Platelet Parameters as Biomarkers for Thrombosis Risk in Cancer: A Systematic Review and Meta-analysis.

Cancer-associated thrombosis (CAT) is a major cause of both morbidity and mortality in cancer patients. Platelet count has been investigated as a predictor of CAT in various settings while knowledge on platelet activation parameters is sparse. This report provides a systematic review and meta-analysis on available literature on associations between platelet count and/or function and arterial and venous thrombosis in adult cancer patients. The review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. PubMed and Embase were searched up to March 2022. The National Heart, Lung, and Blood Institute's tools were used for quality assessment. In total, 100 studies were included which investigated the association between CAT and platelet count (n = 90), platelet indices (n = 19), and platelet function/activation markers (n = 13) in patients with solid cancers (n = 61), hematological cancers (n = 17), or mixed cancer types (n = 22). Eighty-one studies had venous thrombosis as their outcome measure, while 4 had arterial thrombosis and 15 studies had both. We found significantly elevated odds ratio of 1.50 (95% confidence interval: 1.19-1.88) for thrombosis with higher platelet counts. We saw a tendency toward an association between markers of platelet activation in forms of mean platelet volume and soluble P selectin and both arterial and venous thrombosis. Only one study investigated dynamic platelet function using flow cytometry. In conclusion, platelet count is associated with CAT across different cancer types and settings. Platelet function or activation marker analysis may be valuable in assisting thrombosis risk assessment in cancer patients but is sparsely investigated so far.

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.

Prognostic Impact of the International Society on Thrombosis and Hemostasis Disseminated Intravascular Coagulation Score in Sepsis: A Systematic Review.

The International Society on Thrombosis and Haemostasis (ISTH) diagnostic criteria for disseminated intravascular coagulation (DIC) are widely used for DIC diagnosis. However, the prognostic value of the score may vary between different patient populations and settings. This systematic review investigated the association between the ISTH DIC score and mortality in sepsis patients. A literature search was conducted in PubMed and Embase. Inclusion criteria were studies including adult and pediatric patients hospitalized with sepsis, using any sepsis definition, and investigating the association between mortality and the ISTH DIC score. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. In total, 42 studies were included. A positive association between the ISTH DIC score and mortality was consistently reported, with odds ratios of death in DIC versus non-DIC patients ranging from 1.125 (95% confidence interval [CI]: 0.838-1.511) to 21.008 (95% CI: 1.408-313.405) in adults and from 1.378 (95% CI: 1.004-1.893) to 2.99 (95% CI: 0.54-16.6) in pediatric populations. However, the DIC score only had a low-moderate positive predictive value for mortality, as area under receiver-operator characteristics ranged from 0.602 (95% CI: 0.575-0.630) to 0.815 (95% CI: 0.676-0.954) in adults. Of note, only few studies adjusted for potential confounders such as age, gender, and comorbidity. The ISTH DIC score is consistently associated with sepsis-related mortality but is not a strong positive predictor for mortality. Nevertheless, the score may still have a prognostic value and its use in sepsis is encouraged.

Platelet Function Testing: Update and Future Directions.

Platelets play a key role in maintaining normal hemostasis and are also recognized as partners in the development of arterial thrombosis. Today, platelet function testing is used for very different clinical purposes; first, for investigation of platelet dysfunction in acute bleeding and diagnosis of platelet disorders in patients with long-lasting bleeding tendency, and second, for testing the efficacy of antiplatelet therapy in patients with increased thromboembolic risk. Moreover, it has been discussed whether platelet function testing can be used for prediction of bleeding risk (e.g., prior to major surgery). Ever since light transmission aggregometry was introduced, laboratories around the world have worked on testing platelet function, and during the last decades a wide range of new methods has emerged. Besides the clinical utility of platelet function testing, the present review summarizes the test principles and advantages and disadvantages of the different methods, depending on the purpose for which it is to be used. A critical step in investigation of platelet function is the preanalytical factors that can substantially affect test results. Therefore, this review also provides an overview of preanalytical variables that range from patient-related factors such as smoking, coffee, and exercise prior to blood sampling to selection of anticoagulant, needle gauge, and time from blood sampling to analyses. Finally, this review outlines further perspectives on platelet function testing for clinical practice and for research purposes.

Mechanical Heart Valves, Pregnancy, and Bleeding: A Systematic Review and Meta-Analysis.

