Endothelial dysfunction markers syndecan-1 and thrombomodulin are associated with higher albuminuria levels in type 2 diabetes with no history of clinical cardiovascular disease.

INTRODUCTION: Individuals with type 2 diabetes and increased albuminuria, a well-established marker of microvascular complications, are at a higher risk for cardiovascular disease (CVD) and premature mortality. Therefore, a better understanding of the underlying pathophysiology is needed to improve risk stratification and tailor prevention and intervention. METHODS: We conducted a cross-sectional study including 463 individuals with type 2 diabetes, various degrees of albuminuria and without CVD. We analysed the association between albuminuria and markers of endothelial function (thrombomodulin and syndecan-1), thrombin generation (thrombin-antithrombin complex, prothrombin fragment 1 + 2), fibrinogen, platelet function (activation using soluble plasma selectin and aggregation using Multiplate® Analyzer) using regression models. RESULTS: In the study cohort 33 % were women, the mean ± SD age was 65 ± 9 years, and median [IQR] diabetes duration was 15 [9-20] years. In total, 344 (74 %) individuals had normal albuminuria, 87 (19 %) moderately- and 32 (7 %) severely increased albuminuria levels. Higher markers of endothelial function and fibrinogen were independently associated with higher albuminuria levels (p < 0.01). No association between albuminuria and markers of thrombin generation and platelet was demonstrated. CONCLUSION: We demonstrated an independent association between albuminuria and markers of endothelial function and fibrinogen in individuals with type 2 diabetes and no history of CVD.

Thromboprophylaxis in oesophageal cancer patients-a study protocol for a randomised, controlled trial (TOP-RCT).

BACKGROUND: The purpose of the study is to examine if prolonged thromboprophylaxis decreases the risk of thrombosis after intended curative surgery for oesophageal cancer. Study results are expected to inform a guideline for thromboprophylaxis after oesophageal cancer surgery. The perspective is to reduce morbidity and mortality in this critically ill patient group. Thrombosis is the second-most common cause of cancer death after the cancer itself. The risk of thrombosis depends on the cancer type, and upper gastrointestinal cancers are considered high risk. This risk is further increased when patients undergo surgery. However, only few studies have investigated the peri- and postoperative coagulation profile in oesophageal cancer patients. Due to this lack of knowledge, prophylaxis is currently restricted to 5000 IU (international units) low-molecular weight heparin daily from surgery until discharge from hospital (approximately 10 days), whereas patients with gastric cancer receive 30 days of treatment. The present study examines whether a 30-day treatment is superior and safe, compared with the current standard treatment. METHODS: The study is a randomised controlled trial. Inclusion is ongoing, and we aim to include 100 patients. Blood samples are drawn before and after surgery, and the coagulation is extensively examined. The primary endpoint is the difference in plasma levels of prothrombin fragment 1 + 2 (F1 + 2) 30 days after surgery between the intervention and the standard group. Furthermore, patients are examined with ultrasound to screen for asymptomatic venous thrombotic events (VTE). Secondary endpoints are incidence of bleeding, symptomatic and asymptomatic VTE and mortality 30 days 1 one year after surgery. DISCUSSION: The study will provide valuable information on the perioperative coagulation profile and VTE risk of oesophageal cancer patients. The study seeks to aid in optimising the postoperative thromboprophylaxis, and the perspective is to reduce morbidity and mortality in this at-risk patient population. TRIALS REGISTRATION: The trial was prospectively registered at the EU Clinical Trials Register with ID 2021-001335-24 on 30 June 2021 and at ClinicalTrials.gov with study identifier NCT05067153.

Elevated Thrombin Generation and Venous Thromboembolism Incidence in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy Compared with Minimally Invasive Rectal Surgery.

