Fibrin/fibrinogen Degradation Products Research Articles

The clinical significance of TAT, PIC, TM, and t-PAIC in vascular events of BCR/ABL-negative myeloproliferative neoplasms

Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α2- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events.

The relationship between serum coagulation parameters and the recurrence of chronic subdural hematoma.

The aim is to investigate the relationship between serum coagulation parameters (PT, APTT, D-D and FDP) before hospitalization and recurrence of chronic subdural hematoma (CSDH). 236 patients with CSDH who were diagnosed for the first time and had complete medical records were followed up for at least 90days. Fifty patients (21.2%) had relapsed. Univariate analysis was conducted including general data, imaging data and test results. Serum coagulation parameters (PT, APTT, D-D and FDP) were detected for all CSDH patients. The study identified several factors that exhibited a significant correlation with chronic subdural hematoma (CSDH) recurrence. These factors included advanced age (p = 0.01), hypertension (p = 0.04), liver disease (p = 0.01), anticoagulant drug use (p = 0.01), antiplatelet drug use (p = 0.02), bilateral hematoma (p = 0.02), and single-layer hematoma (p = 0.01). In addition, the presence of fibrin/fibrinogen degradation products (FDP) exceeding 5mg/L demonstrated a significant relationship with CSDH recurrence (P < 0.05). Notably, the combined assessment of D-dimer (D-D) and FDP exhibited a significant difference, particularly regarding recurrence within 30days after surgery (P < 0.05). The simultaneous elevation of serum FDP and D-D levels upon admission represents a potentially novel predictor for CSDH recurrence. This finding is particularly relevant for patients who experience recurrence within 30days following surgical intervention. Older individuals with CSDH who undergo trepanation and drainage should be closely monitored due to their relatively higher recurrence rate.

Evaluation of preoperative coagulation function changes and deep vein thrombosis incidence in elderly patients with hip fractures.

This study involved an analysis of preoperative deep vein thrombosis (DVT) incidence and changes in coagulation function among elderly patients suffering from hip fractures. The objective was to offer guidance on the prevention and management of preoperative DVT in the lower extremities of elderly individuals with hip fractures. A total of 282 elderly individuals with a hip fracture were enrolled and divided into two groups based on the location of the fracture: femoral intertrochanteric fracture (FIF, 161 individuals) and femoral neck fracture (FNF, 121 individuals). The two groups were compared with respect to baseline characteristics, including gender, age, and comorbid chronic diseases. Furthermore, the analysis encompassed the incidence of preoperative DVT in both lower extremities, along with seven coagulation parameters and platelet count before the surgical procedure. There was no significant difference in baseline information between the two groups. The incidence of preoperative DVT in the FIF group was higher than that in the FNF group, along with a significantly higher percentage of patients exhibiting increased levels of D-dimer and fibrinogen/fibrin degradation products (FDPs). Preoperative hypercoagulability and a greater prevalence of DVT were observed in elderly individuals with FIF compared to individuals with FNF. This indicates that clinicians should pay attention to elderly patients with FIFs, especially those with increased D-dimer and FDP levels.

Early prediction for massive fresh frozen plasma transfusion based on fibrinogen/fibrin degradation products and D-dimer in patients with blunt trauma: a single-center, retrospective cohort study.

This study aimed to examine the association of fibrinogen/fibrin degradation product (FDP) values in comparison with D-dimer and fibrinogen (Fib) values and the need for massive fresh frozen plasma (FFP) transfusion in patients with blunt trauma. This retrospective study included patients with blunt trauma aged ≥ 18years who were transported directly to the tertiary care hospital between April, 2012, and March, 2021. Massive FFP transfusion was defined as a composite outcome of at least 10 units of FFP or death for any cause except for cerebral herniation, within 24h after hospital arrival. We evaluated the diagnostic accuracy of predicting the need for massive FFP transfusions using FDP, D-dimer, and Fib levels at the time of hospital arrival. A total of 2160 patients were eligible for the analysis, of which 167 fulfilled the criteria for the composite outcome. The area under the curve and 95% confidence interval for FDP, D-dimer, and Fib levels were 0.886 (0.865-0.906), 0.885 (0.865-0.906), and 0.771 (0.731-0.810), respectively. When the cutoff values of FDP and D-dimer were set at 90μg/mL and 45μg/mL, the sensitivity values were 77% and 78%, the positive predictive values were 28% and 27%, and the negative predictive values were both 98%, respectively. In contrast, the sensitivity of Fib was low regardless of the cutoff value. FDP and D-dimer levels at the time of hospital arrival showed a higher predictive accuracy for the need for massive FFP transfusion than Fib.

