Predictive value of immunoglobulin G, activated partial thromboplastin time, platelet, and indirect bilirubin for delayed viral clearance in patients infected with the Omicron variant.

Background: Omicron is the recently emerged highly transmissible severe acute respiratory syndrome coronavirus 2 variant that has caused a dramatic increase in coronavirus disease-2019 infection cases worldwide. This study was to investigate the association between demographic and laboratory findings, and the duration of Omicron viral clearance. Methods: Approximately 278 Omicron cases at the Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine were retrospectively analyzed between August 11 and August 31, 2022. Demographic and laboratory data were also collected. The association between demographics, laboratory findings, and duration of Omicron viral clearance was analyzed using Pearson correlation analysis and univariate and multivariate logistic regression. Results: Univariate logistic regression analyses showed that a prolonged viral clearance time was significantly associated with older age and lower immunoglobulin (Ig) G and platelet (PLT) levels. Using multinomial logistic regression analyses, direct bilirubin, IgG, activated partial thromboplastin time (APTT), and PLT were independent factors for longer viral shedding duration. The model combining direct bilirubin, IgG, APTT, and PLT identifies patients infected with Omicron whose viral clearance time was ≥7 days with 62.7% sensitivity and 83.4% specificity. Conclusion: These findings suggest that direct bilirubin, IgG, PLT, and APTT are significant risk factors for a longer viral shedding duration in patients infected with Omicron. Measuring levels of direct bilirubin, IgG, PLT, and APTT is advantageous to identify patients infected with Omicron with longer viral shedding duration.

Anti-factor Xa vs aPTT for heparin monitoring in extracorporeal membrane oxygenation.

PURPOSE: The goal of this study was to evaluate the correlation of anti-factor Xa (anti-Xa) and activated partial thromboplastin time (aPTT) measures with heparin dosing in adult patients on extracorporeal membrane oxygenation (ECMO) support. METHODS: This was a retrospective cohort study evaluating adult patients managed on ECMO for at least 24 hours who received unfractionated heparin for systemic anticoagulation and were monitored per protocol using anti-Xa and/or aPTT coagulation assays. The primary outcome was the correlation between aPTT and anti-Xa measures. The secondary outcomes included, but were not limited to, the number of hemorrhagic and thrombotic events. RESULTS: Twenty-seven patients were included in this study. In the 227 events where both laboratory values were collected, a weak correlation was found between anti-Xa and aPTT (Spearman's correlation coefficient = 0.4, P = 0). In the 12 hemorrhagic events that occurred, aPTT was collected for only 10 events. Fifty percent of those events were associated with supratherapeutic aPTT, while none of the hemorrhagic events were associated with a supratherapeutic anti-Xa level. Two thrombotic events occurred, one of which had subtherapeutic anti-Xa and aPTT and the other of which had neither an anti-Xa nor aPTT measure on the day the event occurred. CONCLUSION: In a population of patients on ECMO, many of whom had coronavirus disease 2019 (COVID-19), there was a weak association between aPTT and anti-Xa measures. Hemorrhagic evens were more common than thrombotic events; however, a relationship between these events and aPTT or anti-Xa levels was not determined. The applicability of these findings to an ECMO population without COVID-19 is unknown and will require further study.

Acquired Factor VIII Inhibitors: A Case Study.

The physiology of hemostasis is one of high complexity that involves the initiation, amplification, and propagation of the many moving parts of the hemostatic system and its regulatory mechanisms. It is imperative that clinical laboratory professionals have a strong understanding of the many intricacies of the physiology of coagulation and its in vitro testing. An elongated activated partial thromboplastin time can have several causes, and the correct cause must be elucidated in a timely manner for proper treatment. A mixing study with normal pooled plasma should be performed to evaluate for the presence of an inhibitor vs factor deficiency. Factor inhibitors, specifically factor VIII in this case study, should be titered so that the clinician can decide which treatment may work best for the patient. Continued monitoring of factor levels and inhibitor titers should be conducted to follow the resolution or progression of inhibitor presence.

[Mechanism and clinical treatment strategy of heparin resistance].