INTRODUCTION: Surgical treatment of colorectal cancer carries a risk for venous thromboembolism (VTE). We investigated changes in coagulation and fibrinolysis and the VTE incidence within 30 days in patients undergoing open cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) for peritoneal metastases from colorectal cancer and minimally invasive surgery (MIS) for localized rectal cancer. METHODS: This cohort study included 45 CRS + HIPEC and 45 MIS patients. Blood samples were obtained preoperatively, at the end of surgery, and postoperative day (POD) 1, 3 to 4, and 5 to 7. Systematic ultrasonographic screening for VTE was performed between POD 3 and 7. Computed tomography scan was performed if complications were suspected. The primary endpoint was the difference in mean change (Δ) with [95% confidence intervals] from preoperative to end of surgery in prothrombin fragment 1 + 2 (F1 + 2) levels. Secondary endpoints were the difference in mean change in biomarkers of coagulation and fibrinolysis from preoperative to POD 5 to 7 and the VTE incidence. RESULTS: F1 + 2 levels increased from preoperative to the end of surgery in both groups. The mean increase from preoperative to end of surgery in F1 + 2 levels was significantly greater in CRS + HIPEC patients than MIS patients: Δ1,322 [1,040:1,604] pmol/L, p < 0.01. The VTE incidence was significantly higher after CRS + HIPEC than MIS (24 vs. 5%, p = 0.01). CONCLUSION: F1 + 2 levels were increased after both procedures, but to a far greater extent following CRS + HIPEC. The VTE incidence within 30 days was significantly higher in patients treated with CRS + HIPEC than in MIS patients.

Immature platelets and platelet reactivity in patients with acute ST-segment Elevation Myocardial Infarction using whole blood flow cytometry with SYTO-13 staining.

BACKGROUND: Reduced effect of antiplatelet therapy has been reported in patients with ST-segment elevation myocardial infarction (STEMI). Multiple factors may concur to explain this, including increased amount of highly reactive immature platelets. OBJECTIVES: To investigate the association between immature platelets and reactivity determined with multicolour flow cytometry using the SYTO-13 dye in STEMI patients. METHODS: We conducted an observational study of 59 patients with acute STEMI. Blood samples were obtained within 24 h after admission and after loading doses of dual antiplatelet therapy. For comparison, samples were obtained from 50 healthy individuals. Immature platelets and platelet reactivity were investigated using multicolour flow cytometry including the SYTO-13 dye that binds to platelet RNA and thus provides a method for subdividing platelets into immature and mature platelets. Additionally, we assessed platelet aggregation, serum-thromboxane B2 levels and standard immature platelet markers. RESULTS: Immature platelets were more reactive than mature platelets in both STEMI patients and healthy individuals (p-values < 0.05). STEMI patients had lower platelet aggregation and thromboxane B2 levels than healthy individuals. We found a positive association between automatically determined immature platelet markers and CD63 expression on activated platelets (Spearman's rho: 0.27 to 0.58, p-values < 0.05). CONCLUSIONS: Our study shows that immature platelets identified with a multicolour flow cytometric method using the SYTO-13 dye are more reactive than mature platelets in patients with acute STEMI and in healthy individuals. The presence of immature platelets may be important for the overall platelet reactivity, which may have implications for the effect of antiplatelet therapy.

Acute and subacute effects of strenuous exercise on platelet aggregation, coagulation and fibrinolysis in patients with stable coronary artery disease.

