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Theories of Blood Coagulation

James P. Riddel Jr, MS, RN, CPNP

Bradley E. Aouizerat, PhD
Christine Miaskowski, RN, PhD
David P. Lillicrap, MD, FRCPC

Although the concept of the coagulation cascade

represented a significant advance in the understanding of coagulation and served for many years as a
useful model, more recent clinical and experimental
observations demonstrate that the cascade/waterfall
hypothesis does not fully and completely reflect the
events of hemostasis in vivo. The goal of this article
is to review the evolution of the theories of coagulation and their proposed models to serve as a tool
when reviewing the research and practice literature
that was published in the context of these different
theories over time.
Key words: coagulation, coagulation cascade, cellbased theory of coagulation, bleeding disorders

emostatic mechanisms have evolved to protect

against the threat of fatal hemorrhage. The interaction between platelets and clotting factors results in the
generation of a protective hemostatic plug, whose function is to staunch the flow of blood at the site of vascular injury. To balance this, the fibrinolytic system has
evolved to recanalize occluded vessels as healing occurs
to restore perfusion through an injured vessel in which
the protective clot has formed. Despite the existence of
many fail-safe mechanisms designed to regulate hemostasis, a variety of disorders exist that are associated
either with a hemorrhagic or a prothrombotic diathesis
(Loscalzo, 2003).

2007 by Association of Pediatric Hematology/Oncology Nurses

DOI: 10.1177/1043454206298693

The purpose of this article is to describe the changes

that have occurred in the understanding of physiologic
processes involved in hemostasis.

Overview of Hemostasis
Hemostasis is a dynamic process whereby blood
coagulation is initiated and terminated in a rapid and
tightly regulated fashion (Nathan, Orkin, Ginsburg, &
Look, 2003). Blood coagulation (the cessation of blood
loss from a damaged vessel) is part of an important host
defense mechanism. Upon vessel injury, platelets adhere
to macromolecules in subendothelial tissues at the site
of injury and then aggregate to form the primary hemostatic plug. Platelets stimulate the local activation of
plasma coagulation factors, which leads to the generation of a fibrin clot that reinforces the platelet aggregate.
Later, as wound healing occurs, the platelet aggregate
and fibrin clot are broken down and removed.
Hemostasis is regulated by 3 basic components
namely, the vascular wall, platelets, and the coagulation
James P. Riddel Jr, MS, RN, CPNP, is a pediatric nurse practitioner and
doctoral student in the Division of Hematology at Childrens Hospital and
Research Center Oakland, Oakland, California. Bradley E. Aouizerat,
PhD, is a basic scientist and professor of genetics in the Department of
Physiological Nursing & Institute for Human Genetics at the University of
California, San Francisco. Christine Miaskowski, PhD, RN, is a nurse scientist and professor of nursing in the Department of Physiological Nursing
at the University of California, San Francisco. David P. Lillicrap, MD,
FRCPC, is a hematologist and professor in the Department of Pathology &
Molecular Medicine at Queens University, Kingston, Ontario, Canada.
Address for correspondence: James P. Riddel Jr, MS, RN, CPNP, Division
of Hematology, Childrens Hospital and Research Center Oakland, 747
52nd Street, Oakland, CA 94609-1809; e-mail: jriddel@mail.cho.org.

Journal of Pediatric Oncology Nursing, Vol 24, No 3 (May-June), 2007: pp 123-131


Riddel et al






Figure 1. Classic Theory of Coagulation as Proposed by Paul

Morawitz, in Which the Prothrombin, by Calcium Activation,
Yielded Thrombin, Converting Fibrinogen to Fibrin

cascade. Normal hemostasis occurs as the result of a set

of regulated processes to accomplish 2 functions; first,
it maintains blood in a fluid, clot-free state, and second,
it induces a rapid and localized hemostatic plug at the
site of vascular injury (Kumar, Abbas, & Faousto,
2005). Blood coagulation occurs when the enzyme
thrombin is generated that proteolyzes soluble plasma
fibrinogen, forming the insoluble fibrin polymer or
clot. Mechanisms that restrict the formation of platelet
aggregates and fibrin clots to sites of injury are necessary to maintain the fluidity of the blood (Hoffbrand,
Catovsky, & Tuddenham, 2005).

