Dade Behring - HEMOSTASIS

Hemostasis Basics - Programmed Learner

Hemostasis Basics
Programmed Learner

Table of Contents
Topic
Introduction
Diane Sgafer, Sherry Rush
Platelets, Vascular and Clotting Factors
Peggy Cleary
Extrinsic Pathway
Vickie Coulter
Intrinsic Pathway
Fern Collins
Natural Inhibitors
Rita White
Fibrinolysis
Yvonne Wimby

Introduction
Blood is of prime importance in the normal physiologic function of our major organ systems. In or
der for it to be effective, blood must be in a liquid or non-coagulated state. Another important func
tion of blood is to maintain an intact circulatory system following trauma. The process by which
blood is maintained fluid within the vessel walls and the ability of the system to prevent excessive
blood loss upon injury is termed hemostasis. The balance between the forces that cause blood to soli
dify or to remain fluid is very delicate and involves several interacting systems.

When you cut yourself, the process of coagulation begins by the formation of a blood clot. This is
followed shortly after by digestion or breakdown of the clot. Patients clot and/or bleed because of a
variety of identifiable hemostatic abnormalities. Logical and effective treatment depends upon the
proper identification of the abnormality. The coagulation or hemostasis laboratory performs tests to
determine the cause and to monitor the proper treatment of the defect.
This educational module will teach you a systematic and practical approach to understanding the
laboratory's role in diagnosis and therapy of bleeding and clotting disorders.

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Platelets, Vascular and Clotting Factors

a brief review of their function

Objectives:
1. Describe the role platelets play in normal hemostasis.
2. Describe hemostasis and the various factors involved with coagulation.

Glossary:

Platelets -
small, anuclear cytoplasmic disks. In an unstimulated state, the shape is discoid.
Hemostasis -
the process in circulation where the blood is maintained fluid in vessels and without
majo ross in case of injury.
Coagulation factors -
Components that exist in the circulation and supply the necessary constituents for clot
formation.

Hemostasis:
The property of the circulation where the circulating fluid is maintained within the blood vessels is
referred to as hemostasis. The process depends on a delicate and complex interplay of at least 4 sys
tems: vascular, plasma coagulation factors, platelets and fibrinolytic system.

Vascular System:
Blood normally flows smoothly through the vascular system without cellular adherence to the ves
sel wall. The thin layer of endothelial cells lining the inner surface of the various vessels helps to
maintain a thrombo-resistant surface. When vascular injury occurs following trauma or in certain
vessel diseases, the endothelial cells interact with platelets and clotting factors to form a blood clot
at the site of injury.

Platelets and Hemostasis:

Platelets and Hemostasis: The platelet has at least a fourfold function: (1) In response to vascular in
jury, platelets are stimulated to initiate the formation of a primary hemostatic plug, (2) the platelet
contributes phospholipid (sometimes referred to as platelet factor 3 or PF3) to the coagulation cas
cade, (3) they help maintain vascular integrity through endothelial support and (4) platelets may
have a role in inflammatory response, possibly by activating the fifth component of complement.

There is a sequence of events which occurs at the site of vascular injury. First, the platelet is attrac
ted to the exposed sub-endothelial layer of collagen and adheres to it. To accomplish this, the plate
let undergoes a shape change. Secondly, the platelets release intrinsic adenosine diphosphate (ADP),
among other substances. The released ADP stimulates other platelets to stick together at the wound

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site, and, thirdly, aggregation occurs. In this process, platelets adhere to each other to form a begin
ning plug. Finally, coagulation occurs and fibrin forms around the platelet aggregate to initiate re
pair. (See figure 1)

Coagulation Factors:
The coagulation factors circulate in the plasma as cofactors or as procoagulants, and, when activated
supply some of the components needed for clot formation. According to the international nomencla
ture system, coagulation cofactors and procoagulants were assigned roman numerals in the order of
their discovery and don't correspond to their location in the coagulation sequence of activation. (See
figure 2) The coagulation factors are generated in the liver cells, except for Factor VIII (at least the
Von Willebrand's portion), which is produced in multiple organs, possibly the endothelial cells and
megakarocytes. The model generally used to describe the mechanism of coagulation is the cascade
system. The cascade is separated into three areas: the intrinsic system, commonly measured by the
aPTT test, which is activated by surface contact; the extrinsic system, commonly measured by the
PT test, which is activated by vascular injury, and, the common pathway, which is set into motion by
activation from the intrinsic and/or the extrinsic pathway. Because of the variety of constituents in
volved with the common pathway, there are several different tests that could be used to monitor ac
tivity. The systems and tests are described in later sections of this module.

