Thrombosis Research 124 (2009) e13e18

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Thrombosis Research
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / t h r o m r e s

Regular Article

Management of bleeding and of invasive procedures in patients with platelet

disorders and/or thrombocytopenia: Guidelines of the Italian Society for
Haemostasis and Thrombosis (SISET)
A. Tosetto h,, C.L. Balduini a, M. Cattaneo b, E. De Candia c, G. Mariani d, A.C. Molinari e, E. Rossi f, S. Siragusa g
a

Clinica Medica III, Universit di Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia
U.O.C. Medicina III, Dipartimento di Medicina, Chirurgia e Odontoiatria, Polo San Paolo, Universit di Milano, Milano
c
Dipartimento di Medicina Interna e Geriatria, Universit Cattolica, Roma
d
Dipartimento di Ematologia, Universit L'Aquila, L'Aquila
e
Centro Emolia e Trombosi, IRCCS Istituto Gaslini, Genova
f
Servizio di Immunoematologia e Medicina Trasfusionale, Ospedale Sacco, Milano
g
Cattedra ed U.O. di Ematologia, Dipartimento di Medicina Interna, Malattie Cardiovascolari e Nefrourologiche, Universit degli Studi, Palermo
h
Hemophia and Thrombosis Center, Hematology Department, S. Bortolo Hospital, Via Rodol 37, 36100 Vicenza - Italy
b

a r t i c l e

i n f o

Article history:
Received 15 May 2009
Received in revised form 11 June 2009
Accepted 14 June 2009
Available online 24 July 2009

a b s t r a c t
The optimal management of bleeding or its prophylaxis in patients with disorders of platelet count or
function is controversial. The bleeding diathesis of these patients is usually mild to moderate: therefore,
transfusion of platelet concentrates may be inappropriate, as potential adverse effects might outweigh its
benet. The availability of several anti-hemorrhagic drugs further compounds this problem, mainly because
the efcacy/suitability of the various treatment options in different clinical manifestations is not well
dened. In these guidelines, promoted by the Italian Society for Studies on Haemostasis and Thrombosis
(Societ Italiana per lo Studio dell'Emostasi e della Trombosi [SISET]), we aim at offering the best available
evidence to help the physicians involved in the management of patients with disorders of platelet count or
function. Literature review and appraisal of available evidence are discussed for different clinical settings and
for different available treatments, including platelet concentrates (PC), recombinant activated factor VII,
desmopressin, antibrinolytics, aprotinin and local hemostatic agents.
2009 Elsevier Ltd. All rights reserved.

Introduction
Patients with thrombocytopenia or platelet function disorders usually
show a mild to moderate haemorrhagic diathesis, mainly mucocutaneous
[1]. Haemorrhages are most frequently observed after trauma or surgery,
and only the most severe forms may present spontaneous hemorrhagic
symptoms. From an epidemiological point of view, patients with
inherited platelet function disorders or thrombocytopenia are very rare
[2,3], while acquired forms are much more common, due to the extensive
use of antiplatelet drugs for primary or secondary prophylaxis of arterial
thromboembolism or of myelotoxic agents for cancer treatment. Patients
on antiplatelet drugs who undergo surgical interventions may experience
excessive bleeding, requiring increased used of blood-derived products
for their control [46] and with an increased all-cause mortality [5].
Platelet concentrates (PC) have long been employed in the prophylaxis and treatment of bleeding in patients with platelet disorders. More
recently, antihaemorrhagic drugs have became available (antibrinolytics, desmopressin, recombinant activated factor VII [rFVIIa]) that can
reduce the need for blood-derived products in the treatment or preven Corresponding author.
E-mail address: tosetto@hemato.ven.it (A. Tosetto).
0049-3848/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2009.06.009

tion of spontaneous bleeding episodes and bleeding following surgery or

invasive procedures [7]. On the other hand, the efcacy and suitability of
the various treatment options in different clinical manifestations is not
well dened, in particular with relation to invasive procedures in
patients with platelet disorders.
In 2005, the Italian Society of Thrombosis and Haemostasis (SISET)
promoted the development of guidelines for the management of hemorrhagic emergencies in patients with inherited or acquired platelet disorders. These guidelines were driven by the goals of optimizing and
standardizing the prophylaxis and treatment of bleeding events in these
patients across different Centres, with potential improvements in terms
of efcacy, safety and cost-effectiveness.
Target users of these guidelines include Hospital Physicians involved
in the management of bleeding episodes or bleeding-risk procedures,
such as Anaesthesists, Emergency Physicians, Surgeons, Gynaecologists/
Obstetricians, Transfusionists, Haematologists, and Internists.