INTRODUCTION: Strenuous exercise may occasionally cause coronary thrombosis with myocardial infarction and sudden cardiac death. MATERIALS AND METHODS: Patients with stable coronary artery disease (CAD) (n = 164) and healthy individuals (n = 25) performed strenuous exercise on a bicycle ergometer. Blood was drawn at baseline, immediately after exercise and 2 h later. Platelet aggregation was measured with Multiplate® Analyzer. Thrombin generation was determined using a thrombogram and by measuring prothrombin fragment 1 + 2 (F1 + 2). A clot lysis assay was used to investigate fibrinolysis. RESULTS: From baseline to immediately after exercise, thrombin receptor activating peptide (TRAP)-induced platelet aggregation increased in CAD patients (Δ77 AU × min, 95 % confidence interval (CI): 46;107) and in healthy individuals (Δ153 AU × min, 95%CI: 75;232). Endogenous thrombin potential (ETP) was unaffected by exercise, whilst F1 + 2 increased (Δ17%, 95%CI: 11;24) in CAD patients. Fibrin clot lysis time increased by 9 % (95%CI: 1-17) in CAD patients and by 26 % (95%CI: 8;45) in healthy individuals. When comparing baseline to 2 h post-exercise, TRAP-induced platelet aggregation remained slightly elevated in both CAD patients (Δ53 AU × min, 95%CI: 22;84) and healthy individuals (Δ140 AU × min, 95%CI: 62;219). In contrast, ETP and F1 + 2 decreased in CAD patients (Δ-6 %, 95%CI: -10;-1 and Δ-8 %, 95%CI: -14;-2). Moreover, clot lysis time decreased (Δ-19 %, 95%CI: -27;-11) in patients with CAD and returned to baseline in healthy individuals. All p-values were <0.05. CONCLUSIONS: Platelet aggregation and F1 + 2 were substantially elevated immediately after exercise in CAD patients, indicating a pro-thrombotic state. After 2 h of recovery, they exhibited a markedly increase in fibrinolysis. Similar results were observed in healthy individuals.

Impaired Whole-Blood Fibrinolysis is a Predictor of Mortality in Intensive Care Patients.

Background Altered fibrinolysis is considered to play a crucial role in the development of coagulopathy in sepsis. However, routine laboratory tests for fibrinolysis are currently very limited, and the impact of fibrinolytic capacity on clinical outcome is poorly investigated. Objectives To assess whole-blood fibrinolysis in patients admitted to the intensive care unit (ICU) and compare fibrinolysis in sepsis patients with nonsepsis patients. Further, to investigate associations between fibrinolytic capacity and 30-day mortality and venous thromboembolism (VTE). Methods This study was designed as a prospective cohort study. Adult ICU patients were included at the Aarhus University Hospital, Denmark. All patients had a blood sample obtained the morning after admission. A modified thromboelastometry (ROTEM®) analysis with tissue plasminogen activator (ROTEM®-tPA) was used to assess fibrinolysis. The primary endpoint was difference in ROTEM®-tPA lysis time between sepsis patients and nonsepsis patients. Results ROTEM®-tPA revealed fibrinolytic impairment in sepsis patients ( n = 30) compared with nonsepsis ICU controls ( n = 129), with longer lysis time (median [interquartile range] 3,600 [3,352-3,600] vs. 3,374 seconds [2,175-3,600], p < 0.01), lower maximum lysis (23 [8-90] vs. 94% [14-100], p = 0.02), and lower fibrinolysis speed (0.41 [0.0-1.4] vs. 1.6 mm/min [0.1-2.7], p = 0.01). In the composite ICU population, 61% (97/159) demonstrated prolonged lysis time indicating impaired fibrinolytic capacity. These patients had higher 30-day mortality (adjusted odds ratio [OR]: 2.26 [0.83-6.69]) and VTE risk (OR: 3.84 [0.87-17.8]) than patients with normal lysis time. Conclusion Sepsis patients showed impaired fibrinolysis measured with ROTEM®-tPA compared with nonsepsis patients and ROTEM®-tPA lysis time was associated with 30-day mortality and VTE in the entire ICU cohort.