Primary Hemostasis:
Following injury to a blood vessel, all of the systems are activated. For sake of ease, the hemostatic
process is divided into 2 components; primary hemostasis and secondary hemostasis. Primary hemos
tasis depends upon the response of the platelet and blood vessel wall to the injury. When the small
blood vessels are injured, blood platelets adhere and aggregate at the site of injury, reducing and fi
nally arresting bleeding.

Secondary Hemostasis:
Secondary Hemostasis starts when the cascade system of Coagulation is activated by substances re
leased at the time of blood vessel injury.

These coagulation factors, which are proteins, with the exception of Calcium and Thromboplastin,
can conveniently be divided into three families: the fibrinogen, prothrombin, and contact family. The
fibrinogen family includes fibrinogen, Factors V, VIII, and XIII. The prothrombin family includes
Factors II, VII, IX, X, Protein C and Protein S. The contact family of plasma coagulation proteins in
clude: Factor XII or Hageman factor, Factor XI, Fletcher factor or Prekallikrein (PK), Fitzgerald fac
tor or High Molecular Weight Kininogen (HMWK) and possibly the Passovoy factor. They are all in
volved in the mechanism that generates insoluble fibrin as a final product, by means of the
coagulation cascade. Disorders of secondary hemostasis many times involve a change in the coagula
tion proteins. These changes can be a decreased level of a particular factor or a defect in the way the
factor functions.

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TOPIC REVIEW

1. T or F. Platelet Factor 3 (PF3) is found in the plasma.

2. Which of the following groups of factors are involved

in the contact phase of coagulation?

a) IX, X, VII, II
b) VII, II, PK, XIII
c) XII, X, HMWK, V
d) XII, PK, XI, HMWK

3. What makes up the coagulation cascade?

1.
2.
3.

4. Briefly describe hemostasis.

Answers

Extrinsic Pathway
Objectives:
1. Know the role the "extrinsic pathway" plays in hemostasis.
2. List the components and the functions of the factors of the "extrinsic pathway".
3. List two major uses of the prothrombin time (PT).

Glossary:

Enzyme:
Organic compound, frequently a protein, capable of accelerating or producing by
catalytic action some change in a substrate for which it is often specific.
Extrinsic pathway:
Pathway in which fibrin is formed as the result of the release of tissue thromboplastin
into the circulation.
Prothrombin time:
A laboratory coagulation test which measures the general level of clottability of a
plasma sample. It is sensitive to the factors of the extrinsic clotting system.
INR:
International Normalized Ratio which provides a convenient method for standardizing
the monitoring of Warfarin therapy.
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Introduction:
Hemostasis is defined as a property of circulation whereby blood is maintained within a vessel and
the ability of the system to prevent excessive blood loss when injured. One of the major compo
nents needed to provide hemostasis is the coagulation system which involves the clotting proteins or
clotting factors. The coagulation factors, except for calcium and thromboplastin, are proteins and
are involved in a sequential reaction or coagulation cascade. The last step of the cascade leads to in
soluble fibrin as the end product. The reactions leading to fibrin formation can be divided into the
extrinsic, intrinsic and common pathways. The extrinsic pathway is initiated by the release of tissue
thromboplastin (Factor III) which is exposed to the blood when there is damage to the blood vessel.
Factor VII which is a circulation coagulation factor, forms a complex with tissue thromboplastin
and calcium. This complex rapidly converts Factor X to the enzyme form Factor Xa. Factor Xa cata
lyzes the prothrombin (Factor II) to thrombin (Factor IIa) reaction which is needed to convert fibri
nogen (Factor I) to fibrin. See figure 3 for "coagulation cascade" diagram depicting the extrinsic, in
trinsic and common pathways. The Prothrombin Time or PT is a laboratory screening test used to
detect coagulation disorders. It measures the activity of the factors of the extrinsic pathway includ
ing factors II, V, VII, X, and fibrinogen. The extrinsic factors not measured in the PT test are Fac
tors III (Thromboplastin), and IV (Calcium). The PT is also used to monitor oral anticoagulant ther
apy such as warfarin.