Methods
Guidelines development. The general methodology for the development of the SISET guidelines has been detailed elsewhere [8]. For the

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A. Tosetto et al. / Thrombosis Research 124 (2009) e13e18

development of the present guidelines, the SISET Executive Committee

charged one chairman (AT) with the development of the present
guidelines, and invited an expert panel made of members of the society
selected for their expertise in research and clinical practice of plateletassociated bleeding disorders (CB, MC, ED, GM, ACM, ER, SS) from the
elds of haematology, internal medicine and transfusion medicine.
Selection of patient population. Since quantitative or qualitative
platelet disorders are highly heterogeneous both in terms of pathophysiology and specic treatment, the panel of experts predened the
inclusion/exclusion criteria dening the patient population to which
the present guidelines could be applicable. Inclusion criteria are
detailed in Table 1 and take account of the inherited and acquired
platelet disorders that were considered (see also ref. [2,3] ). The panel
excluded from the present guidelines those patients with peripheral
platelet destruction (i.e., thrombocytopenia due to autoimmune disease, disseminated intravascular coagulation, microangiopathy or
extracorporeal circulation and heparin-induced thrombocytopenia).
The panel was aware that platelet function abnormalities in patients
with liver, renal or bone marrow dysfunction are very heterogeneous,
as in these patients the risk of bleeding may be modied by concurrent
impairment of other haemostatic factors. Therefore, in patients with
acquired platelet disorders the present guidelines could be applied only
after a careful evaluation has provided strong clinical evidence for the
presence of a platelet disorder, based on clinical history and exclusion of
other possible causes of bleeding.
Denitions. For the formulation of the present guidelines, the panel
of experts adopted the following denitions for relevant clinical entities.
Major bleeding: Any bleeding associated with a decrease in
haemoglobin levels of 3 g/dL (or a 9% reduction in hematocrit),
intracranial bleeding, intraocular bleeding, joint bleeding, retroperitoneal bleeding, bleedings requiring angiographic intervention.
Patients at high bleeding risk: Any patient with a known severe
platelet disorder (Glanzmann's thrombasthenia, Bernard-Soulier syndrome, use of platelet GPIIb/IIIa inhibitors); patients with platelet
disorders or thrombocytopenia and with a personal history of spontaneous bleeding; patients with thrombocytopenia having a platelet
count b50,000 uL. Platelet dysfunction induced by antiplatelet drugs
or associated with liver or kidney disease was considered at low risk of
bleeding (unless having experienced previous bleeding).
Table 1
Inclusion criteria for the present guidelines.
Congenital or hereditary disorders of platelet function or count
Congenital amegakaryocytic thrombocytopenia
Amegakaryocytic thrombocytopenia with radio-ulnar synostosis
Familial platelet disorder and predisposition to acute myelogenous leukemia
Thrombocytopenia with absent radii
Dyserythropoietic anemia with thrombocytopenia
X-linked thrombocytopenia with thalassemia
Paris-Trousseau type thrombocytopenia
Jacobsen's syndrome
Mediterranean macrothrombocytopenia
Bernard-Soulier syndrome
MYH9-related disorders
Wiskott-Aldrich syndrome
X-linked thrombocytopenia
Gray platelet syndrome
Montreal platelet syndrome
Autosomal dominant thrombocytopenia
Glanzmann's Thrombasthenia
Storage Pool Deciency
Hermansky-Pudlak syndrome
Chediak-Hygashi syndrome
Quebec Platelet Disorder
Montreal Platelet syndrome
Scott syndrome
Acquired disorders of platelet functions
Drug-induced (e.g., antiplatelet drugs; heparin-induced thrombocytopenia:
excluded)
Associated with liver, renal, bone marrow failure

Surgery or procedures at high bleeding risk: neurosurgery, vascular

surgery, surgery of mucous membranes (urogenital, oral, and otorhinolaryngological); spinal/peridural anaesthesia, solid organ biopsy
were all considered at high bleeding risk.
Literature search. Literature search was performed using the MEDLINE (January 1966 to February 2009) and EMBASE (January 1980 to
February 2009) electronic databases. For each topic, two reviewers
performed study selection independently, with disagreements resolved
through discussion and by the opinion of a third reviewer, if necessary.
Detailed information on search strategies and results are available upon
request. Selected articles were ranked according to a hierarchy of evidence levels, including systematic reviews, controlled clinical trials,
uncontrolled clinical trials and case series. In the absence of evidences, a
formal consensus method was applied.

