NORMAL AND ABNORMAL HAEMOSTASIS
J F MUSTARD MD PhD
Department of Pathology, McMaster University
Hamilton, Canada
M A PACKHAM PhD
Department of Biochemistry
University of Toronto, Canada
1 Mechanisms of normal haemostasis
2
Effcctsofmodificationsofthehaemostaticmechanism
a Blood coagulation and fibrin formation
b Platelet adherence to subeadothelium
c Platelet aggregation
d Thrombocytopenia
3 Conclusions
References
The arrest of bleeding at an injury site is one of the first steps
in the process of repair. The three major components of this
process are: (0 blood coagulation, (ii) blood platelets, and
(iii) the vessel wall. Bleeding from an injured vessel will be
arrested if an impervious and pressure-resistant mass forms
and blocks the opening, or if the pressure in the space outside
the damaged vessel becomes greater than that inside it. The
size of the vessel and the type of injury are important determinants of the effectiveness of the haemostatic process. If a
large artery or vein is transected, fatal blood loss may occur
almost immediately. A mass capable of preventing the blood
loss cannot form in such a vessel. In medium-sized arteries and
veins, vessel contraction, fall in blood pressure, and the
haemostatic mechanism may be capable of arresting bleeding
in many cases. In small arteries and veins, and in arterioles
and venules, the haemostatic mechanism is adequate to
prevent excessive blood loss in normal subjects.
Mechanisms of Normal Haemostasis
Injury to a vessel causes a change in the characteristics of
the vessel surface that allows platelets to adhere to the injured
site and activates the coagulation sequence. In response to the
injury, the vessel wall may contract. In severed small vessels
or in puncture wounds of larger vessels, vessel contraction
may be sufficient to seal the injury site (Macfarlane, 1972;
Senyi et al. 1975). In the majority of vessels, however, blood
loss at an injury site is mainly arrested by the formation of a
haemostatic plug. The principal mechanisms involved in the
formation of the plug are: (i) platelet adherence to the vessel
wall, (ii) activation of the coagulation mechanism, (iii) release
and loss of platelet constituents, including ADP, (iv) formation of thromboxane A2 and the prostaglandin endoperoxides, (v) platelet aggregation and further acceleration of
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blood coagulation by the aggregated platelets, and (vi) fibrin
formation.
Platelets can adhere to subendothelial structures such as
collagen, basement membrane, and the microfibrils around
elastin (Baumgartner et al. 1976). Of these vessel wall constituents, only collagen has been shown to cause thereleaseof platelet granule contents. In addition, if the endothelial cells or
subendothelium become coated with thrombin, this promotes
platelet adherence and the plateletreleasereaction (E M Essien,
J P Cazenave, S Moore and J F Mustard, in preparation).
As fibrin polymerizes, it creates an adhesive surface for
platelets (Niewiarowski et al. 1972) and, if this occurs on
the endothelium or on the subendothelial structures, it too
can promote platelet adherence to the vessel wall. The
importance of these various mechanisms in platelet accumulation at an injury site on a vessel wall is still unsettled
but some studies in perfused vessels have indicated that
collagen plays a major part in the formation of a large platelet
mass (Baumgartner et al. 1976).
The exposed subendothelial structures can also activate the
coagulation pathways. Collagen activates factor XII (Niewiarowski et al. 1966; Wilner et al. 1968) and platelets that have
interacted with collagen are reported to activate factor XI
(Walsh, 1972). In addition, thromboplastin is associated with
the surface of the endothelial cells and it has been suggested
that when they are damaged the thromboplastin becomes
available for the clotting reaction (Nemerson & Pitlick,
1972). When the vessel wall is injured, an activator of plasminogen is also released (Nilsson & Pandolfi, 1970). Furthermore, activated factor XII activates a plasminogen proactivator (Kaplan et al. 1976).
Both collagen and thrombin can stimulate platelets to
release the contents of their granules, in particular the contents of their amine storage granules (Holmsen, 1975).
