Journal of Blood Medicine Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Platelet Count and Bleeding in Patients Receiving Anticoagulant Therapy for Venous Thromboembolism: Lesson from the RIETE Registry This article was published in the following Dove Press journal: Journal of Blood Medicine Pierpaolo Di Micco 1 Abstract: Major bleeding is one of the most dangerous complications for patients under- Manuel Monreal 2 going anticoagulant treatment for VTE. Several clinical scores have been planned to identify 1 patients at higher risk of bleeding, and most of them take into consideration the number of Department of Internal Medicine and Emergency Room, Ospedale Buon platelets in particular if lower than normal. Here we report the clinical experience made with Consiglio Fatebenefratelli, Naples, Italy; the RIETE registry concerning anticoagulant treatment in the presence of different values of 2 Department of Internal Medicine, platelets and their related risk of bleeding. Hospital Universitari Germans Trias i Pujol, Universidad Autónoma de Keywords: thrombocytopenia, venous thromboembolism, bleeding, bleeding risk Barcelona, Badalona, Barcelona, Spain The Risk of Bleeding During Anticoagulation Morbidity and mortality of patients affected by venous thromboembolism (VTE) is a major health problem because it is the third cause of mortality for vascular diseases in Western countries. Moreover, VTE is also associated with a number of recurrent episodes and for this reason there are several risk factors that influence VTE recurrences as far as other complications, such as major bleeding. An appro- priate clinical approach based on the knowledge of these risk factors may facilitate the use of antithrombotic therapy to identifypatients that may benefit from careful management. Early identification of clinical complications may facilitate supportive measures, thus reducing morbidity and mortality for VTE. A number of variables, identified by several articles, including age, cancer, history of bleeding, anemia, thrombocytopenia, renal insufficiency, intensity and duration of anticoagulant ther- apy or use of concomitant drugs, have been associated with a worse outcome in patients with VTE.1,2 However, the role of platelet count in the outcome in patients treated for VTE is still matter of discussion. The incidence of bleeding associated with therapeutic doses of unfractionated heparin, low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKAs) is around 10–17% per year for all events, 2–5% per year for major bleeding, and 0.5–1% per year for fatal bleeding.3 The reported annual occurrence of intracranial bleeding, which represents the most feared bleeding complication because of its high disability and fatality rate, is in the range of 0.2–0.4%.4–6 Stratification of the individual risk of bleeding prior to initiation of therapy in patients with acute VTE has the potential to assist clinicians in making decisions about the proper intensity and duration of antic- oagulant therapy. A number of prognostic scores have been developed with variable Correspondence: Pierpaolo Di Micco Email pdimicco@libero.it grades of complexity and reproducibility.7–10 Unfortunately however, none of the submit your manuscript | www.dovepress.com Journal of Blood Medicine 2019:10 453–456 453 DovePress © 2019 Di Micco and Monreal. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress. http://doi.org/10.2147/JBM.S234053 com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Di Micco and Monreal Dovepress evaluated bleeding scores has an adequate accuracy and three-month rate of major bleeding and fatal bleeding in power to accurately identify VTE patients at increased risk patients with VTE.11,12 of major bleeding. Our data confirmed that patients with a very low plate- let count had a higher rate of major bleeding, 1.2% of these patients had <80,000 platelets/μL and revealed that Platelet Count at Baseline and these patients had increased risk for major bleeding and Bleeding During Anticoagulation fatal bleeding than those with normal platelet count. Platelets count is very important before to start an antith- Moreover, the follow up showed in the study confirmed rombotic treatment as testified by previous studies and by that this worse outcome was evident from the first week of the presence of thrombocytopenia as one of the variables treatment and was found both in patients initially present- in some risk assessment tools to identify patients at risk for ing with pulmonary embolism (PE) and in those with deep bleeding after a VTE.11,12 However, a confirm of this vein thrombosis (DVT), and persisted after multivariate evidence was also underlined by a study that investigated adjustment. To confirm this clinical aspect, the study tes- 21,887 longitudinal blood counts in a multicenter cohort of tified that the increase in bleeding risk was low (less than 776 patients with different levels of platelets’ count and two-fold) in patients with only mild abnormalities in pla- found a U-shaped curve for the relationship between plate- telet count, but similar to some variables (i.e., age, body let count and risk of major bleeding.5 So after this evi- weight, BMI and so on) appearing in most validated scores dence we were interested to know if such a relationship for predicting the risk of major bleeding. Statistical analy- could also be found in VTE patients receiving sis on this study was based on data reported as percentage, anticoagulation. and frequencies; data were analyzed with SPSS software We used the data in the RIETE (Registro Informatizado (version 15, SPSS, Chicago, IL, USA), p was considered Enfermedad Trombo Embólica) registry to compare the to be significant if its values were < 0.05; The Fisher exact three-month outcomes of patients with acute VTE accord- test and the odds ratio and 95% confidence intervals were ing to their platelet count at baseline. We categorized calculated. patients as having very low-(<80,000/μL), low-(80,000/μL Our study had several important limitations. First, to 150,000/μL), normal-(150,000/μL to 300,000/μL), high- only a one-time measure of platelet counts limited relia- (300,000/μL to 450,000/μL), or very high (>450,000/μL) bility and clarity of reported findings. Platelet count platelet count at baseline, and compared their three-month should be considered as a dynamic monitor for a patient who is taking anticoagulants after a thrombotic event as outcomes in 43,078 patients with acute VTE. Of the studied VTE; this monitor is useful not