Management of bleeding episodes in patients with inherited or acquired

platelet disorders
Platelet concentrate (PC). In patients with thrombocytopenia, the
risk of spontaneous bleeding is associated with platelet count. The
bleeding risk is negligible when platelet count is N50 109 /L but it
dramatically increases for platelet counts b1020 109 /L. This
evidence derives from studies of patients with post-chemotherapy
bone marrow aplasia and autoimmune thrombocytopenia [911] and
should therefore be interpreted cautiously. No randomized controlled
trials (RCTs) are available indicating the target platelet count to be
achieved by PC replacement therapy for the optimal treatment of
individual bleeding episodes.
No RCTs have been conducted for the management of spontaneous
bleeding episodes in patients with platelet function disorders, while
some indirect evidence exists on the use of PC transfusion for the
prevention of haemorrhagic complications during surgery (see
below). A few cases of PC transfusion for the management of bleeding
in patients with platelet disorders have been reported: one case of
hematuria in a woman with Glanzmann's thrombasthenia was successfully treated with 6 U of PC [12]; a post-extraction haemorrhage in
a patient with Glanzmann's thrombasthenia was successfully treated
with 6 U of PC [13] (Level of evidence 3).
Use of PC should be considered with caution in patients who have
undergone recent coronary artery stent implantation (either bare-metal
stent, BMS or drug-eluting stent, DES). In these patients, stent
thrombosis has been reported after PC infusion with a frequently fatal
outcome [14]. Therefore, in patients with coronary BMS or DES, use of PC
should be reserved for the treatment of life-threatening hemorrhages
only, especially in the rst three-six months after stent implantation [15].
rFVIIa (Eptacog alpha [activated], NovoSeven). rFVIIa was successfully employed in the management of two severe bleeding episodes in
patients with aplastic anemia refractory to platelet transfusion, in
combination with PC transfusion (although ineffective) [16]. In another
8 thrombocytopenic patients, administration of rFVIIa was effective (i.e.
bleeding arrested) in 6/9 cases [17]. rFVIIa was employed for the
successful control of a post-surgical bleeding episode after revision of a
arteriovenous stula in a patient treated with acetylsalicylic acid (ASA)
[18]. rFVIIa was also successfully used for the management of two
episodes of massive bleeding in two patients treated with the GPIIb/IIIainhibitor tiroban [19,20]. rFVIIa was reported to stop intractable bleeding following splenectomy in a patient with myeloproliferative disease
[21]. Infusion of rFVIIa in 7 patients with various platelet disorders
(5 patients with Glanzmann's thrombasthenia, 1 with Bernard-Soulier
syndrome [BSS], and 1 with storage pool disease [SPD]), resulted in
arrest of bleeding in 10/28 episodes, with BSS and SPD showing better
response compared to Glanzmann's thrombasthenia [22]. rFVIIa was
successfully used in the management of 108 bleeding episodes in
patients with Glanzmann's thrombasthenia [23]; two venous thromboembolic events were reported (Level of evidence 3).

