Exercise and hypoxia-induced hypercoagulability is counterbalanced in women in part by decreased platelet reactivity.

Hypoxia plays an important role in several pathologies, e.g. chronic obstructive pulmonary disease and obstructive sleep apnea syndrome, and is linked to an increased thrombosis risk. Furthermore, oxygen deprivation is associated with hypercoagulability. In this study, we investigated the effect of gender and exercise on the coagulation potential under hypoxic conditions at high altitude by assessing thrombin generation (TG) and platelet activation. Hereto, ten healthy volunteers were included (50 % male, median age of 27.5 years). The measurements were conducted first at sea level and then twice at high altitude (3883 m), first after a passive ascent by cable car and second after an active ascent by a mountain hike. As expected, both the passive and active ascent resulted in a decreased oxygen saturation and an increased heart rate at high altitude. Acute mountain sickness symptoms were observed independently of the ascent method. After the active ascent, platelet, white blood cell and granulocyte count were increased, and lymphocytes were decreased, without a gender-related difference. FVIII and von Willebrand factor were significantly increased after the active ascent for both men and women. Platelet activation was reduced and delayed under hypobaric conditions, especially in women. TG analysis showed a prothrombotic trend at high altitude, especially after the active ascent. Women had a hypercoagulable phenotype, compared to men at all 3 timepoints, indicated by a higher peak height and endogenous thrombin potential (ETP), and shorter lag time and time-to-peak. In addition, ETP and peak inhibition by thrombomodulin was lower in women after the active ascent, compared to men. Interestingly, data normalisation for subject baseline values indicated an opposing effect of altitude-induced hypoxia on α2-macroglobulin levels and TG lag time between men and women, decreasing in men and increasing in women. We conclude that hypoxia increases TG, as well as FVIII and VWF levels in combination with exercise. In contrast, platelets lose their responsiveness at high altitude, which is most pronounced after heavy exercise. Women had a more pronounced prothrombotic phenotype compared to men, which we theorize is counterbalanced under hypobaric conditions by decreased platelet activation.

Venous Thromboembolism and Primary Thromboprophylaxis in Perioperative Pancreatic Cancer Care.

Recent studies have shown that patients with pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant chemo(radio)therapy followed by surgery have an improved outcome compared to patients treated with upfront surgery. Hence, patients with PDAC are more and more frequently treated with chemotherapy in the neoadjuvant setting. PDAC patients are at a high risk of developing venous thromboembolism (VTE), which is associated with decreased survival rates. As patients with PDAC were historically offered immediate surgical resection, data on VTE incidence and associated preoperative risk factors are scarce. Current guidelines recommend primary prophylactic anticoagulation in selected groups of patients with advanced PDAC. However, recommendations for patients with (borderline) resectable PDAC treated with chemotherapy in the neoadjuvant setting are lacking. Nevertheless, the prevention of complications is crucial to maintain the best possible condition for surgery. This narrative review summarizes current literature on VTE incidence, associated risk factors, risk assessment tools, and primary thromboprophylaxis in PDAC patients treated with neoadjuvant chemo(radio)therapy.

Haemostatic differences between SARS-CoV-2 PCR-positive and negative patients at the time of hospital admission.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with thrombosis. We conducted a cohort study of consecutive patients, suspected of SARS-CoV-2 infection presented to the emergency department. We investigated haemostatic differences between SARS-CoV-2 PCR positive and negative patients, with dedicated coagulation analysis. The 519 included patients had a median age of 66 years, and 52.5% of the patients were male. Twenty-six percent of the patients were PCR-positive for SARS-CoV-2.PCR positive patients had increased levels of fibrinogen and (active) von Willebrand Factor (VWF) and decreased levels of protein C and α2-macroglobulin compared to the PCR negative patients. In addition, we found acquired activated protein C resistance in PCR positive patients. Furthermore, we found that elevated levels of factor VIII and VWF and decreased levels of ADAMTS-13 were associated with an increased incidence of thrombosis in PCR positive patients. In conclusion, we found that PCR positive patients had a pronounced prothrombotic phenotype, mainly due to an increase of endothelial activation upon admission to the hospital. These findings show that coagulation tests may be considered useful to discriminate severe cases of COVID-19 at risk for thrombosis.

Identification of high thrombotic risk triple-positive antiphospholipid syndrome patients is dependent on anti-cardiolipin and anti-ß2glycoprotein I antibody detection assays.

