Usefulness of Fibrinogen/Fibrin Degradation Products Value in Differential Diagnosis Between Acute Ischemic Stroke and Acute Aortic Dissection.

A post-marketing surveillance study reported fatalities following tissue plasminogen activator administration in acute aortic dissection (AAD) with the symptoms of acute ischemic stroke (AIS) patients. Therefore, it is important to discriminate AAD from AIS. The present study aimed to investigate whether fibrinogen/fibrin degradation products (FDP) value can be useful in differential diagnosis between AAD and AIS. The study group comprised 20 AAD patients (10 men and 10 women; age 63.9 ± 13.6 years) and 159 AIS patients (91 men and 68 women; age 74.2 ± 10.6 years) who were transported to our hospital from 2007 to 2012. The AAD cases were further divided into patent-type AAD and thrombosed-type AAD. FDP values were significantly higher in the AAD group than in the AIS group (18.15 [5.2 - 249.9] µg/ml vs. 2.3 [1.5 - 4.45] µg/ml ; P < 0.001). In AAD groups, FDP values were significantly higher in the patent-type AAD group (n = 9) than in the thrombosed type AAD group (n = 11) (293.2 µg/ml [63.1 - 419.6 µg/ml ] vs. 5.6 µg/ml [3.8 - 7.9 µg/ml ]. FDP values were significantly higher in patients with AAD than in those with AIS, especially those with patent-type AAD compared with AIS patients. High FDP values may be a useful marker for differential diagnosis between patent-type AAD and AIS.

D-Dimer Plasma Levels Parallel the Clinical Response to Omalizumab in Patients with Severe Chronic Spontaneous Urticaria.

Omalizumab is very effective in the majority of patients with severe chronic spontaneous urticaria (CSU), but its mechanism of action is still unclear. In CSU the coagulation cascade is activated with an intensity that parallels the disease severity, and elevated plasma D-dimer levels are associated with a poor response to both antihistamines and cyclosporin. We measured D-dimer plasma levels before and after the first administration of omalizumab in 32 patients with severe CSU. A number of clinical and laboratory parameters were recorded, including the urticaria activity score, presence of angioedema, disease duration, C-reactive protein, anti-nuclear, and anti-thyroid antibodies. Baseline D-dimer levels were elevated in 19 (59%) cases. Omalizumab induced a complete response in 25 patients (78%), in most cases already after the first administration. At baseline, 14/25 responders had increased D-dimer plasma levels versus 5/7 non-responders. All responders showed a dramatic decrease of D-dimer plasma levels after the first administration of the drug (from 1,024 ± 248 [mean ± SE] to 251 ± 30 ng/mL; p = 0.003). In contrast, non-responders did not show any reduction in D-dimer levels after omalizumab administration (from 787 ± 206 to 1,230 ± 429 ng/mL; p = ns). In conclusion, plasma levels of D-dimer are frequently elevated in patients with severe CSU before omalizumab administration and decrease according to the clinical response of the disease to the drug, suggesting a possible effect of omalizumab on coagulation activation and fibrin degradation in a subset of CSU patients.

FDP/fibrinogen ratio reflects the requirement of packed red blood cell transfusion in patients with blunt trauma.

PURPOSE: To find factors that predict the requirement of packed red blood cells (pRBC) transfusion in patients with blunt trauma on arrival at the hospital. METHODS: We conducted blood tests in trauma patients whose trauma severity was suspected as being 3 and over in the Abbreviated Injury Scale. Patients were divided into the blood transfusion (BT) and control groups according to the requirement of pRBC transfusion within 24h after arrival. RESULTS: We analyzed 347 patients (BT group, n=14; control group, n=333). On univariate analysis, there were significant differences in Glasgow Coma Scale (GCS), rate of positive FAST (focused assessment with sonography for trauma) finding, hematocrit, international normalized ratio of prothrombin time, activated partial thromboplastin time, fibrinogen (Fib), and level of fibrin degradation products (FDP). On multivariable analysis, positive FAST finding, GCS, Fib, and FDP influenced the requirement of pRBC transfusion. In the area under the receiver operating characteristic curve analysis, Fib and FDP were markers that predicted the requirement of pRBC transfusion. The FDP/Fib ratio had a better correlation with the requirement of pRBC transfusion than FDP or Fib. CONCLUSIONS: The FDP/Fib ratio can be easily measured and may be a predictor of the need for pRBC transfusion.

Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care.