A. Tosetto et al. / Thrombosis Research 124 (2009) e13e18

The risk of venous and arterial thromboembolic events associated

with rFVIIa therapy has also been reported in other studies [24]. In a
controlled clinical trial, the incidence of thromboembolic events
reported in patients with intracranial hemorrhage (but without
platelet disorders) was 7% in patients treated with rFVIIa vs. 2% in
the placebo group (p = 0.12) [25] . The recommended dosage regimen
of rFVIIa is 60120 g per kg body weight; the recommended initial
dose is 90 g per kg body weight, administered by intravenous bolus
injection. If needed, further injections may be repeated at two-hour
intervals. A few reported cases suggest that the efcacy of rFVIIa may
be reduced if platelet count is extremely low. Control of acidosis and
hypothermia is also required [26].
Desmopressin (DDAVP, Minirin, Emosint). Several studies have
demonstrated that desmopressin can correct the prolonged bleeding
time in patients with platelet disorders [2737]. Desmopressin also
shortens the bleeding time in uremic patients [38] and in patients
with liver cirrhosis [28,39]. Two studies showed that desmopressin
reduced the antiplatelet effect of the GPIIb/IIIa complex inhibitor
eptibatide, by shortening the PFA-100 closure time [40,41]. However,
both PFA-100 and bleeding time are surrogate endpoints, and few data
are available on the efcacy of desmopressin for the prevention or
treatment of bleeding in patients with platelet function disorders.
Moreover, desmopressin is less effective in reducing the bleeding time
in patients with Glanzmann's thrombasthenia.
Desmopressin was successfully employed in the management of
bleeding in 12 patients with bone marrow failure (due to acute leukemia
or myelodisplastic syndromes; platelet count of 2,000-71,000 /l) [42].
Desmopressin was used, in combination with platelet transfusion, in
the management of massive gastric bleeding in a uremic patient [43],
and an dental post-surgical bleeding in another uremic patient [44]. In
one case, desmopressin was successfully used to control a severe
epistaxis in a patient treated with clopidogrel [45]. Desmopressin was
also used to control major bleeding after cardiac surgery in two small
series of patients taking ASA [46] (Level of evidence 3).
Isolated cases of myocardial infarction have been reported, but incidence data are not available. Hyponatremia has been reported, especially after repeated infusions in children below the age of three. The
recommended initial dose is 0.3 g/kg of body weight, administered by
subcutaneous or intravenous route. Injection can be repeated 12 hours
later, if necessary [47].
Antibrinolytics and Aprotinin. Some studies have reported the use
of tranexamic acid, aprotinin and aminocaproic acid in the management of bleeding in patients with platelet disorders. However, since
these agents were always used in association with platelet transfusion,
no denite conclusions can be drawn about the effectiveness of these
drugs (Level of evidence 4).

Recommendations
We suggest that PC can be used to treat major bleeding in patients
with disorders of platelet function or thrombocytopenia (Grade C). PC
from one apheresis unit or 8 U of PCs should be used (at least 50
70 108 plt/kg of body weight); in case of alloimmunization, patients
should receive typed PC (Good Practice Point [GPP]).
We suggest that rFVIIa can be used to treat major bleeding in patients
with disorders of platelet function or thrombocytopenia in case of PC
refractoriness on unavailability of typed PC in alloimmunized patients
(Grade C). A dose of 90 ug/kg I.V. is recommended, followed by two
other injections after two and four hours, if clinically required (GPP).
We suggest that rFVIIa can be used treat major bleeding in patients
with disorders of platelet function or thrombocytopenia when bleeding
is not resolved by platelet concentrates alone (Grade D).
We suggest that conservative, local therapies (e.g., suturing,
packing) should be used to treat minor bleeding in patients with
disorders of platelet function or thrombocytopenia; in case of failure

e15

(or of impossibility to apply local measures) desmopressin or

antibrinolytics should be used (Grade D).

