D-dimer kit with a High FDP/D-Dimer Ratio is Useful for Diagnosing Thrombotic Diseases

Introduction Although D-dimer is a useful biomarker of thrombosis, there are many D-dimer kits, with high and low fibrinogen and fibrin degradation products (FDP)/ D-dimer ratios. Methods Plasma D-dimer levels were measured using three different kits in critically ill patients to examine the usefulness of such measurements for detecting the thrombotic diseases and determining the correlation with the FDP and FDP/D-dimer ratio. Results Although three D-dimer kits showed marked utility for diagnosing disseminated intravascular coagulation (DIC) and peripheral arterial and venous thromboembolism (PAVTE), the D-dimer levels determined using the three kits varied among diseases. Indeed, one D-dimer kit showed a high FDP/D-dimer ratio, and another kit showed a low FDP/D-dimer ratio. D-dimer kit with low FDP/D-dimer ratio tended to have high cut-off values and low specificity for diagnosing DIC and PAVTE. In D-dimer kit with high FDP/D-dimer ratio, FDP/D-dimer ratios in patients with thrombosis was significantly higher than that in patients without thrombosis. Conclusion All three D-dimer kits show utility for detecting thrombotic diseases. However, the D-dimer levels determined using the kits varied due to differences in the FDP/D-dimer ratio. In combination with the FDP level, a D-dimer kit with a high FDP/D-dimer ratio may be useful.

Determinants of severity among hospitalised COVID-19 patients: Hospital-based case-control study, India, 2020

Background Risk factors for the development of severe COVID-19 disease and death have been widely reported across several studies. Knowledge about the determinants of severe disease and mortality in the Indian context can guide early clinical management. Methods We conducted a hospital-based case control study across nine sites in India to identify the determinants of severe and critical COVID-19 disease. Findings We identified age above 60 years, duration before admission >5 days, chronic kidney disease, leucocytosis, prothrombin time > 14 sec, serum ferritin >250 ng/mL, d-dimer >0.5 ng/mL, pro-calcitonin >0.15 μg/L, fibrin degradation products >5 μg/mL, C-reactive protein >5 mg/L, lactate dehydrogenase >150 U/L, interleukin-6 >25 pg/mL, NLR ≥3, and deranged liver function, renal function and serum electrolytes as significant factors associated with severe COVID-19 disease. Interpretation We have identified a set of parameters that can help in characterising severe COVID-19 cases in India. These parameters are part of routinely available investigations within Indian hospital settings, both public and private. Study findings have the potential to inform clinical management protocols and identify patients at high risk of severe outcomes at an early stage.

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.

Plasma levels of leucocyte elastase-generated cross linked fibrin degradation products (E-XDP) are elevated in chronic venous disease

Patients with chronic venous disease (CVD) have elevated levels of leucocyte elastase (LE) released from the activation of leucocytes. In acute deep venous thrombosis (DVT), LE can degrade fibrin from the thrombus resulting in cross-linked fibrin degradation products (E-XDP) being released into the bloodstream. In patients with CVD the levels and significance of circulating E-XDP are unknown. We aimed to investigate the association between plasma E-XDP concentration and severity of CVD. Levels of E-XDP were quantified with a specific enzyme-linked immunosorbent assay (ELISA) in plasma from 142 consecutively recruited CVD patients (mean age 64 years, (range 23–89), 81 were females and 61 males). Patients were also divided into three groups based on CVD severity using the C-class of the Clinical-Etiological-Anatomical-Pathophysiological (CEAP) classification, with C 0–1 class as the reference group, C 2–3 as the second group and C 4–6 as the third group with the most severely affected patients. We found significantly elevated levels of E-XDP in patients with C 4–6 compared with patients with C 0–1 (p = 0.007) and increased with increasing disease severity across the groups (p = 0.02). Significant independent association was observed between levels of E-XDP and the classes C 4–6 after adjustment for age and sex (p < 0.05), but the association was no longer significant after further adjustment for use of statins, use of anticoagulants and history of DVT (p = 0.247). This exploratory study shows that E-XDP levels are elevated in patients with CVD, encouraging further studies on the role of E-XDP in CVD.