BACKGROUND: In the current epidemic of Ebola virus disease in western Africa, many aid workers have become infected. Some of these aid workers have been transferred to specialised hospitals in Europe and the USA for intensified treatment, providing the potential for unique insight into the clinical course of Ebola virus disease under optimised supportive measures in isolation units. METHODS: A 38-year-old male doctor who had contracted an Ebola virus infection in Sierra Leone was airlifted to University Hospital Frankfurt, Germany, on day 5 after disease onset. Within 72 h of admission to the hospital's high-level isolation unit, the patient developed signs of severe multiorgan failure, including lungs, kidneys, and gastrointestinal tract. In addition to clinical parameters, the diagnostic work-up included radiography, ultrasound, pulse contour cardiac output technology, and microbiological and clinical chemistry analyses. Respiratory failure with pulmonary oedema and biophysical evidence of vascular leak syndrome needed mechanical ventilation. The patient received a 3 day treatment course with FX06 (MChE-F4Pharma, Vienna, Austria), a fibrin-derived peptide under clinical development for vascular leak syndrome. After FX06 administration and concurrent detection of Ebola-virus-specific antibodies and a fall in viral load, vascular leak syndrome and respiratory parameters substantially improved. We gave broad-spectrum empiric antimicrobial therapy and the patient needed intermittent renal replacement therapy. The patient fully recovered. FINDINGS: This case report shows the feasibility of delivery of successful intensive care therapy to patients with Ebola virus disease under biosafety level 4 conditions. INTERPRETATION: The effective treatment of vascular leakage and multiorgan failure by combination of ventilatory support, antibiotic treatment, and renal replacement therapy can sustain a patient with severe Ebola virus disease until virological remission. FX06 could potentially be a valuable agent in contribution to supportive therapy. FUNDING: University Hospital of Frankfurt.

Fibrinogen ß-derived Bß(15-42) peptide protects against kidney ischemia/reperfusion injury.

Ischemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgß, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgß chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgß-derived Bß(15-42) peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.

D-dimer testing: A narrative review.

D-dimer containing species are soluble fibrin degradation products derived from plasmin-mediated degradation of cross-linked fibrin, i.e., 'D-dimer'. D-dimer can hence be considered a biomarker of in vivo activation of both coagulation and fibrinolysis, the leading clinical application in daily practice of which is ruling out venous thromboembolism (VTE). D-dimer has been further evaluated for assessing the risk of VTE recurrence and helping define optimal duration of anticoagulation treatment in VTE, for diagnosing disseminated intravascular coagulation (DIC), and for screening those at enhanced risk of VTE. D-dimer assays should however be performed as intended by regulatory agencies, as their use outside these indications might make them a laboratory-developed test (LDT). This narrative review is aimed at: (1) reviewing the definition of D-dimer, (2) discussing preanalytical variables affecting D-dimer measurement, (3) reviewing and comparing the assays performance and some postanalytical variables (e.g., different units and age-adjusted cutoffs), and (4) discussing the interest of D-dimer measurement across different clinical settings, including pregnancy, cancer, and coronavirus disease 2019 (COVID-19).

The fibrin-derived peptide Bbeta15-42 protects the myocardium against ischemia-reperfusion injury.

In the event of a myocardial infarction, current interventions aim to reopen the occluded vessel to reduce myocardial damage and injury. Although reperfusion is essential for tissue salvage, it can cause further damage and the onset of inflammation. We show a novel anti-inflammatory effect of a fibrin-derived peptide, Bbeta15-42. This peptide competes with the fibrin fragment N-terminal disulfide knot-II (an analog of the fibrin E1 fragment) for binding to vascular endothelial (VE)-cadherin, thereby preventing transmigration of leukocytes across endothelial cell monolayers. In acute or chronic rat models of myocardial ischemia-reperfusion injury, Bbeta15-42 substantially reduces leukocyte infiltration, infarct size and subsequent scar formation. The pathogenic role of fibrinogen products is further confirmed in fibrinogen knockout mice, in which infarct size was substantially smaller than in wild-type animals. Our findings conclude that the interplay of fibrin fragments, leukocytes and VE-cadherin contribute to the pathogenesis of myocardial damage and reperfusion injury. The naturally occurring peptide Bbeta15-42 represents a potential candidate for reperfusion therapy in humans.

Venous thrombosis in emergency department: diagnosis, treatment, and disposition.