Platelet Function and Maturity and Related microRNA Expression in Whole Blood in Patients with ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Reduced effect of antiplatelet therapy has been reported in patients with ST-segment elevation myocardial infarction (STEMI). MicroRNAs (miRs) may influence platelet function and maturity, and subsequently the effect of antiplatelet therapy. OBJECTIVES: We aimed to explore the association between miR expression and platelet function and maturity in patients with acute STEMI and healthy individuals. METHODS: We performed an observational study of STEMI patients admitted directly to primary percutaneous coronary intervention. Patients were treated with antiplatelet therapy according to guidelines. Within 24 hours after admission, blood samples were obtained to measure: the expression of 10 candidate miRs, platelet function markers using advanced flow cytometry, platelet aggregation, serum thromboxane B2, and platelet maturity markers. Furthermore, blood samples from healthy individuals were obtained to determine the normal variation. RESULTS: In total, 61 STEMI patients and 50 healthy individuals were included. STEMI patients had higher expression of miR-21-5p, miR-26b-5p, and miR-223-3p and lower expression of miR-150-5p, miR423-5p, and miR-1180-3p than healthy individuals. In STEMI patients, the expression of miR-26b-5p showed the most consistent association with platelet function (all p-values <0.05, Spearman's rho ranging from 0.27 to 0.41), while the expression of miR-150-5p and miR-223-3p showed negative associations with platelet function. No association between miR expression and platelet maturity markers was observed. CONCLUSION: In patients with STEMI, the expression of six miRs was significantly different from healthy individuals. The expression of miR-26b-5p may affect platelet function in acute STEMI patients and potentially influence the effect of antiplatelet therapy.

Thrombin Generation Markers as Predictors of Cancer-Associated Venous Thromboembolism: A Systematic Review.

Venous thromboembolism (VTE) is a main contributor to morbidity and mortality in cancer patients. Biomarkers with the potential to predict cancer-associated VTE are continually sought. Of these, markers of thrombin generation present a likely option. The present systematic review examines the ability of three widely used biomarkers of thrombin generation: prothrombin fragment 1.2 (F1.2), thrombin-antithrombin complex (TAT), and ex vivo thrombin generation, to predict VTE in both solid and hematologic adult cancer patients. Relevant studies were identified in the PubMed and Embase databases, and the review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Each study was evaluated using the quality assessment tool from the National Heart, Lung, and Blood Institute. The review protocol was published on PROSPERO with identifier CRD42022362339. In total, 24 papers were included in the review: 11 reporting data on F1.2, 9 on TAT, and 12 on ex vivo thrombin generation. The quality ratings of the included studies varied from good (n = 13), fair (n = 8), to poor (n = 3) with a high heterogenicity. However, F1.2, TAT complex, and ex vivo thrombin generation were all found to be associated with the development of VTE. This association was most pronounced for F1.2. Furthermore, the determination of F1.2 was able to improve the precision of several established risk assessment scores. In conclusion, markers of thrombin generation were found to be elevated in cancer patients with VTE, and particularly, F1.2 was found to be a promising predictor of cancer-associated VTE.

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.

Impact of Stereotactic Body Radiotherapy on Thrombin Generation and Platelet Aggregation in Patients with Non-Small Cell Lung Cancer.

Patients with localized non-small cell lung cancer (NSCLC) considered unfit for surgery are at substantially increased risk of venous thromboembolism. Radiotherapy may further increase this risk. We aim to investigate the impact of stereotactic body radiotherapy (SBRT) on thrombin generation and platelet aggregation. We included 110 patients with localized NSCLC treated with SBRT. Blood samples were obtained prior to SBRT, immediately after SBRT completion, and 4-6 weeks following SBRT. Ex vivo and in vivo thrombin generations were analyzed using a calibrated automated thrombogram and commercial enzyme-linked immunosorbent assays. Platelet aggregation was evaluated using multiple electrode aggregometry. No significant differences were found in ex vivo or in vivo thrombin generation between blood samples before and immediately after SBRT treatment. Platelet aggregation was lower immediately after SBRT than before SBRT (TRAP: P = 0.04 and ASPI: P = 0.02) but remained within the reference interval. SBRT did not affect in vivo and ex vivo thrombin generation or platelet aggregation. SBRT did not cause prothrombotic changes in the coagulation in this study population of SBRT-treated patients with localized NSCLC.

