European Heart Journal Supplements (2001) 3 (Supplement Q), Q3–Q7
Haemostasis and thrombosis: an overview
H. Rasche
Department of Hematology, Center of Internal Medicine, Zentralkrankenhaus, Bremen, Germany
The present review provides a review of haemostasis and
thrombosis. It describes the basic mechanisms of the blood’s
coagulable states, as well as their associated bleeding and
thromboembolic disorders. Endothelial cells present a nonthrombogenic surface. In contrast, after contact of blood with a
synthetic surface (e.g. mechanical heart valves) local thrombus
formation and embolism can occur. Anticoagulant therapy is
required to prevent these complications in patients with
artificial implants.
(Eur Heart J Supplements 2001; 3 (Suppl Q): Q3–Q7)
© 2001 The European Society of Cardiology
Key Words: Haemostasis, thrombosis, bleeding disorders,
thrombophilia.
Introduction
Maintenance of blood fluidity within the vascular system is
an important human physiological process. The term
‘haemostasis’ refers to the normal response of the vessel to
injury by forming a clot that serves to limit haemorrhage.
Thrombosis is pathological clot formation that results when
haemostasis is excessively activated in the absence of
bleeding (‘haemostasis in the wrong place’). Essential
components of fluidity, haemostasis and thrombosis are the
blood flows produced by the cardiac cycle, the vascular
endothelium and the blood itself. Under normal
physiological conditions there is a delicate equilibrium
(eucoagulability) between the pathological states of
hypercoagulability and hypocoagulability in the circulating
blood (Fig. 1).
Astrup[1], in 1958, first described the phenomenon of socalled haemostatic balance. It would appear that, at that time,
the prevalent notion regarding the haemostatic balance was
that a clot that formed in response to injury orchestrated its
own destruction by stimulating fibrinolytic activity. This
concept has now been extended by the observations that
blood has a strong tendency to clot and that the intact
vasculature requires major antithrombotic systems to prevent
clot formation[2,3]. Under normal circumstances, endothelial
cells present a non-thrombogenic surface that does not
attract plasma proteins and blood cells. Following contact of
blood with damaged tissue or a synthetic surface, however,
deposition of proteins and thrombus formation is observed.
Indeed, thrombosis and related events such as embolization
remain the greatest obstacles to the use of artificial devices
in a clinical setting (e.g. after heart valve replacement)[4].
Correspondence: Prof. Dr H. Rasche, Department of Hematology,
Center of Internal Medicine, Zentralkrankenhaus St.-Jürgen-Str. 1,
D-28205 Bremen, Germany.
1520-765X/01/0Q0003 + 05 $35.00/0
T
h
r
o
m
b
o
s
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s
Blood flow
Vascular endothelium
Blood constituents
Hypercoagulable
state
Normal
haemostasis
Hypocoagulable
state
B
l
e
e
d
i
n
g
Figure 1
The balance of normal haemostasis
(eucoagulable state). Hypercoagulable states and
thrombosis are induced by altered blood flow (e.g.
stasis, turbulences), defects in the endothelium and
changes in the blood constituents (e.g. reduced
inhibitor capacity of the coagulation system, reduced
activity of the fibrinolytic system). Hypocoagulable
states and bleeding are caused primarily by reduced
activity of procoagulant factors (e.g. in haemophilia),
thrombocytopenia and antithrombotic drugs.
The eucoagulable state and
haemostasis
Vascular endothelium, the cellular monolayer that lines the
entire cardiovascular system, is strategically located at the
interface between blood and tissues. It provides a protective
barrier that separates blood from highly reactive elements in
the deeper layers of the vessel wall[5,6]. Endothelial cells are
exposed to a variety of biochemical and biomechanical
stimuli. The finding that specific fluid mechanical forces,
including shear stress, influence endothelial structure and
function has provided a framework for a mechanistic
understanding of flow-dependent processes in haemostasis
and thrombosis[7,8]. Inert platelets, as well as plasma factors,
normally circulate in close contact with the endothelium.
