Fibrinolytic Alterations in Sepsis: Biomarkers and Future Treatment Targets

Aggerbeck

et al. 2021

IJMS

Self Cite

Background: Septic shock patients are prone to altered fibrinolysis, which contributes to microthrombus formation, organ failure and mortality. However, characterisation of the individual patient’s fibrinolytic capacity remains a challenge due to a lack of global fibrinolysis biomarkers. We aimed to assess fibrinolysis in septic shock patients using a plasma-based fibrin clot formation and lysis (clot–lysis) assay and investigate the association between clot–lysis parameters and other haemostatic markers, organ dysfunction and mortality. Methods: This was a prospective cohort study including adult septic shock patients (n = 34). Clot–lysis was assessed using our plasma-based in-house assay. Platelet count, activated partial thromboplastin time (aPTT), international normalised ratio (INR), fibrinogen, fibrin D-dimer, antithrombin, thrombin generation, circulating fibrinolysis markers and organ dysfunction markers were analysed. Disseminated intravascular coagulation score, Sequential Organ Failure Assessment (SOFA) score and 30-day mortality were registered. Results: Three distinct clot–lysis profiles emerged in the patients: (1) severely decreased fibrin formation (flat clot–lysis curve), (2) normal fibrin formation and lysis and (3) pronounced lysis resistance. Patients with abnormal curves had lower platelet counts (p = 0.05), more prolonged aPTT (p = 0.04), higher lactate (p < 0.01) and a tendency towards higher SOFA scores (p = 0.09) than patients with normal clot–lysis curves. Fibrinogen and fibrin D-dimer were not associated with clot–lysis profile (p ≥ 0.37). Conclusion: Septic shock patients showed distinct and abnormal clot–lysis profiles that were associated with markers of coagulation and organ dysfunction. Our results provide important new insights into sepsis-related fibrinolysis disturbances and support the importance of assessing fibrinolytic capacity in septic shock.

Section: Introductionmentioning

confidence: 99%

Fibrin Network Formation and Lysis in Septic Shock Patients

Aggerbeck

et al. 2021

IJMS

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“…39 Yet, ROTEM/TEG might be limited providing detailed analysis of changes in fibrinolysis induced by cytoreductive surgery with HIPEC. 54,55 Elevated PAI-1, indicating suppressed fibrinolysis, was reported after cytoreductive surgery with HIPEC in the study by Delhorme et al 41 Additionally, the authors reported significantly in-creased PAI-1 at postoperative day 5 in patients with postoperative bleeding complications following cytoreductive surgery with HIPEC with oxaliplatin. 41 However, fibrinolysis was sparsely investigated and no consistent effect of cytoreductive surgery with HIPEC on fibrinolysis was found.…”

Section: Discussionmentioning

confidence: 94%

Changes in Coagulation in Cancer Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Treatment (HIPEC)—A Systematic Review

Lundbech

Damsbo

Krag

et al. 2023

Semin Thromb Hemost

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Venous thromboembolism and postoperative bleeding are complications of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this systematic review was to summarize current knowledge on the effect of cytoreductive surgery with HIPEC on coagulation and fibrinolysis within 10 days after surgery. Studies were identified in PubMed, Embase, and Web of Science on December 12, 2022. Data on biomarkers of coagulation and fibrinolysis measured preoperatively up to the 10th postoperative day were extracted. Among 15 included studies, 13 studies reported markers of primary hemostasis. Eleven studies found reduced platelet count following cytoreductive surgery with HIPEC and two studies reported reduced platelet function. Twelve studies reported impaired secondary hemostasis until postoperative day 10 indicated by prolonged international normalized ratio, prothrombin time, and activated partial thromboplastin time. Fibrinogen was decreased in three studies from preoperative to postoperative day 3 switching to increased levels until postoperative day 10. In accordance, three studies found reduced maximum amplitude and maximum clot firmness by thromboelastography/thromboelastometry (ROTEM/TEG) on the first postoperative day indicating impaired clot strength. Four studies demonstrated increased d-dimer, factor (F) VIII, and thrombin generation during the 10 postoperative days. Four studies investigated fibrinolysis by ROTEM/TEG and plasminogen activator inhibitor-1 (PAI-1) after cytoreductive surgery with HIPEC reporting contradictive results. In conclusion, a decrease in platelet count and subtle changes in secondary hemostasis were found following cytoreductive surgery with HIPEC. Data on the effect of cytoreductive surgery with HIPEC on fibrinolysis are sparse and this needs to be further investigated.

“…Although there was some heterogeneity in the study population, dogs with sepsis were hypercoagulable and hypofibrinolytic relative to normal dogs. Depressed fibrinolysis combined with increased fibrinogen thus contributes to a prothrombotic risk in dogs with sepsis, as it does in humans ( 46 , 47 ). Our results support recommendations that sepsis represents a risk factor for thrombosis in dogs that can warrant thromboprophylaxis ( 48 , 49 ).…”

Section: Discussionmentioning

confidence: 99%

Increased thrombin activatable fibrinolysis inhibitor activity is associated with hypofibrinolysis in dogs with sepsis

et al. 2023

IntroductionDisorders of coagulation are well-recognized in dogs with sepsis, but data regarding fibrinolysis disorders are limited. We aimed to characterize fibrinolysis in dogs with sepsis compared to healthy controls. We hypothesized that dogs with sepsis would be hypofibrinolytic, and that hypofibrinolysis would be associated with non-survival.MethodsThis was a prospective observational cohort study. We enrolled 20 client-owned dogs with sepsis admitted to the Cornell University Hospital for Animals and 20 healthy pet dogs. Coagulation and fibrinolytic pathway proteins including antiplasmin activity (AP), antithrombin activity (AT), thrombin activatable fibrinolysis inhibitor activity (TAFI), D-dimer concentration, fibrinogen concentration, and plasminogen activity were measured and compared between groups. Overall coagulation potential, overall fibrinolysis potential, and overall hemostatic potential were calculated from the curve of fibrin clot formation and lysis over time.ResultsCompared to healthy controls, dogs with sepsis had lower AT (P = 0.009), higher AP (P = 0.002), higher TAFI (P = 0.0385), and higher concentrations of fibrinogen (P < 0.0001) and D-dimer (P = 0.0001). Dogs with sepsis also had greater overall coagulation potential (P = 0.003), overall hemostatic potential (P = 0.0015), and lower overall fibrinolysis potential (P = 0.0004). The extent of fibrinolysis was significantly negatively correlated with TAFI. No significant differences were observed between survivors and non-survivors.DiscussionDogs with sepsis were hypercoagulable and hypofibrinolytic compared to healthy dogs, suggesting potential utility of thromboprophylaxis in this patient population. The association between high TAFI and low overall fibrinolysis potential might provide a potential mechanism for this hypofibrinolysis.