Coronavirus disease 2019 and coagulopathy: other prothrombotic coagulation factors.

There is an increasing evidence supporting the existence of coagulopathy in coronavirus disease 2019 (COVID-19) patients. Most of reports are mainly focused on d-dimer. Our objective is to describe coagulation parameters in these patients that could be involved in a hypercoagulate state and to test platelet function to see if there are short closure times. We analyzed coagulation samples from 80 patients admitted with COVID-19 in our hospital. We also tested platelet function by closure times in a small subgroup of patients. Most of samples had increased d-dimer (96.2%) (median of d-dimer: 1158 ng/ml FEU), increased fibrinogen (75.2%) (median: 5.23 g/l), increased factor VIII (86%) (median: 264.8 U/dl), decreased protein S (22.5% of women, 62.5% of men) (median: 62.8 and 68.5 U/dl, respectively), decreased protein C (7.6%) (median: 100 U/dl), decreased factor XII (25.3%) (median: 90.3 U/dl) and decreased antithrombin activity (21%) (median: 86 U/dl). International normalized ratio was higher than normal in 24 patients (30%) (median: 1.13). The activated partial thromboplastin time ratio was below the normal range in nine patients (11.2%) and above normal in three (3.75%) (median: 0.93). The closure times were short in the 20% and 40% of samples of collagen and ADP and collagen and epinephrine, respectively. Twelve of the 80 patients (15%) had a thrombotic event and all had several abnormal coagulation parameters related with increased thrombotic risk. The results of this study support a hypercoagulability state in COVID-19 patients and it may help to explain the microvascular thrombosis caused by the inflammatory response.

Pravastatin inhibits fibrinogen- and FDP-induced inflammatory response via reducing the production of IL-6, TNF-α and iNOS in vascular smooth muscle cells.

Atherosclerosis is a chronic inflammatory response of the arterial wall to pro­atherosclerotic factors. As an inflammatory marker, fibrinogen directly participates in the pathogenesis of atherosclerosis. Our previous study demonstrated that fibrinogen and fibrin degradation products (FDP) produce a pro­inflammatory effect on vascular smooth muscle cells (VSMCs) through inducing the production of interleukin­6 (IL­6), tumor necrosis factor­α (TNF­α) and inducible nitric oxide synthase (iNOS). In the present study, the effects of pravastatin on fibrinogen­ and FDP­induced expression of IL­6, TNF­α and iNOS were observed in VSMCs. The results showed that pravastatin dose­dependently inhibited fibrinogen­ and FDP­stimulated expression of IL­6, TNF­α and iNOS in VSMCs at the mRNA and protein level. The maximal inhibition of protein expression of IL­6, TNF­α and iNOS was 46.9, 42.7 and 49.2% in fibrinogen­stimulated VSMCs, and 50.2, 49.8 and 53.6% in FDP­stimulated VSMCs, respectively. This suggests that pravastatin has the ability to relieve vascular inflammation via inhibiting the generation of IL­6, TNF­α and iNOS. The results of the present study may aid in further explaining the beneficial effects of pravastatin on atherosclerosis and related cardiovascular diseases. In addition, they suggest that application of pravastatin may be beneficial for prevention of atherosclerosis formation in hyperfibrinogenemia.

How I manage venous thromboembolism risk in hospitalized medical patients.

Venous thromboembolism is a significant cause of illness and death worldwide. Large bodies of evidence support the heightened risk status of hospitalized medical patients, and that prophylactic measures significantly reduce the risk of thrombosis, yet these patients often fail to receive adequate prophylactic therapy. This failure may be accounted for by a lack of awareness of the relevant indications, poorly designed implementation systems, and clinical concerns over the side effects of anticoagulant medications. This article briefly summarizes our understanding of the clinical factors relevant to the evaluation of venous thromboembolism risk in hospitalized medical patients. We describe our approach to the use of thromboprophylaxis, through which we aim to minimize the disease burden of this under-recognized and preventable pathology.

HIV is associated with thrombophilia and high D-dimer in children and adolescents.

BACKGROUND AND OBJECTIVE: Atherosclerosis and other cardiovascular diseases associated with thrombosis appear more relevant and anticipated in HIV-infected patients after combination antiretroviral therapy (cART) has reduced AIDS-related diseases and has improved survival. The association between viral replication and coagulation abnormalities in a cohort of HIV-infected children and adolescents was investigated here. METHODS: Protein S, protein C anticoagulant and antithrombin activity, together with fibrinogen, D-dimer, high-sensitive C-reactive protein and homocysteine were assayed in a cross-sectional study among a cohort of HIV-infected children and adolescents. Results in patients with high viral load (HVL, HIV-RNA > 1000 copies/ml) were compared with those in patients with a lower replication (LVL), adjusting for other demographic, clinical and therapeutic covariates. RESULTS: Eighty-eight patients (mean age 13.5 years, CD4 30%, 72% with LVL) were enrolled. A prevalence of protein S and protein C deficiency of 51 and 8% was, respectively, found. HVL group compared to LVL showed a significant reduction of protein S, protein C and antithrombin activities, and an increase of D-dimer levels. The independent association of HVL with decreased protein S activity (-11.2%, P = 0.04) and increased D-dimer levels (+0.13 microg/ml, P = 0.004) was confirmed in the multivariate model. CONCLUSIONS: HIV-infected children and adolescents present high prevalence of thrombophilic abnormalities. The multivariate model confirmed that high viral replication is independently associated with decrease of protein S and increase of D-dimer, suggesting the advantage of suppressive therapy on coagulation homeostasis and the opportunity of an active control of cardiovascular risk factors starting at a younger age.