Historical Sketch
Hippocrates, Aristotle, Celsius, and Galen were fully
aware of the fact that freshly drawn blood usually clots
within minutes. They described in detail various internal and superficial bleeding tendencies. A common
observation was that blood congealed on cooling. It was
thought that by leaving a wound in contact with air, the
blood cooled, stopping the hemorrhage. However, they
did not associate blood coagulability with a concept of
hemostasis (Nichols & Bowie, 2001).
Two thousand years later in the early 1720s, French
surgeon Jean-Louis Petit noted that hemostasis after
amputation of a limb was caused by clots forming in
the blood vessels. This observation was the first time
blood clotting was related to hemostasis. In 1828,
Swiss physician Friedrich Hopff (Nichols & Bowie,
2001) noted that the well-known familial bleeding tendency in males was associated with pronounced
hypocoagulability, now recognized as hemophilia, an
X chromosomelinked disorder. Therefore, coagulability was essential to prevent bleeding. This recognition of abnormal coagulation and its association with
bleeding led to a rapid increase in research into the


phenomenon of blood coagulation. During the 19th

century, German pathologist Rudolf Virchow in 1860
(Nichols & Bowie, 2001) described thrombi (blood
clots) and their tendency to embolize. Platelets were
discovered, and their function was established, along
with discovery of the various components of the
coagulation process.
These advances led to the classic theory of coagulation described by Paul Morawitz in 1905 (Morawitz,
1958). He convincingly assembled 4 coagulation factors in his scheme of coagulation (Figure 1). In the
presence of calcium and thromboplastin, prothrombin
was believed to be converted to thrombin. In turn, the
thrombin converted fibrinogen to fibrin, enabling the
formation of a fibrin clot. Morawitz posited that all
the ingredients of clotting were present in circulating
blood and that the fact that such blood did not normally
clot was due to the lack of a wettable surface in the
blood vessels. This classic theory persisted for 40 years.

The Coagulation/Waterfall Cascade

The modern understanding of the biochemical
processes of coagulation began in the 1940s, when Paul
Owren (1947) recognized that a bleeding diathesis in a
young woman could not be explained by the 4-factor
concept, positing that she lacked a fifth coagulation factor in her plasma. Throughout the 1940s and 1950s,
several more coagulation factors were discovered.
Coagulation factors were designated by roman numerals. Importantly, the numeric system that was adopted
assigned the number to the factor according to the
sequence of discovery and not to the point of interaction in the cascade. By 1957, the following factors
were described: von Willebrand factor (VWF) (von
Willebrand, 1931), factor (F) V (Owren, 1947), FVII
(Alexander, Goldstein, Landwehr, & Cook, 1951),
FVIII (Patek & Stetson, 1936), FIX (Aggeler et al.,
1952; Briggs et al., 1952; Shulman & Smith, 1952), and
FXI (Rosenthal, Dreskinoff, & Rosenthal, 1953). Two
groups described FX deficiency (Hougie, Barrow,
& Graham, 1957; Telfer, Denson, & Wright, 1956).
However, what was not clear was how these multiple
factors interacted to convert prothrombin to thrombin,
resulting in the formation of a fibrin clot. The development of this knowledge proved to be an essential contribution to the understanding of the blood coagulation
mechanism (Roberts, 2003).

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Theories of Blood Coagulation

In the 1960s, 2 independent groups of biochemists

introduced a model of coagulation as a series of steps in
which activation of each clotting factor led to the activation of another, culminating in a burst of thrombin
generation. The article proposing the cascade model by
Macfarlane (1964) appeared in the journal Nature and
was shortly followed by the waterfall model
reported by Davie and Ratnoff (1964) in the journal
This model (Figure 2) described each clotting factor as a proenzyme that could be converted to an
active enzyme. The cascade and waterfall models
suggested that the clotting sequences were divided
into 2 pathways. Coagulation could be initiated via an
intrinsic pathway, so named because all the components were present in blood, or by an extrinsic pathway, in which the subendothelial cell membrane
protein, tissue factor (TF), was required in addition to
circulating components. The initiation of either pathway resulted in activation of FX and the eventual generation of a fibrin clot through a common pathway
(Luchtman-Jones & Broze, 1995).