Maternal fibrinogen/fibrin degradation products to high density lipoprotein cholesterol ratio for predicting delivery of small and large for gestational age infants: a pilot study

BackgroundThe purpose of this pilot study was to investigate associations between fibrinogen/fibrin degradation products (FDP) to high density lipoprotein-cholesterol (HDL-C) ratio (FHR) of mothers and the risk of delivering large/small for gestational age (LGA/SGA) infants and to evaluate the predictive power of FHR on LGA/SGA.MethodsThis study retrospectively reviewed 11,657 consecutive women whose lipid profiles and FDP levels were investigated at the time of admission for delivery at a specialized hospital. The FHR was calculated, and perinatal outcomes, including clinical parameters, were analyzed.ResultsThe prevalence of SGA was 9% (n = 1034), and that of LGA was 15% (n = 1806) in this cohort study. FHR was significantly lower in women who delivered SGA infants (4.0 ± 3.2 vs. 4.7 ± 3.3 mg/mmol, P < 0.01) and higher in women who delivered LGA infants (5.7 ± 3.8 vs. 4.7 ± 3.3 mg/mmol, P < 0.01) compared with those who delivered infants of normal size for their gestational age. Women in the top quartile for FHR (> 5.9 mg/mmol) had a 2.9-fold higher risk of delivering LGA infants [adjusted odds ratio (OR) = 2.9, P < 0.01] and a 47% lower risk of delivering SGA infants (adjusted OR = 0.47, P < 0.01) than those in the bottom quartile (< 2.7 mg/mmol). In addition, adding FHR to the conventional models significantly improved the area under the curve for the prediction of delivering LGA (0.725 vs. 0.739, P < 0.01) and SGA (0.717 vs. 0.727, P < 0.01) infants.ConclusionThese findings suggest that the FHR calculated in late pregnancy is an innovative predictor of delivering LGA and SGA infants. Combining FHR with perinatal parameters could thus enhance the predictive ability for predicting the delivery of LGA/SGA infants.

Unreliability of Serum- or Plasma-based Assays of D-dimer or Fibrin (Fibrinogen) Degradation Product for Diagnosing Periprosthetic Joint Infection: A Prospective Parallel Study.

The ability of D-dimer to diagnose periprosthetic joint infection (PJI) before revision hip or knee arthroplasty is still controversial, and the differences in diagnostic ability between serum- or plasma-based assays of D-dimer and fibrin (fibrinogen) degradation product (FDP) are uncertain. The prospective parallel study was performed to determine the ability of D-dimer to diagnose PJI before revision hip or knee arthroplasty, and the differences in diagnostic ability between serum- or plasma-based assays of D-dimer and FDP. Patients undergoing knee or hip arthroplasty at our institution were prospectively enrolled into the following groups: those without inflammatory diseases who were undergoing primary arthroplasty ("Prim" group), those with inflammatory arthritis who were undergoing primary arthroplasty ("Prim/Inflam"), those undergoing revision arthroplasty because of aseptic failure ("Rev/Asept"), or those undergoing revision arthroplasty because of PJI ("Rev/PJI"). The ability of preoperative levels of D-dimer or FDP in serum or plasma to diagnose PJI in each group was assessed using areas under receiver operating characteristic curves (AUCs) and other diagnostic performance indicators. The diagnostic performance of these assays was compared with that of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). In the final analysis, Prim included 42 patients; Prim/Inflam, 40; Rev./Asept, 62; and Rev./PJI, 47. D-dimer assays led to AUCs of 0.635 in serum and 0.573 in plasma, compared to 0.593 and 0.607 for FDP. Even in combination with CRP or ESR, these assays failed to perform as well as the combination of CRP and ESR for diagnosing PJI. Levels of D-dimer or FDP in serum or plasma, whether used alone or together with CRP or ESR, are unreliable for diagnosing PJI before revision arthroplasty.