Simultaneous Use of Factor XIII and Fibrin Degradation Products in Diagnosing Early Cases of NEC and Neonatal SEPSIS

Purpose: The study examined the use of factor XIII and fibrin degradation products in diagnosing early cases of NEC and neonatal sepsis. Methods: Sixty neonates were divided into two groups. 30 preterm neonates suspected with early NEC Diagnosis of NEC was confirmed by modified Bell’s score and 30 preterm neonates with symptoms of neonatal sepsis; where sepsis was confirmed by blood culture and CRP. Laboratory evaluation of FDPs and plasma factor XIII was done for all the patients. The study was carried out in a tertiary NICU of the pediatric department, Ain Shams University Hospital. All enrolled neonates had a matched mean birth weight and gestational age. They were either moderate preterms >32 weeks, but <34 weeks, and late preterms >34 weeks, but <37 weeks). Results: The results indicate a correlation between FDPs and the laboratory data of group B, and it was found out that FDPs were negatively correlated with TLC, Plate-lets, and CRP, reflecting FDPs increase with bone marrow suppression and progression of sepsis. Factor XIII was significantly lower in the group with NEC as compared to the group of sepsis (p<0.001), while FDPs level was significantly higher in the group with sepsis (p<. 0.001). The correlation between the clinical stages of NEC BELL's score and the level of Initial factor XIII level revealed that the factor level is negatively correlated with stage I of BELL's score. The follow-up revealed that there was no correlation between BELL's score and the level of follow-up factor XIII. On follow-up, the current study demonstrated that TLC, CRP, FDPS, PTT were significantly increased in the sepsis group with p values of 0.021,, 0.001, 0.001 and 0.01. The current study found significantly higher partial thromboplastin time (PTT) in the group with sepsis Conclusion: Factor XIII level can predict early cases of NEC and can differentiate it from neo-natal sepsis.

Plasma levels of D-dimer and fibrin degradation products correlate with bullous pemphigoid severity: a cross-sectional study

Bullous pemphigoid (BP), the most frequent blistering dermatosis in the elderly, is associated with increased mortality. The severity of BP can be assessed by detecting the anti-BP180 immunoglobulin G (IgG) concentration, but the lab test is not available in many community clinics. BP patients are usually in a hypercoagulable state with increased levels of D-dimer and fibrin degradation products (FDPs). We aimed to evaluate the use of D-dimer and FDPs in assessing BP severity. We compared the levels of plasma D-dimer, plasma FDPs, eosinophil counts, eosinophil cationic protein, and serum anti-BP180 IgG concentration between 48 typical BP patients and 33 Herpes zoster (HZ) patients (control group). Correlational analyses were conducted to determine the relationships between the lab values and common BP severity markers. The plasma D-dimer and FDP levels were higher in BP patients than in HZ controls (D-dimer: 3297 ± 2517 µg/L vs. 569.70 ± 412.40 µg/L; FDP: 9.74 ± 5.88 mg/L vs. 2.02 ± 1.69 mg/L, respectively, P < 0.0001). Significant positive correlations were found between D-dimer/FDP levels and BP severity markers (i.e. anti-BP180 IgG concentration [D-dimer: r = 0.3928, P = 0.0058; FDP: r = 0.4379, P = 0.0019] and eosinophil counts [D-dimer: r = 0.3625, P = 0.0013; FDP: r = 0.2880, P = 0.0472]) in BP patients. We also found an association between FDP and urticaria/erythema lesions (r = 0.3016, P = 0.0372), but no other BPDAI components. In 19 BP patients with complete remission after systemic glucocorticoid treatment, D-dimer and FDP levels decreased post-therapy (D-dimer: 5559 ± 7492 µg/L vs. 1738 ± 1478 µg/L; P < 0.0001; FDP: 11.20 ± 5.88 mg/L vs. 5.13 ± 3.44 mg/L; P = 0.0003), whereas they did not in BP patients with treatment resistant. Plasma D-dimer and FDP are convenient markers to evaluate BP severity assistant on BPDAI and eosinophil counts. FDP is also helpful for inflammatory lesions in BP patients.

A novel homozygous variant of the thrombomodulin gene causes a hereditary bleeding disorder

