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

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.

Postoperative bleeding and venous thromboembolism in colorectal cancer patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a systematic review and meta-analysis.

PURPOSE: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival for selected patients with peritoneal metastases from colorectal cancer. Previous studies report conflicting rates of postoperative bleeding and venous thromboembolism (VTE) after CRS + HIPEC. The aim of the present study was to systematically review the literature and to estimate the overall 30-day incidence of postoperative bleeding and the overall 90-day incidence of VTE after CRS + HIPEC. METHODS: Studies were identified in PubMed, Embase, and Web of Science on 29 April 2021. Data were extracted for a qualitative synthesis and to estimate an overall mean incidence in the meta-analysis. RESULTS: Fourteen studies with a total of 3268 patients were included in the systematic review. Postoperative bleeding incidence rates within 30 days ranged from 1.7 to 8.3% with an overall 30-day postoperative bleeding incidence with [95% CI] at 4.2 [2.6;6.2]%. VTE incidence rates within 90 days ranged from 0.2 to 13.6% with an overall 90-day VTE incidence with [95% CI] at 2.7 [1;5.2]% after CRS + HIPEC. CONCLUSION: This systematic review and meta-analysis indicate a low risk for postoperative bleeding within 30 days and VTE within 90 days after CRS + HIPEC for peritoneal metastases from colorectal cancer.

Fibrinolysis and Remote Ischemic Conditioning: Mechanisms and Treatment Perspectives in Stroke.

Stroke is a leading cause of death and disability. Intravenous thrombolysis and mechanical thrombectomy have greatly improved outcomes in acute ischemic stroke (AIS). However, only a minority of patients receive reperfusion therapies, highlighting the need for novel neuroprotective therapies. Remote ischemic conditioning (RIC), consisting of brief, intermittent extremity occlusion and reperfusion induced with an inflatable cuff, is a potential neuroprotective therapy in acute stroke. The objective of this narrative review is to describe the effect of RIC on endogenous fibrinolysis and, from this perspective, investigate the potential of RIC in the prevention and treatment of stroke. A systematic literature search was performed in PubMed, and human studies in English were included. Seven studies had investigated the effect of RIC on fibrinolysis in humans. Long-term daily administration of RIC increased endogenous fibrinolysis, whereas a single RIC treatment did not acutely influence endogenous fibrinolysis. Fifteen studies had investigated the effect of RIC as a neuroprotective therapy in the prevention and treatment of stroke. Long-term RIC administration proved effective in reducing new cerebral vascular lesions in patients with established cerebrovascular disease. In patients with acute stroke, RIC was safe and feasible, though its clinical efficacy as a neuroprotectant is yet unproven. In conclusion, a single RIC treatment does not affect fibrinolysis in the acute phase, whereas long-term RIC administration may increase endogenous fibrinolysis. Increased endogenous fibrinolysis is unlikely to be the mediator of the acute neuroprotective effect of RIC in stroke patients, whereas it may partly explain the reduced stroke recurrence associated with long-term RIC treatment.

Remote ischemic preconditioning does not influence lectin pathway protein levels in head and neck cancer patients undergoing surgery.

