Our study analyzed the influence of an abnormal PlC at baseline on outcome in VTE patients undergoing long-term VKA therapy. A number of previous studies found that patients with low PlC are at an increased risk for major and fatal bleeding during the course of anticoagulant therapy. Hence, VTE patients with low PlC present a particularly challenging therapeutic dilemma because they are at increased risk for bleeding if anticoagulation is prescribed, and for recurrent VTE in the absence of treatment. In our study, patients categorized as having very low and very high PlC receiving VKA therapy were a not negligible proportion and they had a significant increased risk for major bleeding, describing a U-shaped curve. Mild PlC disorders, even if nonstatistically significant, confirmed the increased rate of bleeding and the U-shaped trend. We, however, found additional differences among subgroups in their severity, but not in time course or site of bleeding. At variance with previously reported findings,9 the rate of fatal bleeding was significantly higher in patients with very low PlC, but not in the very high PlC subgroup. Moreover, we found no differences in the site of bleeding, even though in other studies intracranial hemorrhage was the major cause of death associated with VKA treatment.12
In patients with very low PlC, we found a higher rate of active and advanced cancer, and most studies reported a higher incidence of hemorrhagic complications in patients with malignancy during the course of oral anticoagulant therapy.13 These findings could explain the higher rate of fatal bleeds in this subgroup. The first period of anticoagulation is associated with a higher rate of bleeding, probably because of the presence of occult lesions unmasked at the beginning of anticoagulant therapy, and to a less adequate dose adjustment in that period.13 In our cohort, the timing of bleeding did not differ significantly among subgroups, but we observed that in patients with abnormal PlC, over 40% of bleeds occurred within the first month after VKA therapy was started, and in patients with very low PlC the rate was 54%. Finally, there were no differences in the duration of VKA treatment or INR values at the time of hemorrhage. Overtherapeutic INR levels (higher than 3.0) were most often represented, both in very low and very high PlC subgroups, as previously reported.14,15
Several studies have analyzed the relationship between PlC and outcome, but they assumed this relationship to be linear and divided the continuous PlC value arbitrarily at specific cut points.16,17 In 2013, RIETE investigators showed that a PlC lower than 100,000/μL is an independent predictor for fatal bleeding in patients on anticoagulant therapy for acute VTE, and it represents an item of the RIETE score for fatal bleeding.5 Furthermore, a number of studies reported the influence of increased PlC on the rate of symptomatic VTE and outcome in cancer patients,19,20 whereas a previous study in patients with essential thrombocytopenia found a U-shaped curve for the correlation between PlC and major bleeding (MB).21 Consistent with our results, the previous findings from RIETE investigators reported a statistically significant increased risk of MB in patients with low or high PlC and treated with different anticoagulant drugs for acute VTE,9 but our findings do not confirm a statistically significant higher rate of fatal bleeding in very high PlC subgroup. Furthermore, our study showed that altered PlC at baseline was associated with important comorbidities, such as severe renal impairment, active cancer, recent bleeding complication, and anemia (Table 1). Thus, it is difficult to declare whether an altered PlC at baseline should be considered a risk factor for bleeding complications and mortality, or if these poor outcomes could be influenced by many comorbidities and a greater frailty in a patient presenting acute VTE and abnormal PlC at baseline.
Our study has some limitations. Firstly, the study design does not allow to prove the causality of relationship between MB and altered PlC. Secondly, concerning the platelets count's monitoring, because of a lack in prospective values of PlC after the index event. We have no data about PlC at the time of bleeding. In our database, we have no information about the causes of abnormal PlC, probably because of cancer or chemotherapy in thrombocytopenic patients, and secondary to infection, inflammation, iron deficiency, tissue damage, hemolysis, severe exercise, malignancy, or other causes11 in most patients with thrombocytosis.
Moreover, previous studies showed that the presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome causing an increased risk of bleeding,22,23 but this hypothesis cannot be confirmed for all patients reported in the RIETE registry because they are selected after a recent VTE and not for chronic platelets’ disorders. Furthermore, we have no data on the presence of liver cirrhosis, which could cause thrombocytopenia and potentiates the response to VKA therapy by impairing coagulation and making INR control difficult,11 because in our cohort we recorded generically chronic liver diseases. And lastly, on the anticoagulation side, we have only partial data on INR at bleeding time (Fig. 4) that is well known to be less predictive for hemorrhages than the time in therapeutic range used to evaluate the intensity of anticoagulation.24
In summary, in patients with a recent VTE recorded in the RIETE registry, we found a nonlinear, U-shaped, relationship between PlC at baseline and major bleeding in patients on long-term therapy with VKA for acute VTE. Patients with consistently abnormal PlC had a number of comorbidities, such as metastatic cancer, renal insufficiency, chronic liver disease, anemia, recent major bleeding, and a greater mortality, thus suggesting that a very low or very high PlC at baseline might be a sign of greater frailty. Our findings may be of help to identify patients who require closer surveillance on risk of bleeding, but further dedicated studies are needed to evaluate the causality of these relationships.