© 2001 The European Society of Cardiology
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H. Rasche
Vessel injury
Table 1 Antithrombotic properties of endothelium
contributing to vascular patency
Endothelial factors
Biological functions
Surface, ICAM
Absent activation of hemostasis
ADPase
Prostacyclin (prostaglandin I2)
Nitric oxide
Inhibitors of platelet activation
Thrombomodulin
Heparan sulphate
Inhibitors of blood coagulation
t-PA, u-PA, PAI
Modulators of fibrinolysis
Endothelin
Prostacyclin
Vasoconstriction and vasodilatation
Collagen
Contact activation
Tissue factor
XIa
VIIa
IXa
Activated platelets
VIIIa
vWF
TFPI
PL
Thrombomodulin is a membrane protein which binds to thrombin
to form the protein C activation complex. ADPase=adenosine
diphosphatase; ICAM=inter-cellular adhesion molecule;
PAI=plasminogen activator inhibitor; t-PA=tissue plasminogen
activator; u-PA=urokinase plasminogen activator.
Xa
AT
Platelet adhesion
AT
TM
PC, PS
Fibrinogen
PL
Va
PL
AT
AT
Thrombin
Platelet aggregation
t-PA/u-PA
AT
PAI
Under normal physiological conditions, platelets do not
adhere to the endothelial cells or to one another, nor do they
bind adhesive proteins that are present in the surrounding
plasma. On encountering temporary dysfunction of the
vessel wall related, for example, to desquamation of
endothelial cells, the ‘latent’ activation of the haemostatic
mechanisms plays a major role in maintaining the structural
and functional integrity of the vascular system. Excessive
activation of haemostatic mechanisms is prevented by
protective endothelial factors (Table 1), inhibitors of the
coagulation system (Fig. 2) and the diluting effects of the
flowing blood.
In the case of traumatic vascular injury with endothelial
disruption (e.g. the cut end of a divided vessel), activation
of platelets and coagulation factors evokes a vigorous
response[9]. Platelets are anchored to the subendothelium by
links formed between cellular adhesion molecules/adhesive
receptors and adhesive ligands/counter-receptors in the
blood and connective tissues (Table 2). Once adherent to the
subendothelium the platelets spread out over the surface,
and additional platelets, which are delivered by the flowing
blood, adhere first to the basal layer and then to one another
through inter-platelet bridges provided by fibrinogen,
forming a clot of aggregated cells (first phase of haemostasis). Platelet aggregation requires activation of platelets
by adenosine diphosphate, which is released from platelet
storage organelles.
Fibrin formation represents the second phase of haemostasis. It is triggered by pro-coagulant factors (e.g.
fibrinogen, factor V, von Willebrand factor) secreted by the
platelets, by tissue factor as a critical component of vascular
elements (extrinsic pathway), and by contact activation
(intrinsic pathway) of the coagulation system. Once factor
Xa is formed it converts pro-thrombin to thrombin (common
pathway), which induces fibrin strand formation. The
platelet membranes provide sites for orderly surface
Eur Heart J Supplements, Vol. 3 (Suppl Q) December 2001
Fibrin
XIIIa
Plasmin
CLOT
AP
Wound healing
Recanalization
Figure 2
Basic mechanisms in haemostasis and
thrombosis. Injury induces activation of platelets and
initiation of the clotting cascade. Activation of
coagulation is triggered by contact and by tissue
factor, an intrinsic membrane protein. Key events are
the formation of factor Xa, and the prothrombin–
thrombin and fibrinogen–fibrin conversions. There
are remarkable feedback reactions. Circles indicate
sites of inhibitor action. The protein C anticoagulant
pathway (thrombomodulin [TM], protein C [PC] and
protein S [PS]) inactivates factors Va and VIIIa,
thereby shutting down thrombin formation and
preventing clot extension. AP=antiplasmin; AT=
antithrombin; PAI = plasminogen activator inhibitor;
PL=phospholipid; TFPI=tissue factor pathway
inhibitor; t-PA=tissue plasminogen activator; u-PA=
urokinase plasminogen activator; vWF=von Willebrand
factor.
packing of activated coagulation proteins (factors V and
VIII) that urge them to generate thrombin at high rates. The
fibrin mesh binds the platelets together and contributes to
their attachment to the vessel defect, mediated by binding
the platelet receptor glycoproteins and by interactions with
other adhesive proteins such as thrombospondin, fibronectin
and vitronectin.