Among the contents of these granules are ADP, ATP, and
vasoactive amines, particularly serotonin (5-hydroxytryptamine). ADP causes platelets to change from a disc shape to
a more rounded form with pseudopodia. In this altered form,
platelets can adhere to each other and to platelets that have
adhered to surfaces such as the collagen in the damaged wall.
In addition, when platelets are stimulated with collagen or
thrombin, a platelet phospholipase A2 is activated and catalyses the hydrolysis of the ester bond involving arachidonate in
platelet phospholipids (Bills el al. 1976). The arachidonate is
then acted upon by a cyclo-oxygenase that converts it to
unstable prostaglandin endoperoxides (PGG2 and PGH2)
and thromboxane A2 (Hamberg & Samuelsson, 1974;
Smith et al. 1974; Hamberg et al. 1975; Malmsten et al.
1975). These short-lived compounds can themselves cause
platelets to change shape, aggregate, and release their granule
contents. In addition, thrombin can cause platelets to change
shape and aggregate through a mechanism which appears to
be independent of released ADP and the formation of the
unstable intermediates of the prostaglandin pathway (Packham et al. 1977). All these aggregation and release-inducing
mechanisms act synergistically with each other to promote
the formation of platelet aggregates (Packham et al. 1977).
It is these mechanisms that are thought to be largely responsible for the formation of a platelet mass at an injury site in a
vessel wall.
When these agents stimulate platelets to aggregate, a membrane phospholipoprotein (platelet factor 3) becomes available
on the surface of the aggregated platelets (Hardisty & Hutton,
NORMAL AND ABNORMAL
HAEMOSTASIS
1
JFMustard&MAPackham
NORMAL AND ABNORMAL HAEMOSTASIS
The administration of the coumarin-type of anticoagulant
to dogs or rabbits in doses which double the prothrombin
time does not impair primary haemostasis (Bergqvist &
Arfors, 1976a; Johnsson & Olsson, 1976). However, if the
drugs are administered in doses that profoundly depress the
coumarin-sensitive clotting factors, re-bleeding through the
haemostatic plug occurs frequently (Zucker, 1947; Newland
&Nordoy, 1967; Bergqvist & Arfors, 1976a).
A defect in the extrinsic pathway of coagulation does not
aggravate the bleeding tendency in animals with a defect in
the intrinsic pathway of coagulation involving factors VIII or
IX (Dodds, 1974). When dogs with factor-Vm or factor-DC
deficiency were crossed with dogs with factor-VII deficiency,
the progeny with both defects did not have a more severe
bleeding tendency than those with factor-VIII or factor-DC
deficiency alone (Dodds, 1974). If dicoumarol is given to
factor-DC-deficient dogs in doses sufficient to reduce the
factor-VII levels to less than 2 %, only a slight prolongation of
the bleeding time is observed and the frequency of re-bleeding
is not increased (Hovig et al. 1967). All this evidence indicates
that it is the intrinsic pathway of coagulation rather than the
extrinsic pathway that is most important in the formation of a
stable haemostatic plug.
Humans with a congenital defect of factor XII do not show
abnormal haemostasis (Ratnoff & Colopy, 1955), and thus it
is apparent that there must be alternative methods of activating the coagulation mechanism. The activation of factor
XI by platelets that have interacted with collagen (Walsh,
1972) may by-pass factor XII and result in normal haemostasis. In keeping with this concept are the observations that
the rare individuals with factor-XI deficiency have a haemorrhagic tendency, although it is less severe than the haemorrhagic tendencies in patients with factor-VEQ deficiency
(Forbes & Ratnoff, 1972).
Patients with a functional defect of factor X have a bleeding
tendency similar to that of classical haemophiliacs (Denson
et al. 1970; Girolami et al. 1970). In the uncommon cases of
prothrombin deficiency, the severity of the bleeding problem
seems to be related to the level of prothrombin (Shapiro et al.
1969; Josso et al. 1970; Kattlove et al. 1970). Congenital
factor-V deficiency is also rare, but it is associated with a
moderately severe defect in haemostasis (Owren, 1947).
