Are platelet transfusions harmful in acquired thrombotic thrombocytopenic purpura at the acute phase? experience of the <scp>F</scp>rench thrombotic microangiopathies reference center
Authors: Ygal Benhamou, Jean‐Luc Baudel, Alain Wynckel, Lionel Galicier, Elie Azoulay, François Provôt, Frédéric Pène, Jean‐Paul Mira, Claire Presne, Pascale Poullin, Jean‐Michel Halimi, Etienne Rivière, Tarik Kanouni, Amélie Seguin, Christiane Mousson, Aude Servais, Dominique Bordessoule, Pierre Perez, Mohamed Hamidou, Dominique Chauveau, Agnès Veyradier, Paul Coppo
Journal: American Journal of Hematology (2015)

To the Editor: Thrombotic thrombocytopenic purpura (TTP) is a specific form of thrombotic microangiopathy (TMA) characterized by thrombocytopenia, erythrocyte fragmentation, and widespread microvascular thrombi responsible for multi-organ failure of variable severity 1. Surprisingly, while a profound thrombocytopenia is a typical feature of the disease, severe hemorrhage is a rare cause of mortality. Nevertheless, in case of severe bleeding or when an invasive procedure is needed (i.e., catheter insertion, spinal puncture), platelets transfusion may be required, although sudden clinical deteriorations and fatalities suggestive of a worsening of TTP within few hours after a platelet transfusion were reported 2, 3. To date, controversies remain on the effect of platelet transfusions during TTP 4-6. In light of the uncertain risk of platelet transfusions in TTP and the lack of recently published data, we retrospectively reviewed admission data of all TTP patients with a severe acquired ADAMTS13 deficiency (<10% of activity in normal plasma) enrolled in the French TMA Reference Centre registry, in order to better assess the risk of platelet transfusions at the acute phase of TTP. From October 2000 to December 2011, 353 patients with an acquired idiopathic TTP were treated according to consensual guidelines. Of these patients, available data on platelet transfusion were present for 339 patients. Among these, 148 (43%) received at least one platelet concentrate (transfused group) with a median number of transfusions of 1 (interquartile range, 1–2), ranging from 1 to 24. Transfusions were mostly (n = 120, 81%) performed before TTP diagnosis was made and among all transfused patients, 98 patients (66%) received a transfusion exclusively before the first therapeutical plasma exchange (TPE). Main indications of platelet transfusion were isolated thrombocytopenia (n = 102), active bleeding (n = 9), invasive procedures (n = 18), and catheter insertion (n = 16), or neurological deterioration related to ischemic events (n = 3). The number of patients transfused with platelets was significantly lower in centers that enrolled more than five patients during the study period, when compared to those that enrolled fewer patients (40% vs. 57%, respectively, P = 0.01). Death rate and flare-up episodes were comparable between transfused and non-transfused patients without differences in the use of immunomodulatory drugs between groups. In contrast, relapses were more frequently observed in transfused patients when compared to non-transfused patients (27% vs 17%, respectively, P = 0.03) (Table 1). Time to platelet count recovery was also comparable between transfused and non-transfused patients (18.5 [IQR, 10–33] days vs 16.5 [IQR, 7–28] days, respectively; Log Rank test P = 0.14). However, a positive correlation was found between the number of platelet transfusions and time to platelet count recovery (Rs 0.301; P = 0.02). A clinical deterioration (as defined by a new neurological or cardiovascular event that occurred within 24 hr after platelet transfusion, or a significant aggravation of a pre-existing neurological or myocardial symptom), was reported in 54 cases (36%). It consisted in cerebral involvement (n = 40 cases, mainly coma or vigilance disturbances [n = 16], focal deficiency [n = 15] and seizure [n = 5]) and myocardial involvement (n = 21 cases, mainly cardiac arrest [five cases], myocardial infarction [n = 3], and acute congestive heart failure [n = 5]). Notably, two patients in this group died suddenly in a context of cardiac arrest during platelet transfusion. Only cerebral and renal involvement on admission were tightly associated with the occurrence of clinical deterioration after platelet transfusion (P = 0.07 and P = 0.01, respectively). Platelet transfusion had no significant impact on time to platelet count recovery, flare-up episodes, relapses as well as on the plasma volume required to achieve remission (Table 2). However, clinical deterioration was more prevalent in patients who received more than one platelet transfusion (P = 0.039). Moreover, patients who experienced a clinical deterioration after platelet transfusion died more frequently (P = 0.001) (Table 2). The prevalence of clinical deterioration was comparable between patients who received platelets before and those who received platelets after TPE initiation. Similarly, when compared to patients who received only one platelet transfusion, those who received more than one transfusion had more frequently a clinical deterioration (45% vs. 28%, respectively, P = 0.03) and died more frequently (25.8% vs. 10.5%, respectively P = 0.024), whereas platelet count before transfusion was comparable between both groups. According to the univariate analysis, cerebral involvement and MDRD (Modification of the Diet in Renal Disease) on admission, and the transfusion class (transfusion =1 or >1) were tested by multivariable analysis. Cerebral involvement on admission was the only independent variable associated with the occurrence of clinical deterioration after platelet transfusion, with an odds ratio of 3.3 (95% confidence interval: 1.49–7.35; P = 0.003). We report from this large cohort that platelet transfusions are frequently performed in acquired TTP, mostly prior to recognition of the disease and in less experienced centers. In up to one-third of cases, it is rapidly followed by clinical deterioration, but without significant impact on survival and treatment duration. However, we found that repeated platelet transfusions were followed by clinical deterioration and death, whereas neither time from platelets administration to first TPE nor the fact that transfusions were usually carried out before TPE initiation could be clearly associated with death or clinical deterioration. Clinical deterioration following platelet transfusions could be explained by the large amounts of unusually large von Willebrand factor multimers at time of platelet transfusion, precipitating platelet clumping. Therefore, we initially hypothesized that platelets administration before TPE was harmful, as opposed to platelets administered during TPE sessions. However, we found here that cerebral involvement on admission was the only independent predictive factor of clinical deterioration; therefore, this condition should not represent a relevant indication of platelet transfusion, unless related to an imaging-proven cerebral hemorrhage. In conclusion, platelet transfusions in TTP are mainly performed prophylactically as a result of only severe thrombocytopenia. Repeated transfusions may be associated with more death and clinical deterioration. Although it cannot be totally excluded that repeated platelet transfusions and deteriorations could reflect the severity of the underlying disease, we suggest from our results that platelets administration in this disease should be limited to active bleeding or when invasive procedures are mandatory. Patients were recruited with the help of the members of the Reference Centre for Thrombotic Microangiopathies (CNR-MAT) (listed in Appendix). Authors thank S. Thouzeau, S. Savigny, S. Capdenat (Laboratoire d'Hématologie, Hôpital Antoine Béclère, AP-HP, Clamart) and S. Malot (Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP, Paris) for technical assistance. The members of