Persistent hypofibrinolysis in severe COVID-19 associated with elevated fibrinolysis inhibitors activity.

Hypercoagulability and reduced fibrinolysis are well-established complications associated with COVID-19. However, the timelines for the onset and resolution of these complications remain unclear. The aim of this study was to evaluate, in a cohort of COVID-19 patients, changes in coagulation and fibrinolytic activity through ROTEM assay at different time points during the initial 30 days following the onset of symptoms in both mild and severe cases. Blood samples were collected at five intervals after symptoms onset: 6-10 days, 11-15 days, 16-20 days, 21-25 days, and 26-30 days. In addition, fibrinogen, plasminogen, PAI-1, and alpha 2-antiplasmin activities were determined. Out of 85 participants, 71% had mild COVID-19. Twenty uninfected individuals were evaluated as controls. ROTEM parameters showed a hypercoagulable state among mild COVID-19 patients beginning in the second week of symptoms onset, with a trend towards reversal after the third week of symptoms. In severe COVID-19 cases, hypercoagulability was observed since the first few days of symptoms, with a tendency towards reversal after the fourth week of symptoms onset. A hypofibrinolytic state was identified in severe COVID-19 patients from early stages and persisted even after 30 days of symptoms. Elevated activity of PAI-1 and alpha 2-antiplasmin was also detected in severe COVID-19 patients. In conclusion, both mild and severe cases of COVID-19 exhibited transient hypercoagulability, reverted by the end of the first month. However, severe COVID-19 cases sustain hypofibrinolysis throughout the course of the disease, which is associated with elevated activity of fibrinolysis inhibitors. Persistent hypofibrinolysis could contribute to long COVID-19 manifestations.

Extracellular vesicles are a late marker of inflammation, hypercoagulability and COVID-19 severity.

Exacerbated inflammation and coagulation are a hallmark of COVID-19 severity. Extracellular vesicles (EVs) are intercellular transmitters involved in inflammatory conditions, which are capable of triggering prothrombotic mechanisms. Since the release of EVs is potentially associated with COVID-19-induced coagulopathy, the aim of this study was to evaluate changes in inflammation- and hypercoagulability-related EVs during the first month after symptom onset and to determine whether they are associated with disease severity. Blood samples of patients with mild or severe forms of the disease were collected on three occasions: in the second, third and fourth weeks after symptom onset for the quantification by flow cytometry of CD41A (platelet glycoprotein IIb/IIIa), CD162 (PSGL-1), CD31 (PECAM-1) and CD142 cells (tissue factor). Analysis of variance (ANOVA) with repeated measures, Kruskal-Wallis and correlation tests were used. Eighty-five patients were enrolled, 71% of whom had mild disease. Seventeen uninfected individuals served as controls. Compared to controls, both mild and severe COVID-19 were associated with higher EV-CD31+, EV-CD41+ and EV-CD142+ levels. All EV levels were higher in severe than in mild COVID-19 only after the third week from symptom onset, as opposed to C-reactive protein and D-dimer levels, which were higher in severe than in mild COVID-19 earlier during disease progression. EV levels were also associated with C-reactive protein and D-dimer levels only after the third week of symptoms. In conclusion, EVs expressing CD41A, CD31, TF, and CD162 appear as late markers of COVID-19 severity. This finding may contribute to the understanding of the pathogenesis of acute and possibly long COVID-19.

Acquired von willebrand syndrome secondary to monoclonal gammopathy of undetermined significance: long-term remission after treatment with bortezomib.

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder that can precede the diagnosis of multiple myeloma. MGUS is characterized by the presence of a monoclonal paraprotein without evidence of multiple myeloma or other lymphoplasmacytic malignancies. Even though MGUS is an asymptomatic condition that does not require management strategies other than periodic follow-up to prevent complications, secondary nonmalignant diseases may arise, requiring control of the plasma cell clone. Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that occurs in patients with no prior personal or family history of bleeding. It is associated with several other disorders, such as neoplasia, mainly hematological (including MGUS and other lymphoproliferative disorders), autoimmune, infectious and cardiac diseases. At diagnosis, patients usually present with cutaneous and mucosal bleeding, including gastrointestinal bleeding. Here, we report a case of a patient with MGUS who developed AVWS after one year of follow-up. The patient was refractory to glucocorticoids and cyclophosphamide and achieved remission only after monoclonal paraprotein was eradicated following treatment with bortezomib and dexamethasone. Our report sdemonstrates that, for refractory cases, eradication of the monoclonal paraprotein may be necessary to treat bleeding complications due to MGUS-associated AVWS.

Enhanced type I interferon gene signature in primary antiphospholipid syndrome: Association with earlier disease onset and preeclampsia.