The definitive haemostatic plug that seals off the
haemorrhagic leak is a platelet–fibrin thrombus. Over-
Haemostasis and thrombosis
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Table 2 Synergistic interaction of the major platelet glycoprotein receptors with constituents of the vessel wall
and blood in cases of vascular injury
Platelets: adhesion molecules/receptors
Plasma/vessel wall:
ligands/counter-receptors
Biological function in
haemostasis and thrombosis
GPIa/Iia
GPIb/IX/V
Collagen,
von Willebrand factor
Adhesion and activation of platelets
(shape change, secretion)
GPIIb/IIIa
Fibrinogen, von Willebrand factor,
vitronection
Platelet aggregate formation
Activation of platelet ligand-binding sites is also achieved through agonists (serotonin, thromboxane A2, adenosine diphosphate,
adrenaline, thrombin) that bind to G-protein-coupled seven-transmembrane receptors. GP=glycoprotein.
whelming thrombosis induced by activated haemostasis in
the vascular bed outside the region of vascular defect is
counteracted by the dilution effects of the flowing blood, by
the antithrombotic capacity of the haemostatic system and
by local activation of fibrinolysis. Furthermore, fibrinolysis
with clot solution paves the way for wound healing (third
phase of haemostasis).
Hypocoagulable states
and bleeding disorders
Abnormal bleeding is the result of defective vascular
function or disturbed haemostasis after injury. Endothelial
cell permeability is influenced by the functional adaptations
that join the cells to their neighbours. Vessel permeability is
increased by vasodilatation, by thrombocytopenia and by
antithrombotic drugs. The great variety of congenital
bleeding disorders provides clear evidence of the key role
played by single participants of normal haemostasis.
Bernard–Soulier syndrome is caused by abnormality of the
glycoprotein (GP)Ib/V/IX complex, which results in
decreased platelet adhesion to vessel wall subendothelium.
In patients with Glanzmann thrombasthenia, platelet
aggregation is absent because of a deficiency in GPIIa/IIIb.
The bleeding tendency in patients with ‘von Willebrand’
disease (deficiency of the ligand), ‘storage pool’ disease
(deficiency of platelet granules containing adenosine
triphosphate/adenosine diphosphate) and in the haemophilias (deficiency in factors VIII or IX) is very well known.
From these examples, is it apparent that all of the factors
referred to above (along with some that are not) are needed
for normal haemostasis, because a severe deficiency of one
cannot be compensated for by normal activity/concentration
of the others.
Antithrombotic drugs induce a hypocoagulable state and
a bleeding tendency. Haemorrhage is an important and often
preventable side effect of anticoagulant and antiplatelet
therapy. Models have been developed to estimate the risk of
major bleeding. They are based on the identification of
independent risk factors for drug-related bleeding, such as a
history of stroke, a history of gastrointestinal bleeding,
older age and higher levels of anticoagulation[10].
Hypercoagulable states and
thromboembolic disorders
Injury to the vessel wall or endothelial dysfunction, a
decrease in blood flow and thrombophilia of the blood
(Virchow’s triad) induce thrombosis. Hypercoagulable
states arise from an imbalance between the procoagulant/
pre-thrombotic and anticoagulant/antithrombotic forces of
the blood. A noticeable feature in all of these conditions is
the focal nature of the pathological event. In general,
although congenital thrombophilia is an established risk
factor for venous thromboembolic disease[11], the
association with arterial thrombosis is not so evident[12,13].
This is probably due to the complexity of pathogenesis of
arterial thrombosis. Furthermore, even the clinical
phenotypes of venous thrombosis differ in the various forms
of thrombophilia (Tables 3 and 4). In fact, systemic
alterations in the haemostatic mechanism typically give rise
to local thrombotic lesions in discrete segments of the
vascular bed. The pathophysiological basis for this
observation is not completely understood[14].
In most thrombophilias, impaired neutralization of
thrombin or a failure to control the generation of thrombin
causes thrombosis (Fig. 2). Whether platelet hyperaggregability (‘sticky platelet syndrome’) is a risk factor for
venous or arterial thrombosis is under discussion[15]. The
clinical significance of gene polymorphisms of platelet
glycoproteins must be established. The demonstration that
congenital factor VIII deficiency is associated with
decreased mortality from ischaemic heart disease[16,17], and
the association of elevated factor VIII levels with venous
thrombotic disease[18] support the hypothesis that factor
VIII concentration has a direct impact on the occurrence of
thrombotic events. The same might be true for factors VII,
IX and XI, and fibrinogen. Paradoxically, several recent
studies suggest that increased plasma activity levels due to
gene polymorphism of factor XIII may be associated with a
decreased risk for arterial and venous thrombosis[19,20].