the Reference Center for Thrombotic Microangiopathies (CNR-MAT) are: Azoulay Elie (Service de Réanimation Médicale, Hôpital Saint-Louis, Paris); Barbay Virginie (Laboratoire d'Hématologie, CHU Charles Nicolle, Rouen); Bonmarchand Guy (Service de Réanimation, CHU Charles Nicolle, Rouen); Bordessoule Dominique (Service d'Hématologie, Hôpital Dupuytren, Limoges); Charasse Christophe (Service de Néphrologie, Centre Hospitalier de Saint-Brieuc); Chauveau Dominique (Département de Néphrologie et Transplantation d'Organes, CHU Rangueil, Toulouse); Choukroun Gabriel (Service de Néphrologie, Hôpital Sud, Amiens); Coindre Jean-Philippe (Service de Néphrologie, CH Le Mans); Coppo Paul (Service d'Hématologie, Hôpital Saint-Antoine, Paris); Corre Elise (Service d'Hématologie, Hôpital Saint-Antoine, Paris); Delmas Yahsou (Service de Néphrologie, Hôpital Pellegrin, Bordeaux); Deschenes Georges (Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris); Devidas Alain (Service d'Hématologie, Hôpital Sud-Francilien, Corbeil-Essonnes); Fain Olivier (Service de Médecine Interne, Hôpital Jean Verdier, Bondy); Frémeaux-Bacchi Véronique (Laboratoire d'Immunologie, Hôpital Européen Georges Pompidou, Paris); Galicier Lionel (Service d'Immunopathologie, Hôpital Saint-Louis, Paris); Guidet Bertrand (Service de Réanimation Médicale, Hôpital Saint-Antoine, Paris); Halimi Jean-Michel (Service de Néphrologie Pédiatrique, Hôpital Bretonneau, Tours); Hamidou Mohamed (Service de Médecine Interne, Hôtel-Dieu, Nantes); Herbrecht Raoul (service d'Oncologie et d'Hématologie, Hôpital de Hautepierre, Strasbourg); Jacobs Frédéric (Service de Réanimation Médicale, Hôpital Antoine Béclère, Clamart); Joly Bérangère (Service d'Hématologie Biologique, Hôpital Antoine Béclère, Clamart); Kanouni Tarik (Unité d'Hémaphrèse, Service d'Hématologie, CHU de Montpellier); Lautrette Alexandre (Service de Néphrologie Pédiatrique B, Hôpital Hôtel-Dieu, Clermont-Ferrand); Le Guern Véronique (Unité d'Hémaphérèse, Service de Médecine Interne, Hôpital Cochin, Paris); Loirat Chantal (Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris); Mira Jean-Paul (Service de Réanimation Médicale, Hôpital Cochin); Moulin Bruno (Service de Néphrologie, Hôpital Civil, Strasbourg); Mousson Christiane (Service de Néphrologie, CHU de Dijon); Ojeda Uribe Mario (Service d'Hématologie, Hôpital Emile Muller, Mulhouse); Ouchenir Abdelkader (Service de Réanimation, Hôpital Louis Pasteur, Le Coudray); Parquet Nathalie (Unité de Clinique Transfusionnelle, Hôpital Cochin, Paris); Peltier Julie (Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Paris); Perez Pierre (Service de Réanimation polyvalente, CHU de Nancy); Poullin Pascale (Service d'hémaphérèse et d'autotransfusion, Hôpital la Conception, Marseille); Pouteil-Noble Claire (Service de Néphrologie, CHU Lyon-Sud, Lyon); Presne Claire (Service de Néphrologie, Hôpital Nord, Amiens); Provôt François (Service de Néphrologie, Hôpital Albert Calmette, Lille); Ribeil Jean-Antoine (Service de Thérapie Cellulaire, Hôpital Necker-Enfants Malades, Paris); Rondeau Eric (Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Paris); Saheb Samir (Unité d'Hémaphérèse, Hôpital la Pitié-Salpétrière, Paris); Schlemmer Benoît (Service de Réanimation Médicale, Hôpital Saint-Louis, Paris); Seguin Amélie (Service de Réanimation Médicale, CHU de Caen); Stépanian Alain (Laboratoire d'Hématologie, Hôpital Louis Mourier, Colombes); Vernant Jean-Paul (Service d'Hématologie, Hôpital la Pitié-Salpétrière, Paris); Veyradier Agnès (Service d'Hématologie Biologique, Hôpital Antoine Béclère, Clamart); Vigneau Cécile (Service de Néphrologie, Hôpital Pontchaillou, Rennes); Vrtovsnick François (Service de Néphrologie, Hôpital Bichat, Paris); Wynckel Alain (Service de Néphrologie, Hôpital Maison Blanche, Reims); Wolf Martine (Service d'Hématologie Biologique, Hôpital Antoine Béclère, Clamart); Zunic Patricia (Service d'Hématologie, Groupe Hospitalier Sud-Réunion, la Réunion).