Anticoagulant therapy is essential in pregnant women with mechanical heart valves to prevent valve thrombosis. The risk of bleeding complications in these patients has not gained much attention. This systematic review and meta-analysis investigate the prevalence of bleeding peri-partum and post-partum in women with mechanical heart valves and also investigate whether bleeding risk differed across anticoagulant regimens or according to delivery mode. The present study was conducted according to The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Studies reporting bleeding prevalence in pregnant women with mechanical heart valves receiving anticoagulant therapy were identified through PubMed and Embase on December 08, 2021. Data on bleeding complications, delivery mode, and anticoagulation therapy were extracted. A total of 37 studies were included, reporting 423 bleeding complications in 2,508 pregnancies. A meta-analysis calculated a pooled prevalence of 0.13 (95% confidence interval [CI]: 0.09-0.18) bleeding episodes per pregnancy across anticoagulant regimens. The combination of unfractionated heparin (UFH) and vitamin K antagonist (VKA) and single VKA therapy showed the lowest risk of bleeding (8 and 12%). Unexpectedly, the highest risk of bleeding was found in women receiving a combination of low-molecular-weight-heparin (LMWH) and VKA (33%) or mono-therapy with LMWH (22%). However, this could be dose related. No difference in bleeding was found between caesarean section versus vaginal delivery (p = 0.08). In conclusion, bleeding episodes are common during pregnancy in women with mechanical heart valves receiving anticoagulant therapy. A combination of UFH and VKA or VKA monotherapy showed the lowest risk of bleeding.

Platelet Function in Acute Kidney Injury: A Systematic Review and a Cohort Study.

Acute kidney injury (AKI) patients have increased bleeding risk, which could be partially due to acquired platelet dysfunction. We conducted a systematic review and a cohort study to investigate platelet function and count in AKI and their association with AKI-related bleeding and mortality. Through a systematic literature search in PubMed and Embase, we identified 9 studies reporting platelet function and 56 studies reporting platelet count or platelet indices in AKI patients. Overall, platelet aggregation was reduced in AKI patients in nonintensive care unit (ICU) settings but not in ICU settings, except that reduced aggregation was associated with renal replacement therapy. Thrombocytopenia in AKI was frequent and often predictive of mortality. In our cohort study, we prospectively included 54 adult ICU patients who developed AKI within 24 hours of ICU admission and 33 non-AKI ICU controls. Platelet function was measured with light transmission aggregometry and flow cytometry. AKI patients bled more frequently than non-AKI patients (p = 0.04), and bleeding was associated with increased 30-day mortality in AKI (p = 0.02). However, platelet function was not different between AKI and non-AKI patients (aggregation: all p > 0.52; flow cytometry: all p > 0.07) and platelet function was not associated with bleeding in AKI. In conclusion, a reduced platelet count is frequent in AKI, but the literature on platelet function in AKI is sparse. In a cohort study, we demonstrated that patients with AKI within 24 hours of ICU admission exhibited increased bleeding tendency but this was not associated with reduced platelet function.

The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment.

The fibrinolytic system is a key player in keeping the haemostatic balance, and changes in fibrinolytic capacity can lead to both bleeding-related and thrombosis-related disorders. Our knowledge of the fibrinolytic system has expanded immensely during the last 75 years. From the first successful use of thrombolysis in myocardial infarction in the 1960s, thrombolytic therapy is now widely implemented and has reformed treatment in vascular medicine, especially ischemic stroke, while antifibrinolytic agents are used routinely in the prevention and treatment of major bleeding worldwide. Despite this, this research field still holds unanswered questions. Accurate and timely laboratory diagnosis of disturbed fibrinolysis in the clinical setting remains a challenge. Furthermore, despite growing evidence that hypofibrinolysis plays a central role in, e.g., sepsis-related coagulopathy, coronary artery disease, and venous thromboembolism, there is currently no approved treatment of hypofibrinolysis in these settings. The present review provides an overview of the fibrinolytic system and history of its discovery; measurement methods; clinical relevance of the fibrinolytic system in diagnosis and treatment; and points to future directions for research.

Dynamic Hemostasis and Fibrinolysis Assays in Intensive Care COVID-19 Patients and Association with Thrombosis and Bleeding-A Systematic Review and a Cohort Study.