AIM: The Authors describe diagnosis, treatment and therapy of deep venous thrombosis in Emergency Department following the last guidelines indications. DISCUSSION: Deep venous thrombosis of the legs, ranges from asymptomatic, incidentally discovered emboli to massive embolism causing immediate death. Chronic sequelae of venous thromboembolism (deep venous thrombosis and pulmonary embolism) include the post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension. Acute pulmonary embolism may occur rapidly and unpredictably and may be difficult to diagnose. Diagnosis and treatment can reduce the risk of death, and appropriate primary prophylaxis is usually effective. Patients treated for acute pulmonary embolism appear to be more times as likely to die of recurrent thromboembolism in the next year.

Venous thromboembolism in COVID-19: A meta-summary of cases.

OBJECTIVES: To summarize cases of venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) among coronavirus disease (COVID-19) patients and discuss their symptoms, diagnostic method, clinical features, and prognosis. METHODS: All major databases were searched for relevant studies published between December 1, 2019 and May 5, 2021. RESULTS: A total of 233 articles were identified, 22 describing 48 patients were included. A total of 79.1% had PE and 20.9% had DVT. Most patients were men, with a mean age of 56 years. Comorbidities were present in 70.8%, and 85.4% had at least one risk factor of VTE. 56.3% had received anticoagulation therapy. Most patients were treated in the general ward. Complications occurred in 27.1% of the patients, and recovery was achieved in 80.4%. CONCLUSION: Venous thromboembolism must be suspected even in patients who had received prior anticoagulant regimens or in stable cases, especially in males, the elderly, and patients with comorbidities and high D-dimer levels.

COVID-19 associated coagulopathy and thrombosis in cancer.

Cancer patients are at risk for a more severe COVID-19 infection as well as an adverse outcome of such infection. This may be caused by the cancer itself (e.g haematological malignancies and lung cancer) or due to immune suppression caused by anti-cancer treatment. Severe COVID-19 infections are often complicated by a coagulopathy that clinically results in a high incidence of venous thromboembolic disease. Cancer itself is associated with a hypercoagulable state and a markedly increased incidence of thromboembolic complications, hence the combination of cancer and COVID-19 may amplify this risk. COVID-19 vaccination seems safe and effective in most cancer patients although adapted and bespoke vaccination schemes may increase the seroconversion rate and immune response in selected patients. Specific management strategies to improve outcomes of cancer patients in COVID-19 (e.g. higher intensity antithrombotic prophylaxis) are lacking and should be evaluated in clinical studies simultaneously focusing on efficacy and safety.

Bbeta(15-42) protects against acid-induced acute lung injury and secondary pseudomonas pneumonia in vivo.

RATIONALE: Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide Bbeta(15-42) was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bbeta(15-42) in ALI has not been addressed so far. OBJECTIVES: To investigate the therapeutic potential of Bbeta(15-42) in ALI and secondary pneumonia induced by Pseudomonas aeruginosa. METHODS: The effect of the fibrin-derived peptide Bbeta(15-42) was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bbeta(15-42) on inflammation, bacterial clearance, and survival were evaluated. MEASUREMENTS AND MAIN RESULTS: After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with Bbeta(15-42). Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bbeta(15-42) during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. CONCLUSIONS: The fibrin-derived peptide Bbeta(15-42) exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.

Coagulopathy in moderate head injury. The role of early administration of low molecular weight heparin.

INTRODUCTION: Abnormalities in blood coagulation are relatively common after traumatic brain injury (TBI). We prospectively studied the safety of the early antithrombotic prophylaxis with low molecular weight heparin. METHODS: We prospectively evaluated 61 patients with moderate TBI. Patients requiring surgical treatment and/or with injuries in other systems were excluded. Coagulation studies included among others prothrombin time (PT), plasma fibrinogen levels and D-dimer levels. Blood samples were collected on admission and 24 h, 48 h, and 72 h later. Prophylaxis was started within 24 hours with tinzaparin. RESULTS: In 42 of 61 patients a form of disseminated intravascular coagulation (DIC) was detected. The severity of head injury was correlated with the severity of the coagulation disorders. The PT was prolonged in the first two days. Plasma fibrinogen levels dropped initially and increased to above normal values 2-3 days later. D-dimer levels were significantly elevated and in 19 patients remained elevated throughout the study period. Clinical manifestations of DIC were not observed. CONCLUSIONS: Patients with moderate TBI are at a serious risk of developing brain intravascular microthrombosis. Our study supports the early use of low molecular weight heparin.