OBJECTIVE: Recently, two studies demonstrated that a relevant percentage of primary antiphospholipid syndrome (PAPS) patients had an upregulation of interferon (IFN) genes. However, 20%-28% of these patients had anti-dsDNA, a highly specific systemic lupus erythematosus (SLE) autoantibody. This study aimed to determine the prevalence of the type I IFN signature in the peripheral blood mononuclear cells of PAPS patients without specific SLE autoantibodies and search for its clinical associations. METHODS: Fifty-three PAPS patients (Sydney's criteria) were consecutively selected and age-matched with 50 healthy controls. A third group of nonimmune-mediated thrombophilia patients was also included. The expression of 41 IFN-induced genes was analyzed using real time quantitative PCR. A principal component analysis determined which genes composed the IFN signature, and the z-score was calculated. An ROC curve defined the signature cut-off. RESULTS: Six genes remained in the IFN signature DNAJA1, IFIT5, IFI27, MX1, IFI6, and TYK2. The ROC cutoff was 3.9-fold (AUC = 0.706, S = 0.49, E = 0.86, PPV = 0.79, NPV = 0.61). The type I IFN signature was present in 49% of the patients with PAPS compared with 14.0% of the healthy controls and 17% of the nonimmune-mediated thrombophilia patients (p < .0001). The IFN signature was associated with a younger age at the first antiphospholipid syndrome event (p = .023) and with preeclampsia (p = .032). CONCLUSION: Our results indicate that PAPS patients without lupus-specific antibodies have an enhanced type I IFN gene signature that is not observed in nonimmune-mediated thrombophilia. Also, this overexpression of type I IFN-regulated genes associated with an earlier onset of antiphospholipid syndrome event and preeclampsia.

Subjective results of joint lavage and viscosupplementation in hemophilic arthropathy.

OBJECTIVE: To assess whether joint lavage, viscosupplementation and triamcinolone improve joint pain, function and quality of life in patients with severe hemophilic arthropathy. METHODS: Fourteen patients with knee and/or ankle hemophilic arthritis with and without involvement of other joints underwent joint lavage and subsequent injection of hylan G-F20 and triamcinolone in all affected joints. The patients answered algo-functional questionnaires (Lequesne and WOMAC), visual analog scale for pain (VAS) and SF-36 preoperatively, and at one, three, six and twelve months postoperatively. RESULTS: Sixteen knees, 15 ankles, 8 elbows and one shoulder were treated in 14 patients. Six patients had musculoskeletal bleeding [ankle (1), leg muscle (2) and knees (4)] at 3 months affecting the results. Pain did not improve significantly. Function improved (WOMAC p=0.02 and Lequesne p=0.01). The physical component of SF-36 improved at all time points except at 3 months, with best results at one-year follow-up (baseline = 33.4; 1 month = 39.6; 3 months= 37.6; 6 months 39.6 and 1 year = 44.6; p < 0.001). CONCLUSION: Joint lavage followed by injection of triamcinolone and hylan G-F20 improves function and quality of life progressively up to a year, even in severe hemophilic arthropathy. Level of Evidence IV, Case Series.

Resultados subjetivos da lavagem articular e viscossuplementação na artropatia hemofílica / Subjective results of joint lavage and viscosupplementation in hemophilic arthropathy

Objetivo: Avaliar se lavagem articular, viscossupplementação e triancinolona melhoram a dor, função e qualidade de vida de pacientes com artropatia hemofílica grave. Métodos: Quatorze pacientes com poliartrite hemofílica do joelho e/ou tornozelo com ou sem envolvimento de outras articulações foram submetidos a lavagem articular e subsequente injeção de hilano G-F20 e triancinolona em todas as articulações afetadas. Os pacientes responderam aos questionários algo funcionais (Lequesne e WOMAC), escala visual analógica parador (EVA) e SF-36 no pré-operatório, um, três, seis e 12 meses de pós-operatório. Resultados: Dezesseis joelhos, 15 tornozelos,oito cotovelos e um ombro foram tratados em 14 pacientes. Seis pacientes tiveram sangramento musculoesquelético [tornozelo (1),músculo da perna (2) e joelhos (4)] próximo da avalição de três meses afetando os resultados. A dor não melhorou significativamente.A função melhorou (WOMAC p = 0,02, Lequesne p = 0,01).O componente físico do SF-36 melhorou em todos os momentos,exceto em três meses, com melhores resultados após um ano(pré-operatório = 33.4; um mês = 39,6; três meses = 37,6; seismeses = 39,6; um ano = 44,6; p <0,001). Conclusão: A lavagem articular seguida da injeção de triancinolona e hilano G-F20 melhora a função e a qualidade de vida na artropatia hemofílica grave. Nível de Evidência IV, Série de Casos.