Heparin resistance is becoming a hot issue of clinical concern. In critically ill patients, heparin resistance can lead to failure of anticoagulation therapy or increase the risk of major bleeding. Prompt recognition of heparin resistance can help to precisely adjust heparin dosage and avoid deterioration and adverse events. Heparin resistance can be mechanistically classified into the antithrombin-mediated and the non-antithrombin-mediated. Common etiologies include heparin-induced thrombocytopenia, severe infections such as severe COVID-19, treatment with extracorporeal circulation or extracorporeal membrane oxygenation (ECMO), and use of factor Xa reversal agents; heparin resistance is now often identified by the concordance of activated partial thromboplastin time (APTT) ratio with anti-FXa. Common clinical management strategies include antithrombin supplementation and replacement of anticoagulant drugs (e.g., direct thrombin inhibitors), but their safety and efficacy still need to be further validated.

Correlation between partial thromboplastin time and thromboelastography in adult critically ill patients requiring bivalirudin for extracorporeal membrane oxygenation.

STUDY OBJECTIVE: Thromboelastography (TEG) offers a more dynamic assessment of hemostasis over activated partial thromboplastin time (aPTT). However, the clinical utility of TEG in monitoring bivalirudin during extracorporeal membrane oxygenation (ECMO) remains unknown. The purpose of this study was to evaluate the correlation between aPTT and TEG in adult ECMO patients anticoagulated with bivalirudin. DESIGN: Multicenter, retrospective, cohort study conducted over a 2-year period. SETTING: Two academic university medical centers (Banner University Medical Center) in Phoenix and Tucson, AZ. PATIENTS: Adult patients requiring ECMO and bivalirudin therapy with ≥1 corresponding standard TEG and aPTT plasma samples drawn ≤4 h of each other were included. The primary endpoint was to determine the correlation coefficient between the standard TEG reaction (R) time and bivalirudin aPTT serum concentrations. MEASUREMENTS AND MAIN RESULTS: A total of 104 patients consisting of 848 concurrent laboratory assessments of R time and aPTT were included. A moderate correlation between TEG R time and aPTT was demonstrated in the study population (r = 0.41; p < 0.001). Overall, 502 (59.2%) concurrent assessments of TEG R time and aPTT values showed agreement on whether they were sub-, supra-, or therapeutic according to the institution's classification for bivalirudin. The 42.2% (n = 271/642) discordant TEG R times among "therapeutic" aPTT were almost equally distributed between subtherapeutic and supratherapeutic categories. CONCLUSIONS: Moderate correlation was found between TEG R time and aPTT associated with bivalirudin during ECMO in critically ill adults. Further research is warranted to address the optimal test to guide clinical decision-making for anticoagulation dosing in ECMO patients.

Whole-blood Point-of-Care Activated Partial Thromboplastin Time Ratio (APR) is not Accurate Enough to Monitor Heparin Therapy in Patients with Severe Respiratory Failure Secondary to SARS-Cov-2 Infection Supported with Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO).

Support with VV-ECMO requires anticoagulation with unfractionated heparin to prevent thrombotic complications. This must be monitored due to bleeding risk. A point-of-care (POC) method of testing aPTT and APR was evaluated for agreement with laboratory methods. In a prospective observational study, patients supported on VV-ECMO as a result of severe respiratory failure secondary to Covid-19 infection were given heparin as part of standard therapy. The aPTT was measured (i) at the bedside using the Hemochron Signature Elite device and (ii) at the hospital laboratory. Duplicate results were compared. Agreement between the POC and laboratory tests was poor, as assessed using the Bland-Altman method. The maximum difference between POC and laboratory methods was 133% and the minimum was 0%. Overall bias was 7.3% and limits of agreement were between -43.8% and 58.5%. Correlation increased when results were normalised to platelet count and creatinine. This POC test is insufficiently accurate for use as the primary method of heparin monitoring in patients requiring VV-ECMO for Covid-19. Platelets and renal function may influence the result of this whole blood POC test.

Risk stratification and prognostic value of prothrombin time and activated partial thromboplastin time among COVID-19 patients.