FIXa and 2 downstream products of the cascade,

FXa and thrombin, proteolytically cleave FVIII, forming
FVIIIa, a cofactor in the next reaction. Finally, FIXa
and FVIIIa together with Ca2+ (which may come
largely from activated platelets) and negatively charged
phospholipids (the major constituents of cell membranes) form a trimolecular complex termed tenase.
Tenase then converts FX to FXa, yet another protease
(Boron & Boulpaep, 2005).
In a parallel series of interactions, FXa binds to the
cofactor FVa, itself a downstream factor that participates in positive feedback with the present reaction to
generate a complex with enzymatic activity known as
prothombinase. This complex converts the proenzyme
prothrombin to its enzyme form, thrombin. Thrombin
acts on fibrinogen to generate the fibrin monomer,
which rapidly polymerizes to form the fibrin clot.
During clinical laboratory analysis of blood clotting,
the intrinsic pathway of blood coagulation is evaluated
using the activated partial thromboplastin time (PTT)
(R. Hoffman et al., 2005).
Extrinsic Pathway

Intrinsic Pathway
The intrinsic pathway consists of a cascade of protease reactions initiated by factors that are present
within the blood. When in contact with a negatively
charged surface such as glass or the membrane of
an activated platelet, a plasma protein called FXII
(Hageman factor) becomes FXIIa (the suffix a indicates that this is the activated form of FXII). A
molecule called high molecular weight kininogen
(HMWK), a product of platelets that may in fact be
attached to the platelet membrane, helps anchor FXII
to the charged surface and thus serves as a cofactor.
However, this HMWK-assisted conversion of FXII to
FXIIa is limited in speed.
Once a small amount of FXIIa accumulates, this
protease converts prekallikrein to kallikrein, with
HMWK as an anchor. In turn, the newly produced
kallikrein accelerates the conversion of FXII to
FXIIa, an example of positive feedback. In addition
to amplifying its own generation by forming
kallikrein, FXIIa (together with HMWK) proteolytically cleaves FXI, forming FXIa. In turn, FXIa (also
bound to the charged surface by HMWK) proteolytically cleaves FIX to FIXa, which is also a protease.

Journal of Pediatric Oncology Nursing 24(3); 2007

The extrinsic pathway also includes protein cofactors and enzymes. This pathway is initiated by the formation of a complex between TF on cell surfaces and
FVIIa that is located outside the vascular system.
Nonvascular cells constitutively express the integral
membrane protein TF (variably known as FIII or tissue
thromboplastin), which is a receptor for the plasma
protein FVII (Kumar et al., 2005).
When an injury to the endothelium allows FVII to
come into contact with TF, the TF nonproteolytically
activates FVII to FVIIa. The mechanism of the initial
conversion of the zymogen FVII to FVIIa is still
debated but is most likely due to autocatalytic activation
and not a TF effect (M. Hoffman & Monroe, 2005).
This binding of FVIIa to TF forms an enzyme complex
that activates FX to FXa. The FVIIa/TF complex, similar in function to the tenase complex, converts FX to its
active form (FXa), which binds to the cofactor FV and
is bound on membrane surfaces in the presence of calcium ions to generate the prothrombinase complex. The
prothrombinase complex converts prothrombin to
thrombin, which converts fibrinogen to fibrin to generate the fibrin clot. During laboratory analysis of blood
clotting, the extrinsic pathway of blood coagulation is


Riddel et al

Figure 2. The Coagulation Cascade Model

The point of integration between the intrinsic and extrinsic pathways in this model occurs with factor IX activation. HMWK, high molecular weight kininogen.


