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1.
Clin Chem Lab Med ; 60(1): 7-17, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34714985

RESUMO

Coronavirus disease 2019 (COVID-19) is a life-threatening infectious disease caused by Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). In response to the still ongoing pandemic outbreak, a number of COVID-19 vaccines have been quickly developed and deployed. Although minor adverse events, either local (e.g., soreness, itch, redness) or systematic (fever, malaise, headache, etc.), are not uncommon following any COVID-19 vaccination, one rare vaccine-associated event can cause fatal consequences due to development of antibodies against platelet factor 4 (PF4), which trigger platelet activation, aggregation, and possible resultant thrombosis, often at unusual vascular sites. Termed thrombosis with thrombocytopenia syndrome (TTS) by reporting government agencies, the term vaccine-induced (immune) thrombotic thrombocytopenia (VITT) is more widely adopted by workers in the field. In response to increasing reports of VITT, several expert groups have formulated guidelines for diagnosis and/or management of VITT. Herein, we review some key guidelines related to diagnosis of VITT, and also provide some commentary on their development and evolution.


Assuntos
Vacinas contra COVID-19/efeitos adversos , Trombocitopenia , Trombose , COVID-19/prevenção & controle , Humanos , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombose/induzido quimicamente , Trombose/diagnóstico
3.
Clin Appl Thromb Hemost ; 27: 10760296211066945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34905962

RESUMO

INTRODUCTION: Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients' baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. METHODS: Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. RESULTS: Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. CONCLUSIONS: We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.


Assuntos
Arginina/análogos & derivados , COVID-19/tratamento farmacológico , Tempo de Tromboplastina Parcial/métodos , Ácidos Pipecólicos/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Sulfonamidas/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombose/tratamento farmacológico , Idoso , Arginina/farmacologia , Arginina/uso terapêutico , COVID-19/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Pipecólicos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , SARS-CoV-2 , Sulfonamidas/farmacologia , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente
4.
Clin Appl Thromb Hemost ; 27: 10760296211068487, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34907794

RESUMO

BACKGROUND: Cases of thrombosis with thrombocytopenia syndrome (TTS) have been reported following vaccination with AZD1222 or Ad26.COV2.S. This review aimed to explore the pathophysiology, epidemiology, diagnosis, management, and prognosis of TTS. METHODS: A systematic review was conducted to identify evidence on TTS till 4th September 2021. Case reports and series reporting patient-level data were included. Descriptive statistics were reported and compared across patients with different sexes, age groups, vaccines, types of thrombosis, and outcomes. FINDINGS: Sixty-two studies reporting 160 cases were included from 16 countries. Patients were predominantly females with a median age of 42.50 (22) years. AZD1222 was administered to 140 patients (87·5%). TTS onset occurred in a median of 9 (4) days after vaccination. Venous thrombosis was most common (61.0%). Most patients developed cerebral venous sinus thrombosis (CVST; 66.3%). CVST was significantly more common in female vs male patients (p = 0·001) and in patients aged <45 years vs ≥45 years (p = 0·004). The mortality rate was 36.2%, and patients with suspected TTS, venous thrombosis, CVST, pulmonary embolism, or intraneural complications, patients not managed with non-heparin anticoagulants or IVIG, patients receiving platelet transfusions, and patients requiring intensive care unit admission, mechanical ventilation, or inpatient neurosurgery were more likely to expire than recover. INTERPRETATION: These findings help to understand the pathophysiology of TTS while also recommending diagnostic and management approaches to improve prognosis in patients. FUNDING: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.


Assuntos
Vacinas contra COVID-19/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome
6.
Yonsei Med J ; 62(11): 1032-1041, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34672137

RESUMO

PURPOSE: The ferric chloride (FeCl3)-induced thrombosis model is widely used for thrombosis research. However, it lacks standardization with uncertainty in the exact mechanism of thrombosis. This study aimed to characterize thrombus formation in a mouse model. MATERIALS AND METHODS: We investigated thrombus formation and stability using various FeCl3 concentrations (10%, 20%, 30%, 40%, and 50%, w/v) in carotid arteries of the Institute of Cancer Research (ICR) and C57BL/6N mice using the FeCl3-induced thrombosis model. We also investigated thrombus histopathology using immunohistochemistry and electron microscopy. RESULTS: Higher FeCl3 concentrations induced dose-dependent, faster, larger, and more stable thrombus formation in both strains of mice. However, the ICR mice showed better dose-responses in thrombus formation and stability compared to the C57BL/6N mice. Thrombi were fibrin- and platelet-rich without significant changes across FeCl3 concentrations. However, the content of red blood cells (RBCs) increased with increasing FeCl3 concentrations (p for trend <0.001) and inversely correlated with time to occlusion (r=-0.65, p<0.001). While platelets and fibrin were evenly distributed over the thrombus, RBCs were predominantly located near the FeCl3 treatment area. Transmission electron microscopy showed that RBCs attached to and were surrounded by aggregates of degranulated platelets, suggesting their potential role in platelet activation. CONCLUSION: Faster and larger thrombus formation is induced in a dose-dependent manner by a wide range of FeCl3 concentrations, but the stable thrombus formation requires higher FeCl3 concentrations. Mouse strain affects thrombus formation and stability. RBCs and their interaction with platelets play a key role in the acceleration of FeCl3-induced thrombosis.