BACKGROUND: COVID-19 is a viral disease caused by a new strain of corona virus. Currently, prognosis and risk stratification of COVID-19 patients is done by the disease's clinical presentation. Therefore, identifying laboratory biomarkers for disease prognosis and risk stratification of COVID-19 patients is critical for prompt treatment. Therefore, the main objective of this study was to assess the risk stratification and prognostic value of basic coagulation parameters and factors associated with disease severity among COVID-19 patients at the Tibebe Ghion Specialized Hospital, COVID-19 treatment center, Northwest Ethiopia. METHODS: A follow-up study was conducted among conveniently recruited COVID-19 patients attended from March to June 2021. Socio-demographic and clinical data were collected using a structured questionnaire and checklist, respectively. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were analyzed by the HUMACLOT DUE PLUS® machine. Descriptive statistics were used to summarize the socio-demographic and clinical characteristics of study participants. Kruskal Wallis tests were used to compare the difference between parametric and non-parametric continuous variables, respectively. The area under the receiver operating characteristic curve (AUC) was used to evaluate the value of PT and APTT in the risk stratification and disease prognosis of COVID-19 patients. Ordinal logistic regression was used to identify the factors associated with disease severity and prognosis. A P-value < 0.05 was defined as statistically significant for all results. RESULT: Baseline PT at a cut-off value ≥ 16.25 seconds differentiated severe COVID-19 patients from mild and moderate patients (AUC: 0.89, 95% CI: 0.83-0.95). PT also differentiated mild COVID-19 patients from moderate and severe patients at a cut-off value ≤ 15.35 seconds (AUC: 0.90, 95% CI: 0.84-0.96). Moreover, alcohol drinkers were a 3.52 times more likely chance of having severe disease than non-drinkers (95% CI: 1.41-8.81). A one-year increment in age also increased the odds of disease severity by 6% (95% CI: 3-9%). An increment of ≥ 0.65 seconds from the baseline PT predicted poor prognosis (AUC: 0.93, 0.87-0.99). CONCLUSIONS AND RECOMMENDATIONS: Prolonged baseline PT was observed in severe COVID-19 patients. Prolonged baseline PT was also predicted to worsen prognosis. An increase from the baseline PT was associated with worsen prognosis. Therefore, PT can be used as a risk stratification and prognostic marker in COVID-19 patients.

Coagulation parameters abnormalities and their relation to clinical outcomes in hospitalized and severe COVID-19 patients: prospective study.

There has been growing attention toward the predictive value of the coagulation parameters abnormalities in COVID-19. The aim of the study was to investigate the role of coagulation parameters namely Prothrombin concentration (PC), activated Partial thromboplastin Time (aPTT), D-Dimer (DD), Anti Thrombin III (ATIII) and fibrinogen (Fg) together with hematological, and biochemical parameters in predicting the severity of COVID-19 patients and estimating their relation to clinical outcomes in hospitalized and severe COVID-19 Patients. In a prospective study, a total of 267 newly diagnosed COVID-19 patients were enrolled. They were divided into two groups; hospitalized group which included 144 patients and non-hospitalized group that included 123 patients. According to severity, the patients were divided into severe group which included 71 patients and non-severe group that included 196 patients who were admitted to ward or not hospitalized. Clinical evaluation, measurement of coagulation parameters, biochemical indices, outcome and survival data were recorded. Hospitalized and severe patients were older and commonly presented with dyspnea (P ≤ 0.001). Differences in coagulation parameters were highly significant in hospitalized and severe groups in almost all parameters, same for inflammatory markers. D-dimer, AT-III and LDH showed excellent independently prediction of severity risk. With a cut-off of > 2.0 ng/L, the sensitivity and specificity of D dimer in predicting severity were 76% and 93%, respectively. Patients with coagulation abnormalities showed worse survival than those without (p = 0.002). Early assessment and dynamic monitoring of coagulation parameters may be a benchmark in the prediction of COVID-19 severity and death.

[Critical coronavirus disease 2019 complicated with heparin resistance in 2 patients].

