Asymptomatic Venous Thromboembolism After Hepatobiliary–Pancreatic Surgery: Early Detection Using D‐dimer and Soluble Fibrin Monomer Complex Levels

Background D-dimer increases during pregnancy and is problematic to use in the diagnosis of venous thromboembolism. Fibrin monomer represents an alternative biomarker for venous thromboembolism. However, to be useful in pregnancy, the fibrin monomer concentration should be stable throughout pregnancy and during postpartum. Methods To describe the course of fibrin monomer concentration during pregnancy and the postpartum period in healthy pregnant women and to compare their within-subject biological variation (CVI) with non-pregnant women. Blood samples were obtained every fourth week during pregnancy and three samples after delivery in 20 healthy women and every fourth week during a 40-week period in 19 healthy non-pregnant women. Fibrin monomer (STA Liatest FM, Stago) was analysed in duplicates for all samples. Concentrations of fibrin monomer in pregnant and non-pregnant women were compared and the CVI for fibrin monomer was calculated. Results The median fibrin monomer concentration in pregnant women was 6.2 mg/L (2.5 and 97.5 percentiles 3.7–10.8 mg/L) and in non-pregnant women 4.8 mg/L (3.6–8.2) ( P < 0.01). The fibrin monomer concentration was relatively stable during pregnancy, although a few unexplained high fibrin monomer concentrations were found during pregnancy/postpartum. Fibrin monomer CVI in pregnancy and postpartum was 20.6% (95% CI 18.3, 23.5) and in non-pregnant 16.1% (13.7, 18.9). Conclusions For clinical purposes, fibrin monomer concentration can be considered stable during pregnancy, although it is slightly higher than in non-pregnant women. Pregnant and non-pregnant women have the same CVI. The suitability of fibrin monomer in venous thromboembolism diagnosis in pregnant women should be validated in further studies.

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Significance of D-dimer and soluble fibrin testing in screening of incident venous thromboembolism

Vascular Failure ◽

10.30548/vascfail.3.1_26 ◽

2019 ◽

Vol 3 (1) ◽

pp. 26-30

Author(s):

Shozo Yano ◽

Yuri Yoshida ◽

Yasuko Notsu ◽

Asako Fukuma ◽

Eri Nitta ◽

...

Keyword(s):

Venous Thromboembolism ◽

Soluble Fibrin ◽

D Dimer

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New Combinational Assay Using Soluble Fibrin and D-Dimer Determinations: A Promising Strategy for Identifying Patients with Suspected Venous Thromboembolism

PLoS ONE ◽

10.1371/journal.pone.0092379 ◽

2014 ◽

Vol 9 (3) ◽

pp. e92379 ◽

Cited By ~ 3

Author(s):

Shahsoltan Mirshahi ◽

Claudine Soria ◽

Basile Kouchakji ◽

Gérald Kierzek ◽

Jeanne Yvonne Borg ◽

...

Keyword(s):

Venous Thromboembolism ◽

Soluble Fibrin ◽

Promising Strategy ◽

D Dimer

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A monoclonal antibody that recognizes a neo-antigen exposed in the E domain of fibrin monomer complexed with fibrinogen or its derivatives: its application to the measurement of soluble fibrin in plasma

Blood ◽

10.1182/blood.v88.6.2109.bloodjournal8862109 ◽

1996 ◽

Vol 88 (6) ◽

pp. 2109-2117 ◽

Cited By ~ 39

Author(s):

G Soe ◽

I Kohno ◽

K Inuzuka ◽

Y Itoh ◽

M Matsuda

Keyword(s):

Monoclonal Antibody ◽

Beta Chain ◽

Aggregation Assay ◽

Soluble Fibrin ◽

Amino Terminal ◽

Conformation Changes ◽

Fibrin Monomer ◽

Latex Beads ◽

Thrombotic Diseases ◽

D Dimer

Using urea-solubilized human fibrin monomer as an immunogen, we raised in mice a battery of monoclonal antibodies that reacted with the immunogen but not with urea-treated or native fibrinogen. Although they all failed to react with acid-solubilized fibrin monomer (acid-FM) alone, an antibody designated as IF-43 was found to recognize acid-FM, which was bound with fibrinogen or its derivatives to form a 1:2 complex of soluble fibrin. The epitope for this antibody, thus, appears to be exposed most probably by conformation changes induced in the acid- FM molecule upon formation of the complex. Because IF-43 was able to recognize fibrin-derived plasmic fragment E treated with urea but not the thrombin- and urea-treated amino-terminal disulfide knot of fibrinogen, the presence of the A alpha (52–78) residue segment seems to be prerequiste for the epitope expression. The antibody was found to react with soluble fibrin monomer spiked to normal plasma dose- dependently up to 200 micrograms/mL. By an aggregation assay using latex beads coated with IF-43, we found that concentrations of soluble fibrin monomer in plasma derived from patients with thrombotic diseases were mostly elevated, but not necessarily correlated with those of the D-dimer, reflecting another aspects of the disease. Furthermore, the soluble fibrin monomer in plasma derived from patients with thrombotic diseases was found to be depleted solely of the A peptides, but not the B peptides, based on its subunit polypeptide compositions lacking the beta-chain on immunoblotting.