Journal of Pediatric Oncology Nursing 24(3); 2007

Theories of Blood Coagulation

evaluated using the prothombin time (PT) (R. Hoffman

et al., 2005). Regardless of whether FXa arises by the
intrinsic or extrinsic pathway, the cascade then proceeds along the common pathway.

complex of FVIIa and TF activated not only FX but

also FIX. More recent observations have led to the
conclusion that activity of the FVIIa/TF complex is
the major initiating event in hemostasis in vivo
(M. Hoffman & Monroe, 2005).

Common Pathway
The common pathway begins with the activation of
FX within the intrinsic pathway, the extrinsic pathway,
or both. FXa from either the intrinsic or extrinsic pathway is the first protease of the common pathway. FXa,
in the presence of FV, Ca2+, and phospholipids,
converts prothrombin to its active form, thrombin
(Harmening, 2002). The main action of thrombin is to
catalyze the proteolysis of the soluble plasma protein
fibrinogen to form fibrin monomers that remain soluble. Fibrin monomers then polymerize to form a gel of
fibrin polymers that trap blood cells. Thrombin also
activates FXIII, which is converted to FXIIIa and
mediates the covalent cross-linking of the fibrin polymers to form a mesh termed stable fibrin, which is less
soluble than fibrin polymers (Boron & Boulpaep,
2005). Thrombin can catalyze the formation of new
thrombin from prothrombin and can catalyze the formation of the cofactors FVa and FVIIIa, resulting in
efficient amplification of coagulation. Because the
common pathway contains the factors FX, FV, and FII
(any deficiency in which may lead to a hemorrhagic
disorder), these factors may be monitored by both the
PT and the PTT (Harmening, 2002).
Although these concepts represented a significant
advance in the understanding of coagulation and
served for many years as a useful model, more recent
clinical and experimental observations demonstrate
that the cascade/waterfall hypothesis does not fully
and completely reflect the events of hemostasis in
vivo (M. Hoffman & Monroe, 2001). In recent years,
deficiencies of this scheme have become apparent.
First, no explanation existed for the absence of a clinical bleeding tendency in deficiencies of FXII,
prekallikrein, or high molecular weight kininogen,
even though deficiencies in any one of these factors
markedly prolong surface-activated coagulation
assays for hemostasis in vitro. Second, no explanation
existed for why FVIII or FIX deficiency caused clinically severe bleeding, even though the extrinsic pathway would be expected to bypass the need for FVIII
and FIX (Hoffbrand et al., 2005).
These key observations led to a revision of earlier
models of coagulation. A vital observation was that a

Journal of Pediatric Oncology Nursing 24(3); 2007

Cell-Based Model of Coagulation

A major development over the past 15 years was the
discovery that exposure of blood to cells that express
TF on their surface is both necessary and sufficient to
initiate blood coagulation in vivo. This finding led to
the belief that the intrinsic pathway (the contact system)
does not have a true physiological role in hemostasis
(Hoffbrand et al., 2005). Very recent evidence suggests
that although FXII deficiency does not result in bleeding problems, the absence of FXII does protect against
pathological thrombosis (Kleinschnitz et al., 2006).
This hypothesis and the experimental evidence to support it were collected by several investigators and presented in a series of articles authored by a group from
the Department of Pathology at Duke University and
the University of North Carolina (G. A. Allen, Monroe,
Roberts, & Hoffman, 2000; M. Hoffman & Monroe,
2001; M. Hoffman, Monroe, & Roberts, 1996; Kjalke,
Monroe, Hoffman, Oliver, & Ezban, 1998; Kjalke,
Monroe, Hoffman, Oliver, Ezban, et al., 1998; Monroe,
Hoffman, & Roberts, 1996).
In the cell-based model, hemostasis requires the formation of an impermeable platelet and fibrin plug at the
site of vessel injury, but it also requires that the procoagulant substances activated in this process remain
localized to the site of injury. The process of blood
coagulation is initiated by the exposure of cells expressing TF to flowing blood. Tissue factor is expressed constitutively on cells such as smooth muscle cells and
fibroblasts but not on resting endothelium. Tissue factor
is present in the membranes of cells surrounding the
vascular bed but is normally not in contact with blood
(Dahback, 2005). It is exposed to the circulating blood
by disruption of the endothelium or by activation of
endothelial cells or monocytes (OShaughnessy,
Makris, & Lillicrap, 2005). Mounting evidence suggests that TF is present in blood on cellular microparticles. These membrane fragments derive from various
cell types: white blood cells, endothelium, and
platelets, which may play a more important role in
pathological hemostasis (thrombosis) as opposed to
normal clotting (Osterud & Bjorklid, 2006).