[Individualized "minimal invasive" anticoagulation controlled with D-dimer-antigen testing - a concept]. / Individualisierte "minimal invasive" Antikoagulation unter Kontrolle von D-Dimer-Antigen-Bestimmungen. Ein Konzept.

The aim of the proposed concept is to use anticoagulant therapy in prophylaxis and therapy of thromboembolic events only to an extent that the coagulation activation is just not any longer detectable. It results an individualized anticoagulation tailored to the coagulation activation of the patient (individualized "minimal invasive" anticoagulation). Intensity and control of efficiency are to be monitored by measurement of in vivo coagulation activation, e.g. by D-dimer-antigen measurement. Especially with the use of the new oral anticoagulants such a saver anticoagulant therapy - as far as possible from bleeding risk - could open up new indications, which so far are not used because of safety reasons. More patients at risk could be prevented from thromboembolic events. The proposed concept is based on pathophysiological considerations and own clinical experience. It should be evaluated for efficiency in clinical studies.

[Clinical significance of D-dimer activity in thrombosis of patients with return of spontaneous circulation after cardiopulmonary resuscitation].

OBJECTIVE: To investigate the clinical significance of D-dimer contents in peripheral blood for monitoring the efficacy of thrombolytic therapy in patients with return of spontaneous circulation (ROSC) of cardiopulmonary resuscitation (CPR) cardiopulmonary resuscitation after cardiac arrest. METHODS: Forty-seven patients with sudden cardiac arrest received CPR according to 2005 American Heart Association (AHA) guidelines for CPR and emergency cardiovascular care (ECC). At the early stage of ROSC, those patients underwent head and breast CT scan if they were in a state of unconsciousness and had unstable vital signs. If intracranial hemorrhage, dissection of aorta and pneumothorax were rule out, and those patients who maintained blood circulation for over 24 hours were included. The expression of D-dimer contents in peripheral blood was determined at 0, 1, 2, 4, 8, 12 h after CPR in all patients. And the patients were randomly divided into control and experiment groups. Prior to thrombolysis, the patients whose D-dimer more than 512 µg/L were classified as Group A (n = 17); those whose D-dimer below 512 µg/L Group B (n = 14); and the remaining control group whose family members refused thrombolytic therapy Group C (n = 16). The general data, Glasgow coma scale, survival rate and the change of D-dimer in peripheral blood were analyzed. RESULTS: In Group A, D-dimer level began to increase significantly at CPR 1 hour. It peaked at CPR 2 hours then decreased gradually. The final survival rate was 67%. The survival rate and GCS were higher than those of Groups B and C. In Group B, the D-dimer concentrations began to increase gradually at CPR1 hour, peaked at CPR 12 hours and then decreased. The survival rate and GCS was lower than those of Group A and similar to those of Group C. Group C was control group with no thrombolysis. CONCLUSION: For those ROSC patients with D-dimer concentrations significantly higher than usual, the pathogenesis of cardiac arrest may be concerned with thromboembolism, thrombosis in circulatory system and hyperviscosity. After an initiation of thrombolytic therapy, blocked blood vessels are recanalized, blood circulation improves and the cause of cardiac arrest is removed. Thus their survival rate becomes better. For those with D-dimer concentrations no higher than usual, the cause of cardiac arrest is not concerned with thromboembolism, thrombolytic therapy can not improve the patient outcome. And the final survival rate remains unchanged. The significance of thrombolytic therapy is none.

Methodological Issues and Controversies in COVID-19 Coagulopathy: A Tale of Two Storms.

Venous thromboembolism, occlusion of dialysis catheters, circuit thrombosis in ECMO devices, all in the face of prophylactic and sometimes even therapeutic anti-coagulation, are frequent features of COVID-19 coagulopathy. The trials available to guide clinicians are methodologically limited. There are several unresolved controversies including 1) Should all hospitalized patients with COVID-19 receive prophylactic anti-coagulation? 2) Which patients should have their dosage escalated to intermediate dose? 3) Which patients should be considered for full-dose anti-coagulation even without a measurable thromboembolic event and how should that anti-coagulation be monitored? 4) Should patients receive post-discharge anti-coagulation? 5) What thrombotic issues are related to the various medications being used to treat this coagulopathy? 6) Is anti-phospholipid anti-body part of this syndrome? 7) How do the different treatments for this disease impact the coagulation issues? The aims of this article are to explore these questions and interpret the available data based on the current evidence.