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Influence of means of prevention of adverse effects of space flight on the plasma component of the system of regulation of the aggregate state of human blood

Russian Journal of Occupational Health and Industrial Ecology ◽

10.31089/1026-9428-2020-60-11-818-820 ◽

2020 ◽

Vol 60 (11) ◽

pp. 818-820

Author(s):

Dmitry S. Kuzichkin ◽

Aleksey Yu. Kochergin

Keyword(s):

Adverse Effects ◽

Human Blood ◽

Space Flight ◽

Physical Activities ◽

Thrombin Time ◽

Soluble Fibrin ◽

Antiorthostatic Hypokinesia ◽

Fibrin Monomer ◽

The Impact ◽

D Dimer

Introduction. It is known that the factors of space flight shift the coagulation balance of blood in the direction of procoagulant. The effect of space flight factors on the hemostatic potential of human blood with the simultaneous effect of preventive measures and compensation for their adverse effects has not been practically studied. The aim of study was to study the effect of physical exertion, electromyostimulation, mechanical stimulation of the foot, and blood-substituting solutions on the main indicators of the human hemostasis system in experiments with 21-hour antiorthostatic hypokinesia, 7-day "dry" water immersion, and 120-day isolation in a hermetic volume. Materials and methods. Concentrations of fibrinogen, plasminogen, soluble fibrin-monomer complexes, D-dimer, antithrombin III, protein C, and α2-antiplasmin were determined in citrate plasma; values of thrombin time, activated partial thromboplastin time, and prothrombin time. Results. It was found that the infusion of blood-substituting colloidal solution "venofundin" prevents the tendency to increase the level of soluble fibrin-monomer complexes observed during 21-hour antiorthostatic hypokinesia. Electromyostimulation leads to increased levels of fibrinogen and D-dimer during 7-day immersion. The complex of physical activities used in the experiment with 120-day isolation helps to reduce the level of D-dimer. Conclusions. The results indicate that when modeling the impact of space flight factors, a favorable hypocoagulation effect is provided by an infusion of venofundin, as well as a complex of balanced physical activities.

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Effect of new chalcone analogues on hemostasis in animals with experimental «сytokine storm»

Тромбоз, гемостаз и реология ◽

10.25555/thr.2021.3.0986 ◽

2021 ◽

Author(s):

Д.И. Поздняков ◽

В.М. Руковицина ◽

А.В. Сосновская ◽

Е.А. Олохова

Keyword(s):