We express our gratitude to Sanofi Spain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Pharma AG for supporting this Registry. Bayer Pharma AG's support was limited to the part of RIETE outside Spain, which accounts for a 22.24% of the total patients included in the RIETE Registry. We also thank the RIETE registry Coordinating Center, S & H Medical Science Service, for their quality control data, logistic, and administrative support and Salvador Ortiz, Universidad Autónoma de Madrid and Statistical Advisor S & H Medical Science Service for the statistical analysis of the data presented in this article.
Coordinator of the RIETE Registry: Manuel Monreal (Spain).
RIETE Steering Committee Members: Hervè Decousus (France).
Paolo Prandoni (Italy).
Benjamin Brenner (Israel).
RIETE National Coordinators: Raquel Barba (Spain).
Pierpaolo Di Micco (Italy).
Laurent Bertoletti (France).
Sebastian Schellong (Germany).
Inna Tzoran (Israel).
Abilio Reis (Portugal).
Marijan Bosevski (R.Macedonia).
Henri Bounameaux (Switzerland).
Radovan Malý (Czech Republic).
Philip Wells (Canada).
Manolis Papadakis (Greece).
RIETE Registry Coordinating Center: S & H Medical Science Service.
Members of the RIETE Group.
SPAIN: Adarraga MD, Andújar V, Arcelus JI, Ballaz A, Barba R, Barrón M, Bascuñana J, Blanco-Molina A, Casado I, Castejón-Pina N, de Miguel J, del Molino F, del Toro J, Diaz JA, Falgá C, Fernández-Capitán C, Font L, Gallego P, Garcia-Bragado F, Gómez V, González J, Grau E, Grimón A, Guijarro R, Guirado L, Gutiérrez J, Hernández-Blasco L, Hernández-Huerta S, Jara-Palomares L, Jaras MJ, Jiménez D, Lacruz B, Lecumberri R, Lobo JL, López-Jiménez L, López-Reyes R, López-Sáez JB, Lorente MA, Lorenzo A, Madridano O, Maestre A, Marchena PJ, Martin-Antorán JM, Martin-Martos F, Monreal M, Morales MV, Nauffal D, Nieto JA, Núñez MJ, Odriozola M, Otero R, Pagán B, Pedrajas JM, Pérez G, Peris ML, Pons I, Porras JA, Riera-Mestre A, Rivas A, Rodriguez-Dávila MA, Rosa V, Ruiz-Giménez N, Sabio P, Sampériz A, Sánchez R, Sanz O, Soler S, Suriñach JM, Tiberio G, Tolosa C, Trujillo-Santos J, Uresandi F, Valero B, Valle R, Vela J, Vela L, Vidal G, Vilar C, Villalobos A, Villalta J, Xifre B, BELGIUM: Vanassche T, Verhamme P, CANADA: Wells P, CZECH REPUBLIC: Hirmerova J, Malý R, ECUADOR: Salgado E, FRANCE: Bertoletti L, Bura-Riviere A, Farge-Bancel D, Hij A, Mahé I, Merah A, Moustafa F, GERMANY: Schellong S, GREECE: Babalis D, Papadakis M, Tzinieris I, ISRAEL: Braester A, Brenner B, Tzoran I, ITALY: Apollonio A, Barillari G, Bucherini E, Ciammaichella M, Cola S, Di Micco P, Enea I, Ferrazzi P, Guida A, Lessiani G, Lodigiani C, Maida R, Mastroiacovo D, Pace F, Pasca S, Pesavento R, Pinelli M, Piovella C, Prandoni P, Rota L, Tiraferri E, Tonello D, Tufano A, Visonà A, Zalunardo B, LATVIA: Belovs A, Sablinskis K, Skride A, PORTUGAL: Ribeiro F, Ribeiro JL, Sousa MS, REPUBLIC OF MACEDONIA: Bosevski M, Zdraveska M, SWITZERLAND: Alatri A, Bounameaux H, Calanca L, Mazzolai L.
M. Giorgi-Pierfranceschi, P. Di Micco, and M. Monreal contributed to concept and design of the study, analysis and interpretation of data, and writing the contents. C. Cattabiani and A. Guida contributed to revising the intellectual content; all authors contributed to patients’ enrolment and approved the final version of this article.
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