The haemodynamics of the flowing blood and surface
properties influence local thrombus formation in patients
following prosthetic heart valve replacement[21,22]. Many
different materials (e.g. pyrolytic carbon coatings on rigid
substrates) have been used to improve the biocompatibility
Eur Heart J Supplements, Vol. 3 (Suppl Q) December 2001
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H. Rasche
Table 3 Genetic susceptibility to thromboembolic discorders
Hereditary thrombophilia
Frequency in a
normal white population
Clinical significance
Platelet receptor polymorphisms
Homocysteinuria
Hyperhomocysteinaemia
Approximately 15%
Very rare
5–20%
Not established
Premature arterial and venous thrombosis
Possible association with vTE
Antithrombin deficiency, protein C deficiency,
protein S deficiency
<0·5%
Established risk factors for vTE; associated with arterial
thrombotic disease, particularly in young individuals
with cerebral ischaemia
Activated protein C resistance/factor V Leiden
Prothrombin G20210A
3–5%
2%
Established risk factors for vTE
No major cardiovascular risk factor; possible
association in young women with myocardial
infarction or cerebrovascular events in children
vTE=venous thromboembolic disease.
Table 4 Sites of thrombosis in acquired hypercoagulable states
Acquired thrombophilia
Sites of thrombosis
Paroxysmal nocturnal hemoglobinaemia, myeloproliferative disorders
Antiphospholipid antibody syndrome
Visceral veins
Arteries and veins (including retina, placenta); recurrent
thrombosis of MHV?
Microvessels (exceptions: liver, lung)
Subcutaneous microvessels
Cerebral veins and sinuses
Thrombotic thrombocytopenic purpura
Coumarin induced
L-Asparaginase induced
Taken together with the types of thrombosis in congenital thrombophilia (Table 3), it becomes evident that there is a systemic defect–local
phenotype paradox[14]. MHV=mechanical heart valve.
of the mechanical valves. Some form of activation of the
haemostatic system remains inevitable, however. Low-flow
areas, stagnation zones, turbulent flow fields and cell
damage, including haemolysis[23], may all promote
adhesion and aggregation of platelets, as well as fibrin
formation.
Patients with mechanical heart valves have an incidence
of inheritable thrombophilic disorders that is comparable to
that in the general population. There are no prospective data
available concerning whether congenital thrombophilia is
prevalent in patients who have recurrent thrombosis after
valve implantation despite adequate antithrombotic therapy.
However, a retrospective analysis has described a group of
patients with high prevalence of acquired hypercoagulable
state, the so-called antiphospholipid syndrome[24,25].
Conclusion
Blood vessels and blood circulation affect quality of life in
many ways. They provide an essential nutritive function for
tissues, but can also become affected by disorders or trauma,
resulting in bleeding and thrombosis. Our understanding of
these physiological and pathophysiological conditions has
improved significantly over recent years. Our insight is
Eur Heart J Supplements, Vol. 3 (Suppl Q) December 2001
broadening from simple vessel leakage or vessel occlusion to
the basic mechanical, cellular, biochemical and molecular
mechanisms. Whereas once only 2% of all hereditary
thrombophilias could be explained, we are now able to
identify the cause of venous thromboembolism in the
majority of cases. However, we still lack a complete
understanding of the correlation between thrombophilia and
the tendency for thrombi to develop in other parts of the
vascular tree or thrombosis in patients with artificial
implants that are in contact with blood (e.g. mechanical heart
valves). Nevertheless, current insights will give rise to future
research in the field of drug development[26].
In the past, efforts to develop antiplatelet agents focused
on substances that blocked the biochemical reactions that
are involved in platelet activation and aggregation.
Advances can be expected in the development of substances
that inhibit platelet recruitment and adhesion at sites of
vascular injury[27]. Conventional anticoagulant strategies
focus on blocking the initiation of coagulation, preventing
thrombin generation and inhibiting thrombin activity.
Another approach to attenuate thrombogenesis is to enhance
endogenous anticoagulant pathways[28], rather than to block
specific clotting factors. It is reasonable to assume that we
can look forward to an exciting era of novel antithrombotic
drugs that will augment the treatment options for venous
thromboembolic, as well as for cardiovascular diseases.
Haemostasis and thrombosis
Acknowledgement: I thank Carin Albrecht for preparing the
manuscript and Eva Schwiering for preparing the graphics.
References
[1] Astrup T. The hemostatic balance. Thromb Diath Haemorrh 1958;
2: 347–56.
[2] Gaffney PJ, Edgell TA, Whitton CM. The hemostatic balance:
Astrup revisited. Haemostasis 1999; 29: 58–71.
[3] Coleman RW, Hirsh J, Marder VJ, Clowes AW, George JN
(editors). Hemostasis and thrombosis. Basic principals and clinical practice. Philadelphia: Lippincott Williams & Wilkins, 2001.