BACKGROUND: Cancer patients who undergo tumor removal, and reconstructive surgery by transfer of a free tissue flap, are at high risk of surgical site infection and ischemia-reperfusion injury. Complement activation through the lectin pathway (LP) may contribute to ischemia-reperfusion injury. Remote ischemic preconditioning (RIPC) is a recent experimental treatment targeting ischemia-reperfusion injury. The study aims were to investigate LP protein plasma levels in head and neck cancer patients compared with healthy individuals, to explore whether RIPC affects LP protein levels in head and neck cancer surgery, and finally to examine the association between postoperative LP protein levels and the risk of surgical site infection. METHODS: Head and neck cancer patients (n = 60) undergoing tumor resection and reconstructive surgery were randomized 1:1 to RIPC or sham intervention administered intraoperatively. Blood samples were obtained preoperatively, 6 hours after RIPC/sham, and on the first postoperative day. LP protein plasma levels were measured utilizing time-resolved immunofluorometric assays. RESULTS: H-ficolin and M-ficolin levels were significantly increased in cancer patients compared with healthy individuals (both P ≤ 0.02). Conversely, mannan-binding lectin (MBL)-associated serine protease (MASP)-1, MASP-3, collectin liver-1 (CL-L1), and MBL-associated protein of 44 kilodalton (MAp44) levels were decreased in cancer patients compared with healthy individuals (all P ≤ 0.04). A significant reduction in all LP protein levels was observed after surgery (all P < 0.001); however, RIPC did not affect LP protein levels. No difference was demonstrated in postoperative LP protein levels between patients who developed surgical site infection and patients who did not (all P > 0.13). CONCLUSIONS: The LP was altered in head and neck cancer patients. LP protein levels were reduced after surgery, but intraoperative RIPC did not influence the LP. Postoperative LP protein levels were not associated with surgical site infection.

Thrombin generation, thrombin-antithrombin complex, and prothrombin fragment F1+2 as biomarkers for hypercoagulability in cancer patients.

BACKGROUND: Thrombin generation, thrombin-antithrombin complex (TAT) levels, and prothrombin fragment 1+2 (F1+2) have shown potential as biomarkers of thromboembolic risk. The aims were to establish reference intervals for these three biomarkers and to assess the levels in patients with localized cancer compared with healthy individuals. METHODS: We included 124 healthy individuals (57 females and 67 males; aged 21-66 years), 86 patients with low-stage primary lung cancer, and 57 patients with localized head and neck cancer. Thrombin generation was determined by the calibrated automated thrombogram using platelet-poor-plasma reagent containing 1 pM tissue factor and 4 µM phospholipids. TAT and F1+2 were measured using commercial enzyme-linked immunosorbent assays. Reference intervals were calculated as mean ± 1.96 × standard deviation (thrombin generation and F1+2) or 2.5th to 97.5th percentiles (TAT). RESULTS: The reference intervals for thrombin generation parameters were: lag time 4.4-9.4 min, peak thrombin 46-288 nM, time-to-peak thrombin 8-15 min, and endogenous thrombin potential 554-1952 nM x min. The reference interval for TAT was ≤13 µg/l, and for F1+2 it was 47-320 pmol/l. Both low-stage primary lung cancer and head and neck cancer patients had significantly higher TAT (p <0.0001) and F1+2 (p < 0.0001) concentrations than healthy individuals. However, this was not reflected in the thrombin generation assay. CONCLUSION: Reference intervals for thrombin generation, TAT as well as F1+2 were established. Patients with localized cancer had significantly elevated TAT and F1+2. TAT and F1+2 may hold potential for identifying hypercoagulation in cancer patients.

Effect of remote ischemic preconditioning on hemostasis and fibrinolysis in head and neck cancer surgery: A randomized controlled trial.

INTRODUCTION: The aim of this randomized controlled trial was to investigate if remote ischemic preconditioning (RIPC) reduced platelet aggregation and increased fibrinolysis in cancer patients undergoing surgery and thereby reduced the risk of thrombosis. MATERIALS AND METHODS: Head and neck cancer patients undergoing tumor resection and microsurgical reconstruction were randomized 1:1 to RIPC or sham intervention. RIPC was administered intraoperatively with an inflatable tourniquet by four cycles of 5-min upper extremity occlusion and 5-min reperfusion. The primary endpoint was collagen-induced platelet aggregation measured with Multiplate as area-under-the-curve on the first postoperative day. Secondary endpoints were markers of primary hemostasis, secondary hemostasis, and fibrinolysis. Clinical data on thromboembolic and bleeding complications were prospectively collected at 30-day follow-up. An intention-to-treat analysis was performed. RESULTS: Sixty patients were randomized to RIPC (n = 30) or sham intervention (n = 30). No patients were lost to follow-up. The relative mean [95% confidence interval] collagen-induced platelet aggregation was 1.26 [1.11;1.40] in the RIPC group and 1.17 [1.07;1.27] in the sham group on the first postoperative day reported as ratios compared with baseline (P = 0.30). Median (interquartile range) 50% fibrin clot lysis time was 517 (417-660) sec in the RIPC group and 614 (468-779) sec in the sham group (P = 0.25). The postoperative pulmonary embolism rate did not differ between groups (P = 1.0). CONCLUSIONS: RIPC did not influence hemostasis and fibrinolysis in head and neck cancer patients undergoing surgery. RIPC did not reduce the rate of thromboembolic complications.