Increased plasma DR-70 (fibrinogen-fibrin degradation products) concentrations as a diagnostic biomarker in dogs with neoplasms.

Tumor biomarkers have used widely in clinical oncology in human medicine. Only a few studies have evaluated the clinical utility of tumor biomarkers for veterinary medicine. A test for fibrinogen and fibrin degradation products (DR-70) has been proposed as an ideal biomarker for tumors in humans. The clinical value of DR-70 for veterinary medicine however has yet to be determined. Investigate the diagnostic value of DR-70 concentrations by comparing them between healthy dogs and dogs with tumors. Two hundred sixty-three dogs with different types of tumors were included. Sixty healthy dogs also were recruited for comparison. The DR-70 concentrations were measured in all recruited individuals by ELISA. Clinical conditions were categorized based on histopathology, cytology, ultrasound examination, radiology, clinical findings, and a combination of these tests. The median concentration of DR-70 was 2.130 ± 0.868 μg/mL in dogs with tumors, which was significantly higher than in healthy dogs (1.202 ± 0.610 μg/mL; P < .0001). With a cut-off of 1.514 μg/mL, the sensitivity and specificity of DR-70 were 84.03% and 78.33%, respectively. The area under curve was 0.883. The DR-70 concentration can be an effective tumor biomarker in veterinary medicine. Increased DR-70 concentrations were not affected by tumor type, sex, age, or body weight. However, in dogs with metastatic mast cell tumors and oral malignant melanoma, DR-70 concentrations were significantly increased. Additional studies, including more dogs with nonneoplastic diseases, are needed to further evaluate the usefulness of DR-70 as a tumor biomarker.

Net reclassification index in comparison of prognostic value of disseminated intravascular coagulation diagnostic criteria by Japanese Society on Thrombosis and Hemostasis and International Society on Thrombosis and Haemostasis: a multicenter prospective cohort study

BackgroundWe compared the prognostic value of the Japanese Society on Thrombosis and Hemostasis (JSTH) disseminated intravascular coagulation (DIC) diagnostic criteria with that of the International Society on Thrombosis and Haemostasis (ISTH) DIC diagnostic criteria for 28-day in-hospital mortality.MethodsWe conducted a multicenter prospective cohort study involving two hematology departments, four emergency departments, and one general medicine department in Japan between August 2017 and July 2021. We assessed three ISTH DIC diagnostic criteria categories using low cutoff levels of D-dimer (low D-dimer), high cutoff levels of D-dimer (high D-dimer), and fibrinogen/fibrin degradation products (FDP) as fibrin-related markers. The main outcome was diagnosis-based category additive net reclassification index (NRI).ResultsA total of 222 patients were included: 82 with hematopoietic disorders, 86 with infections, and 54 with other diseases. The 28-day in-hospital mortality rate was 14% (n = 31). The DIC rates diagnosed by the JSTH, ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were 52.7%, 47.3%, 42.8%, and 27.0%, respectively. The overall category additive NRI by JSTH DIC diagnosis vs. ISTH-low D-dimer, high D-dimer, and FDP DIC diagnosis were − 10 (95% confidence interval [CI]: −28 to 8, p = 0.282), − 7.8 (95% CI: −26 to 10, p = 0.401), and − 11 (95% CI: −26 to 3, p = 0.131), respectively.ConclusionsJSTH criterion showed the highest sensitivity for DIC diagnosis that did not improve but reflected the same prognostic value for mortality evaluated using ISTH DIC diagnosis criteria. This finding may help clinicians to use JSTH DIC criterion as an early intervention strategy in patients with coagulopathy.

Efficacy of Coagulofibrinolytic Markers for Postoperative Prediction of Venous Thromboembolism in Colorectal Surgery Patients: A Retrospective Observational Study.