Warfarin is a drug used in patient therapy to prevent thrombosis. It inhibits the synthesis of the vita
min K dependent factors, factors II, VII, IX and X by blocking the regeneration of vitamin K and
shows a dose dependent effect. As more warfarin is ingested orally, the greater the reduction in the
functional levels of vitamin K dependent factors. See Figure 4 for the effect of warfarin on the syn
thesis of clotting factors. Because 3 of the 4 factors affected by warfarin are evaluated by the PT
test, it is commonly used to monitor therapy.

The PT test is performed by adding tissue thromboplastin and calcium to plasma and measuring the
time for clot formation. It can be performed either manually by tilt tube method or mechanically by
use of a fibrometer or a photo-optical instrument. The PT reagent used in the testing provides the tis
sue thromboplastin and calcium. The sources of thromboplastin can be human or rabbit brain, lung,
placental, brain/lung combination, or produced by recombinant technology. The necessary calcium
is added to the reagent either at the time of manufacture or prior to testing.

The PT can be done as either a one-stage or a two-stage assay, although the one-stage procedure is
the most widely used and preferred. Thromboplastin reagent (0.2 ml) is warmed at 37C then forci
bly added to plasma (0.1ml) which also has been heated to 37C and a timer is started. As soon as the
clot forms indicating fibrin formation, the timing stops and the time is recorded to the nearest tenth
of a second. The expected normal range for a PT is 10-14 seconds depending on the type of reagent
used.
Variation in the composition and responsiveness of PT reagents have necessitated the use for stan
dardization. The International Normalized Ratio or INR was developed for the purpose of standard
izing the monitoring of warfarin therapy.
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Several factors may contribute to the differing degrees of responsiveness observed for various
thromboplastin reagents. Some of these include the species and tissue source, the relative
concentrations of other components of the reagent formula etc. The responsiveness of the
thromboplastin reagent needs to be considered to make the PT an effective way of monitoring
warfarin treatment. The responsiveness of a thromboplastin reagent toward plasma samples from
patients receiving warfarin is described by a value called the International Sensitivity Index (ISI).

The calculation of the INR is obtained by using the following calculation:

ISI
INR =
( Patient PT
Mean of Normal Population PT )
The lower the ISI, the more responsive the reagent. The differences in the responsiveness of throm
boplastins to the reduction of clotting factors II, VII and X are responsible for the difference in dos
age of oral anticoagulants.
In summary, defects in the normal hemostatic mechanism can be listed as two types. One is the fail
ure of any of the processes that lead to the hemostatic plug formation which may lead to a bleeding
disorder and inappropriate activation of the hemostatic mechanism which may cause thrombosis.
Laboratory investigations and determinations are needed to identify the eXact nature of the underly
ing bleeding disorder. Screening tests such as the PT are initially performed. Based on these results,
further, more complex testing may be needed leading to follow-up corrective action and treatment.

TOPIC REVIEW

1. The prothrombin time is a screening test used to

evaluate the ____________ pathway of coagulation.

2. T or F. The PTT test is the most common method

used for monitoring oral anti-coagulant therapy?

3. What is the advantage of a thromboplastin reagent

which has a lower ISI value?