Patients admitted to the intensive care unit (ICU) with coronavirus disease 2019 (COVID-19), the infectious pathology caused by severe acute respiratory syndrome coronavirus 2, have a high risk of thrombosis, though the precise mechanisms behind this remain unclarified. A systematic literature search in PubMed and EMBASE identified 18 prospective studies applying dynamic coagulation assays in ICU COVID-19 patients. Overall, these studies revealed normal or slightly reduced primary hemostasis, prolonged clot initiation, but increased clot firmness. Thrombin generation assay parameters generally were equivalent to the control groups or within reference range. Fibrinolysis assays showed increased clot resistance. Only six studies related their findings to clinical outcome. We also prospectively included 51 COVID-19 patients admitted to the ICU. Blood samples were examined on day 1, 3-4, and 7-8 with platelet function tests, rotational thromboelastometry (ROTEM), in vivo and ex vivo thrombin generation, and clot lysis assay. Data on thrombosis, bleeding, and mortality were recorded during 30 days. Primary hemostasis was comparable to healthy controls, but COVID-19 patients had longer ROTEM-clotting times and higher maximum clot firmness than healthy controls. Ex vivo thrombin generation was similar to that of healthy controls while in vivo thrombin generation markers, thrombin-antithrombin (TAT) complex, and prothrombin fragment 1 + 2 (F1 + 2) were higher in ICU COVID-19 patients than in healthy controls. Impaired fibrinolysis was present at all time points. TAT complex and F1 + 2 levels were significantly higher in patients developing thrombosis (n = 16) than in those without. In conclusion, only few previous studies employed dynamic hemostasis assays in COVID-19 ICU-patients and failed to reveal a clear association with development of thrombosis. In ICU COVID-19 patients, we confirmed normal platelet aggregation, while in vivo thrombin generation was increased and fibrinolysis decreased. Thrombosis may be driven by increased thrombin formation in vivo.

Thrombin: A Pivotal Player in Hemostasis and Beyond.

The serine protease thrombin, a naturally derived enzyme, plays a key role in hemostasis by converting fibrinogen to fibrin and activating coagulation factor XIII whereby the fibrin clot is stabilized. Furthermore, thrombin activates platelets through protease-activated receptors on the platelet surface. Conversely, thrombin also exerts anticoagulant effects, enhancing the protein C activity while complexed with thrombomodulin. During recent years, it has become evident that thrombin has significant effects beyond hemostasis, as it contributes also to modulation of the endothelium, promotes inflammation and angiogenesis, and plays a role in tumor progression. Yet, due to the very short half-life and almost immediate inhibition in fluid phase by antithrombin, thrombin itself remains elusive, and only indirect measurement of thrombin generation is possible. This review provides a description of structure and mechanisms of action of thrombin both in physiological and pathological processes. Furthermore, it summarizes laboratory tests that measure in vivo or ex vivo thrombin generation, and presents knowledge on the value of these biomarkers in bleeding disorders, cardiopulmonary bypass surgery, and thromboembolic risk assessment in different patient populations. Finally, this review outlines further perspectives on using thrombin generation biomarkers for research purposes and in clinical practice.

Fibrinolytic Alterations in Sepsis: Biomarkers and Future Treatment Targets.

Sepsis is a life-threatening condition which develops as a dysregulated immune response in the face of infection and which is associated with profound hemostatic disturbances and in the most extreme cases disseminated intravascular coagulation (DIC). In addition, the fibrinolytic system is subject to alterations during infection and sepsis, and impaired fibrinolysis is currently considered a key player in sepsis-related microthrombus formation and DIC. However, we still lack reliable biomarkers to assess fibrinolysis in the clinical setting. Furthermore, drugs targeting the fibrinolytic system have potential value in sepsis patients with severe fibrinolytic disturbances, but these are still being tested in the preclinical stage. The present review provides an overview of key fibrinolytic changes in sepsis, reviews the current literature on potential laboratory markers of altered fibrinolysis in adult sepsis patients, and discusses future perspectives for diagnosis and treatment of fibrinolytic disturbances in sepsis patients.

Efficacy and Safety of Antifibrinolytic Drugs in Pediatric Surgery: A Systematic Review.