A low rate of the incidence of venous thromboembolism (VTE) after surgeries that are preoperatively classified as having high risk of VTE has been reported in recent years. We seek to identify the optimal cases to receive perioperative pharmacologic thromboprophylaxis. In this study, we evaluated the incidence rate of VTE among patients undergoing colorectal surgery who did not receive perioperative pharmacologic thromboprophylaxis, and the ability of coagulofibrinolytic markers to predict the postoperative development of VTE. We retrospectively analyzed the rate of postoperative development of VTE in 70 patients undergoing elective colorectal surgery without perioperative pharmacologic thromboprophylaxis and the ability of coagulofibrinolytic markers to predict the development of VTE. The incidence of VTE was observed in 11 patients (15.7%); all cases were asymptomatic and distal-type deep vein thrombosis (DVT). Comparisons of time course changes in perioperative coagulofibrinolytic markers between patients with and without DVT revealed significant differences in soluble fibrin (SF), thrombin-antithrombin complex (TAT), fibrin/fibrinogen degradation product (FDP) and D-dimer. Dynamic postoperative physiological coagulofibrinolytic responses were shown, but all four markers at each postoperative point demonstrated moderate accuracy (median area under the curve [AUC]: 0.788, median sensitivity: 0.865, median specificity: 0.644) for predicting the development of DVT. The incidence of postoperative VTE was low in patients with colorectal surgery even in those who did not receive perioperative pharmacologic thromboprophylaxis. SF, TAT, FDP and D-dimer were useful for predicting the development of DVT when we set cut-off values taking the physiological perioperative coagulofibrinolytic responses into consideration.

High Plasma tPAPAI-1C Levels May Be Related to a Poor Prognosis in Patients with Severe or Critical COVID-19: A Single-Center Retrospective Study

Severe novel coronavirus disease 2019 (COVID-19) patients have a high incidence of thrombotic complications and mortality. The pathophysiology of coagulopathy involves fibrinolytic system impairment and vascular endothelial damage. This study examined coagulation and fibrinolytic markers as outcome predictors. In an observational study of 164 COVID-19 patients admitted to our emergency intensive care unit, hematological parameters on days 1, 3, 5, and 7 were retrospectively compared between survivors and nonsurvivors. Nonsurvivors had a higher APACHE II score, SOFA score, and age than survivors. Nonsurvivors also had a significantly lower platelet count and significantly higher plasmin/α2plasmin inhibitor complex (PIC), tissue plasminogen activator/plasminogen activator inhibitor-1 complex (tPAPAI-1C), D-dimer, and fibrin/fibrinogen degradation product (FDP) levels than survivors throughout the measurement period. The 7-day maximum or minimum values of the tPAPAI-1C, FDP, and D-dimer levels were significantly higher in nonsurvivors. A multivariate logistic regression analysis showed that the maximum tPAPAI-1C (OR = 1.034; 95% CI,1.014-1.061; p = 0.0041) was an independent factor affecting mortality, with an area under the curve (AUC) of 0.713 (optimum cut-off of 51 ng/mL; sensitivity, 69.2%; and specificity, 68.4%). COVID-19 patients with poor outcomes exhibit exacerbated coagulopathy with fibrinolysis inhibition and endothelial damage. Consequently, plasma tPAPAI-1C might be a useful predictor of the prognosis in patients with severe or critical COVID-19.

The Combination of the Lactate Dehydrogenase/Hemoglobin Ratio with the PLASMIC Score Facilitates Differentiation of TTP from Septic DIC Without Identification of Schistocytes.

In some cases, differentiating thrombotic thrombocytopenic purpura (TTP) from septic disseminated intravascular coagulation (DIC) without measuring ADAMTS13 activity is critical for urgent lifesaving plasma exchange. To investigate whether PLASMIC score without identifying the presence of schistocytes, D-dimer, fibrin/fibrinogen degradation products (FDP), FDP/D-dimer ratio, prothrombin time-international normalized ratio (PT-INR), lactate dehydrogenase (LD), hemoglobin (Hb), and LD/Hb ratio are useful in differentiating patients with TTP from those with septic DIC. Retrospective analysis was conducted on the medical records of the patients with septic DIC (32 patients) or TTP (16 patients). The PLASMIC score and other laboratory measurements all were helpful in differentiating TTP from septic DIC. When dichotomized between high risk (scores 6-7) and intermediate-low risk (scores 0-5), the PLASMIC score predicted TTP with a sensitivity of 75.0% and a specificity of 100%. However, 4 of 16 patients with TTP and 19 of 32 patients with septic DIC showed comparable PLASMIC scores of 4 or 5, making it difficult to distinguish between the two by PLASMIC score alone. Among the measurements examined, the LDH/Hb ratio was the most useful for differentiation. Receiver operating characteristic analysis of the LD/Hb ratio for predicting TTP revealed a cutoff of 53.7 (IU/10 g) (sensitivity 0.94, specificity 0.91). If the LD/Hb ratio was less than 53.7, it was unlikely that the patient had TTP. A combination of the LD/Hb ratio and the PLASMIC score may be useful for distinguishing between TTP and DIC and identifying patients who need rapid plasma exchange or caplacizumab administration.