The angiotensin-converting enzyme I/D polymorphism does not impact training-induced adaptations in exercise capacity in patients with stable coronary artery disease.

Systematic exercise training effectively improves exercise capacity in patients with coronary artery disease (CAD), but the magnitude of improvements is highly heterogeneous. We investigated whether this heterogeneity in exercise capacity gains is influenced by the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. Patients with CAD (n = 169) were randomly assigned to 12 weeks of exercise training or standard care, and 142 patients completed the study. The ACE polymorphism was determined for 128 patients (82% males, 67 ± 9 years). Peak oxygen uptake was measured before and after the 12-week intervention. The ACE I/D polymorphism frequency was n = 48 for D/D homozygotes, n = 61 for I/D heterozygotes and n = 19 for I/I homozygotes. Baseline peak oxygen uptake was 23.3 ± 5.0 ml/kg/min in D/D homozygotes, 22.1 ± 5.3 ml/kg/min in I/D heterozygotes and 23.1 ± 6.0 ml/kg/min in I/I homozygotes, with no statistical differences between genotype groups (P = 0.50). The ACE I/D polymorphism frequency in the exercise group was n = 26 for D/D, n = 21 for I/D and n = 12 for I/I. After exercise training, peak oxygen uptake was increased (P < 0.001) in D/D homozygotes by 2.6 ± 1.7 ml/kg/min, in I/D heterozygotes by 2.7 ± 1.9 ml/kg/min, and in I/I homozygotes by 2.1 ± 1.3 ml/kg/min. However, the improvements were similar between genotype groups (time × genotype, P = 0.55). In conclusion, the ACE I/D polymorphism does not affect baseline exercise capacity or exercise capacity gains in response to 12 weeks of high-intensity exercise training in patients with stable CAD.Clinical trial registration: www.clinicaltrials.gov (NCT04268992).

Impaired fibrinolysis and increased clot strength are potential risk factors for thrombosis in lymphoma.

Thrombosis and bleeding are significant contributors to morbidity and mortality in patients with hematological cancer, and the impact of altered fibrinolysis on bleeding and thrombosis risk is poorly understood. In this prospective cohort study, we investigated the dynamics of fibrinolysis in patients with hematological cancer. Fibrinolysis was investigated before treatment and 3 months after treatment initiation. A dynamic clot formation and lysis assay was performed beyond the measurement of plasminogen activator inhibitor 1, tissue- and urokinase-type plasminogen activators (tPA and uPA), plasmin-antiplasmin complexes (PAP), α-2-antiplasmin activity, and plasminogen activity. Clot initiation, clot propagation, and clot strength were assessed using rotational thromboelastometry. A total of 79 patients were enrolled. Patients with lymphoma displayed impaired fibrinolysis with prolonged 50% clot lysis time compared with healthy controls (P = .048). They also displayed decreased clot strength at follow-up compared with at diagnosis (P = .001). A patient with amyloid light-chain amyloidosis having overt bleeding at diagnosis displayed hyperfibrinolysis, indicated by a reduced 50% clot lysis time, α-2-antiplasmin activity, and plasminogen activity, and elevated tPA and uPA. A patient with acute promyelocytic leukemia also displayed marked hyperfibrinolysis with very high PAP, indicating extreme plasmin generation, and clot formation was not measurable, probably because of the extremely fast fibrinolysis. Fibrinolysis returned to normal after treatment in both patients. In conclusion, patients with lymphoma showed signs of impaired fibrinolysis and increased clot strength, whereas hyperfibrinolysis was seen in patients with acute promyelocytic leukemia and light-chain amyloidosis. Thus, investigating fibrinolysis in patients with hematological cancer could have diagnostic value.

Bleeding patients on extracorporeal membrane oxygenation have reduced platelet aggregation and plasma fibrinogen: a longitudinal observational study.