Bbeta15-42 (FX06) reduces pulmonary, myocardial, liver, and small intestine damage in a pig model of hemorrhagic shock and reperfusion.

OBJECTIVE: The fibrin-derived peptide Bbeta15-42 (also called FX06) has been shown to reduce myocardial infarct size following ischemia/reperfusion. Hemorrhagic shock (HS) followed by volume resuscitation represents a similar scenario, whereby a whole organism is vulnerable to reperfusion injury. DESIGN: We subjected male farm-bred landrace pigs ( approximately 30 kg) to HS by withdrawing blood to a mean arterial pressure of 40 mm Hg for 60 minutes. Pigs were then resuscitated with shed blood and crystalloids for 60 minutes, and at this time, FX06 (2.4 mg/kg, n = 8) or vehicle control (phosphate buffered saline; 2.4 mg/kg, n = 7) was injected as an intravenous bolus. SETTING: University hospital laboratory. SUBJECTS: Anesthetized male farm-bred landrace pigs. MEASUREMENTS AND MAIN RESULTS: Data are presented as mean +/- sd. Five hours after resuscitation, controls presented acute lung injury (Pao2/Fio2-ratio <300 mm Hg; extra-vascular lung water index (marker for lung injury): 9.0 +/- 1.8 mL/kg) and myocardial dysfunction/damage (cardiac index: 4.3 +/- 0.25 L/min/m; stroke volume index: 30 +/- 6 mL/m; cardiac TnT levels: 0.58 +/- 0.25 ng/mL). In contrast, FX06-treated animals showed significantly improved pulmonary and circulatory function (Pao2/Fio2-ratio >*400 mm Hg; extra-vascular lung water index: *5.2 +/- 2.1 mL/kg, cardiac index: *6.3 +/- 1.4 L/min/m; stroke volume index: *51 +/- 11 mL/m; cardiac TnT levels: *0.11 +/- 0.09 ng/mL; *p < 0.05). Also, tissue oxygenation (tpO2; mm Hg) was significantly improved during reperfusion in FX06-treated pigs when compared with controls (liver 51 +/- 4 vs. *65 +/- 4; serosa 44 +/- 5 vs. *55 +/- 7; mucosa 14 +/- 4 vs. *26 +/- 4). Finally, FX06 reduced accumulation of myeloperoxidase-positive cells (mainly neutrophils) in myocardium, liver, and small intestine and reduced interleukin-6 plasma levels (*p < 0.05; compared with controls). CONCLUSION: We conclude that in a pig model of HS and reperfusion, administration of FX06 during reperfusion protects shock- susceptible organs such as heart, lung, liver, and small intestine.

General practitioner use of D-dimer in suspected venous thromboembolism: historical cohort study in one geographical region in the Netherlands.

OBJECTIVES: To investigate how many general practitioner (GP)-referred venous thromboembolic events (VTEs) are diagnosed during 1 year in one geographical region and to investigate the (urgent) referral pathway of VTE diagnoses, including the role of laboratory D-dimer testing. DESIGN: Historical cohort study. SETTING: GP patients of 47 general practices in a demarcated geographical region of 161 503 inhabitants in the Netherlands. PARTICIPANTS: We analysed all 895 primary care patients in whom either the GP determined a D-dimer value or who had a diagnostic work-up for suspected VTE in a non-academic hospital during 2015. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes of this study were the total number of VTEs per year and the diagnostic pathways-including the role of GP determined D-dimer testing-of patients urgently referred to secondary care for suspected VTE. Additionally, we explored the use of an age-adjusted D-dimer cut-off. RESULTS: The annual VTE incidence was 0.9 per 1000 inhabitants. GPs annually ordered 5.1 D-dimer tests per 1000 inhabitants. Of 470 urgently GP-referred patients, 31.3% had a VTE. Of those urgently referred based on clinical assessment only (without D-dimer testing), 73.8% (96/130) had a VTE; based on clinical assessment and laboratory D-dimer testing yielded 15.0% (51/340) VTE. Applying age-adjusted D-dimer cut-offs to all patients aged 50 years or older resulted in a reduction of positive D-dimer results from 97.9% to 79.4%, without missing any VTE. CONCLUSIONS: Although D-dimer testing contributes to the diagnostic work-up of VTE, GPs have a high detection rate for VTE in patients who they urgently refer to secondary care based on clinical assessment only.