Total Hip Arthroplasty Patients with Distinct Postoperative Fibrinolytic Phenotypes Require Different Antifibrinolytic Strategies

Bleeding patients exhibit different fibrinolytic phenotypes after injury, and the universal use of tranexamic acid (TXA) is doubted. We aimed to evaluate the efficacy of postoperative antifibrinolytic treatment in total hip arthroplasty (THA) patients with different fibrinolytic phenotypes. A retrospective analysis was conducted in 238 patients who underwent THA. Patients were divided into two groups by different fibrinolytic phenotypes (non-fibrinolytic shutdown and fibrinolytic shutdown), determined by the LY30 level on postoperative day 1 (POD1). The two groups were further stratified into four sub-groups based on different postoperative TXA regimens (Group A received no TXA postoperatively, while Group B did). Hidden blood loss (HBL), decline of hemoglobin (ΔHb), D-dimer (D-D), fibrinogen/fibrin degradation product (FDP), prothrombin time (PT), activated partial thromboplastin time (APTT), and demographics were collected and compared. The clinical baseline data were comparable between the studied groups. In patients who presented non-fibrinolytic shutdown postoperatively, Group B suffered significantly lower HBL and ΔHb than Group A on POD3 and POD5. In patients who presented postoperative fibrinolytic shutdown, Group B failed to benefit from the postoperative administration of TXA when compared to Group A. No difference was found in postoperative levels of D-D, FDP, PT, and APTT. Postoperative antifibrinolytic therapy is beneficial for THA patients who presented non-fibrinolytic shutdown postoperatively, while the efficacy and necessity should be considered with caution in those with fibrinolytic shutdown. LY30 is a promising parameter to distinguish different fibrinolytic phenotypes and guide TXA administration. However, further prospective studies are needed to confirm these findings.

Prevalence and risk factors of preoperative deep venous thromboembolism in spinal fracture

To investigate the incidence of lower extremity deep vein thrombosis (DVT) before surgery in patients with spinal fracture and analyze its risk factors. The clinical data of 1 046 patients with spinal fracture who underwent surgery from October 2017 to December 2020 were retrospectively analyzed, including patient's age, gender, body mass index (BMI), smoking history, complications, the time from injury to diagnosis of DVT, blood index results on admission. The complications included hypertension, osteoporosis, diabetes, coronary heart disease, chronic obstructive pulmonary disease (COPD), anemia, obesity, hypokalemia, hyponatremia, hypoproteinemia, renal insufficiency, spinal cord injury;blood index results on admission included hematocrit (HCT), creatinine (Cre), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein(LDL), D-dimer(D-D), fibrin/fibrinogen degradation products(FDP), and C-reactive protein(CRP). The patients were divided into group according to whether DVT was diagnosed by the lower extremity venous ultrasonography after admission to pre-operation. The patients with DVT were set as the DVT group, and the patients without DVT were set as the non-DVT group. First, the above-mentioned possible risk factors were analyzed by univariate analysis, and then the risk factors of DVT before spinal fracture surgery were analyzed by multivariate Logistic regression. Among 1 046 patients with spinal fracture, 137 had DVT before operation and 909 had no DVT. There were significant differences in age, the incidence of preoperative osteoporosis, diabetes, anemia, hypoalbuminemia, the levels of LDL, plasma D-D, FDP, and CRP between the two groups (P<0.05). Multivariate Logistic regression analysis showed that osteoporosis (OR=3.116, 95%CI:1.816-5.346, P<0.001), hypoproteinemia (OR=2.508, 95%CI:1.583-3.974, P<0.001), preoperative serum LDL>4.645 mmol/L(OR=2.586, 95%CI:1.394-4.798, P<0.001), plasma D-D>558.00 ng/ml (OR=23.916, 95%CI:15.108-37.860, P<0.001), FDP>13.81 µg/ml(OR=3.873, 95%CI:2.614-5.739, P<0.001) and age were independent risk factors for the occurrence of DVT before spinal fracture surgery, and the incidence of DVT in patients aged 36-50, 51-65 and over 65 years was 2.49, 2.59 and 4.02 times of those aged 18-35 years, respectively. The incidence of preoperative DVT in patients with spinal fracture is 13.10%(137/1 046). Preoperative complicating osteoporosis, hypoalbuminemia, serum LDL>4.645 mmol/L, plasma D-D> 558.00 ng/ml, FDP> 13.81 µg/ml and age are risk factors for DVT. And the older the patient, the higher the risk of DVT.