OBJECTIVE: To explore the diagnosis process and treatment experience of severe coronavirus disease 2019 (COVID-19) patients with heparin resistance (HR). METHODS: The medical team of the First People's Hospital of Lianyungang admitted 2 severe COVID-19 patients with HR in intensive care unit (ICU) during their support to the designated hospital for the treatment of COVID-19 patients in Lianyungang City in November 2021. The clinical features, laboratory examinations, imaging features, treatment and prognosis of the two patients were analyzed. RESULTS: Both severe COVID-19 patients received mechanical ventilation, 1 patient was treated with extracorporeal membrane oxygenation (ECMO) support. Both patients were complicated with lower extremity deep venous thrombosis and HR phenomenon under routine dose anticoagulant therapy. The maximum daily dose of unfractionated heparin exceeded 35 000 U (up to 43 200 U), the 2 patients failed to meet the standard of anticoagulation treatment, and the course of disease was prolonged. After that, argatroban was given 0.4 µg×kg-1×min-1 combined with anticoagulant therapy, the activated partial thromboplastin time (APTT) of patients undergoing ECMO could be maintained at 55-60 seconds and the activated coagulation time (ACT) of them could be maintained at 180-200 seconds. After ECMO support or later sequential mechanical ventilation, both patients recovered and were discharged, and deep venous thrombosis was also effectively controlled. CONCLUSIONS: HR phenomenon often occurs during the treatment of severe COVID-19 patients, the anticoagulation regimen should be adjusted in time, and the anticoagulation effect combined with argatroban is clear.

Would Tracking Coagulation Together with Inflamation Markers be a Prospect for COVID-19 Disease Prognosis?

BACKGROUND: The purpose of this study is to evaluate the prognostic roles of hemostatic tests including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, and antithrombin III in the progression of disease, monitorization of severe, mild and moderate cases, and also to show their relationship with inflammatory markers including C-reactive protein (CRP), procalcitonin, and interleukin-6 (IL-6). METHODS: The study comprised 604 patients (360 men and 244 women) with confirmed SARS-CoV-2 infection admitted to Emergency Department of Istanbul Faculty of Medicine between March 15 and April 15, 2020. The variations in the concentration of coagulation tests and inflammatory markers were observed from the admission to hospital to the 10th day with three-day periods. RESULTS: PT level and PT activity of severe cases were significantly different compared to mild cases (p = 0.012, p = 0.010, respectively). Similarly, aPTT and D-dimer levels in severe cases were significantly higher compared to the mild cases. However, fibrinogen levels of mild cases were significantly lower compared to either moderate or severe cases (p < 0.001, for both). The PT, PT activity, aPTT, and D-Dimer levels in severe cases were significantly different compared with the mild cases. However, fibrinogen level was the highest in severe cases, and higher than either mild or moderate cases. CONCLUSIONS: Our findings reveal the vital importance of measuring coagulation parameters at the time of admission and monitoring them at regular intervals in clinical monitoring of COVID-19 patients, in determining the severity of the disease in terms of the patient's prognosis, and in choosing and applying the appropriate treatment at the right time.

Evaluation of heparin infusion rates in patients with intravenous drug misuse.

To evaluate the hypothesis that patients with a history of intravenous drug misuse (IVDM) initiated on weight-based heparin infusions require higher than expected infusion rates to achieve therapeutic activated partial thromboplastin time (aPTT). This study is a multicenter, retrospective chart review of patients with a history of IVDM who were admitted to an acute care site between 10/1/2015 and 9/30/2020 and treated with continuous heparin infusions. Patients were identified using ICD9 and ICD10 codes and included if they had a documented history of IVDM within the past six months. Variables of particular interest included: median heparin infusion rates to maintain therapeutic aPTT, average time to reach therapeutic aPTT, and International Society of Thrombosis and Haemostasis Criteria for moderate to severe bleeding. Of the 41 patients who met the inclusion and exclusion criteria, 39 achieved therapeutic aPTT while on a weight-based heparin infusion. All heparin infusions were initiated at a rate of 18 units/kg/hr then titrated per institutional heparin infusion protocols. The mean time to therapeutic aPTT was 38.48 h ± 26.4 h with a mean infusion rate of 27.64 ± 7.14 units/kg/hr. To maintain therapeutic anticoagulation, infusion rates 150% higher than the initial rate were required. Of the 39 patients who achieved therapeutic aPTT, 85% (33) met criteria for heparin resistance, defined as greater than 35,000 units of heparin daily. No statistical significance could be derived from this retrospective chart review as therapeutic heparin rates were evaluated in comparison to initial infusion rate, rather than a control group. The findings in this study demonstrate a possible clinical association of the reduced antithrombin activity previously described in opiate misusers. To efficiently achieve therapeutic anticoagulation, it may be appropriate to consider use of heparin antiXa monitoring in place of aPTT or utilization of increased initial heparin infusion rates.