Platelet Aggregation ◽

Antithrombin Iii ◽

Serum Levels ◽

Thrombin Time ◽

Cytokine Storm ◽

Reference Drug ◽

Soluble Fibrin ◽

Fibrin Monomer ◽

Antithrombin Iii Activity ◽

D Dimer

Введение. «Цитокиновый шторм» представляет собой расстройство иммунной системы с выраженной гиперцитокинемией, характеризующееся развитием коагуляционных нарушений с высоким уровнем летальности. Цель исследования: оценить влияние новых аналогов халкона на изменение реакций гемостаза у крыс в условиях экспериментального «цитокинового шторма». Материалы и методы. Исследование было выполнено на 80 крысах- самцах линии Wistar, разделенных на 8 равных групп по 10 особей. «Цитокиновый шторм» моделировали путем внутрибрюшинного введения липополисахарида в дозе 10 мг/кг. Исследуемые соединения в дозе 20 мг/кг интраперитонеально и препарат сравнения — гепарин (20 ЕД/кг, подкожно) вводили через 60 мин после моделирования патологии. Через 24 ч в сыворотке крови у крыс оценивали содержание фибриногена, D-димера, растворимых фибрин-мономерных комплексов (РФМК), активность антитромбина III (АТ-III), тромбиновое время (ТВ) и степень АДФ-стимулированной агрегации тромбоцитов. Результаты. Применение аналогов халкона способствовало восстановлению гемостатических реакций, что выражалось в снижении концентраций фибриногена, D-димера, РФМК, степени агрегации тромбоцитов и повышении активности АТ-III и ТВ. При этом в ряду изучаемых веществ соединение, содержащее гидроксил во 2-м положении и метильную группу в 5-м положении, проявляло несколько больший уровень фармакологической активности, нежели остальные исследуемые соединения. Заключение. На основании полученных данных можно предположить актуальность дальнейшего изучения аналогов халкона как средств, нормализующих гемостаз при гиперцитокиновых расстройствах. Background. «Cytokine storm» is a disorder of the immune system with severe hypecytokinemia, characterized by the development of coagulation disorders with a high level of mortality. Objectives: to evaluate the effect of new chalcone analogues on changes of hemostasis reactions in rats under the conditions of an experimental «cytokine storm». Materials/Methods. The study was performed on 80 male Wistar rats divided into 8 equal groups of 10 individuals. The «cytokine storm» was modeled in animals by intraperitoneal injection of lipopolysaccharide at a dose of 10 mg/kg. The test-compounds at a dose of 20 mg/kg intraperitoneally and the reference drug — heparin (20 U/kg, subcutaneously) were administered 60 minutes after the pathology simulation. After 24 hours, the serum levels of fi brinogen, D-dimer, soluble fibrin-monomer complexes, antithrombin III activity, thrombin time, and the degree of ADP-stimulated platelet aggregation were evaluated in rats. Results. The study showed that the use of chalcone analogues contributed to the restoration of hemostasis reactions, which was expressed in a decrease in theconcentration of fibrinogen, D-dimer, soluble fibrin-monomer complexes, the degree of platelet aggregation, and an increase in antithrombin III activity and thrombin time. At the same time, among the studied substances, the compound containing hydroxyl in the 2nd position and the methyl group in the 5th position showed a slightly higher level of pharmacological activity than the other test compounds. Conclusions. Based on the obtained data, it is actuality to assume the relevance of further study of chalcone analogues as agents that normalize hemostasis in hypercytokine disorders.

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Measurement of soluble fibrin monomer-fibrinogen complex in plasmas derived from patients with various underlying clinical situations

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613469 ◽

2003 ◽

Vol 89 (05) ◽

pp. 832-836 ◽

Cited By ~ 15

Author(s):

Yumiko Kazahaya ◽

Yuichi Shintani ◽

Kensuke Yamazumi ◽

Yutaka Eguchi ◽

Shin Koga ◽

...

Keyword(s):

Molecular Markers ◽

Disseminated Intravascular Coagulation ◽

Degradation Products ◽

Research Society ◽

Distinct Entity ◽

Soluble Fibrin ◽

Intravascular Coagulation ◽

Fibrin Degradation Products ◽

Fibrin Monomer ◽

D Dimer

SummaryWe previously reported a monoclonal antibody named IF-43 that specifically recognizes thrombin-modified fibrinogen (desAA- and desAABB- fibrin monomer) bound with fibrinogen or other D1 domain-containing plasmic fragments such as fragments X, Y, and D1, but not intact fibrinogen or cross-linked fibrin degradation products (XDP). Here, we tentatively named such complexes, soluble fibrin monomer (FM) -fibrinogen complex.By utilizing IF-43, we have developed a kit to measure soluble FM-fibrinogen complex and compared the profiles with those of two established molecular markers for thrombo-embolic disorders: i.e. the thrombin-antithrombin complex (TAT) and the D-dimer in plasma of patients who underwent surgery without any thrombo-embolic complications. The result indicated that soluble FM-fibrinogen complex is a distinct entity from the two established molecular markers. We have also attempted to observe their profiles in patients with the disseminated intravascular coagulation syndrome (DIC). Although the profiles of soluble FM-fibrinogen complex in individual patients appeared to vary from one patient to the other, the plasma level of soluble FM-fibrinogen complex was found to be increased at the initial phase of disseminated intravascular coagulation syndrome. Thus, the soluble FM-fibrinogen complex may serve as an independent molecular marker for the detection of thrombin generation and the diagnosis of thrombosis. The soluble FM-fibrinogen complex may also serve as a risk factor for thrombosis, because it may precipitate as insoluble complexes beyond its threshold in plasma, or when it is modified by thrombin.Part of this paper was originally presented at the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

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Evaluation of Soluble Fibrin Monomer Complex in Patients with Sars-Cov-2 COVID-19 Infection

Blood ◽

10.1182/blood-2020-136717 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 27-28

Author(s):

Meera Sridharan ◽

Aneel A. Ashrani ◽

Dong Chen ◽

Nahla M. Heikal ◽

Ariela L. Marshall ◽

...