Decreased low-density lipoprotein and the presence of pulmonary arterial hypertension among newly diagnosed drug-naïve patients with systemic lupus erythematosus: D-dimer as a mediator.

Pulmonary arterial hypertension (PAH) is commonly associated with systemic lupus erythematosus (SLE). The present study investigated the relationship between coagulation and changes in lipid parameters in newly-diagnosed patients with SLE in the presence of PAH and whether the coagulation parameters were mediators between lipids and PAH presence. A total of 301 subjects scheduled for new-onset drug-naïve SLE were consecutively enrolled. Baseline data for patients without PAH and with PAH were gathered and compared. Coagulation and lipid parameters were compared across patients without lipid regulating and anticoagulation medications. Multivariable logistic regression model was applied to examine potential predictors of PAH in SLE. The relationships between them were examined using Spearman's correlation analysis. The relationship between coagulation index and lipids with SLE-PAH was evaluated using mediation analysis. Female patients accounted for 88.0% of the 301 subjects, and the average age was 32 years (range, 25-45 years). A total of 40 patients (13.3%) had PAH, and the average pulmonary artery systolic pressure (sPAP) was 55.825±26.67 mmHg. Patients with PAH were older and had higher levels of fibrin/fibrinogen degradation products (FDP), D-dimer, C-reactive protein, lower levels of complement 3, complement 4 and 25-hydroxy vitamin D3 compared with the non-PAH group. Multivariable logistic regression analysis showed that age and D-dimer were independent predictor factors for PAH. Among patients without lipid regulating and anticoagulation medications, patients in the PAH group had higher levels of D-dimer and FDP, and lower low-density lipoprotein (LDL) levels compared with patients without PAH. There was also a positive relationship between sPAP and D-dimer and FDP, and a negative relationship between sPAP and total cholesterol and LDL. Mediation analysis indicated that 25.61% of the effect of low LDL on PAH presence in systemic lupus erythematosus was mediated by D-dimer. Overall, the effect of low LDL on SLE-PAH appeared to be mediated by D-dimer, which mediated 25.61% of this effect.

Alveolar rhabdomyosarcoma with massive bone marrow infiltration and disseminated intravascular coagulation mimicking acute leukemia.