Objective: To assess whether joint lavage, viscosupplementation and triamcinolone improve joint pain, function and quality of life in patients with severe hemophilic arthropathy. METHODS: Fourteen patients with knee and/or ankle hemophilic arthritis with and without involvement of other joints underwent joint lavage and subsequent injection of hylan G-F20 and triamcinolone in all affected joints. The patients answered algo-functional questionnaires (Lequesne and WOMAC), visual analog scale for pain (VAS) and SF-36 preoperatively, and at one, three, six and twelve months postoperatively. RESULTS: Sixteen knees, 15 ankles, 8 elbows and one shoulder were treated in 14 patients. Six patients had musculoskeletal bleeding [ankle (1), leg muscle (2) and knees (4)] at 3 months affecting the results. Pain did not improve significantly. Function improved (WOMAC p=0.02 and Lequesne p=0.01). The physical component of SF-36 improved at all time points except at 3 months, with best results at one-year follow-up (baseline = 33.4; 1 month = 39.6; 3 months= 37.6; 6 months 39.6 and 1 year = 44.6; p < 0.001). CONCLUSION: Joint lavage followed by injection of triamcinolone and hylan G-F20 improves function and quality of life progressively up to a year, even in severe hemophilic arthropathy. Level of Evidence IV, Case Series.

Viscossuplementação em pacientes com artropatia hemofílica / Viscosupplementation in patients with hemophilic arthropathy

Objetivo: Avaliar se a viscossuplementação com ácido hialurônico em pacientes com artropatia hemofílica grave associada com triancinolona após a lavagem articular com soro fisiológico melhora a dor, a rigidez, a função e a qualidade de vida. Métodos: Onze pacientes com artrite hemofílica de joelhos com e sem acometimento de outras articulações (tornozelos e cotovelos) foram submetidos a lavagem articular com soro fisiológico e subsequente infiltração de hilano e triancinolona em todas as articulações acometidas. Responderam os questionários algo-funcionais (WOMAC e Lequesne), escala analógica visual para dor (VAS) e SF-36, no pré-operatório, e com um e três meses de pós-operatório. Resultados: A dor (VAS e WOMAC dor) e a rigidez (WOMAC rigidez) não apresentaram melhora significativa (p=0,3; p=0,2; p=0,1, respectivamente). Porém a função apresentou uma melhora significativa dada pelo WOMAC função e total (11 pontos em média, p=0,04 e p=0,001, respectivamente). A pontuação no questionário de Lequesne não variou significativamente (p=0,1). Porém tantos os componentes mental como físico do SF 36 tiveram melhoras clinicamente relevantes e significativas (p=0,002). Conclusão: A lavagem articular com soro fisiológico seguida pela infiltração de corticosteroide e hilano é efetiva no tratamento da artropatia hemofílica, sobretudo na melhora funcional e na qualidade de vida. Nível de Evidência IV, Série de casos.

Objective: To assess whether viscosupplementation with hyaluronic acid in patients with severe hemophilic arthropathy associated with triamcinolone after washing with saline improves joint pain, stiffness, function and quality of life. Methods: Eleven patients with hemophilic arthritis of the knee with and without involvement of other joints (elbows and ankles) underwent joint lavage with saline and subsequent injection of Hylan and triamcinolone in all affected joints. The patients answered the algo-functional (Lequesne and WOMAC), visual analog scale for pain (VAS) and SF-36 (quality of life) questionnaires preoperatively, and at one and three months postoperatively. Results: Pain (VAS and WOMAC pain) and stiffness (WOMAC stiffness) did not show significant improvement (p = 0.3, p = 0.2, p = 0.1, respectively). However function had significant improvement given by WOMAC total and function (averaging 11 points, p = 0.04 and p = 0.001). There was no significant variation in scores in Lequesne’s questionnaire (p = 0.1), yet both mental and physical components of SF-36 presented clinically relevant and significant improvements (p = 0.002). Conclusion: Joint lavage with saline followed by injection of corticosteroids and Hylan is effective in the treatment of hemophilic arthropathy, especially in functional improvement and quality of life. Level ofEvidence IV, Case series.

Viscosupplementation in patients with hemophilic arthropathy.

OBJECTIVE: To assess whether viscosupplementation with hyaluronic acid in patients with severe hemophilic arthropathy associated with triamcinolone after washing with saline improves joint pain, stiffness, function and quality of life. METHODS: Eleven patients with hemophilic arthritis of the knee with and without involvement of other joints (elbows and ankles) underwent joint lavage with saline and subsequent injection of Hylan and triamcinolone in all affected joints. The patients answered the algo-functional (Lequesne and WOMAC), visual analog scale for pain (VAS) and SF-36 (quality of life) questionnaires preoperatively, and at one and three months postoperatively. RESULTS: Pain (VAS and WOMAC pain) and stiffness (WOMAC stiffness) did not show significant improvement (p = 0.3, p = 0.2, p = 0.1, respectively). However function had significant improvement given by WOMAC total and function (averaging 11 points, p = 0.04 and p = 0.001). There was no significant variation in scores in Lequesne's questionnaire (p = 0.1), yet both mental and physical components of SF-36 presented clinically relevant and significant improvements (p = 0.002). CONCLUSION: Joint lavage with saline followed by injection of corticosteroids and Hylan is effective in the treatment of hemophilic arthropathy, especially in functional improvement and quality of life. Level of Evidence IV, Case series.