This study investigated changes in coagulation and associations with occurrence of bleeding and thrombosis during extracorporeal membrane oxygenation (ECMO) therapy. The study included 100 adult ECMO-patients. Standard coagulation parameters, platelet aggregation and thromboelastometry (ROTEM®) were compared with healthy controls. Data on bleeding and thrombosis were collected until recovery or death. Mortality data were collected 30 days after weaning from ECMO. During ECMO therapy, 53 patients experienced at least one moderate or major bleed. Among these, 42 (79%) patients experienced the first bleeding on day 1 or 2. Platelet aggregation and ROTEM® revealed a hypocoagulable state in ECMO patients when compared with healthy controls. Patients bleeding on day 1 or 2, had lower platelet count (p = 0.04), poorer platelet aggregation and lower levels of fibrinogen (p < 0.01) than patients not bleeding on day 1 or 2. Further, ROTEM® clot propagation was reduced in bleeding patients (p < 0.001). Mortality was higher among bleeding patients than patients not bleeding on day 1 or 2 (67% versus 34%, p < 0.01). Congruity existed between ROTEM® measurements and standard coagulation assays, but plasma fibrinogen had a stronger association with bleeding than ROTEM® measurements. The present study does not support ROTEM® analysis as a routine part of coagulation monitoring during ECMO therapy.

Kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon in an infant girl.

Key Clinical Message: We report a successful treatment course of an infant with mediastinal Kaposiform hemangioendothelioma. As the current complex of diseases is rare and calls for highly specialized treatment, large prospective studies are lacking. This case provides an example of balanced treatment complicated by Kasabach-Merritt phenomenon, life-threatening infections, and pericardial effusion. Abstract: Kaposiform hemangioendothelioma (KHE) and tufted angioma are vascular benign tumors that can be associated with the rare condition Kasabach-Merritt Phenomenon (KMP). KMP is characterized by consumption coagulopathy with severe thrombocytopenia, hypofibrinogenemia, and elevated D-dimer. We here report successful treatment of a female infant with a mediastinal KHE where treatment was complicated by KMP, life-threatening infections, and pericardial effusion. Due to the absence of randomized clinical trials, there is currently no standardized treatment protocol available for KHE. In our case, the infant was treated successfully with prednisolone, vincristine, and sirolimus.

Prophylaxis with low dose tranexamic acid in acute myeloid leukemia patients undergoing intensive chemotherapy.

Patients suffering from acute myeloid leukemia (AML) carry a high risk of serious bleeding complications due to severe thrombocytopenia for long periods of time during treatment. Prior to prophylactic platelet transfusion becoming the standard of care, intracranial bleeding was a major contributor to death in AML patients. However, despite prophylactic platelet transfusions, up to 79% of patients with AML experience clinically significant bleeding during treatment. Antifibrinolytics are effective and well tolerated hemostatic agents widely used in many patient groups, and in this study, we investigated the effect of low dose tranexamic acid (TXA) in patients with AML and thrombocytopenia. We compared bleeding and thrombosis between 113 thrombocytopenic AML patients receiving TXA 500 mg three times daily (n = 36) versus no-TXA (n = 77). Clinical information was obtained systematically from electronic medical records, and laboratory data were collected from the laboratory information system. No difference was demonstrated in number of patients with at least one bleeding episode (TXA: 89% vs. no-TXA: 93%, p = 0.60), median number of bleeding days (TXA: 2.5 days vs. no-TXA 2.0 days, p = 0.30), bleeding location or transfusion needs between the two groups. However, platelet count was found to be a significant risk factor for bleeding, with a probability of bleeding of 35% with a platelet count below 5 × 109/L (logistic regression, p < 0.01). We found no difference in thromboembolic events between the two groups (TXA: 8% vs. no-TXA 10%, p = 0.99). In conclusion, treatment with low dose TXA is safe, but we found no evidence to suggest that it reduces bleeding in AML patients with thrombocytopenia.

Platelets and the Lectin Pathway of Complement Activation in Patients with Systemic Lupus Erythematosus or Antiphospholipid Syndrome.