Assuntos
Trombose , Aceleração , Animais , Cloretos , Eritrócitos , Compostos Férricos , Camundongos , Camundongos Endogâmicos C57BL , Trombose/induzido quimicamente
7.
BMJ Case Rep ; 14(10)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34706921

RESUMO

Cerebral venous sinus thrombosis (CVST) following novel coronavirus-2019 (nCoV-19) vaccination is a rare adverse effect. We report the first case of CVST associated with ChAdOx1 vaccination, with positive anti-platelet factor 4 (PF4) antibodies, from India. A 44-year-old woman developed a thunderclap headache 4 days after the first dose of the adenoviral vector vaccine ChAdOx1 (Covishield). Physical examination was unremarkable barring mild neck stiffness with no focal neurological deficits. MRI identified right transverse sinus thrombosis. Laboratory tests revealed raised D-dimer and thrombocytopenia; anti-PF4 antibodies were subsequently identified, consistent with thrombosis with thrombocytopenia syndrome (TTS). She was treated with non-heparin anticoagulation and intravenous immunoglobulin and made an uneventful recovery. Early recognition of adenoviral vector vaccine-related TTS, which resembles heparin-induced thrombocytopenia syndrome, is important as heparin and heparin analogues are best avoided in the treatment.


Assuntos
Vacinas contra COVID-19/efeitos adversos , Trombose dos Seios Intracranianos , Trombocitopenia , Trombose , Adulto , COVID-19 , Feminino , Humanos , Trombose dos Seios Intracranianos/induzido quimicamente , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente , Vacinação/efeitos adversos
8.
Acute Med ; 20(3): 223-226, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34679140

RESUMO

Serious thromboembolic events with concurrent thrombocytopenia, sometimes accompanied by bleeding, have occurred very rarely following administration of the ChAdOx1 nCoV-19 vaccine. We report the case of a 59-year-old male with an unremarkable medical history who presented to the emergency department with increasing breathlessness five days after receiving the first dose of ChAdOx1 nCov-19. The patient's blood results showed mild thrombocytopenia and a very high D-dimer, and a pulmonary embolism was confirmed through a CT pulmonary angiogram, which led to a provisional diagnosis of vaccine-induced immune thrombotic thrombocytopenia. The condition was then treated with immunoglobulin and intravenous argatroban in line with the guidance from the Expert Haematology Panel focussed on Vaccine-induced Thrombosis and Thrombocytopenia before conversion to apixaban.


Assuntos
Vacinas contra COVID-19/efeitos adversos , Trombocitopenia , Trombose , Vacinação/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Trombocitopenia/induzido quimicamente , Trombocitopenia/diagnóstico , Trombose/induzido quimicamente , Trombose/diagnóstico
9.
Blood Adv ; 5(22): 4662-4665, 2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34587255

RESUMO

We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a young man diagnosed 13 days after Ad26.COV2.S COVID-19 (Johnson & Johnson/Janssen) vaccination. He presented to us with 5 days of progressive left leg pain, thrombocytopenia, hypofibrinogenemia, and markedly elevated d-dimers, but without radiographically demonstrable thrombosis. Despite negative imaging, we initiated treatment of presumptive VITT given the striking clinical picture that included the timing of his recent adenovirus-based COVID-19 vaccine, leg symptoms, marked thrombocytopenia, and consumptive coagulopathy. He received intravenous immune globulin, prednisone, and argatroban and was discharged 7 days later much improved. His positive platelet factor 4 enzyme-linked immunosorbent assay antibody test returned after treatment was initiated. To our knowledge, this is the first reported case of VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis. Our patient highlights the importance of knowing vaccine status and initiating treatment as soon as possible in the right clinical setting, even in the absence of radiographic evidence of thrombus. Early VITT recognition and treatment provide an opportunity to prevent serious thrombotic complications.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19 , Trombocitopenia , Trombose , COVID-19/prevenção & controle , Humanos , Masculino , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente , Trombose/tratamento farmacológico , Vacinação/efeitos adversos
10.
Clin Appl Thromb Hemost ; 27: 10760296211040110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34541935