In agreement with the observations in humans, animals
with deficiencies of factors X or XI have been found to have
bleeding tendencies whereas animals with factor-XII deficiency do not (Dodds, 1974). When dogs with defects in
factors Vin and DC were crossed, the heterozygous females
had a greater bleeding tendency than the heterozygotes with a
single defect, but most of the males with the combined defects
did not have a more severe haemorrhagk disorder than those
with a single defect (Dodds, 1974).
The principal problem in all these congenital disorders of
coagulation appears to be insufficient thrombin generation
and hence lack of enough fibrin to stabilize the initial mass of
aggregated platelets. If the fibrin that forms is not stabilized,
haemostasis is also impaired. Congenital defects in factor
Xin (fibrin-stabilizing factor) have been described. Patients
with this disorder have a severe bleeding tendency and wound
healing is impaired (Duckert, 1970).
A platelet-rich haemostatic plug is gradually transformed
into a fibrin mass over a 24-hour period. In haemophilic
nnimqls, the amount of fibrin formed during this transformation is less than in normal animals (Hovig et al. 1968b).
2 Effects of Modifications of the Haemostatic Mechanism
a Blood Coagulation and Fibrin Formation
The initial adherence of platelets and the formation of a
mass of aggregated platelets in response to vessel wall injury
appears to be largely independent of blood coagulation, since
a platelet mass forms rapidly at an injury site in dogs or
rabbits given heparin in doses sufficient to inhibit blood coagulation (Hovig et al. 1967; Bergqvist & Arfors, 1976a). In
animals treated in this manner, no fibrin forms around the
haemostatic plugs. A characteristic observation, however, is
that frequent re-bleeding through the plugs occurs, indicating
that they are unstable (Hovig et al. 1967; Bergqvist & Arfors,
1976a). When higher doses of heparin are used, platelet
interaction with collagen is inhibited and primary haemostatic plug formation is impaired (Hovig, 1963; Rowsell et al.
1967).
In dogs with marked impairment of the intrinsic pathway of
coagulation because of defects in either factor VHI or factor
IX, a platelet mass forms when a vessel in the microcirculation is transected, and this platelet mass is similar to that
found in normal animals (Hovig et al. 1967). The haemostatic plugs in these animals, however, are unstable because
fibrin does not form around the platelet aggregates. Rebleeding through the plugs occurs frequently and results in
the eventual formation of plugs that are larger than normal.
In human patients with haemophilia, platelet masses form
at the mouths of transected vessels but the plugs appear to be
deficient in fibrin (JOTgensen & Borchgrevink, 1964).
The extrinsic pathway of coagulation seems to be of less
importance in haemostasis than the intrinsic pathway1. In
animals with factor-VII deficiency, haemostatic plugs form in
a normal period of time and appear to be stable (Hovig et al.
1967). However, severe factor-VII deficiency in both man and
dogs is associated with a bleeding tendency (Rizza, 1972;
Dodds, 1974).
I See Emouf, pp.213-218, and Ingram, pp. 261-264, in this Bulletin.—Eo.
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1966; Joist et al. 1974). This phospholipoprotein accelerates
several steps of the blood coagulation sequence (factor-X
activation and the conversion of prothrombin to thrombin)
(Mustard & Packham, 1971). The surface of the aggregated
platelets serves as a site where thrombin can form rapidly in
amounts in excess of the capacity of the anticoagulant
mechanisms of blood to inhibit it. The thrombin has additional effects on the platelets and also causes the formation of
polymerizing fibrin which adheres to the surface of the platelet mass. Fully polymerized fibrin forms a mesh around the
platelets and, if it contains no active thrombin, it becomes a
relatively non-adhesive surface for platelets (Hovig et al.
1968a).
The platelet mass forms a factor from platelet arachidonate
which is chemotactic for polymorphonuclear leucocytes
(Turner et al. 1975); platelets also make available a factor that
interacts with the fifth component of complement (C5) to
form a material that is chemotactic for leucocytes (Wekslcr &
Coupal, 1973). These tend to accumulate around the platelet
mass soon after its formation.
Plate I: A-C illustrates the appearance of several parts of a
haemostatic plug.