Answers

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Intrinsic Pathway

Objectives:
1. Define activated partial thromboplastin time (aPTT)
2. Describe two major uses of the aPTT

Glossary:

Activated partial thromboplastin time (APTT)

One of the tests used for screening patients for a bleeding tendency. Specifically, ade-
quate levels of the coagulation factors XII, XI, IX, VIII, X, V and II must be present for
the test to be normal. The test also serves as the basis for other test procedures such as
certain factor assay tests.
Intrinsic
Originating from within

The intrinsic pathway of Coagulation is activated when circulating Factor XII comes in contact with
and is bound to a negatively charged surface. This causes a change in the molecular configuration
of Factor XII and in concert with HMWK and prekallikrein it becomes an active enzyme, XIIa.
This activated enzyme is then able to bring about a similar change in Factor XI. After activation,
Factor XIa, in a calcium dependent reaction, converts Factor IX to its active form, Factor IXa. A
phospholipid surface is also needed for Factor IXa conversion and is provided by activated plate
lets, as Platelet Factor Three (PF3). Factor IX can also be activated by the tissue factor, Factor VII
complex; the initiating complex of the extrinsic pathway. Factor X can be activated to Factor Xa by
either the Factor VIIa complex or by the complex of Factor IXa and Factor VIII. Factor Xa in the
presence of Factor V, calcium and phospholipid surface converts Factor II (prothrombin) to Factor
IIa (thrombin) which converts Factor I (fibrinogen) to fibrin (see Figure 5).

Activated partial thromboplastin time (aPTT) is an assay used to screen for abnormalities of the in
trinsic clotting system. It is also used to monitor the anticoagulant effect of circulating heparin.

An aPTT assay is performed by adding to platelet poor plasma a Factor XII activator, a phospholip
id, and calcium ions. Factors I, II, V, VIII, IX, X, XI, XII, prekallikrein (Fletcher Factor) and high
molecular weight kininogen (HMWK) are measured. An abnormal aPTT result might indicate the
presence of an acquired inhibitor or a deficiency in any of the coagulation factors except Factors
VII and XIII.

For in vitro analysis, some commonly used activators are glass, ellagic acid, kaolin, silica and cel
ite. All of these except glass, are used in aPTT reagents and serve the same function of activating
the clotting mechanism. Phospholipids are platelet substitutes and accelerate the reactions involved.
Sources of phospholipids are rabbit brain, cephalin (dehydrated rabbit brain), bovine brain, and soy
bean.
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When adequate levels of all the coagulation factors are present in plasma, the aPTT test result is nor
mal. Normal ranges of the factors vary from approximately 50-150% of normal. In general an aPTT
reagent should be able to detect factor levels of 30% or less. If aPTT results are prolonged and there
is no indication of a factor deficiency, an acquired inhibitor may be present.

Heparin will also cause a prolonged aPTT. This commercial product is prepared from beef lung or
porcine intestinal mucosa and is administered via intravenous or subcutaneous injection. Heparin
with its plasma co-factor Antithrombin III, inhibits coagulation immediately after being adminis
tered. It is the drug of choice for treating venous thrombosis by preventing fibrin formation.

The aPTT, although useful in monitoring high level heparin therapy, has had variable effectiveness
in monitoring low dose heparin therapy and low molecular weight forms of heparin.

TOPIC REVIEW

1. What screening test is used for detecting

abnormalities in the intrinsic pathway?

2. Name 2 activators used in the aPTT assay.

3. What two coagulation factors are not tested for in an

aPTT assay?

Answers

Natural Inhibitors

Objectives:
1. Name the most important inhibitors of Hemostasis.
2. Know the function of naturally occurring inhibitors.

Glossary:

Antithrombin III
Natural inhibitor of the coagulation system
Protein C
Natural inhibitor of the coagulation system
Protein S
Protein C co-factor

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Once Coagulation is initiated, the body has mechanisms for avoiding massive thrombus formation.
Physiologic balancing of the Hemostatic mechanism to limit uncontrolled bleeding and clotting is
an important aspect in the Hemostatic response. There are a variety of biological control mecha
nisms which aid in the control of blood coagulation. These include the ability of the liver and the re
ticulo-endothelial system to clear activated clotting factors from the circulation, the prevention of
the high concentrations of activated factors at a given location within the circulation by a constant
blood flow, and natural inhibitors in the plasma such as Antithrombin III and the Protein C-S Sys
tem.