Keyword(s):

Symptom Onset ◽

Mayo Clinic ◽

Onset Time ◽

The Other ◽

Onset Date ◽

Thrombin Time ◽

Soluble Fibrin ◽

Fibrin Monomer ◽

Prolonged Aptt ◽

D Dimer

Introduction: In patients with SARS-CoV-2 COVID-19 infection elevated D-dimers are associated with a poor prognosis. Although suggestive of DIC, the majority of patients do not fulfil ISTH criteria for DIC. Studies have demonstrated that when compared to D-dimer, fibrin monomers are more sensitive and specific when differentiating overt DIC from non-overt DIC. Our special coagulation laboratory (SCL) routinely measures soluble fibrin monomer complex (SFMC) as part of our DIC profile in samples with elevated D-dimers. Here we aimed to investigate the percentage of patients with COVID-19 infection with elevated SFMC as performed as part of the DIC profile. Methods: Between April 1st 2020 and July 26, 2020 inpatients at the Mayo Clinic Rochester, MN campus with COVID-19 infection who underwent DIC testing in SCL were identified through SCL database. Patients were excluded if SARS-CoV2 PCR results were not available in the Mayo Clinic electronic medical record (EMR). DIC profile components include prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen and D-dimer. Reflex SFMC is performed if D-dimer is elevated. Data abstracted from EMR included results of laboratory tests, date of COVID-19 symptom onset, date of SARS-CoV2 PCR positivity, and death within 30 days of hospital admission. The ISTH DIC score was calculated and patients were labeled as overt DIC or non-overt DIC based off of ISTH DIC score ≥5. Results: 35 patients (19 female), median age 59 years (28-91) met our study criteria DIC profiles were obtained 6.5 (1-37) days after COVID-19 symptom onset (n=33) with 28 obtained within 14 days of symptom onset. Time to DIC profile from SARS-CoV2 PCR testing was 4 (0-37) days (n=35) with 31 having testing completed within 14 days of PCR positivity. 8 patients were intubated during hospitalization and of the remaining 27, 67% required supplemental oxygen. 21/35 (60%) patients had an elevated fibrinogen (526.5 mg/dL (201-800)) while 19/35 (54%) had a prolonged PT (12.8 seconds (10.1-99.6) and 5/35 (14%) had a prolonged APTT (31 seconds (24-68)). 17 patients with prolonged PT and 3 patients with prolonged APTT had factor activity assays performed (Figure 1A). 9/35 (25%) had thrombocytopenia (230 x 109/L (12-709) and 27/35 (77%) patients had an elevated D-dimer (895 ng/ml FEU (220- >100,000). D-dimer was higher in males than in females (p: 0.049). Of those with elevated D-dimer only 5/27 (18.5%) had an elevated SFMC (5 mcg/ml (5- >1100) (Figure 1B). 4/35 (11%) patients had ISTH DIC scores ≥ 5 and all had score of 5. All of these patients had D-dimer > 2000 ng/ml while only 2 had elevated SFMC however SFMC in both of these patients was < 15 mcg/ml. Of these, one patient with SFMC of 12 mcg/ml had known cirrhosis and the other with an SFMC of 11 mcg/ml had acute decompensation and associated shock liver. This patient also had venous thrombosis 3 days prior to DIC profile and died from complications related to COVID-19 infection. Of the two other patients with high ISTH score and normal SFMC, one had previous chronic thrombocytopenia of < 50 x109/L while the other had concomitant admission for acute and recurrent pancreatitis in the setting of alcoholism with acute intoxication. Six patients died within 30 days of admission and in 2/5 performed SFMC was elevated (Figure1C). Conclusion: Compared to 77% of patients with elevated D-dimers, of those tested only 18.5 % of patients had elevated SFMC. It has been hypothesized that the elevated D-dimer noted in COVID-19 pulmonary infection is a direct consequence of acute lung injury and not overt DIC. Although preliminary, the small percentage of patients with overt DIC by ISTH criteria and normal SFMC in the majority of the current cohort support this hypothesis; however studies in a larger more controlled cohort are needed to confirm these findings. Disclosures Sridharan: Alexion: Honoraria. Pruthi:Merck: Honoraria; Instrumentation Laboratory: Honoraria; HEMA Biologics: Honoraria; Bayer Healthcare: Honoraria; Genentech Inc.: Honoraria; CSL Behring: Honoraria.

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