[4] Kuntze CE, Blackstone EH, Ebels T. Thromboembolism and
mechanical heart valves: a randomized study revisited. Ann
Thorac Surg 1998; 66: 101–7.
[5] Wu KK, Thiagarajan P. Role of endothelium in thrombosis and
hemostasis. Annu Rev Med 1996; 47: 315–31.
[6] Preissner KT, Nawroth PP, Kanse SM. Vascular protease receptors: integrating hemostasis and endothelial cell functions.
J Pathol 2000; 190: 360–72.
[7] Turitt VT, Hall CL. Mechanical factors affecting hemostasis and
thrombosis. Thromb Res 1998; 92(suppl 2): 25–32.
[8] Topper JN, Gimbrone MA. Blood flow and vascular gene expression: fluid shear stress as a modulator of endothelial phenotype.
Mol Med Today 1999; 5: 40–6.
[9] Rosenfeld SJ, Gralnick HR. Adhesive interactions in hemostasis.
Acta Haematol 1997; 97: 118–25.
[10] Dalen JE, Hirsh J (editors). Sixth ACCP consensus conference on
antithrombotic therapy. Chest 2001; 119(suppl 1).
[11] Seligsohn U, Lubetzky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222–31.
[12] Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors
and arterial thrombotic disease. Thromb Haemost 2001; 85:
584–95.
[13] Hellstern P, Bach J, Haubelt H, Preiss A, Winkelmann BR,
Sengers J. Gene polymorphisms of haemostasis and coronary risk
[in German]. Med Klin 2001; 96: 217–27.
[14] Rosenberg RD, Aird WC. Mechanism of disease: vascular-bedspecific hemostasis and hypercoagulable states. N Engl J Med
1999; 340: 1555–64.
Q7
[15] Mammen EF. Sticky platelet syndrome. Semin Thromb Hemost
1999; 25: 361–5.
[16] Rosendaal FR, Varekamp J, Brocker-Vriends AH et al. Mortality
and causes of death in Dutch hemophiliacs 1973–1986. Br J
Haematol 1989; 71: 71–6.
[17] Triemstra M, Rosendaal FR, Smit C, Van der Ploeg HM, Briet E.
Mortality in patients with hemophilia. Changes in a Dutch population from 1986–1992 and 1973–1986. Ann Intern Med 1995;
123: 823–7.
[18] Koster T, Blann AD, Briet E, Vandenbroucke JP, Rosendaal FR.
Role of clotting factor VIII and effect of von Willebrand factor on
occurrence of deep-vein thrombosis. Lancet 1995; 345: 152–5.
[19] Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH,
Grant PJ. Association of a common polymorphism in the factor
XIII gene with venous thrombosis. Blood 1999; 93: 906–8.
[20] Elbaz A, Corier O, Canaple S, Chedru F, Cambien F, Amarenco P.
The association between the Val34Leu polymorphism in the
factor XIII gene and brain infarction. Blood 2000; 95: 586–91.
[21] Engbers GH, Feijen J. Current techniques to improve the blood
compatibility of biomaterial surfaces. Int J Artif Organs 1991; 14:
199–205.
[22] Weston MW, La Borde DV, Yoganathan AP. Estimation of the
shear stress on the surface of an aortic leaflet. Ann Biomed Eng
1999; 27: 572–9.
[23] Ellis JT, Wick TM, Yoganathan AP. Prothesis-induced hemolysis:
mechanisms and quantification of shear stress. J Heart Valve Dis
1998; 7: 376–86.
[24] Gencbay M, Turan E, Degertekin M, Eksi N, Mutlu B, Unalp A.
High prevalence of hypercoagulable states in patients with recurrent thrombosis of mechanical heart valves. J Heart Valve Dis
1998; 7: 598–600.
[25] Horstkotte D, Riess H. Thromboembolic complications following
heart valve replacement: the role of patient-related coagulability.
Comments. J Heart Valve Dis 1998; 7: 601–9.
[26] Matthias FR, Rasche H (editors). Recent advances in anticoagulant and antiplatelet therapy [in German]. Stuttgart: F.K.
Schattauer-Verlag, 1998.
[27] Bennett JS, Mousa S. Platelet function inhibitors in the year 2000.
Thromb Haemost 2001; 85: 395–400.
[28] Key NS, Bach RR. Tissue factor as a therapeutic target. Thromb
Haemost 2001; 85: 375–6.
Eur Heart J Supplements, Vol. 3 (Suppl Q) December 2001