXTRINSIC
Lesion
Platelet
Contact activation
aggregation (collagen, cell fragments, glass)
Tissue factor (TF)
TFPI
Thrombin
XII
XIIa
XI
VIIa
XIa
Ca2+
IX
VIII
VII
Ca2+/PL
IXa
Prot. Ca/Prot. S
IX
Ca2+/PL
AT III
VIIIa
X
V
Ca2+/PL
Xa
Prot. Ca/Prot. S
X
Ca2+/PL
AT III
Va
Prothrombin
XIII
Ca2+
Thrombin
XIIIa
AT III
Fibrinogen
Fibrins
FibrinI
Ca2+
A
B
TAFIa
Fibrinopeptides Plasminogen
Fibrin
degradation
products
Plasmin
Plasminogen activator
Blood coagulation cascade with certain regulatory elements
Fibrinogen = factor I
Prothrombin = factor II
* T his model was developed in vitro and is now known not to reflect in vivo coagulation
Cell-based model
of coagulation*
Initiation
Xa
TF
-
VI
Ia
X
Amplification
Thrombin
IXa
TF - VIIa
Free vWF
Prothrombin
Va
IX
Propagation
XI
Fibrinogen
XIII
VIII/vWF
Prothrombin
V
Villa
Thrombin
XIIIa
XIa
X
Tissue factorexpressing cell
Va
XIa
P-selectin
IXa
VIlla
Xa
Va
Fibrin
activated platelet
CD40L PAR 1;4
Gp IIb/IIIa
P2Y12/ADP
De Caterina et al. Eur Heart J 2007;28:880-913.
©The European Society of Cardiology 2007; with permission of Oxford University Press
* T his more recent model is considered to more accurately reflect in vivo coagulation
Fibrinolysis
Tissue
plasminogen activator
Factor XIa, XIIa,
Kallikrein
Plasminogen
Plasminogen
activator inhibitors
α2-antiplasmin
Urokinase
Thrombin-activated
fibrinolysis inhibitor
Thrombin
Plasmin
D-dimer
Fibrin
Inhibits
Other fibrin
degradation
products (FDPs)
Activates
Fibrinolysis is a process with the main function
to dissolve fibrin clots in blood vessels. The
fibrinolytic system allows the body to clear clot
fragments safely which avoids the risk of floating
clots. Floating clots can cause serious damage
to the lungs, the heart and brain. Fibrinolysis
comprises a proenzyme, plasminogen, which
can be converted to the active enzyme plasmin.
Plasmin cleaves the fibrin clot into smaller
fragments that can then be expelled by the body
and detected i.e. by modern D-dimer tests.
Coagulation disorders
Disorder
Associated abnormality
Prevalence*
Hemophilia A
Factor VIII deficiency
Hemophilia B
Factor IX deficiency
6.6–12.8 in
100,000 males
1.2–2.7 in
100,000 males
1 in 100,000
Hypocoagulation
Inherited
Hemophilia C
Factor XI deficiency
von Willebrand disease
von Willebrand factor
(vWF) deficiency
Defect or deficiency in
glycoprotein (GP)Ib, the
receptor for vWF
Factor V deficiency
Bernard-Soulier
syndrome
Factor V deficiency
(parahemophilia/ Owren
parahemophilia)
Factor X deficiency
Congenital
dysfibrinogenemia/
afibrinogenemia
Factor X deficiency;
amyloidosis
Abnormality in fibrin
(factor I); can result in
bleeding disorders or in
thrombotic tendency;
many subtypes named
after the cities in which
they were first described
(Amsterdam, Detroit,
Wiesbaden)
Up to 1 in 100
<1 in 1,000,000
1 in 1,000,000
1 in 500,000
1 in 1,000,000
Acquired
Disseminated
intravascular coagulation
(DIC)
Vitamin K deficiency
Liver failure
Acquired
dysfibrinogenemia
Dysregulation of
coagulation and
fibrinolysis due to various
causes (e.g. bacterial
toxins, some cancers)
Disturbed gastrointestinal
uptake of vitamin K;
dietary deficiency
Decreased production of
coagulation factors by
the liver
Abnormality in fibrin;
most commonly
associated with severe
liver disease; can result in
bleeding disorders or in
thrombotic tendency
Approx 1 in 100 of all
hospitalised patients
Variable depending on
underlying cause
Variable depending on
underlying cause
Variable depending on
underlying cause
Hypercoagulation
Inherited
Factor V Leiden
Mutation in factor V that
stops inactivation by
protein C
Congenital thrombophilia
Various types, including
antithrombin III eficiency,
protein C deficiency,
protein S deficiency,
abnormalities in
fibrinogen
Up to 5 in 100; clinical
outcome varies
according to whether
patient is homozygous
or heterozygous for the
mutation
Unknown overall
Acquired
Antiphospholipid
syndrome (Hughes
syndrome)
Antibodies to cell
membrane phospholipids
Heparin-induced
thrombocytopenia (HIT)
Immune reaction to
heparin
1–5 in 100 have
antiphospholipid
antibodies; prevalence of
syndrome unknown
Incidence approx 1–5%
in patients treated with
heparin
* Per given number of the general population unless otherwise stated
Summary of standard
hemostasis tests
The following lists some commonly used global
hemostasis tests. Not all tests are included, and
not all tests listed will be required for all patients.
Reference ranges vary depending on the assay
used and therefore may be laboratory specific
Prothrombin time (PT)
•Measure of the performance of the extrinsic/tissue
factor and common pathways
•Performed on blood plasma; time to clot after addition
of tissue factor (factor III)
•Generally reported as international normalised ratio (INR)
•INR relates the results obtained with a test and normal
sample under particular analytical conditions to
standardise between analytical systems:
INR = PTtest
PTnormal
ISI
Where ISI = International Sensitivity Index
(as given by manufacturer)
•Reference ranges:
PT ~10–14 seconds (variable depending on assay)
INR 0.9–1.2 (2.0–3.0 for patients on warfarin)
Partial thromboplastin time/activated partial
thromboplastin time (PTT/aPTT)
•Measure of the performance of the intrinsic/contact
activated and common pathways
•Performed on blood plasma; time to clot after addition
of phospholipid and an activator
•Reference range: 25–93 seconds (variable depending
on assay). Shortening of PTT has little clinical
relevance
Thrombin time
•Measure of hemostatically active fibrinogen.
Also reflects presence of heparin/heparin-like substances
•Performed on blood plasma; time to clot after addition of
thrombin
•Reference range: <22 seconds (variable depending on assay)
Fibrinogen
•Measure of clotting ability
•Reference range: 200–400 mg/dL (variable depending on
assay used)
Platelet function test
•Measure of platelet function. Used to assess abnormal
bleeding (e.g. easy bruising, menorrhagia, epistaxis). Also
used to monitor antiplatelet therapy
•Various assays available
D-dimer
•Assesses fibrin deposition and stabilisation
(i.e. clot formation)
•Used to help diagnose conditions such as venous
thromboembolism (VTE) and disseminated intravascular
coagulation (DIC). Also used to guide thromboprophylaxis
PT result
PTT result
Condition
Prolonged
Normal
Normal
Prolonged
Prolonged
Prolonged
Normal
Normal or slightly
prolonged
Liver disease; vitamin K deficiency;
decreased or defective factor VII
Decreased or defective factor VIII, IX
or XI (hemophilia); von Willebrand
disease; lupus anticoagulant (delays
in vitro coagulation)
Decreased or defective factor I,
II, V or X; severe liver disease;
disseminated intravascular
coagulation
May indicate normal hemostasis, but
tests may be normal in mild forms of
deficiencies