Riddel et al

Table 1.

Summary of the 4 Phases of Coagulation, as Proposed by the Current Cell-Based Theory of Coagulation
Process Stages in Hemostasis

Vascular endothelium and
circulating blood cells are
perturbed; interaction of
plasma-derived FVIIa with
tissue factor




Thrombin activates platelets,

cofactors FVa and FVIII on
the platelet surface, and FXI
on the platelet surface

Results in the production of

a significant level of thrombin
activity, generation of a stable
plug at the site of injury, and
cessation of blood loss

Clotting process is limited to

avoid thrombotic occlusion
in surrounding normal areas
of the vasculature

It is best to consider the highly interwoven array of

physical, cellular, and biochemical processes that
contribute to hemostasis as a series of process stages
(phases) rather than pathways. The phases of initiation, propagation, and termination illustrate the intricate processes involved in the maintenance of
vascular integrity (Loscalzo, 2003). The 4 phases of
coagulation comprising the current cell-based theory
of coagulation are summarized in Table 1.
Initiation Phase
The initiation phase is localized to the cells that
express TF, which are found normally outside the vasculature. The FVIIa/TF complex activates small
amounts of FIX and FX. FXa associates with its cofactor, FVa, and forms a prothrombinase complex on the
surface of the TF-bearing cell (M. Hoffman, 2004;
Monroe et al., 1996). FV can be activated by FXa
(Monkovic & Tracy, 1990) or by noncoagulation proteases (D. H. Allen & Tracy, 1995) to produce the FVa
required for prothrombinase assembly (M. Hoffman,
2004; Loscalzo, 2003).
Low-level activity of the TF pathway occurs at all
times within the extravascular space. Coagulation proteins percolate through tissues, leaving the vasculature,
and are found in the lymph roughly in proportion to their
molecular size (Le, Borgs, Toneff, Witte, & Rapaport,
1998). It is likely that FVII is bound to extravascular TF
even in the absence of an injury (M. Hoffman, 2004),
and the extravascular FX and FIX can be activated as
they pass through the tissues. The coagulation process
proceeds to the amplification phase only when damage
to the vasculature allows platelets and FVIII (bound to
VWF) to spill out into the extravascular tissues and to
adhere to TF-bearing cells at the site of injury. Extrinsic
is an appropriate name for the TF pathway because it
can be thought of as operating outside the vasculature
(M. Hoffman, 2004; Loscalzo, 2003).


Amplification Phase
A small amount of thrombin generated on the TFbearing cell has several important functions. A major
function is the activation of platelets, exposing
receptors and binding sites for activated clotting factors. As a result of this activation, the platelets
release partially activated forms of FV onto their surfaces. Another function of the thrombin formed during the initiation phase is the activation of the
cofactors FV and FVIII on the activated platelet surface. In this process, the FVIII/VWF complex is dissociated, permitting VWF to mediate additional
platelet adhesion and aggregation at the site of
injury. In addition, small amounts of thrombin activate FXI and FXIa on the platelet surface during this
phase (Loscalzo, 2003; Oliver, Monroe, Roberts, &
Hoffman, 1999).
Propagation Phase
As large numbers of platelets are recruited to the
site of injury, the propagation phase of clot formation occurs on the surface of activated platelets.
First, FIXa activated during the initiation phase
can now bind to FVIIIa on the platelet surface.
Second, additional FIXa can be supplied by
platelet-bound FXIa. Third, because FXa cannot
move effectively from the TF-bearing cell to the
activated platelet, FXa must be provided directly
on the platelet surface by the FIXa/FVIIIa complex. Fourth, the FXa rapidly associates with FVa
bound to the platelet during the amplification
phase. Finally, the completion of this platelet
prothrombinase assembly leads to a burst of thrombin generation of sufficient magnitude to clot fibrinogen (Dahback, 2005; M. Hoffman, 2004;
Loscalzo, 2003).