Preparation for urgent invasive procedures in patients with

platelet disorders
Platelet concentrate (PC). In a woman with May-Hegglin anomaly,
spinal anaesthesia and Caesarian section were performed after infusion
of 6 U of PC, with no consequent bleeding [48]. A woman with
Hermansky-Pudlak syndrome had successful vaginal delivery after
infusion of 5 U of PC [49]. In 3 patients with Glanzmann's thrombasthenia, dental treatment (removal of tartar from gingival pockets) was
safely performed after administration of 8 U of PC [50]. In a patient with
Glanzmann's thrombasthenia, dental extraction was performed after
infusion of 6 U of PC [13].
In a single patient treated with clopidogrel, the use of PC normalized ADP-induced platelet aggregation [51]. After administration
of PC, coronary revascularization was performed with no bleeding
complications in two series of 12 and 4 patients treated with GPIIb/IIIa
complex inhibitors during the preceding 12 hours [52,53] . In a patient
treated with clopidogrel combined with aspirin, spinal anaesthesia
and drainage of an infected hematoma were performed after PC transfusion [51]. (Level of evidence 3)
In patients with coronary BMS or DES, use of PC before surgery
should be considered with extreme caution, especially in the rst
three-six months after stent placement.
rFVIIa (Eptacog alpha [activated], NovoSeven). rFVIIa was successfully used to control bleeding after insertion of a Hickman catheter in a
patient with thrombocytopenia associated with acute leukemia who
did not respond to administration of platelets and plasma [54] . rFVIIa
was effective for the prevention of bleeding complications in three
patients with Glanzmann's thrombasthenia before invasive procedures (venous catheter removal, endoscopic polypectomy, laparotomy
for intestinal resection [55] and in one patient with Glanzmann's
thrombasthenia before hysterectomy with bilateral annessiectomy
[56]. rFVIIa was also effective for the preparation for 34 invasive
procedures in other patients with Glanzmann's thrombasthenia [23].
In this series, effective haemostasis was achieved in 8/9 major surgeries and 24/25 minor surgeries. (Level of evidence 3)
Desmopressin (DDAVP, Minirin, Emosint). In patients with platelet
disorders or thrombocytopenia, administration of desmopressin
allowed the following invasive procedures without bleeding complications: two surgeries and a dental extraction in 3 patients with undened
platelet disorders (possibly associated with primary platelet secretion
defect) [57], a craniotomy in a patient with May-Hegglin anomaly [58], a
dental extraction and a Caesarean section in a patient with HermanskyPudlak syndrome [59], a tonsillectomy in a patient with Fechtner
syndrome [36], and the reduction of discal herniation in a patient with
deciency of the P2Y12 platelet ADP receptor [60]. Desmopressin administration allowed renal biopsy in small series of uremic patients
[61,62].
Meta-analysis of 3 RCTs of patients treated with ASA undergoing
coronary revascularization showed that the use of desmopressin was
associated with reduction of bleeding risk (OR 0.21, 95% CI 0.07 0.42)
[63]. However, this meta-analysis was based on a small number of
patients, and less favourable overall ndings might be obtained after
the inclusion of the negative results if a more recent RCT [64].
Antibrinolytics. A meta-analysis of 6 RCTs of patients undergoing
coronary revascularization who were possibly on ASA (all patients had
cardiovascular disease, but use of ASA at the time of surgery was not
documented for all of them), showed that tranexamic acid did not
reduce the risk of bleeding [63]. A more recent RCT of patients treated
with ASA undergoing coronary revascularization showed that tranexamic acid (30 mg/kg body weight) signicantly reduced postoperative blood loss [65]. A randomized clinical trial using tranexamic

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A. Tosetto et al. / Thrombosis Research 124 (2009) e13e18

acid in patients on ASA and undergoing coronary revascularization is

now under progress [66]. (Level of evidence 1-)
Aprotinin. Several RCTs have shown the efcacy of aprotinin in the
control of bleeding risk in patients treated with antiplatelet drugs
immediately before coronary revascularization. Administration of
4 106 KIU of aprotinin (2 MU before surgery, 2 MU during priming)
signicantly reduced blood loss compared to placebo [67]. No signicant
differences in efcacy and tolerability were observed with a dose of
6 106 KIU [68]. A signicant reduction of bleeding has also been shown
by other RCTs of patients treated with ASA [6973] or clopidogrel [74]. In
a retrospective study, use of aprotinin was found to be associated with a
lower post-surgical bleeding in patients treated with tiroban [75]. A
meta-analysis of 13 RCTs on the efcacy of aprotinin in reducing bleeding during coronary revascularization in patients who had taken ASA
during the 2 weeks before surgery showed that transfusion requirements were reduced in patients randomized to aprotinin (RR 0.67,
CI 0.61-0.72) [76]. A more marked reduction of bleeding risk was shown
in a meta-analysis of patients currently treated with ASA (RR 0.26, 95%,
CI 0.11-0.61) [63]. (Level of evidence 1+)
However, use of aprotinin may be associated with a greater risk of
organ failure [77,78] and the drug is not currently marketed in several
countries.
Local haemostatics. A local haemostatic (Sealgel) was used in a
series of patients undergoing percutaneous transluminal angioplasty.
Of the 50 patients enrolled, 30 were anticoagulated with aspirin or
ticlopidin. Haemostasis at the arterial puncture site was achieved in
49/50 patients [79]. A reduction of periprocedural bleeding during
cardiac surgery (hence in patients possibly taking antiplatelet drugs)
was achieved in a small , non-randomized, open-label controlled trial
on 93 patients using the FloSeal matrix [80].
Recommendations
We suggest that PC can be used for bleeding prophylaxis in patients
with disorders of platelet function or thrombocytopenia at high personal
bleeding risk and who require high-risk invasive procedures (Grade C).
PC from one apheresis unit or 8 U of PCs should be used (at least 50
70 108 plt/kg of body weight); in case of alloimmunization, patients
should receive typed PC (GPP).
We suggest that rFVIIa can be used for bleeding prophylaxis in
patients with disorders of platelet function or thrombocytopenia at high
personal bleeding risk and who require high-risk invasive procedures, in
case of PC refractoriness or unavailability of typed PC in alloimmunized
patients (Grade C). A dose of 90 ug/kg I.V. is recommended, followed by
two other injections after two and four hours, if clinically required (GPP).
We suggest that tranexamic acid (30 mg/kg body weight) should
be used for bleeding prophylaxis in patients with disorders of platelet
function or thrombocytopenia undergoing aorto-coronary by-pass
surgery (grade A).
We suggest that desmopressin should be used for bleeding prophylaxis in patients with disorders of platelet function or thrombocytopenia
(at low personal bleeding risk) undergoing high-risk surgery, if not
otherwise contraindicated (grade D).
We suggest that conservative, local therapies (e.g., resuturing,
packing, local haemostatics) should be used for bleeding prophylaxis
in patients with disorders of platelet function or thrombocytopenia
undergoing surgery at low bleeding risk (grade D).
Discussion
The choice of the optimal therapy for the management of bleeding or
its prevention in patients with platelet disorders or thrombocytopenia is
complex. Several aspects deserve consideration, like the patient's personal risk and the kind of surgery (e.g., target tissue, organ damage
associated with a potential bleeding into a closed space). The situation is
even more complex for patients requiring invasive procedures after