RESUMO

Since the outbreak of Covid-19 in December, 2019, scientists worldwide have been committed to developing COVID-19 vaccines. Only when most people have immunity to SARS-CoV-2, COVID-19 can reduce even wholly overcome. So far, nine kinds of COVID-19 vaccines have passed the phase III clinical trials and have approved for use. At the same time, adverse reactions after COVID-19 vaccination have also reported. This paper focuses on the adverse effects of thrombosis and thrombocytopenia caused by the COVID-19 vaccine, especially the adenovirus-vector vaccine from AstraZeneca and Pfizer, and discusses its mechanism and possible countermeasures.


Assuntos
Adenoviridae/genética , Vacinas contra COVID-19/efeitos adversos , Vetores Genéticos , Trombocitopenia/induzido quimicamente , Trombose/induzido quimicamente , Vacinação/efeitos adversos , Anticorpos/sangue , Vacinas contra COVID-19/genética , Vacinas contra COVID-19/imunologia , Humanos , Fator Plaquetário 4/imunologia , Medição de Risco , Fatores de Risco , Trombocitopenia/sangue , Trombocitopenia/imunologia , Trombose/sangue , Trombose/imunologia
12.
Blood Adv ; 5(18): 3540-3551, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34474475

RESUMO

Histidine-rich glycoprotein (HRG) is an abundant plasma protein that binds factor XIIa (FXIIa) and inhibits factor XII (FXII) autoactivation and FXIIa-mediated activation of FXI. Polyphosphate (polyP), a potent procoagulant released from activated platelets, may serve as a physiological activator of the contact system. Previously, we showed that HRG binds DNA and neutralizes its procoagulant activity. Consequently, our goal was to determine whether the capacity of HRG to bind polyanions enables it to regulate polyP-induced thrombosis. In a plate-based assay, immobilized polyP bound HRG, FXII, and FXIIa in a zinc-dependent manner. Basal and polyP-induced thrombin generation was greater in plasma from HRG-deficient mice than in plasma from wild-type mice. Intraperitoneal injection of polyP shortened the activated partial thromboplastin time, enhanced thrombin generation, increased thrombin-antithrombin levels, reduced lung perfusion, and promoted pulmonary fibrin deposition to a greater extent in HRG-deficient mice than in wild-type mice, effects that were abrogated with FXII knockdown. HRG thus attenuates the procoagulant and prothrombotic effects of polyP in an FXII-dependent manner by modulating the contact system.


Assuntos
Fator XII , Trombose , Animais , Coagulação Sanguínea , Fator XII/genética , Camundongos , Polifosfatos , Proteínas , Trombose/induzido quimicamente
13.
Thromb Res ; 206: 111-119, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34455128

RESUMO

INTRODUCTION: Leukocytes are found in organizing thrombi and are associated with thrombus growth. However, their role in the initial stage of thrombus formation is not well known. We investigated the role of leukocytes in the early stage of arterial thrombosis by inducing leukopenia. METHODS: In this double-blind, randomized, placebo-controlled study, 72 Institute of Cancer Research mice were randomly treated with intraperitoneal 100 mg/kg cyclophosphamide or normal saline. The primary outcome was time to occlusion after FeCl3 treatment. We also compared thrombus size, histological composition, and association with peripheral blood cell counts between cyclophosphamide and control groups. RESULTS: Cyclophosphamide treatment significantly decreased leukocyte counts by 82.8% compared to placebo (P < 0.001). The time to occlusion was significantly longer in the cyclophosphamide group (3.31 ± 1.59 min) than in the control group (2.30 ± 1.14 min; P = 0.003). The immunoreactivity for Ly6G-positive cells, intracellular histone H3, and released histone H3 in thrombi was significantly reduced in the cyclophosphamide group by 92.8%, 50.2%, and 34.3%, respectively. Time to occlusion had a moderate negative correlation with leukocyte count in peripheral blood (r = -0.326, P = 0.022) in the entire group. CONCLUSIONS: Cyclophosphamide-induced leukopenia attenuated thrombus formation during the early stage of arterial thrombosis. Our findings suggest the potential role of leukocytes in the initial stage of arterial thrombosis.