Background Patients with systemic lupus erythematosus (SLE) have an increased risk of thrombosis even when they do not have antiphospholipid syndrome (APS). Interactions between complement activation and activated platelets have been suggested in SLE and APS and could play a role in the increased thrombosis risk. Objectives To explore factors potentially related to the prothrombotic pathophysiology in patients with SLE, primary APS, and healthy controls, by investigating lectin pathway proteins (LPPs), complement activation, platelet aggregation, and platelet activation. Methods This cross-sectional cohort study included 20 SLE patients, 17 primary APS, and 39 healthy controls. Flow cytometry and light transmission aggregometry were used to assess platelet activation and aggregation. Using time-resolved immunofluorometric assays, the plasma concentrations of 11 LPPs and C3dg, reflecting complement activation, were measured. Results H-ficolin plasma concentrations were higher in SLE and APS patients than in controls ( p = 0.01 and p = 0.03). M-ficolin was lower in SLE than in APS ( p = 0.01) and controls ( p = 0.03). MAp19 was higher in APS patients than in SLE patients ( p = 0.01) and controls ( p < 0.001). In APS patients, MASP-2 and C3dg correlated negatively with platelet activation. Platelet-bound fibrinogen after agonist stimulation and C3dg concentrations correlated negatively with platelet activation. Conclusion We observed significant differences between SLE and APS patients regarding complement proteins and platelet activation. Particularly the negative correlations between MASP-2 and C3dg with platelet activation only observed in APS patients suggest that interactions between complement activation and platelets differ in SLE and APS.

Immature platelets and cardiovascular events in patients with stable coronary artery disease.

Many patients with coronary artery disease (CAD) have reduced the effect of aspirin, which may partly be explained by immature platelets. We aimed to investigate whether immature platelet markers can predict cardiovascular events in a large cohort of stable CAD patients. A total of 900 stable CAD patients were included and followed for a median of 3 years. We measured markers of immature platelets (platelet count, immature platelet count, immature platelet fraction, mean platelet volume, platelet distribution width, platelet mass, and thrombopoietin) using automated flow cytometry and studied their relation to cardiovascular events. Our primary endpoint was a composite of acute myocardial infarction (MI), ischemic stroke, and cardiovascular death. A composite of MI, ischemic stroke, stent thrombosis and all-cause mortality was analyzed as a secondary endpoint. We found no difference in immature platelet markers between CAD patients with or without cardiovascular events. Regression analysis using hazards rates showed that markers of immature platelets did not have any predictive value for endpoints (p-values >.05). Markers of immature platelets did not predict future cardiovascular events during a 3-year follow-up period in CAD patients. This suggests that immature platelets measured in a stable phase does not have a major role in predicting future cardiovascular events.

What is the context? Many patients with coronary artery disease (CAD) have reduced antiplatelet effect of aspirinThe reduced antiplatelet effect of aspirin is most likely multifactorial and may partly be explained by immature plateletsWhat is new? In a cohort of 900 stable CAD patients, we measured markers of immature platelets and studied their relation to cardiovascular events during a 3-year follow-upOur study demonstrated that markers of immature platelets did not predict cardiovascular events in our cohortWhat is the impact? The findings from the present study suggest that immature platelets, measured in a stable phase, do not have a major role in predicting future cardiovascular events in CAD patients.

Modified Rotational Thromboelastometry Protocol Using Tissue Plasminogen Activator for Detection of Hypofibrinolysis and Hyperfibrinolysis.

Viscoelastic testing includes thromboelastography (TEG®) and thromboelastometry (ROTEM®) and is widely used in bleeding patients to detect hypocoagulability and guide transfusion therapy. However, the ability of standard viscoelastic tests to assess fibrinolytic capacity is limited. We here describe a modified ROTEM® protocol with addition of tissue plasminogen activator that can be used to identify hypofibrinolysis or hyperfibrinolysis.