only to evaluate the risk population,1.2% had very low platelet count, while 13% of bleeding per se but mainly because platelet count may had low platelet count, 66% had a normal count, 17% had be modified by several environmental conditions (e.g., a high platelet count and 3.6% had a very high platelet comorbidities and their related therapies). Furthermore, count at baseline. No differences in the rate of VTE recur- not all causes of thrombocytopenia are present in the rences was found in the follow-up period, but the rate of database of RIETE registry and with current variables major bleeding was different for each subgroup: 5.8%, almost 50% of acquired thrombocytopenias (i.e., cancer- 2.6%, 1.7%, 2.3%, and 4.6%, respectively for reported associated thrombocytopenia, chemotherapy-associated groups, underlining a nearly threefold increase of bleedings thrombocytopenia and hypomobility-associated thrombo- for patients receiving anticoagulation with very low plate- cytopenia) may be explained as reported in Table 1. So, lets count. This trend was respected also for the rate of fatal although the baseline test is useful there is a needful test– bleeding: 2.0%, 0.9%, 0.3%, 0.5%, and 1.2%, respectively, test variability during the follow up. In particular, atten- with a double fold increase for patients receiving antic- tion should be given to patients receiving chemotherapy oagulation with very low platelet count. Multivariate ana- because of the possible transient thrombocytopenia, and lysis confirmed this clinical evidence for patients with with recent surgery that may develop transient thrombo- a very low platelet count and a low platelet count had an cytosis. Furthermore, platelet counts should be always increased risk for major bleeding and fatal bleeding com- confirmed by a double-check by any other means pared to those with a normal platelet count. Thus, we found (smear/manual count), in order to avoid false thrombocy- a U-shaped relationship between platelet count and the topenia that are also associated to different platelets’ submit your manuscript | www.dovepress.com Journal of Blood Medicine 2019:10 454 DovePress Dovepress Di Micco and Monreal Table 1 Comorbidities Associated with Thrombocytopenia in Reported Studies Study Cancer-Associated Hypomobility-Associated Other Unidentified Thrombocytopenia Thrombocytopenia Causes Di Micco et al 2012(12) 40% 22% 38% Di Micco et al 2013(11) 41% 19% 40% Giorgi-Pierfranceschi et al 39% 17% 44% 2015(5) morphology. Moreover, despite our efforts to control any thrombocytopenia may be identified, as cancer associated bias from underlying diseases, it is likely that we were thrombocytopenia as chemotherapy associated thrombo- unable to eliminate such bias completely. Finally, cytopenia as hypomobility associated thrombocytopenia a thorough check of all type of thrombocytopenias should (Table 1). Statistical analysis on this study was based on be associated to their severity, in particular when a major χ2-test for categorical variables and p was considered to be bleed has been associated to thrombocytopenia at significant if its values were < 0.05; incidence rates were baseline. calculated as cumulative incidence and compared using the rate ratio. Platelet Count and Bleeding During In summary, we found a linear U-shaped curve for Anticoagulation with VKAs patients with different platelets count at the onset of In a subsequent study, we aimed to analyze the influence VTE and a non-linear U-shaped relationship between of platelets in 37,000 patients receiving long-term therapy platelet count at baseline and major bleeding in patients for VTE with VKAs.5 Overall, 611 patients (1.6%) had receiving anticoagulant therapy for VTE. Compared to a very low platelet count, 4006 (10.8%) had a low platelet other studies in this report we found an increased rate of count, 25,598 (69%) had a normal platelet count, 5,801 fatal bleeding of patients with a very low platelet counts (15.6%) had a high- platelet count and 984 (2.6%) had and this can find a clinical explanation because the a very high platelet count at baseline. Patients with very RIETE registry frequently records patients with several low or very high platelet count levels were more likely to comorbidities that may be associated with thrombocyto- have comorbidities such as metastatic cancer, chronic liver penia and that may be associated to poor outcome per se disease, renal insufficiency, anemia or recent major bleed- as advanced cancer; on the other hand other studies ing. During the course of VKA therapy (mean, 192 days), reported in the Literature have been usually focused there were no differences in the duration or intensity (as only on the outcome of selected population with throm- measured by international normalized ratio levels) of bocytopenia and this bias of selection may influence the treatment between subgroups. The rate of major bleeding different outcome with our results. was 3.6%, 2.1%, 1.9%, 2.1%, and 3.7%, respectively, and the rate of fatal bleeding was 0.98%, 0.17%, 0.29%, Conclusion 0.34%, and 0.50%, respectively. Thus, we confirmed the Our findings may be of help in identifying patients who existence of a non-linear “U-shaped” relationship between require closer observation during anticoagulation platelet count and bleeding in VTE patients undergoing because they are at risk of bleeding, but further dedi- long-term VKA therapy. We also found additional differ- cated studies are needed to evaluate the causality of this ences among subgroups in the severity of bleeding, but not relationship. in time course or site of bleeding. At variance with pre- viously reported findings, the rate of fatal bleeding was significantly higher in patients with very low platelet Ethics count, but not in those with very high platelet count. The authors certify that institutional approval is not However, these data show a clinical limitation because required by their Institutions, because the intellectual prop- not all causes of thrombocytopenia are present as item in erty of reported data is of the RIETE registry; ethic com- the database of the RIETE registry, so whit current clinical mittee that approved the RIETE registry in Fatebenefratelli variables only nearly a 50% of causes of acquired Hospital of Naples was “Comitato Etico Lazio1”. submit your manuscript | www.dovepress.com Journal of Blood Medicine 2019:10 455 DovePress Di Micco and Monreal Dovepress Disclosure 6. Yan Y-D, Zhang C, Shen L, et al. 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