Antithrombin III (AT-III) is the most important inhibitor of the coagulation enzymes. AT-III binds to
activated factors rendering them inactive (Figure 6). The primary function is to inactivate thrombin.
Inactive factors and cofactors are not neutralized by AT-III, since it only binds to the enzymatic fac
tors. The process of binding the active forms of the clotting factors (XIIa, XIa, Xa, IXa) and throm
bin to AT-III is greatly accelerated by heparin to an almost instant neutralization. AT-III inhibits not
only coagulation enzymes but also plasmin and kallikrein.

Patients with decreased AT-III levels are subject to an increased risk of thromboembolism even in ca
ses of slightly reduced AT-III levels, therefore the Antithrombin III assay is an important part of a
prethrombotic workup.

Antithrombin III levels are affected by several other disease states. Individuals suffering from se
vere hepatic disorders such as cirrhosis or acute hepatitis have significantly depressed AT-III levels,
while disease accompanied by inflammation may show elevations.

Protein C is an inhibitor of the activated Factors Va and VIIIa. (See Figure 6) This is itsanticoagu
lant function. Protein C also inactivates tissue plasminogen activator inhibitor (PAI) which increases
the activity of tissue plasminogen activator (tPA) which enhances fibrinolytic activity. Therefore, it
can be said that Protein C has both anticoagulant and fibrinolytic functions. Just as Antithrombin III
has a co-factor which is heparin, Protein C has a co-factor which is Protein S. Both Protein C and
Protein S are vitamin K dependent factors. Enhancement of Protein C anticoagulant functions is ach
ieved by Protein S. Patients with Protein C and/or Protein S deficiencies have a thrombotic tenden
cy. Patients also may acquire deficiencies of Protein C and Protein S with liver disease and dissemin
ated intravascular coagulation (DIC).

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TOPIC REVIEW

1. Name two inhibitors of Coagulation.

1.
2.

2. What is the function of an inhibitor?

3. Deficiencies of Antithrombin III and Protein C result

clinically in __________________.

4. What is the Protein C co-factor?

5. Heparin accelerates __________________ activity.

Answers

Fibrinolysis

Objectives:
1. Define and describe the fibrinolytic system, differentiating between fibrinogenolysis and fibrinolysis.
2. Identify activators of plasminogen.
3. Differentiate between FDP and fdp.

Glossary

Fibrinolysis:
Dissolution and localization of a fibrin clot.
Plasmin:
Active portion of fibrinolytic system: has the ability to dissolve formed fibrin clots;
also has similar effect on other plasma proteins and clotting factors.

The last stage of coagulation is fibrinolysis, which is the dissolution and localization of a fibrin clot.
These functions are carried out by enzymes and their inhibitors. A disruption or breach of the fine
balance of this fibrinolytic system can result in bleeding or thrombosis.
The components of the fibrinolytic system are schematically shown in Figure 7. Fibrinolysis is
mediated by activation of plasminogen to plasmin. This is accomplished by:

Intrinsic activation (plasma based) initiated through Factor XIIa and kallikrien.Thus, the contact
system of coagulation serves as an intrinsic activator.
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Extrinsic activation (cellular based) initiated by way of stimuli such as vascular injury, ischemia,
exercise, stress and pyrogens.

Exogenous (Therapeutic) activation (drug based) includes streptokinase, urokinase and tPA (tissue
plasminogen activator).

Activators of plasminogen convert it to the active enzyme plasmin. Plasmin, in turn, acts to split the
fibrin clot into fibrin degradation products. To balance this activity there are inhibitors. The most im
portant inhibitor of plasminogen activators is PAI-1, which is fast acting. Alpha2-antiplasmin, an
other principal inhibitor of fibrinolysis, inhibits plasmin (See Figure 8).

