or thrombocytopenia: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET)

Thrombosis Research 124 (2009) e13–e18

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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, Università di Pavia, Fondazione IRCCS Policlinico “San Matteo”, Pavia U.O.C. Medicina III, Dipartimento di Medicina, Chirurgia e Odontoiatria, Polo San Paolo, Università di Milano, Milano c Dipartimento di Medicina Interna e Geriatria, Università Cattolica, Roma d Dipartimento di Ematologia, Università L'Aquila, L'Aquila e Centro Emofilia 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, Università degli Studi, Palermo h Hemophia and Thrombosis Center, Hematology Department, S. Bortolo Hospital, Via Rodolfi 37, 36100 Vicenza - Italy b

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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 benefit. The availability of several anti-hemorrhagic drugs further compounds this problem, mainly because the efficacy/suitability of the various treatment options in different clinical manifestations is not well defined. In these guidelines, promoted by the Italian Society for Studies on Haemostasis and Thrombosis (Società 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, antifibrinolytics, 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 [4–6] 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 (antifibrinolytics, 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: [email protected] (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 efficacy and suitability of the various treatment options in different clinical manifestations is not well defined, 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 efficacy, 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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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 fields 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 specific treatment, the panel of experts predefined the inclusion/exclusion criteria defining 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 modified 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. Definitions. For the formulation of the present guidelines, the panel of experts adopted the following definitions 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 Deficiency 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 b10–20 × 109 /L. This evidence derives from studies of patients with post-chemotherapy bone marrow aplasia and autoimmune thrombocytopenia [9–11] 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 first 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 fistula 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 tirofiban [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).

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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 60–120 μg per kg body weight; the recommended initial dose is 90 μg 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 efficacy 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 [27–37]. 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 eptifibatide, 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 efficacy 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 /μl) [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 μg/kg of body weight, administered by subcutaneous or intravenous route. Injection can be repeated 12 hours later, if necessary [47]. Antifibrinolytics 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 definite 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

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(or of impossibility to apply local measures) desmopressin or antifibrinolytics 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 first 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 undefined 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 deficiency 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 findings might be obtained after the inclusion of the negative results if a more recent RCT [64]. Antifibrinolytics. 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) significantly reduced postoperative blood loss [65]. A randomized clinical trial using tranexamic

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acid in patients on ASA and undergoing coronary revascularization is now under progress [66]. (Level of evidence 1-) Aprotinin. Several RCTs have shown the efficacy 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) significantly reduced blood loss compared to placebo [67]. No significant differences in efficacy and tolerability were observed with a dose of 6 × 106 KIU [68]. A significant reduction of bleeding has also been shown by other RCTs of patients treated with ASA [69–73] 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 tirofiban [75]. A meta-analysis of 13 RCTs on the efficacy 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 indefinitely, 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 field 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 efficacy 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 benefit). Furthermore, the urgent and life-threatening character of some hemorrhagic manifestations (major bleedings) requires life-saving procedures that cannot be influenced 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 definitely 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-specific treatment as the first 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 specific 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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