Safety and Pharmacokinetics of Intranasally Administered Heparin.

PURPOSE: Intranasally administered unfractionated heparin (UFH) and other sulfated polysaccharides are potential prophylactics for COVID-19. The purpose of this research was to measure the safety and pharmacokinetics of clearance of intranasally administered UFH solution from the nasal cavity. METHODS: Double-blinded daily intranasal dosing in C57Bl6 mice with four doses (60 ng to 60 µg) of UFH was carried out for fourteen consecutive days, with both blood coagulation measurements and subject adverse event monitoring. The pharmacokinetics of fluorescent-labeled UFH clearance from the nasal cavity were measured in mice by in vivo imaging. Intranasal UFH at 2000 U/day solution with nasal spray device was tested for safety in a small number of healthy human subjects. RESULTS: UFH showed no evidence of toxicity in mice at any dose measured. No significant changes were observed in activated partial thromboplastin time (aPTT), platelet count, or frequency of minor irritant events over vehicle-only control. Human subjects showed no significant changes in aPTT time, international normalized ratio (INR), or platelet count over baseline measurements. No serious adverse events were observed. In vivo imaging in a mouse model showed a single phase clearance of UFH from the nasal cavity. After 12 h, 3.2% of the administered UFH remained in the nasal cavity, decaying to background levels by 48 h. CONCLUSIONS: UFH showed no toxic effects for extended daily intranasal dosing in mice as well as humans. The clearance kinetics of intranasal heparin solution from the nasal cavity indicates potentially protective levels for up to 12 h after dosing.

Hematologic Evaluation of Children with COVID-19 Infection: Mortality Biomarkers.

BACKGROUND: In this study, we investigated the predictive value of routine coagulation parameters including D-dimer, Prothrombin Time (PT), International Normalized Ratio (INR), activated Partial Thromboplastin Time (aPTT) and Complete Blood Count (CBC) test parameters in children with COVID-19 infection. METHODS: Retrospective and observational study carried out in Abuzar Hospital, Ahvaz Jundishapur University of Medical Sciences (Ahvaz, Iran) included COVID-19 patients. RESULTS: Deceased patients (n = 5) compared to alive patients (n = 76) showed higher RDW (p = 0.005), PT (p = 0.005), INR (p = 0.004), PTT (p = 0.009), platelet count (p < 0.001), PLR (p < 0.001), and hospitalization time (p < 0.001). The area under the curve (AUC) of RDW was 0.85 (95% CI 0.75 - 0.96) which indicates its high power for mortality prediction in hospitalized children with COVID-19. We did not find significant differences in parameters in comparison between different severities. CONCLUSIONS: To our knowledge, our study is one of the few studies to evaluate routine coagulation tests and the CBC test parameters predictive value in children with COVID-19. RDW has the most power to predict the mortality of children with COVID-19, followed by PT, INR, aPTT, platelet count, PLR, and hospitalization time have a high power to predict the risk of death in patients.

Major coagulation disorders and parameters in COVID-19 patients.