Local and systemic coagulation marker response to musculocutaneous flap ischemia-reperfusion injury and remote ischemic conditioning: An experimental study in a porcine model.

BACKGROUND: Remote ischemic conditioning (RIC) administered by non-lethal periods of extremity ischemia and reperfusion attenuates ischemia-reperfusion injury. We aimed to investigate the local and systemic coagulation marker response to flap ischemia-reperfusion injury, and the effects of RIC on coagulation markers following flap ischemia-reperfusion injury. METHODS: A musculocutaneous latissimus dorsi flap was subjected to 4 h of ischemia followed by 7 h of reperfusion in 16 female Danish Landrace pigs (39 kg). Systemic venous blood samples were collected 1 h before flap reperfusion. Flap and systemic venous blood samples were collected at reperfusion and hourly during reperfusion. We measured thrombin generation, fibrinogen, von Willebrand factor, antithrombin, thrombin-antithrombin complex, activated partial thromboplastin time (aPTT), and prothrombin time (PT). RIC was performed 1 h before flap reperfusion in the intervention group by three 10-min periods of hind limb ischemia and reperfusion (n = 8). RIC was not performed in the control group (n = 8). RESULTS: Local and systemic coagulation marker changes were comparable following flap ischemia-reperfusion injury. Flap ischemia-reperfusion injury reduced thrombin generation lag time from 2.0 ± 0.3 to 1.6 ± 0.3 min (P < .001), time-to-peak thrombin from 3.5 ± 0.3 to 3.0 ± 0.5 min (P = .001), peak thrombin from 79.6 ± 8.1 to 74.5 ± 7.1 nM (P = .033), endogenous thrombin potential from 211 ± 24 to 197 ± 19 nM × min (P = .01), antithrombin from 0.91 ± 0.07 to 0.79 ± 0.06 103 IU/l (P = .002), and aPTT from 37 ± 21 to 21 ± 9 s (P = .017). RIC increased peak thrombin (P < .001), endogenous thrombin potential (P < .001), and aPTT (P = .019). CONCLUSIONS: The local coagulation marker response to musculocutaneous flap ischemia-reperfusion could be measured systemically by moderate hypercoagulation. RIC did not substantially influence coagulation markers following musculocutaneous flap ischemia-reperfusion injury.

No impact of fish oil supplements on bleeding risk: a systematic review.

INTRODUCTION: Fish oil supplementation may inhibit platelet aggregation and can potentially increase the risk of bleeding. The aim of the present systematic review was to evaluate the effect of fish oil supplements on haemostasis and bleeding risk, and to provide recommendations on whether it is necessary to discontinue fish oil supplementation prior to surgery. METHODS: Studies were identified through PubMed and Embase searches and by reviewing the reference lists of the included papers. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. Included in the review were publications including a minimum of 20 healthy subjects and studies on patients who were undergoing surgery and who had fish oil exposure. RESULTS: In total, 52 publications were included; 32 publications on healthy subjects and 20 publications on patients undergoing surgery. The majority of the included studies were randomised controlled trials or included a control group. Overall, fish oil supplements reduced platelet aggregation in healthy subjects. Fish oil exposure in surgical patients did not increase bleeding or blood transfusions either during or after surgery. CONCLUSION: Fish oil supplements reduced platelet aggregation in healthy subjects. This biochemical effect was not reflected in increased bleeding risk during or after surgery evaluated in randomised controlled trials. Consequently, this systematic review does not support the need for discontinuation of fish oil supplements prior to surgery or other invasive procedures.