A 27-year-old man was admitted with a 2-month history of general fatigue, appetite loss, and back pain, leading to a worsening of his general condition. On admission, laboratory tests showed an increased white blood cell count (15.9 × 109/L), with leucoerythroblastosis (myeloblasts, 1.0%; promyelocytes, 0%; myelocytes, 2.5%; metamyelocytes, 1.5%; band neutrophils, 3.5%; segmented neutrophils, 67.0%; lymphocytes, 18%; erythroblasts, 48%), severe anemia (hemoglobin, 45.0 g/L), and thrombocytopenia (platelet count, 21.0 × 109/L). Biochemical tests revealed elevated lactate dehydrogenase (2582 U/L) level, and coagulation tests showed a prolonged prothrombin time (20.3 s; reference interval: 10.0–13.0), normal fibrinogen (2.24 g/L), elevated fibrinogen-fibrin degradation product (331.9 mg/L), plasmin inhibitor-plasmin complex (9.05 mg/L), thrombin-antithrombin complex (41.2 μg/L), and decreased antithrombin (75.3%) levels. A computed tomography scan revealed systemic lymphadenopathy, splenomegaly, bilateral pleural effusions, and massive ascites. A bone marrow aspirate revealed massive infiltration by large abnormal cells with a basophilic cytoplasm and cytoplasmic vacuoles (Figure 1A). Flow cytometry analysis showed that the abnormal cells expressed only CD56, but no myeloid or lymphoid cell markers. Because he suffered severe disseminated intravascular coagulation (DIC) and worsening hypoxemia due to increased pleural effusions, initial treatment for acute leukemia comprised prednisolone and cytarabine. On Day 2 postadmission, biopsy of the right axillary lymph node was performed. Immunohistological findings from a bone marrow clot and biopsy tissue from the right axillary lymph node revealed diffuse proliferation of abnormal round cells, which expressed desmin (Figure 1B), myogenin, vimentin, and CD56 (Figure 1C), but not cytokeratin and leukocyte antigen. Therefore, a diagnosis of alveolar rhabdomyosarcoma was made. Subsequently, treatment with vincristine, doxorubicin, and cyclophosphamide was initiated, which ameliorated the lymphadenopathy, ascites, and DIC. Although a leukemic phase or bone marrow infiltration is an uncommon manifestation of alveolar rhabdomyosarcoma, flow cytometry and immunohistological analyses of bone marrow specimens can facilitate correct diagnosis. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. The authors received no specific funding for this work. AS, HK, HU, and SK contributed to patient's care. SK performed pathological diagnosis. All authors wrote and reviewed the manuscript. Written informed consent for publication was obtained from the patient. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent for publication was obtained from the patient. All data can be assessed by contacting the corresponding author.

Phenotype-oriented anticoagulant therapy for sepsis: still a work in progress.

Coagulation disorders ranging from subtle changes in coagulation parameters to fatal disseminated intravascular coagulation (DIC) are common in septic patients. Coagulation activation is considered to be one of the most important factors contributing to multiple organ dysfunction syndrome (MODS) in sepsis. Anticoagulant therapy is, therefore, necessary to prevent MODS, but eligibility criteria remain controversial. Sepsis is a highly heterogeneous syndrome, which could explain the negative results of clinical studies on the treatment of sepsis. Recently, sepsis has been subdivided into several phenotypes with different therapeutic outcomes. At present, septic patients with dysfunctional coagulation expressed as increased D-dimer and fibrin/fibrinogen degradation products (FDPs) are considered to be candidates for anticoagulant therapy. In this review, we aimed to describe the features of different septic phenotypes. We also discuss factors that contribute to controversies in this area, and challenges in defining which septic phenotypes are good candidates for anticoagulant therapy.

Exposure to a Postoperative Hypercoagulable State Predicts Poor Prognosis After Transthoracic Esophagectomy in Patients with Esophageal Cancer.

The contribution of postoperative coagulation-fibrinolysis status to prognosis is yet to be fully investigated. Thus, in this study, we aimed to elucidate the relationship between postoperative hypercoagulable state (PHS) after transthoracic esophagectomy and long-term outcome in patients with esophageal cancer. Patients with esophageal cancer who underwent transthoracic esophagectomy were selected from a prospectively maintained database. Based on the trend of postoperative plasma fibrin-fibrinogen degradation product (FDP) levels, patients with PHS were identified. The prognostic significance of PHS was evaluated via multivariate analysis using the Cox regression model. Based on the plasma FDP levels of 172 patients that reached a plateau between POD5 and POD7, we calculated the mean FDP value of POD5, 6, and 7, setting a median value as a cutoff. Consequently, 87 patients were classified as PHS. The overall survival (OS) in the PHS group was determined to be significantly lower than in the non-PHS group (5-year OS; 68% and 80%, p = 0.012). Recurrence-free survival (RFS) in the PHS group was significantly lower than in the non-PHS group (5-year RFS; 60% and 79%, p = 0.017). Using the pathological stage as a covariate in the multivariate analysis, PHS was an independent prognostic factor of OS [hazard ratio (HR) 2.517, p = 0.009] and RFS (HR 1.905, p = 0.041). PHS was found to be an independent negative prognostic factor in patients with esophageal cancer. Possible improvement of the oncological outcome by early postoperative intervention with anticoagulants should be explored in clinical trials.