Here, we describe a 19-year-old Vietnamese woman who experienced several life-threatening bleeding events, including ovarian hemorrhage. Blood analysis revealed decreased fibrinogen level with markedly elevated fibrinogen/fibrin degradation products and D-dimer levels. Despite hemostatic surgery and administration of several medications, such as nafamostat mesylate, tranexamic acid, and unfractionated heparin, the coagulation abnormalities were not corrected, and the patient experienced repeated hemorrhagic events. We found that administration of recombinant human thrombomodulin (rhTM) remarkably improved the patient's pathophysiology. Screening and sequencing of the TM gene (THBD) revealed a previously unreported homozygous variation, c.793T&gt;A (p.Cys265Ser). Notably, the Cys265 residue forms one of three disulfide bonds in the epidermal growth factor (EGF)-like domain 1 of TM. Transient expression experiments using COS-1 cells demonstrated markedly reduced expression of TM-Cys265Ser on the plasma membrane relative to wild-type TM. The TM-Cys265Ser mutant was intracellularly degraded, probably due to EGF-like domain 1 misfolding. The reduced expression of TM on the endothelial cell membrane may be responsible for the disseminated intravascular coagulation-like symptoms observed in the patient. In conclusion, we identified a novel TM variant, c.793T&gt;A (p.Cys265Ser). Patients homozygous for this variant may present with severe bleeding events; rhTM should be considered as a possible treatment option for these patients.

Comparison of patients with acute ischemic stroke with and without COVID-19

Objectives: Information on the incidence of acute ischemic stroke (AIS), which is an important cause of morbidity and mortality, its association with COVID-19, and its course in infected patients in this pandemic period is limited. In this study, it was aimed to compare the demographic, clinical and stroke characteristics, and the laboratory, prognosis and mortality findings of patients with AIS with and without COVID-19. Methods: This study included 43 patients with a positive nasopharyngeal PCR test who were followed up for AIS, and 70 patients without COVID-19 who were followed up for AIS during the same period from the Konya Numune State Hospital, Turkey. Results: Poor prognosis and mortality were found to be significantly higher in the AIS group with COVID-19 compared with the non-COVID-19 AIS group. In the AIS group with COVID-19, a higher rate of intensive care unit (ICU) need (40% vs. 5%), higher intubation rate (35% vs. 3%) and longer hospital stay (12.9 ± 10.8 vs. 6.6 ± 4.0 days) were observed. In the laboratory examinations, C-reactive protein, ferritin, D-dimer, troponin, and lactate dehydrogenase levels were found to be significantly higher in patients with AIS who were positive for COVID-19. An increase in D-dimer, ferritin and thrombocytopenia were found to be associated with mortality in the COVID-19 positive AIS group. Conclusion: Patients with AIS and COVID-19 had a higher rate of ICU need, higher intubation rate, longer hospital stay, higher mortality, and poorer prognosis than those without COVID-19. High levels of ferritin, D-dimer and fibrin degradation products were associated with a poor prognosis.

Laboratory manifestations of COVID-19 associated with hemostatic abnormalities

Hemostatic abnormalities had been reported in COVID-19 patients, which may include disseminated intravascular coagulation (DIC), hypercoagulability, and alterations in platelets parameters. Articles that investigate the alterations of hemostatic abnormalities during the COVID-19 disease (2020-2021) and their predictive value of disease outcome have been thoroughly reviewed. Among the reviewed articles, thrombocytopenia is observed in 5.0-41.7% of COVID-19 patients, which is related to disease severity. Moreover, other platelets parameters, including Platelets/lymphocytes ratio (PLR), Mean platelets volume (MPV), and aggregation, may also be affected. On the other hand, findings of coagulation tests such as D dimer; fibrinogen, Antithrombin (AT), and Fibrin degradation products (FDP) are significantly elevated in COVID-19 patients, while in a single study, most of the patients had positive Lupus anticoagulants (LA) and normal protein C (PC). In the same perspective, these alterations showed significant correlations with disease severity. Overall, hemostatic laboratory markers are significant predictors of COVID-19 disease outcome as indicated by the increased risk of venous and arterial thrombotic events, especially in ICU patients.

Time-to-event assessment for the discovery of the proper prognostic value of clinical biomarkers optimized for COVID-19

In the early days of the pandemic, clinical blood-originated biomarkers for COVID-19 have been investigated to predict patient mortality. A straightforward decision tree with three variables, i.e., lactic dehydrogenase (LDH), high-sensitivity C-reactive protein (CRP), and lymphocyte percentage, has been proposed previously, with more than 90% accuracy. In this work, we highlight the importance of the cohort made publicly available, especially at the beginning of the pandemic where open data were still limited, and complement the findings by incorporating further evaluation. Results confirmed poor short-term prognosis to abnormal levels of some laboratorial indicators, such as LDH, CRP, lymphocytes, interleukin-6, and procalcitonin. Our findings could also provide insights into COVID-19 research, such as key levels of fibrin degradation products, which are directly associated with the Dimerized plasmin fragment D and could indicate active coagulation and thrombosis. Still, we highlight here the prognostic value of interleukin-6, a cytokine that induces inflammatory response.