Assuntos
Leucopenia , Trombose , Animais , Ciclofosfamida/efeitos adversos , Contagem de Leucócitos , Leucócitos , Leucopenia/induzido quimicamente , Leucopenia/tratamento farmacológico , Camundongos , Trombose/induzido quimicamente , Trombose/tratamento farmacológico
14.
Part Fibre Toxicol ; 18(1): 28, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34348736

RESUMO

BACKGROUND: Expanding biomedical application of anatase titanium dioxide (TiO2) nanoparticles (NPs) is raising the public concern on its potential health hazards. Here, we demonstrated that TiO2 NPs can increase phosphatidylserine (PS) exposure and procoagulant activity of red blood cells (RBCs), which may contribute to thrombosis. RESULTS: We conducted in vitro studies using RBCs freshly isolated from healthy male volunteers. TiO2 NPs exposure (≦ 25 µg/mL) induced PS exposure and microvesicles (MV) generation accompanied by morphological changes of RBCs. While ROS generation was not observed following the exposure to TiO2 NPs, intracellular calcium increased and caspase-3 was activated, which up-regulated scramblase activity, leading to PS exposure. RBCs exposed to TiO2 NPs could increase procoagulant activity as measured by accelerated thrombin generation, and enhancement of RBC-endothelial cells adhesion and RBC-RBC aggregation. Confirming the procoagulant activation of RBC in vitro, exposure to TiO2 NPs (2 mg/kg intravenously injection) in rats increased thrombus formation in the venous thrombosis model. CONCLUSION: Collectively, these results suggest that anatase TiO2 NPs may harbor prothrombotic risks by promoting the procoagulant activity of RBCs, which needs attention for its biomedical application.


Assuntos
Nanopartículas , Trombose , Animais , Células Endoteliais , Eritrócitos , Masculino , Nanopartículas/toxicidade , Fosfatidilserinas , Ratos , Trombose/induzido quimicamente , Titânio/toxicidade
16.
Nat Commun ; 12(1): 4663, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341358

RESUMO

Vaccine-induced thrombotic thrombocytopenia with cerebral venous thrombosis is a syndrome recently described in young adults within two weeks from the first dose of the ChAdOx1 nCoV-19 vaccine. Here we report two cases of malignant middle cerebral artery (MCA) infarct and thrombocytopenia 9-10 days following ChAdOx1 nCoV-19 vaccination. The two cases arrived in our facility around the same time but from different geographical areas, potentially excluding epidemiological links; meanwhile, no abnormality was found in the respective vaccine batches. Patient 1 was a 57-year-old woman who underwent decompressive craniectomy despite two prior, successful mechanical thrombectomies. Patient 2 was a 55-year-old woman who developed a fatal bilateral malignant MCA infarct. Both patients manifested pulmonary and portal vein thrombosis and high level of antibodies to platelet factor 4-polyanion complexes. None of the patients had ever received heparin in the past before stroke onset. Our observations of rare arterial thrombosis may contribute to assessment of possible adverse effects associated with COVID-19 vaccination.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/imunologia , Infarto Cerebral/induzido quimicamente , Púrpura Trombocitopênica Idiopática/induzido quimicamente , SARS-CoV-2/imunologia , Trombose/induzido quimicamente , Autoanticorpos/sangue , Autoanticorpos/imunologia , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Infarto Cerebral/diagnóstico por imagem , Angiografia por Tomografia Computadorizada/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Fator Plaquetário 4/imunologia , Púrpura Trombocitopênica Idiopática/diagnóstico por imagem , SARS-CoV-2/fisiologia , Trombose/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Vacinação/efeitos adversos , Trombose Venosa/induzido quimicamente , Trombose Venosa/diagnóstico por imagem
17.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443589

RESUMO

The thrombotic thrombocytopenia syndrome (TTS), a complication of COVID-19 vaccines, involves thrombosis (often cerebral venous sinus thrombosis) and thrombocytopenia with occasional pulmonary embolism and arterial ischemia. TTS appears to mostly affect females aged between 20 and 50 years old, with no predisposing risk factors conclusively identified so far. Cases are characterized by thrombocytopenia, higher levels of D-dimers than commonly observed in venous thromboembolic events, inexplicably low fibrinogen levels and worsening thrombosis. Hyper fibrinolysis associated with bleeding can also occur. Antibodies that bind platelet factor 4, similar to those associated with heparin-induced thrombocytopenia, have also been identified but in the absence of patient exposure to heparin treatment. A number of countries have now suspended the use of adenovirus-vectored vaccines for younger individuals. The prevailing opinion of most experts is that the risk of developing COVID-19 disease, including thrombosis, far exceeds the extremely low risk of TTS associated with highly efficacious vaccines. Mass vaccination should continue but with caution. Vaccines that are more likely to cause TTS (e.g., Vaxzevria manufactured by AstraZeneca) should be avoided in younger patients for whom an alternative vaccine is available.