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188
Br. Med Bull. 1977
NORMAL AND ABNORMAL HAEMOSTASIS J F Mustard & M A Packham
b Platelet Adherence to Subendothelium
Theoretically, interference with platelet adhesion to the
vessel wall could cause abnormal haemostasis. There are
several conditions in which platelet adhesion to the subendothelium is impaired. Platelets from patients with von Willebrand's disease do not adhere normally to damaged vessel
walls (Tschopp et al. 1974) and haemostatic plug formation
appears to be slower than normal (Jurgensen & Borchgrevink,
1964). Hovig & Stormorken (1974) have demonstrated in
electron-microscopical studies that the platelets fail to adhere
initially to the collagen at the lips of the cut vessels. Platelets
in platelet-rich plasma from patients with von Willebrand's
disease aggregate normally in response to ADP, collagen, or
thrombin, although in most cases the platelets do not aggregate in response to the antibiotic ristocetin (Weiss, 1975). The
defect is due to an abnormality of a plasma factor which is
associated with factor V m (Ratnoff, 1974). The factor-Vm
clotting activity and von Willebrand's protein have been
dissociated into two components—a molecule with factorv m activity and a molecule that corrects the abnormalities
of von Willebrand's disease (Bouma et al. 1972; Gralnick
et al. 1973; Weiss & Hoyer, 1973; Austen, 1976). Similar
observations have been made in dogs with von Willebrand's
disease (Dodds, 1974).
Platelet adherence to damaged vessel walls is also impaired
in the Bernard-Soulier syndrome (Weiss et al. 1974; Caen et
al. 1976). This condition is associated with a long bleeding time
in man (Bernard & Soulier, 1948). The defect has been identified
as the lack of glycoprotein I on the platelet membrane
(Nurden & Caen, 1975; Caen et al. 1976).
Vascular defects may also be responsible for abnormal
haemostasis. Scorbutic guinea-pigs have a bleeding tendency
which is probably related to defects in collagen formation that
impair platelet adhesion (Barkhan & Howard, 1959). Con-
' See iectioo 2f, p. 211, of the jwper by Hardiity In thil BuBetbL—ED.
189
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nective tissue diseases such as the Ehlers-Danlos syndrome
are also associated with abnormal bleeding but, in some of
these, defects in platelet function and coagulation factors
have also been observed (Estes, 1972; Dodds, 1974).
A number of drugs inhibit the adherence of platelets to the
subendothelium, although many of them may affect platelet
functions in other ways as well2. The non-steroidal antiinflammatory drugs, some steroids, and penicillin G and
related antibiotics strongly inhibit platelet adherence to
damaged vessel walls (Cazenave et al. 1975; Cazenave et al.
1976a; Cazenave et al. 1977). When platelets that have been
pre-treated with penicillin G or methylprednisolone are
infused into thrombocytopenic animals, the drug-treated
platelets fail to arrest bleeding from a punctured jugular vein
(Cazenave et al. 1976a; Cazenave et al. 1976b). These
observations indicate that the inhibitory effects of these drugs
are directed against the platelets rather than against the vessel
wall or constituents of the plasma. However, these drugs also
inhibit ADP-induced aggregation and the effects of collagen
and thrombin on platelets. Thus impairment of haemostatic
plug formation may be attributable both to inhibition of these
mechanisms and to inhibition of platelet adherence to the
damaged vessel wall.
Under some conditions, non-steroidal anti-inflammatory
drugs such as aspirin or phenylbutazone prolong the bleeding
time in animals and man (Quick, 1966; Packham et al. 1967;
Evans et al. 1968; Weiss et al. 1968; Hirsh et al. 1973; Mielke
et al. 1973; Herrmann & Lacefield, 1974). As well as inhibiting
platelet adherence to damaged vessels, these drugs also
inhibit the platelet cyclo-oxygenase that is responsible for the
formation of the aggregation-inducing intermediates of the
prostaglandin pathway (Hamberg & Samuelsson, 1974;
Roth & Majeros, 1975; Smith et al. 1975). Although most
investigators have reported that aspirin prolongs the bleeding
time in man and animals, some workers have not been able to
demonstrate an effect of aspirin on haemostasis (Bergqvist &
Arfors, 1976a).