Antifibrinolytic drugs are used to reduce blood loss and subsequent transfusions during surgery and following trauma, but the optimal dosing regimen in the pediatric population is still unresolved. The aim of this systematic review was to evaluate efficacy and safety of antifibrinolytic drugs in pediatric surgery and trauma to determine the optimal dosing regimen. A literature search was performed in PubMed, Embase, Cochrane, and Web of Science on May 3, 2020. We included randomized controlled studies investigating the effect of tranexamic acid (TXA), aprotinin, and epsilon-aminocaproic acid, in terms of reducing blood loss, blood transfusions, reoperations, and rebleeds in pediatric patients aged 0 to 18 years undergoing cardiac surgery, noncardiac surgery, or trauma. Fifty randomized controlled trials (RCTs) were included; 28 RCTs investigated cardiac surgery and 22 investigated noncardiac surgery. No RCTs regarding trauma met the inclusion criteria. All antifibrinolytic drugs reduced postoperative blood loss and transfusions when used in pediatric surgery. The dosing regimen varied between studies, but similar effect sizes were found in terms of reduced blood loss regardless of the cumulative dose used. Few studies found adverse events, and no difference in incidence or type of adverse events was seen between the antifibrinolytic and the placebo group. In conclusion, use of antifibrinolytics is efficient and safe in children undergoing surgery. We propose TXA as the drug of choice based on its level of evidence and safety profile; we recommend a dosing regimen composed of a loading dose of 10 to 15 mg/kg prior to surgery followed by 1 to 5 mg/kg/h as continuous infusion throughout surgery.

Procollagen III, N-terminal propeptide (PIIINP): establishment of reference intervals in Northern European adults and children using the MAGLUMI 800 chemiluminescence immunoassay.

Procollagen III, N-terminal propeptide (PIIINP) is used as a biomarker for increased collagen III-synthesis. Reference intervals have not been established for the MAGLUMI 800 chemiluminescence immunoassay (CLIA) in Northern European adults or in children. The present study aimed to establish age-specific reference intervals in a Northern European population. PIIINP serum levels were analysed in healthy blood donors 19-67 years (n = 240) and children 2-18 years (n = 420). Furthermore, we investigated total imprecision and stability at room temperature and at -20 °C and performed a method comparison between MAGLUMI 800 CLIA (Snibe Diagnostics, Shenzhen, China) and ADVIA Centaur CP (Siemens Healthcare Diagnostics, Tarrytown, NY,USA). PIIINP was influenced by age but not sex. We established the following reference intervals: 2-10 years, 18-62 µg/L; 11-18 years, 15-75 µg/L; 19-39 years, 15-55 µg/L; 40-67 years, 14-31 µg/L. Total imprecision for PIIINP on MAGLUMI 800 was acceptable with coefficients of variation of 4.9% in the low range and 9.4% in the high range. PIIINP was stable for 24 h at room temperature after centrifugation and for at least 7 months at -20 °C. MAGLUMI 800 yielded significantly higher PIIINP levels than ADVIA Centaur CP. In conclusion, we established age-specific reference intervals for PIIINP using MAGLUMI 800 CLIA in a large Danish cohort. Our results may be useful for other laboratories wishing to establish PIIINP on the same platform and may provide improved guidance for medical doctors treating both children and adults with fibrotic disorders.

Fibrin Network Formation and Lysis in Septic Shock Patients.

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.

The Role of Platelets in Cancer-Related Bleeding Risk: A Systematic Review.

Cancer patients face an elevated risk of bleeding, and here platelets play a pivotal role. The association between platelet count and bleeding, as well as safe thresholds for prophylactic platelet transfusion, is described mainly in hematological malignancies, and knowledge is sparse for patients with solid tumors. Platelet function tests may further improve bleeding risk assessment in cancer patients. This study provides a systematic review of the available literature on associations between platelet count and/or function and bleeding in adult cancer patients. The review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. PubMed, Embase, and Web of Science were searched up to August 2019. The National Heart, Lung, and Blood Institute's tools were used for quality assessment. In total, 52 studies investigated associations between bleeding and platelet count (n = 40) or function (n = 12) in patients with hematological malignancy (n = 31), solid tumors (n = 11), or both (n = 10). The majority of included studies rated good (n = 23) or fair (n = 25). The association between platelet count and bleeding was most pronounced at platelet counts ≤ 10 × 109/L but was less evident for solid tumors. Overall, reduced platelet function was significantly associated with bleeding risk. Thus, the available evidence supports current guidelines for prophylactic platelet transfusions at platelet count ≤ 10 × 109/L in hematological cancer patients, whereas more evidence is needed in patients with solid tumors. Platelet function analysis may be valuable in assisting bleeding risk assessment in cancer patients but is sparsely investigated so far.