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Theories of Blood Coagulation

Termination Phase
Once a fibrin platelet clot is formed over an area
of injury, the clotting process must be limited to
avoid thrombotic occlusion in surrounding normal
areas of the vasculature. Unless controlled, clotting
could propagate throughout the entire vascular tree
(M. Hoffman, 2004).
Three types of natural anticoagulants regulate clotting: antithrombin (ATIII) inhibits the activity of thrombin and other serine proteases, such as FIXa, FXa,
FXIa, and FXIIa. Binding to heparin-like molecules on
endothelial cells activates antithrombin. Proteins C and
S are characterized by their ability to inactivate the procoagulant cofactors FVa and FVIIIa. Protein C is a vitamin Kdependent plasma glycoprotein that, when
activated, functions as an anticoagulant by inactivating
FVa and FVIIIa. Protein C activity is enhanced by
another vitamin Kdependent inhibitory cofactor, protein S. Protein S functions as a cofactor to protein C by
enhancing its activity against FVa and FVIIIa (Hoppe &
Matsunaga, 2002). In addition, TF pathway inhibitor
(TFPI), a protein secreted by endothelium, complexes
to FXa and to TF/FVIIa, inactivating them to rapidly
limit coagulation (Kumar et al., 2005). Protein C is activated by thrombin that is bound to the transmembrane
protein thrombomodulin (TM) on the surface of intact
endothelial cells. In human plasma, about 30% of protein S circulates as free protein; the remainder is bound
to the complement regulatory protein C4b-binding protein. Only the free form of protein S functions as a
cofactor to activated protein C (Dahback, 2005).

Platelet-Protein Interactions
As previously discussed, primary hemostasis is triggered in response to the damage of the vascular wall
and the exposure of blood to subendothelial tissue.
Several coordinated interactions among tissue components, plasma proteins, and receptors on platelets lead
to the initial sealing of the damaged vessel wall.
Platelets are specialized blood cells that play a central role in the physiologic processes of hemostasis.
The formation of the primary platelet plug is temporally and spatially coordinated with the activation of
the blood coagulation system. Through the process of
adhesion and aggregation, mediated by VWF and fibrinogen, the platelets form an occlusive plug or clot.
Upon damage to the vascular wall, platelets undergo
a series of events such as adhesion, aggregation, release

Journal of Pediatric Oncology Nursing 24(3); 2007

of granule content, and morphological changes that

lead to the formation of the platelet plug. Primary
platelet adhesion is dependent on the interaction
between platelets and VWF, a large multimeric
plasma protein composed of multiple disulphidelinked monomers. The VWF undergoes proteolytic
processing in plasma; this processing is mediated by
a metalloprotease termed ADAMTS 13a disintegrinlike and metalloprotease (reprolysin type) with thrombospondin type 1 motifwhich generates VWF
multimers of all sizes and with different functional
efficiency. The larger multimers are more efficient in
platelet adhesion than the smaller ones. The VWF
mediates platelet adhesion by serving as a bridge
between the tissue and the platelets, binding both to
collagen exposed at sites of vascular injury and to the
platelet membrane glycoprotein Ib-V-IX (GPIb-VIX)
(Dahback, 2005; Sadler, 2005).
Excessive bleeding can result from an increased
fragility of vessels, platelet deficiency or dysfunction,
derangement of coagulation, or a combination of
these. The physiologic significance of the coagulation
pathways is evident given the number of genetic deficiencies that result in bleeding disorders. The activities of platelets and coagulation factors are closely
related. With the exception of FXII deficiency, which
does not cause bleeding, a deficiency in every other
clotting factor has been reported to cause a bleeding
disorder (Kumar et al., 2005).
Three common hereditary bleeding disorders are
hemophilia A (FVIII deficiency), hemophilia B (FIX
deficiency), and von Willebrand disease (VWD), with
the latter being the most common albeit less symptomatic disorder.
Hemophilia A and hemophilia B are both caused
by a functional deficiency of a plasma protein inherited in an X-linked manner. Physiologically, the tissue factor pathway of FX activation requires FVIII
and FIX for normal thrombin generation, and the
absence of either protein severely impairs the ability
to generate thrombin and fibrin. Because of the primary clotting factor deficiency in hemophilia A or
hemophilia B, clot formation is delayed and is not
robust. Thus, patients with hemophilia do not bleed
more rapidly; rather, there is delayed formation of an
abnormal clot (Nathan et al., 2003).
The genes for both FVIII and FIX are located near
the telomere of the long arm of the X chromosome.
Therefore, both hemophilia A and hemophilia B are
inherited as X-linked recessive traits. Numerous