Soluble fibrinogen is cleaved by thrombin to form fibrin monomers. The fibrin monomers aggregate
to form fibrin polymers, unstable fibrin clots. Thrombin also activates factor XIII to an activated en
zyme, factor XIIIa, which in the presence of calcium converts fibrin polymers to a stable fibrin clot.
Plasmin can degrade or split both fibrinogen and fibrin into fragments, X, Y, D and E. Fibrinogen
degradation products (FDP) are the products of fibrinogenolysis and are detected by the FDP assay.
Fibrin degradation products (fdp) are the product of fibrinolysis. The only time D-dimers (cross
linked D-domains) are present is after the degradation of a stable fibrin clot (See Figure 9). These
tests (FDP and D-Dimer) will be described in future modules.

There are many conditions that can affect the fibrinolytic system resulting in an increased or de
creased activity of fibrinolysis. Samples of such conditions are Disseminated Intravascular Coagula
tion (DIC), trauma from surgical procedures or accidents, deficiencies in or consumption of the vari
ous inhibitors and activators of the fibrinolytic system.

Continued study of the fibrinolytic system unlocks it's complexities . Always on the horizons are
newer and more sensitive and specific methods of evaluating this system, thus providing better diag
nostic tools.

TOPIC REVIEW

1. Define Fibrinolysis.

2. T or F Plasmin cleaves fibrin into small fragments.

T or F There are three (3) pathways of activating plasminogen.
T or F D-dimers are fragments only detected when fibrin clots are degraded.
T or F Alpha2-antiplasmin is an activator of plasminogen.
T or F Fibrinolytic assays can be used to Diagnose DIC.

3. What is the main inhibitor of plasmin?

Answers
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Figure 1
Platelet Function

Platelets Endothelial Cells

lining blood vessel

Collagen

Maintenance of normal vascular integrity

Thromboxane A2
PDGF, BTG, PF4
ADP

Aggregation and release of vasoactive

substances and platelet procoagulants

Formation of a hemostatic plug

Figure 1. The response of the blood vessel and platelets to injury

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Figure 2
Characteristics of Coagulation Factors

Molecular Functional Biologic Site of Vitamin K Plasma

Factor
Weight Activity Half-Life Production Dependent Concentration

Fibrinogen 340,000 -------- 90 hrs. Liver No 300-400mg/dL

Serine
Prothrombin 72,000 60 hrs. Liver Yes 10-15mg/dL
Protease

12 - 36
Factor V 330,000 Cofactor Liver No 0.5-1.0mg/dL
hrs.
Serine
Factor VII 48,000 4- 6 hrs. Liver Yes 0.1mg/dL
Protease

Factor VIII:C 70 - 240,000 Cofactor 12 hrs. Liver (?) No 1-2mg/dL

Serine
Factor IX 57,000 20 hrs. Liver Yes 4µg/dL
Protease

Serine
Factor X 58,000 24 hrs. Liver Yes 0.75mg/dL
Protease
Serine
Factor XI 160,000 40 hrs. Liver No 1.2mg/dL
Protease

Serine
Factor XII 80,000 48 - 52 hrs. Liver No 0.4mg/dL
Protease

Serine
Prekallikrein 80,000 48 - 52 hrs. Liver No 0.29mg/dL
Protease

High Molecular
Weight Kininogen
120,000 Cofactor 6.5 days Liver No 0.70mg/dL

Trans
Factor XIII 320,000 3 - 5 days Liver No 2.5mg/dL
Glutaminase

Serine
Protein C 62,000 8 - 12 days Liver Yes 4-5 µg/dL
Protease

Protein S 84,000 Cofactor ------ Liver Yes 25mg/dL

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Figure 3
Coagulation Cascade

Kallikrein Prekallikrein
Activation
HMWK HMWK
Vitamin K dependent factor
XII XIIa Active serine proteases

HMWK Thrombin

XI XIa

Ca++
IX IXa VIII a -Tissue Factor complex
PF3
VIII

Ca++
X Xa
PF3
V Ca++
II IIa

Ca++
XIII XIIIa
FP A&B
I
FM

Ia
Fibrin Clot

Figure 3. The coagulation cascade, including both intrinsic and extrinsic pathways