placement of a drug-eluting coronary stent (DES), in whom use of

double antiplatelet treatment (clopidogrel and ASA) is advocated for
one year and use of ASA is suggested indenitely, even during surgery
[81].
Literature review performed during the development of the
present guidelines has shown an overall lack of high quality studies,
since evidence almost exclusively comes from case reports. Moreover,
many studies are based on surrogate endpoints such as platelet count
or platelet function. Therefore, promotion of clinical research in the
eld of platelet disorders should be a priority. Alternatively, given the
low likelihood of having data from RCTs in a emergency setting,
standardization of the study endpoints would be desirable to improve
comparison of the efcacy of different antihaemorrhagic strategies.
We acknowledge that rFVIIa treatment is expensive, and that we
did not address the economic implications of anti-haemorrhagic
therapies considered here. We decided to avoid this type of analysis
because no ad hoc cost-effectiveness studies are available and because
no RCTs have been performed for most of the issues discussed.
Therefore, no measurement of relevant end-points can be made in
terms of NNT (i.e., estimated number of patients who need to be
treated for one additional patient to benet). Furthermore, the urgent
and life-threatening character of some hemorrhagic manifestations
(major bleedings) requires life-saving procedures that cannot be
inuenced by economic considerations.
For the practical application of these guidelines, it should be
remembered that in many cases of acquired platelet disorders (e.g.,
platelet function disorders in patients with liver, renal or bone marrow
failure) the pathophysiology and clinical severity of the platelet defects
could be very heterogeneous. Other co-existing defects of the plasmatic
or vascular phase of haemostasis can account for a multifactorial nature
of bleeding in these patients (e.g., bleeding in cirrhotic patients with
portal hypertension and hypersplenism). Evaluation of platelet function
is time-consuming and requires considerable technical expertise, thus
being not feasible in an acute setting. Therefore, in many bleeding
patients an acquired disorder of platelet function could be suspected but
not denitely proved. The present guidelines are mainly intended for the
treatment of patients with a previously diagnosed congenital platelet
disorder (e.g., Glanzmann's thrombasthenia) or of patients in whom the
presence of an acquired platelet disorder is likely and deemed to be the
major cause of bleeding after a careful clinical evaluation. We also
excluded from the present guidelines those cases in whom a low platelet
count results from increased peripheral destruction, since the disorders
typically require a disease-specic treatment as the rst line therapy for
bleeding.
As a consequence of these considerations, it is apparent that the
correct implementation of these guidelines requires a fully multidisciplinary evaluation of each single case of bleeding, in particular
when the use of expensive drugs is considered. A specic etiologic
diagnosis should be always strongly pursued, and appreciation of the
bleeding and thrombotic risks of both the patient and of the required
procedures is strongly recommended.

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