The usual doses of non-steroidal anti-inflammatory drugs
do not affect blood coagulation. However, they do interfere
with two components of the contribution that platelets make
to haemostasis, namely, platelet adherence to the damaged
vessel wall and the formation of prostaglandin endoperoxides
and thromboxane A2 from platelet arachidonate. Although
these active, unstable intermediates formed from arachidonate
have attracted a great deal of attention recently, they may not
be crucial for the formation of haemostatic plugs, since the
prolongation of the bleeding time following ingestion of
these drugs is very slight.
The administration of non-steroidal anti-inflammatory
drugs to patients receiving dkoumarol, or to haemophiliacs,
can cause bleeding (Quick, 1966; Kaneshiro et al. 1969;
Kasper & Rapaport, 1972; Bowie & Owen, 1974; de Gaetano
et al. 1975). Hovig et al. (1967) showed that the administration of phenylbutazone to dogs with factor-DC deficiency
impaired the initial formation of haemostatic plugs. Johnsson
& Olsson (1976) showed that aspirin prolonged the bleeding
time of normal dogs that were being treated with warfarin.
In all these cases, both fibrin formation and platelet functions
are impaired, with the result that a severe haemostatic defect
is produced. When non-steroidal anti-inflammatory drugs are
given with coumarin compounds, the drugs displace each
The lack of fibrin may be responsible for the weakness of the
haemostatic plugs in these animals, and for the frequency of
renewed bleeding. In human patients with haemophilia, when
a haemostatic plug is dislodged 24 hours after its formation,
the accumulation of a new platelet mass at the injury site is
impaired and it is assumed that the injured surfaces have
become less reactive to platelets (J0rgensen & Borchgrevink,
1964; Hovig era/. 1968b).
Further evidence for the role of fibrin in stabilizing haemostatic plugs has come from studies of the effect on haemostasis of activating the fibrinolytic mechanism. Infusion of
streptokinase into rabbits, under conditions in which the
breakdown products of fibrinogen or fibrin do not accumulate
in sufficient concentrations to inhibit platelet function,
causes the haemostatic plugs at injury sites to become unstable
and frequent re-bleeding occurs (Hirsh et al. 1968; Bergqvist
& Arfors, 1974). Both these groups of investigators showed
that streptokinase, added to the surface of a haemostatic plug,
lyses the fibrin around the platelet mass and thus causes the
break-up of the plug and re-bleeding. These observations
support the concept that the initial site of fibrin formation is
mainly around the outside of the platelet aggregates. As the
initial haemostatic plug is transformed into a fibrin mass,
fibrin presumably forms in the inner part of the platelet mass
and the plug becomes more resistant to the action of streptokinase. The addition of streptokinase to the surface of a plug
60 minutes after its formation does not dislodge it (Hirsh et al.
1968).
NORMAL AND ABNORMAL HAEMOSTASIS
other from their binding sites on albumin; this results in
higher effective concentrations of both drugs and increases
their abilities to impair haemostasis.
/FMustard&MAPackham
c Platelet Aggregation
Most of the agents that inhibit platelet aggregation have
multiple effects on platelet functions. Therefore few simple
studies have been made of the effect on haemostatic plug
formation of inhibiting only ADP-induced platelet aggregation. Adenosine and some of its analogues inhibit platelet
accumulation at vessel injury sites in the microcirculation
(Born et al. 1964). However, although adenosine is a strong
inhibitor of ADP-induced aggregation, it also increases
cyclic AMP levels in platelets (Haslam, 1975). Thus adenosine could also affect platelet aggregate formation by inhibiting other agents that cause platelet aggregation and the
release reaction (e.g. thrombin and thromboxane A2).
In genera], high concentrations of drugs—such as prostaglandin Ej, methylprednisolone, penicillin G, and pyrimido-pyrimidine compounds—that inhibit ADP-induced
platelet aggregation and the release reaction all impair the
formation of haemostatic plugs and prolong the bleeding
time in most animal experiments (Emmons et al. 1965;
Emmons et al. 1967; Kinlough-Rathbonc et al. 1970;
Cucuianu et al. 1971; Bergqvist & Arfors, 1976b; Cazenave
etal. 1976a; Cazenave et al. 1976b).