Riddel et al

mutations within the FVIII gene have been identified

that result in hemophilia A. The most common
genetic alteration is a gene inversion. In families in
which the index patient has a known molecular
abnormality, genetic screening and carrier detection
are highly accurate (Nathan et al., 2003).
In contrast to the complexity of the FVIII gene, the
FIX gene is considerably smaller, and its defects have
been studied more extensively. More than 60% of the
FIX gene defects are due to missense point mutations, and an identifiable defect in the gene can be
found in nearly all patients (Nathan et al., 2003).
The von Willebrand factor is indispensable for the
efficient initiation of platelet adherence to collagenrich matrices under high shear. There are 2 other
important platelet collagen receptors: GPVI and the
integrin, alpha-2-beta-1, which become engaged after
the binding of VWF to GPIb and rapidly amplify the
collagen-dependent response. An additional function
of VWF is to stabilize the procoagulant cofactor
FVIII in the circulation and to serve as FVIIIs carrier
protein in plasma. FVIII is a critical regulatory cofactor in the eventual deposition of the fibrin clot. The
von Willebrand factor protects FVIII from premature
protein Cmediated proteoloytic degradation, prolonging its half-life in circulation and efficiently
localizing it at the site of vascular injury (Gill, 2004).
Any change in plasma VWF level usually leads to an
associated change in FVIII plasma concentration.
Thus, VWF performs 2 major roles in hemostasis.
First, it mediates the adhesion of platelets to sites of
vascular injury, making it essential for platelet plug
formation. Second, it functions as a carrier protein
that stabilizes coagulation factor FVIII. It is the dysregulation of VWF multimer processing that is associated with the common bleeding disorder, VWD
(Dahback, 2005).
von Willebrand disease is notable for the considerable heterogeneity of its molecular basis. The population
distribution of VWF levels is broad and does not exhibit
a simple genetic basis. Although molecular studies have
been successful in defining the genetic defects associated with VWD types 2 and 3, VWD type 1, the most
common form of VWD, remains a challenge (Brown,
Aledort, & Lee, 2002; Sadler, 2004).
Since 1989 when the structure of the gene for
human VWF was identified, numerous studies have
attempted to identify potential VWF defect(s) that may
lead to an earlier and more accurate diagnosis of VWD
type 1. Due to the complexity of the gene structure,


this has proven a difficult task. Fortunately, 2 recent

studies completed in Europe and Canada have shed
some light on this topic. The studies have confirmed
that the genetic basis of VWD type 1 is highly variable and that there are genes in addition to the VWF
gene that can result in low plasma VWF levels.
However, this work requires validation in independent studies, and additional work needs to be conducted on this subject (James & Lillicrap, 2006).
It is expected that these advances in both our
understanding of hemostasis and knowledge of the
organization of the human genome will pave the way
to novel insights into the genetics of bleeding disorders. This ultimately will lead to more precise diagnostic tools and therapeutic interventions.

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Journal of Pediatric Oncology Nursing 24(3); 2007