FX-06, a fibrin-derived Bbeta15-42 peptide for the potential treatment of reperfusion injury following myocardial infarction.

Several novel interventional and pharmacological therapeutic approaches have been examined in recent years for the prevention of ischemia/reperfusion injury in myocardial infarction; however, most approaches have failed to progress to clinical trials, and the underlying pathological mechanisms of ischemia/reperfusion injury remain poorly understood. The fibrin Bbeta chain-derived peptide FX-06, under development by Ikaria Holdings Inc, is a novel candidate in phase II trials for the prevention of ischemia/reperfusion injury. FX-06 competitively binds to vascular endothelial (VE)-cadherin, thereby inhibiting leukocyte transmigration and initiating VE-cadherin-mediated signaling, which tightens the endothelial barrier and reduces capillary leakage. The sequence of FX-06 resembles that of a physiological peptide, and the compound has been well tolerated in clinical trials. In a phase II trial in patients with acute ST-segment elevation myocardial infarction who were undergoing percutaneous coronary intervention, FX-06 significantly reduced the necrotic core zone compared with placebo. Whether FX-06 treatment can have a clinical benefit remains to be established. Nonetheless, the unique mechanism of action and short half-life that distinguish FX-06 from competitive pharmacological agents would allow its use in combination with other drugs, potentially contributing to a successful pharmacological therapy for the prevention of ischemia/reperfusion injury after decades of disappointing results.

Effect of intravenous FX06 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction results of the F.I.R.E. (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury) trial.

OBJECTIVES: The purpose of this study was to investigate whether FX06 would limit infarct size when given as an adjunct to percutaneous coronary intervention. BACKGROUND: FX06, a naturally occurring peptide derived from human fibrin, has been shown to reduce myocardial infarct size in animal models by mitigating reperfusion injury. METHODS: In all, 234 patients presenting with acute ST-segment elevation myocardial infarction were randomized in 26 centers. FX06 or matching placebo was given as intravenous bolus at reperfusion. Infarct size was assessed 5 days after myocardial infarction by late gadolinium enhanced cardiac magnetic resonance imaging. Secondary outcomes included size of necrotic core zone and microvascular obstruction at 5 days, infarct size at 4 months, left ventricular function, troponin I levels, and safety. RESULTS: There were no baseline differences between groups. On day 5, there was no significant difference in total late gadolinium enhanced zone in the FX06 group compared with placebo (reduction by 21%; p = 0.207). The necrotic core zone, however, was significantly reduced by 58% (median 1.77 g [interquartile range 0.0, 9.09 g] vs. 4.20 g [interquartile range 0.3, 9.93 g]; p < 0.025). There were no significant differences in troponin I levels (at 48 h, -17% in the FX06 group). After 4 months, there were no longer significant differences in scar size. There were numerically fewer serious cardiac events in the FX06-treated group, and no differences in adverse events. CONCLUSIONS: In this proof-of-concept trial, FX06 reduced the necrotic core zone as one measure of infarct size on magnetic resonance imaging, while total late enhancement was not significantly different between groups. The drug appears safe and well tolerated. (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury [F.I.R.E.]; NCT00326976).

The fibrin-derived peptide Bbeta15-42 is cardioprotective in a pig model of myocardial ischemia-reperfusion injury.

OBJECTIVE: The fibrin-derived peptide Bbeta15-42 has been shown to reduce infarct size in rodent models of ischemia-reperfusion injury. To increase its potential for translation into the clinic, we studied the effects of Bbeta15-42 in pigs, whose coronary anatomy is similar to that of humans. In addition, we evaluated the pharmacokinetics and safety of Bbeta15-42 in several species, including humans. DESIGN: Animal study and phase I trial. SETTING: University hospital and contract research laboratories. SUBJECTS: Pigs/healthy volunteers. INTERVENTIONS: Male farm-bred Landrace pigs were subjected to 1 hr of left anterior descending coronary artery occlusion followed by 3 hrs of reperfusion. At the time of reperfusion, Bbeta15-42 (2.4 mg/kg, n = 6) or random peptide (control; 2.4 mg/kg, n = 6) was administered as an intravenous bolus. As a positive control, pigs were subjected to ischemic preconditioning (n = 6). Cardiac damage and hemodynamics were recorded. Biodistribution and pharmacokinetics of Bbeta15-42 were determined in rats and dogs. In a phase I trial involving 30 male healthy volunteers, pharmacokinetics and safety were tested in a randomized, double-blinded, placebo-controlled, parallel-group, single ascending dose study. MEASUREMENTS AND MAIN RESULTS: Bbeta15-42 and ischemic preconditioning significantly reduced myocardial infarct size and troponin I levels. Bbeta15-42 also reduces interleukin-6 levels, underlining its anti-inflammatory properties. Furthermore, in humans, the pharmacokinetics of the peptide Bbeta15-42 were comparable to those of animals, and no serious adverse effects were observed. CONCLUSIONS: Bbeta15-42 elicits cardioprotection in pigs and is clinically safe in phase I testing of humans. This study confirms the new concept of a pathogenic role of fibrin derivatives in myocardial reperfusion injury, which can be inhibited by peptide Bbeta15-42.