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Figure 4
Vitamin K
OH
CH3

2CO2 2O2
CH2 R
CO2
CH2 OH
Warfarin
COOH
Vitamin K
O Expoxide
CH3 Reductase
CH2 Activity
O
HC-COOH
R
COOH
O
γ Carboxyglutamic Vitamin K
Acid Epoxide
Figure 4. Mechanism of action of the anticoagulant drug warfarin
on the vitamin K-dependent synthesis of gamma carboxyglutamic acids
in clotting factors II, Vii, IX, X, Protein C, and Protein S.

Figure 5
ACTIVATED PARTIAL THROMBOPLASTIN TIME

Contact
XII XIIa

XI XIa
Ca++ III, VII

IX IXa
Ca++ Ca++ Provided as Reagents:
VIII Activator, PF3, Ca++
PF3
X Xa Provided as Plasma:
HMWK, PK, XII, XI, IX, VIII, X, V, II & I
Ca++
V
Phospholipid
II IIa

Fibrinogen ( I ) Fibrin

Figure 5. The aPTT is an intrinsic pathway screening test

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Figure 6
INHIBITORS OF COAGULATION SYSTEM
Prekallikrein Kallikrein
HMWK
Surface
XII XIIa
HMWK
Surface
XI XIa
Ca++
Antithrombin
IX IXa
III
Ca++
III VIII
VIII PF3
Ca++ Protein C /
X Xa
Protein S
Ca++
VIII
PF3

(Prothrombin) II IIa (Thrombin)

(Fibrinogen) I Fibrin

Figure 6. Action of natural inhibitors on coagulation system

Figure 7
FIBRINOLYTIC PATHWAY
Intrinsic Activation Exogenous Activation Extrinsic Tissue Activation

Plasminogen

Inhibitors
(Antiactivators)
Plasmin
Inhibitors
(Antiplasmin)

Fibrinogen/Fibrin

Fibrinogen Split Products (FDP) Fibrin Split Products (ftp)

R.E.S

Figure 7. Interaction of the components of the fibrinolytic system 16

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Figure 8
Fibrinoloysis

Plasminogen Plasminogen Plasmin α2-Antiplasmin

Activator

Fibrin Fibrin

Figure 8. Schematic representation of fibrin-associated plasminogen activation

and inhibition by Alpha2-Antiplasmin

Figure 9
FIBRIN (OGEN) DEGRADATION
Thrombin
Fibrinogen Fibrin Monomer Fibrin Polymer (Clot)

Plasmin Plasmin Plasmin

Split/Degradation Products
(X. Y. D. E)

(FDP) (fdp)
(D-dimer)
Cleared by R.E.S

Figure 9. The formation and breakdown of fibrin

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Section 1
Platelets, Vascular and Clotting
Factors
Review Answers
1. F

2. d

3. intrinsic, extrinsic, common

4. Property of circulation where blood is maintained

within vessels without major loss in injury. Defpends on
four systents: factors, platelets, vascular, fibrinolytic.

Section 2
Extrinsic Pathway
Review Answers
1. Extrinsic

2. F

3. intrinsic, extrinsic, common

4. The lower the ISI for a reagent, the more responsive the
reagent. The differences in responsiveness of the
thromboplastin reagent to the reduction of the clotting
factors, II, vII and X are responsible for the difference in
dosage of oral anticoagulants.

Section 3
Inrinsic Pathway
Review Answers
1. APTT

2. Ellagic acid, kaolin, silica and celite

3. VII, XIII, III, IV

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Section 4
Natural Inhibitors
Review Answers
1. Antihrombin III, Protein C, Protein S

2. Balance the hemostatic mechanism to limit uncontrolled

bleeding and clotting.

3. Thrombosis

4. Protein S

5. Antithrombin III

Section 5
Fibrinolysis
Review Answers
1. Dissolution and localization of a fibrin clot.

2.
T
T
T
F
T

3. Alpha2-Antiplasmin (α2-Antiplasmin)

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