Reference intervals for coagulation parameters in non-pregnant and pregnant women

Established reference intervals (RIs) of coagulation parameters generally based on the general population are not applicable to specific women. In order to accurately evaluate the coagulation status of non-pregnant women and pregnant women, specific RIs should be established. Our study recruited 465 non-pregnant women and 1972 pregnant women aged 20–45 years. Eight tests including antithrombin (AT), protein C (PC), free protein S (fPS), lupus anticoagulant (LA), D-dimer, fibrin/fibrinogen degradation products (FDP), coagulation factor VII (FVII), and factor VIII (FVIII) were performed on ACL TOP automated coagulation instrument. The RIs for these tests were established in non-pregnant and pregnant women at different gestational weeks. Compared to the non-pregnant group, the medians of AT and fPS were lower, while the medians of PC, LA normalized ratio, D-dimer, FDP, FVII, and FVIII were higher. During pregnancy, AT and fPS activity showed a decreasing trend, with the increase of gestational age. PC activity, LA normalized ratio, D-dimer concentrations, FDP concentrations, FVII, and FVIII activity presented an increasing trend, with the increase of gestational age. The non-pregnant women-specific RIs and the gestational age-specific RIs of AT, PC, fPS, LA normalized ratio, D-dimer, FDP, FVII, and FVIII needed to be established for accurate clinical diagnoses.

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.

Feasibility of Applying Novel FDP Threshold Criteria to DIC Diagnostic Scoring Systems in Japanese Women with Placental Abruption

<i>Objectiv</i>e: The diagnosis of disseminated intravascular coagulation (DIC) in obstetrics characterized by marked elevation of fibrin/fibrinogen degradation products (FDP) requires specific FDP criteria, however, no reference values are currently available. We previously reported the FDP criteria reflecting the degree of coagulation activity, determined by the quantitative relation between the distributions of FDP and fibrinogen. We aimed to evaluate the feasibility of applying the novel FDP criteria to four existing DIC diagnostic scoring systems, in a retrospective study of Japanese women with placental abruption. <i>Materials and Methods</i>: The study population was 68 pregnant women who had been diagnosed with placental abruption at Okayama Medical Center (Japan) between January 2008 and December 2020. DIC was clinically determined using the following four categories: plasma fibrinogen level < 100 mg/dl, hemorrhage amount at delivery ≥ 2000 g, blood product (red blood cells and fresh frozen plasma) transfusion, and renal dysfunction. Based on our previous report on the artificial intelligence analysis of the FDP distribution function, FDP criteria for the normal upper limit, moderate increase, and marked increase were defined as 20, 32, and 80 μg/ml, respectively. We applied the FDP criteria to compare four current and revised DIC diagnostic scoring systems: Japanese Ministry of Health and Welfare (JMHW), Japanese Association for Acute Medicine (JAAM), International Society on Thrombosis and Haemostasis (ISTH), and pregnancy-modified ISTH (PM-ISTH) DIC score. We used the Kruskal-Wallis test, Wilcoxon rank-sum test, and proportion test for statistical analysis. <i>Results</i>: Clinical DIC was observed in nine cases. Sensitivity was 1.00 in all DIC scoring systems. The current/revised sensitivity of the JMHW, JAAM, ISTH, and PM-ISTH systems was 1.00/1.00, 1.00/1.00, not available (NA)/1.00, and 1.00/NA, respectively. The current/revised specificity of the JMHW, JAAM, ISTH, and PM-ISTH systems was 0.864/0.864, 0.678/0.797, NA/0.864, and 0.424/NA, respectively. The specificity of the revised JMHW and revised ISTH systems was higher than for the current JAAM (<I>P </I>< 0.05) and current PM-ISTH (<I>P </I>< 0.0001) systems. The specificity of the revised JAAM improved from 0.678 to 0.797. <i>Conclusion</i>: Our novel proposed FDP criteria are potentially useful for diagnosis of DIC in placental abruption.