Patients with a congenital absence of clottable fibrinogen
(afibrinogenaemia) show a marked haemorrhagic tendency
(Gugler & LUscher, 1965; Inceman et al. 1966). Platelets
from these patients show a diminished responsiveness to
aggregating agents (Mustard & Packham, 1970). Dogs with
hypofibrinogenaemia also have been reported to have a
severe bleeding tendency (Kammermann et al. 1971). Some
individuals have been found whose plasma contains fibrinogen-like material with abnormal amino acid sequences.
This material clots more slowly than normal fibrinogen upon
the addition of thrombin. In most of these patients haemostasis is only mildly impaired (Ratnoff, 1972).
Fibrinogen deficiency or defective fibrinogen may affect
haemostatic plug formation in two ways: (0 lack of fibrinogen
depresses the response of platelets to aggregating agents,
particularly to ADP; thus the formation of the initial platelet
mass is inhibited, and (if) in the absence of adequate amounts
of normal fibrinogen, insufficient fibrin is formed to stabilize
the initial platelet plugs.
The congenital platelet disorder—thrombasthenia—is associated with a significant bleeding tendency (Caen, 1972). The
principal defect appears to be the inability of the platelets to
aggregate in response to ADP, collagen or thrombin. The
platelets change shape in response to these agents and undergo
the release reaction (Zucker et al. 1966). The defect appears
to be caused by the absence of glycoprotein n on the platelet
membrane (Nurden & Caen, 1974). In individuals with this
disorder, a haemostatic plug does not consist of a mass of
platelets at the end of an injured vessel (Jargensen & Borchgrevink, 1964; Mustard & Packham, 1971). Instead, as blood
extrudes into the extravascular tissues it forms a haematoma
which eventually clots and resists the pressure of the blood
flowing from the cut vessel, thus preventing further blood
loss. If patients with thrombasthenia bleed into a body
cavity or orifice where a haematoma cannot form, they may
suffer a massive loss of blood. Thrombasthenia has been
found in dogs in addition to humans. The affected animals
d Thrombocytopenia
The number of circulating platelets also affects haemostasis;
severe bleeding may occur in thrombocytopenia. However,
the critical number of platelets required for normal haemostasis is much lower than the usual number of circulating
platelets. Bergqvist & Arfors (1973) found that the platelet
count in rabbits had to be less than 40000 per cu. mm before
significantly increased bleeding occurred from injured
vessels. When mesenteric or skin arterioles or venules are
cut in animals with low platelet counts, blood continuously
streams from the ends of the cut vessels. Arrest of bleeding
from these cut vessels in thrombocytopenic animals requires
the transfusion of fresh viable platelets (Firkin et al. 1960) or
external pressure on the vessel.
Harker & Slichter (1972) found a linear relation between
the bleeding time and the platelet count in thrombocytopenic
subjects. They also observed that young platelets were more
haemostatically effective than older platelets in these patients.
Senyi et al. (1975) and Blajchman et al. (1976) have shown
that the bleeding time from a puncture wound in the jugular
vein of thrombocytopenic rabbits is inversely proportional to
the platelet count. Although the infusion of fresh platelets
will arrest bleeding from the injury site, bleeding can also be
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have a similar platelet defect and a bleeding tendency (Dodds,
1974).
Two main types of abnormality of the platelet release
reaction have been recognized (Stuart, 1975; Weiss, 1975).
In the first—"storage pool" disease3—the granule content of
ADP, ATP, serotonin, and calcium is abnormally low. The
platelets aggregate normally upon the addition of ADP but
respond poorly, if at all, to collagen. A mild haemorrhagic
tendency is associated with these defects, indicating that the
ability of platelets to release granule contents is not essential
for haemostasis. The mildness of the defect in this condition
is not surprising in view of the fact that thrombin and the
intermediates formed from arachidonate can induce platelet
aggregation independently of released ADP (KinloughRathbone et al. 1976; Packham et al. 1977). Storage pool
disease is associated with a number of disorders including
the Wiskott-Aldrich and Hermansky-Pudlak syndromes.