Thrombophilia testing in patients with portal vein thrombosis.

Portal vein thrombosis (PVT) is a rare but severe condition. Several risk factors predispose to PVT. However, it remains unclear to which degree thrombophilia contributes to the risk of PVT and whether PVT patients should be routinely referred for thrombophilia testing. The aim of the present study was to investigate the prevalence of thrombophilia in PVT patients to clarify the relevance of thrombophilia testing in PVT patients. Clinical data and results from thrombophilia investigations were systematically obtained from all PVT patients referred to Centre for Hemophilia and Thrombosis, Aarhus University Hospital, Denmark for thrombophilia testing between 1st of January 2010 and 31st of December 2018 (n = 93). The investigated thrombophilias included factor V Leiden and prothrombin G20210A mutations, deficiency of protein S, protein C and antithrombin, antiphospholipid syndrome, and increased levels of factor VIII. The prevalence of thrombophilia was compared to healthy controls obtained from previously published data on thrombophilia distribution in cohorts of the Western European adult general population. Comparing PVT patients with healthy controls, significantly increased odds of presence of lupus anticoagulant (crude odds ratio (OR) 6.2, 95% confidence interval (CI) 1.8-20.6) were found, whereas no significantly increased odds of inherited thrombophilia were demonstrated. In conclusion, routine testing for inherited thrombophilia in PVT patients does not seem indicated. However, PVT patients should still be tested for antiphospholipid antibodies because patients meeting the criteria for antiphospholipid syndrome preferentially should receive vitamin K antagonists as anticoagulant therapy.

Platelet function in preeclampsia - a systematic review and meta-analysis.

Preeclampsia is a serious pregnancy-related complication. Platelets are potentially important in the pathogenesis of preeclampsia, and platelet function analyses may prove as sensitive preeclampsia biomarkers. This study aimed to systematically review and summarise the literature on platelet function markers in preeclampsia. This systematic review was conducted according to PRISMA and registered in PROSPERO. Relevant studies were identified through PubMed and Embase on 15/08/17. As platelet function markers platelet activation, platelet aggregation and platelet adhesion markers were included. If possible, relevant data were extracted for each marker to perform a meta-analysis of the mean difference between women with and without preeclampsia. All 69 included articles underwent quality rating. Some platelet activation markers, especially p-selectin and mean platelet volume (MPV), were significantly increased comparing the two groups of women, while others were not. The meta-analysis demonstrated that, overall, women with preeclampsia had significantly higher MPV than in women without preeclampsia. No significant difference was found regarding platelet aggreg`ation comparing the two groups. Platelet adhesion was investigated in noneof the included studies. In conclusion, further studies are warranted to investigate platelet activation markers future role as predictive markers in preeclampsia. MPV is suggested as the most promising biomarker for evaluating platelet function in preeclampsia.

Platelet function in disseminated intravascular coagulation: A systematic review.

Disseminated intravascular coagulation (DIC) has a well-examined pathophysiology, yet some essential elements remain undetermined. During DIC, platelets play an important role in the development of micro thrombosis, but changes in platelet function parameters and their association with development of DIC have not been established. The present systematic review investigated reported associations between platelet function (activation, aggregation, and adhesion) and DIC. We performed a literature search in Embase and PubMed, following the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) guidelines. In total, 22 articles were included; 14 human studies, seven animal studies, and one with both human and animal subjects. Platelet activation markers were generally reported to be higher in both DIC patients and animals with DIC than healthy controls, and higher among patients with DIC than patients without DIC. Six human and six animal studies investigated platelet aggregation, which were overall reported to be lower in DIC than in non-DIC or in healthy controls in both human and animal studies. Platelet aggregation was deemed to be confounded by low platelet counts, which are known to affect platelet aggregation analyses even within the reference interval. In conclusion, platelet activation analyses showed promise in diagnosis of DIC, but semi-automatization and standardization are warranted before these can be implemented in daily clinical practice. Changes in platelet aggregation analyses during DIC remain inconclusive, and further studies including adjustment for low platelet count are needed to clarify the role of platelet aggregation in DIC.