Coronavirus disease 2019 (COVID-19), with a high prevalence rate, has rapidly infected millions of people around the world. Since viral infections can disrupt the coagulation and homeostasis cascades, various inflammatory and coagulation problems occur due to COVID-19 infection, similar to coronavirus epidemics in 2003 and 2004. According to multiple previous studies, in the present research, we reviewed the most commonly reported problems of COVID-19 patients, such as venous thromboembolism, pulmonary embolism, disseminated intravascular coagulation, etc. and investigated the causes in these patients. Coagulation and inflammatory markers, such as platelets and fibrinogen, C-reactive protein, lactate dehydrogenase, d-dimer, prothrombin time, etc., were also discussed, and the treatment options were briefly reviewed. In addition to coagulation treatments, regular examination of coagulation parameters and thrombotic complications can be helpful in the timely treatment of patients. Therefore, it is helpful to review the coagulation problems in COVID-19 patients. Although all mentioned problems and markers are important in COVID-19, some of them are more valuable in terms of diagnosis and prognosis.

Therapeutic Strategies for Disseminated Intravascular Coagulation Associated with Aortic Aneurysm.

Aortic aneurysms are sometimes associated with enhanced-fibrinolytic-type disseminated intravascular coagulation (DIC). In enhanced-fibrinolytic-type DIC, both coagulation and fibrinolysis are markedly activated. Typical cases show decreased platelet counts and fibrinogen levels, increased concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer, and increased FDP/D-dimer ratios. Thrombin-antithrombin complex or prothrombin fragment 1 + 2, as markers of coagulation activation, and plasmin-α2 plasmin inhibitor complex, a marker of fibrinolytic activation, are all markedly increased. Prolongation of prothrombin time (PT) is not so obvious, and the activated partial thromboplastin time (APTT) is rather shortened in some cases. As a result, DIC can be neither diagnosed nor excluded based on PT and APTT alone. Many of the factors involved in coagulation and fibrinolysis activation are serine proteases. Treatment of enhanced-fibrinolytic-type DIC requires consideration of how to control the function of these serine proteases. The cornerstone of DIC treatment is treatment of the underlying pathology. However, in some cases surgery is either not possible or exacerbates the DIC associated with aortic aneurysm. In such cases, pharmacotherapy becomes even more important. Unfractionated heparin, other heparins, synthetic protease inhibitors, recombinant thrombomodulin, and direct oral anticoagulants (DOACs) are agents that inhibit serine proteases, and all are effective against DIC. Inhibition of activated coagulation factors by anticoagulants is key to the treatment of DIC. Among them, DOACs can be taken orally and is useful for outpatient treatment. Combination therapy of heparin and nafamostat allows fine-adjustment of anticoagulant and antifibrinolytic effects. While warfarin is an anticoagulant, this agent is ineffective in the treatment of DIC because it inhibits the production of coagulation factors as substrates without inhibiting activated coagulation factors. In addition, monotherapy using tranexamic acid in cases of enhanced-fibrinolytic-type DIC may induce fatal thrombosis. If tranexamic acid is needed for DIC, combination with anticoagulant therapy is of critical importance.

Prognostic factors for predicting severity and mortality in hospitalized COVID-19 patients.

BACKGROUND: Coronavirus disease 2019, COVID-19, has reached all the corners of the world and was declared by the WHO as a global pandemic and public health emergency of international concern on the January 31, 2020. Allocating quick and specific biomarkers to predict the disease severity upon admission to hospital became a crucial need. This study, therefore, aimed at exploring the relationship between laboratory results in COVID-19 patients admitted to hospital and the final outcome in these patients. METHODS: Retrospective analysis was performed on the medical records of 310 COVID-19-positive patients admitted to Uhod Hospital, the referral hospital in the area of Madinah, Kingdom of Saudi Arabia, between the April 13 and the July 29, 2020. The association of laboratory results with the survival/mortality outcomes was studied. RESULTS: It was demonstrated that lymphopenia, prolonged aPTT, high INR, high D. dimer and high CK are valuable prognostic predictors of the severity of the disease at early stages that can determine the outcome. Based on the results of the multiple logistic regression, the variables that are associated with death outcome are aPTT, HR, RR, ALT and CK level CONCLUSION: It is proposed to perform these tests on admission to hospital for moderate to severe COVID-19 patients to improve the management of those cases and reduce mortality.

Inhaled nebulised unfractionated heparin for the treatment of hospitalised patients with COVID-19: A multicentre case series of 98 patients.