Essentials Triple-positivity is associated with a high risk for a first thrombotic event and recurrence. Identification of triple-positives is dependent on the solid phase assay used. In triple-positivity, IgM only adds value in thrombotic risk stratification together with IgG. Thrombotic risk in triple-positive patients with IgM only, depends on the platform. ABSTRACT: Background The antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity with the persistent presence of antiphospholipid antibodies (aPL). Triple-positivity (i.e. positivity for lupus anticoagulant [LAC], anti-cardiolipin [aCL] and anti-ß2glycoprotein I [aß2GPI] antibodies) is associated with a high thrombotic risk. Objectives We investigated the variability in triple-positivity detection by measuring the same samples with four commercially available solid phase assays. In addition, the added clinical value of aPL in LAC-positive patients was investigated, as well as the association of IgM triple-positivity and thrombosis. Patients/Methods We included 851 patients from seven European medical centers. Anti-CL and aß2GPI IgG/IgM antibodies were determined by four platforms: BioPlex® 2200, ImmunoCap® EliA, ACL AcuStar® and QUANTA Lite ELISA® . Results Triple-positivity detection by solid phase assays varied, ranging from 89 up to 118 in thrombotic APS patients (n = 258), of which 86 were detected independent of the platform. Lupus anticoagulant positivity resulted in an odds ratio (OR) for thrombosis of 3.4; triple-positivity (irrespective of the isotype) increased the OR from 4.3 up to 5.2, dependent on the platform. Triple-positivity solely for the IgM isotype did not increase the OR for thrombosis compared with LAC positivity. The highest OR for thrombosis was reached for positivity for IgG and IgM aß2GPI and aCL (8.6 up to 28.9). Conclusions Triple-positivity proved to be highly associated with thrombosis, but identification is assay dependent. Within triple-positivity, IgM antibodies only have an added clinical value in patients positive for IgG antibodies.

High prevalence of reduced thrombin generation and/or decreased platelet response in women with unexplained heavy menstrual bleeding.

INTRODUCTION: Heavy menstrual bleeding (HMB) is a condition that affects 20%-30% of women of reproductive age. HMB has a multifactorial pathophysiology, which is incompletely understood. HMB symptoms are very common in patients with established haemostasis defects, likewise, women with heavy menstrual bleeding have a higher prevalence of impaired Von Willebrand factor (VWF) levels and function, thrombocytopenia, impaired platelet function and impaired coagulation. The aim of this study was to quantify the prevalence of impaired platelet function, impaired coagulation and reduced VWF activity in patients with HMB. METHODS: We have used thrombin generation (TG), a flow cytometry-based platelet function test and a flow cytometry-based VWF function test to study haemostasis in 58 women (median age: 48.4 years, range 40-60 years) with HMB. In addition, we determined VWF antigen levels and VWF ristocetin co-factor activity in platelet-poor plasma. Reference ranges of platelet function were measured in whole blood of 123 healthy volunteers, while reference ranges of TG were determined in platelet-poor plasma (PPP) of 126 healthy volunteers. RESULTS: Fourteen (24%) patients with HMB had impaired platelet function and 17 (29.3%) patients had impaired coagulation. Five patients (8.6%) had both impaired platelet function and impaired coagulation. Only 2 (3.4%) patients had an impaired VWF function or levels; one of them was in combination with impaired coagulation. CONCLUSION: Our approach in women with HMB using a high precision platelet function test in combination with thrombin generation showed impaired coagulation or impaired platelet function in more than 40% of the patients.

Comparing thrombin generation in patients with hemophilia A and patients on vitamin K antagonists.

Essentials It is unknown if hemophilia patients with atrial fibrillation need anticoagulation. Endogenous thrombin potentials (ETP) in hemophilia patients and patients on coumarins were compared. Severe hemophilia patients had comparable ETP to therapeutic international normalized ratio (INR). In non-severe hemophilia, 33% had higher ETP than therapeutic INR and may need anticoagulation. Click to hear Dr Negrier's perspective on global assays for assessing coagulation SUMMARY: Background It is unknown whether patients with hemophilia A with atrial fibrillation require treatment with vitamin K antagonists (VKAs) to the same extent as the normal population. Objective To compare hemostatic potential in hemophilia patients and patients on VKAs using thrombin generation (TG). Methods In this cross-sectional study, TG, initiated with 1pM tissue factor, was measured in 133 patients with severe (FVIII < 1%, n = 15) and non-severe (FVIII 1-50%, n = 118) hemophilia A, 97 patients on a VKA with an international normalized ratio (INR) ≥ 1.5 and healthy controls. Endogenous thrombin potential (ETP) (nm*min) was compared according to FVIII level (< 1%, 1-19% and 20-50%) with healthy controls and patients with sub-therapeutic INR (1.5-1.9) and therapeutic INR (≥ 2.0). Medians and interquartile ranges (IQRs) were calculated. Results Compared with healthy controls (898 [IQR 803-1004]), both hemophilia patients and patients on VKAs had lower median ETPs at 304 (196-449) and 176 (100-250), respectively. ETP was quite similar in severe hemophilia patients (185 [116-307]) and patients with a therapeutic INR (156 [90-225]). Compared with patients with therapeutic INR, ETP in patients with FVIII 1-19% and patients with FVIII 20-50% was higher at 296 (203-430) and 397 (219-632), respectively. All patients with therapeutic INR had an ETP < 400. Considering this threshold, 93% of severe hemophilia patients, 70% of patients with FVIII 1-19% and 52% of patients with FVIII 20-50% had an ETP < 400. Conclusion In severe hemophilia patients, TG was comparable to that in patients with a therapeutic INR. In one-third of non-severe hemophilia patients, TG was higher. These results suggest that anticoagulation therapy should be considered in a substantial proportion of non-severe hemophilia patients.