Storage pool disease has also been found in a strain of fawnhooded rats (Tschopp & Zucker, 1972).
In the second type of abnormality of the release reaction,
the content of the storage granules is normal but the response
torelease-inducingagents is impaired. In this condition also,
the platelets respond normally to ADP but poorly to collagen.
Recently, platelets from a patient with this problem have been
shown to have a defect in the cyclo-oxygenase which catalyses
the conversion of arachidonate to the prostaglandin endoperoxides and thromboxane A2 (Malmsten et al. 1975).
The effect on haemostasis of platelets that have been
degranulated with thrombin was studied by Reimers et al.
(1976). These platelets do not have granule contents to
release and they have an additional defect in that they do not
aggregate in response to thrombin although they respond
normally to ADP or collagen. When rabbit platelets degranulated with thrombin were infused into thrombocytopenic
rabbits they were much less effective than normal platelets in
arresting bleeding from punctured jugular veins.
1
See section lefi), pp. 208-209, and itction 2d, p. 210, of the paper by
Hardiity in thii Bulletin.—ED.
190
KM ftull 1Q77
NORMAL AND ABNORMAL HAEMOSTASIS
stopped by the administration of hydrocortisone (Senyi et al.
1975). In this circumstance, haemostasis is probably achieved
by a direct effect of the steroid on the vessel wall that is
independent of platelets, since corticosteroids inhibit platelet
functions (Cazenave et al. 1976a). If platelets are exposed to
methylprednisolone in vitro, washed, and then infused into
thrombocytopenic rabbits, bleeding is not arrested at the site
where the jugular vein has been punctured. Since methylprednisolone inhibits platelet aggregation and release induced
by ADP, thrombin, or collagen, it appears that the corticosteroids can cause haemostasis by a direct effect on the
vessel wall despite their inhibitory effects on platelet functions.
Acquired disorders of haemostasis can occur in thrombocytopenia caused by some viruses (Terada et al. 1966), antiplatelet antibodies (Karpatkin & Lackner, 1975), drugs
/FMustard&MAPackham
(Miescher, 1973) or disseminated intravascular coagulation
(McKay, 1965; Dodds, 1974)*.
3
Conclusions
Effective haemostasis requires vessel wall contraction,
platelet adherence to the injured vessel wall, platelet aggregation, and the formation of thrombin and fibrin. The
intrinsic pathway of coagulation is more important than the
extrinsic. Defective haemostasis may result from abnormalities of any one of these mechanisms and, if two or more
are impaired, very severe bleeding may occur.
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PLATE I
A HAEMOSTATIC PLUG
J F Mustard & M A Packham
(FIG. A-C)
Downloaded from http://bmb.oxfordjournals.org/ at Pennsylvania State University on May 16, 2016
Electron micrographs of a haemostatic plug in a severed mesenteric vessel of a normal dog. The site
from which the section was taken for examination is illustrated in the diagram of the plug in the upper
right-hand corner of each picture
A. At the periphery of the plug there are swollen platelet pseudopodia in contact with each other and
with degranulated platelets. Interspersed among these platelets are dark patches of fibrin. The large
solid dark cells are red blood cells
(magnification x 5150)
B. At the point where the plug is In contact with the connective tissue around the vessel, the platelets
are degranulated and swollen. The platelets are adherent to collagen fibres
(mafniflcicion X 15 700)
C. At the centre of the plug the platelets are adherent to each other, but most of them are intact. No
fibrin is apparent
(rruinlflaclon X 10 400)
PLATE II
FLUID-MECHANICAL AND BIOCHEMICAL INTERACTIONS
IN HAEMOSTASIS
GVR
Born
(FIG. A)
electron micrograph; magnification x 25 000)
Downloaded from http://bmb.oxfordjournals.org/ at Pennsylvania State University on May 16, 2016
A. Platelets aggregated on an endothelial cell in a hamster cheek pouch venule during the
ionophoretic release of ADP at that site on the outside of the vessel. (Unpublished experiment by
N A Begent and G V R Born)