AIMS: To determine the safety and efficacy-potential of inhaled nebulised unfractionated heparin (UFH) in the treatment of hospitalised patients with COVID-19. METHODS: Retrospective, uncontrolled multicentre single-arm case series of hospitalised patients with laboratory-confirmed COVID-19, treated with inhaled nebulised UFH (5000 IU q8h, 10 000 IU q4h, or 25 000 IU q6h) for 6 ± 3 (mean ± standard deviation) days. Outcomes were activated partial thromboplastin time (APTT) before treatment (baseline) and highest-level during treatment (peak), and adverse events including bleeding. Exploratory efficacy outcomes were oxygenation, assessed by ratio of oxygen saturation to fraction of inspired oxygen (FiO2 ) and FiO2 , and the World Health Organisation modified ordinal clinical scale. RESULTS: There were 98 patients included. In patients on stable prophylactic or therapeutic systemic anticoagulant therapy but not receiving therapeutic UFH infusion, APTT levels increased from baseline of 34 ± 10 seconds to a peak of 38 ± 11 seconds (P < .0001). In 3 patients on therapeutic UFH infusion, APTT levels did not significantly increase from baseline of 72 ± 20 to a peak of 84 ± 28 seconds (P = .17). Two patients had serious adverse events: bleeding gastric ulcer requiring transfusion and thigh haematoma; both were on therapeutic anticoagulation. Minor bleeding occurred in 16 patients, 13 of whom were on therapeutic anticoagulation. The oxygen saturation/FiO2 ratio and the FiO2 worsened before and improved after commencement of inhaled UFH (change in slope, P < .001). CONCLUSION: Inhaled nebulised UFH in hospitalised patients with COVID-19 was safe. Although statistically significant, inhaled nebulised UFH did not produce a clinically relevant increase in APTT (peak values in the normal range). Urgent randomised evaluation of nebulised UFH in patients with COVID-19 is warranted and several studies are currently underway.

Investigation of the Molecular Mechanism of Coagulopathy in Severe and Critical Patients With COVID-19.

Coagulopathy is a frequently reported finding in the pathology of coronavirus disease 2019 (COVID-19); however, the molecular mechanism, the involved coagulation factors, and the role of regulatory proteins in homeostasis are not fully investigated. We explored the dynamic changes of nine coagulation tests in patients and controls to propose a molecular mechanism for COVID-19-associated coagulopathy. Coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FIB), lupus anticoagulant (LAC), proteins C and S, antithrombin III (ATIII), D-dimer, and fibrin degradation products (FDPs) were performed on plasma collected from 105 individuals (35 critical patients, 35 severe patients, and 35 healthy controls). There was a statically significant difference when the results of the critical (CRT) and/or severe (SVR) group for the following tests were compared to the control (CRL) group: PTCRT (15.014) and PTSVR (13.846) (PTCRL = 13.383, p < 0.001), PTTCRT (42.923) and PTTSVR (37.8) (PTTCRL = 36.494, p < 0.001), LACCRT (49.414) and LACSVR (47.046) (LACCRL = 40.763, p < 0.001), FIBCRT (537.66) and FIBSVR (480.29) (FIBCRL = 283.57, p < 0.001), ProCCRT (85.57%) and ProCSVR (99.34%) (ProCCRL = 94.31%, p = 0.04), ProSCRT (62.91%) and ProSSVR (65.06%) (ProSCRL = 75.03%, p < 0.001), D-dimer (p < 0.0001, χ2 = 34.812), and FDP (p < 0.002, χ2 = 15.205). No significant association was found in the ATIII results in groups (ATIIICRT = 95.71% and ATIIISVR = 99.63%; ATIIICRL = 98.74%, p = 0.321). D-dimer, FIB, PT, PTT, LAC, protein S, FDP, and protein C (ordered according to p-values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy.

Caution in Using the Activated Partial Thromboplastin Time to Monitor Argatroban in COVID-19 and Vaccine-Induced Immune Thrombocytopenia and Thrombosis (VITT).

INTRODUCTION: Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients' baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. METHODS: Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. RESULTS: Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. CONCLUSIONS: We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.