Assuntos
Vacinas contra COVID-19/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/terapia , Trombose/induzido quimicamente , Trombose/terapia , Anticorpos/sangue , Diagnóstico Diferencial , Heparina/efeitos adversos , Humanos , Fator Plaquetário 4/sangue , Trombocitopenia/etiologia , Trombose/etiologia
19.
Nature ; 596(7873): 565-569, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34233346

RESUMO

Vaccine-induced immune thrombotic thrombocytopaenia (VITT) is a rare adverse effect of COVID-19 adenoviral vector vaccines1-3. VITT resembles heparin-induced thrombocytopaenia (HIT) in that it is associated with platelet-activating antibodies against platelet factor 4 (PF4)4; however, patients with VITT develop thrombocytopaenia and thrombosis without exposure to heparin. Here we sought to determine the binding site on PF4 of antibodies from patients with VITT. Using alanine-scanning mutagenesis5, we found that the binding of anti-PF4 antibodies from patients with VITT (n = 5) was restricted to eight surface amino acids on PF4, all of which were located within the heparin-binding site, and that the binding was inhibited by heparin. By contrast, antibodies from patients with HIT (n = 10) bound to amino acids that corresponded to two different sites on PF4. Biolayer interferometry experiments also revealed that VITT anti-PF4 antibodies had a stronger binding response to PF4 and PF4-heparin complexes than did HIT anti-PF4 antibodies, albeit with similar dissociation rates. Our data indicate that VITT antibodies can mimic the effect of heparin by binding to a similar site on PF4; this allows PF4 tetramers to cluster and form immune complexes, which in turn causes Fcγ receptor IIa (FcγRIIa; also known as CD32a)-dependent platelet activation. These results provide an explanation for VITT-antibody-induced platelet activation that could contribute to thrombosis.


Assuntos
Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Epitopos de Linfócito B/imunologia , Trombocitopenia/induzido quimicamente , Trombocitopenia/imunologia , Trombose/induzido quimicamente , Trombose/imunologia , Adulto , Idoso , Sequência de Aminoácidos , Anticorpos/imunologia , Sítios de Ligação de Anticorpos , Feminino , Heparina/química , Heparina/imunologia , Heparina/metabolismo , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Ativação Plaquetária , Fator Plaquetário 4/imunologia , Receptores de IgG/imunologia
20.
Thromb Res ; 205: 29-39, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34246011

RESUMO

OBJECTIVES: Venous thrombotic events (VTEs) are a frequent complication of non-small cell lung cancer (NSCLC) and are associated with increased morbidity. Immune checkpoint inhibitors (ICIs) are revolutionizing the management of NSCLC, but little is known about their impact on thrombosis. This study aims to define the incidence and clinical relevance of VTEs in NSCLC patients receiving these treatments. METHODS: A retrospective multicentric cohort study including 593 patients from three centers in Canada and France was performed. The cumulative incidence of VTEs after ICIs was estimated using competing risk analysis, and the association of these events with survival and response to treatment was determined. Finally, univariate and multivariate tests were performed to identify VTE risk factors. RESULTS: The cumulative incidence of VTEs in the cohort was 14.8% (95% CI = 7.4-22.2%) for an incidence rate of 76.5 (95% CI = 59.9-97.8) thrombosis per 1000 person-years, with most thromboses occurring rapidly after treatment initiation. VTEs were not correlated with overall survival, progression-free survival, or objective response to ICIs. Age ˂ 65 years old (HR = 2.00; 95% CI = 1.11-3.59) and tumors with PD-L1 1-49% (HR = 3.36; 95% CI = 1.19-9.50) or PD-L1 ≥ 50% (HR = 3.22; 95% CI = 1.21-8.57) were associated with more VTEs after 12 months of ICI initiation. Also, a delay of less than 12 months from diagnosis to the first ICI treatment (HR = 2.06; 95% CI = 1.09-3.89) and active smoking (HR = 2.00; 95% CI = 1.12-3.58) are probable risk factors of VTEs. CONCLUSION: This study suggests that the incidence of VTEs in NSCLC patients treated with ICIs is comparable to what is reported in other cohorts of patients treated with chemotherapy. In our cohort, VTEs were not associated with a decreased survival or response to therapy. Patient age < 65 and tumors with PD-L1 ≥ 1% were associated with a higher risk of VTEs under ICIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Trombose , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Coortes , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Retrospectivos , Trombose/induzido quimicamente , Trombose/epidemiologia
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