The Effects of Sodium Fructose Diphosphate on Coagulation Factor Activity Tests in vitro

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The Effects of Sodium Fructose Diphosphate on Coagulation Factor Activity Tests in vitro

https://doi.org/10.21203/rs.3.rs-4440581/v1

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Sodium fructose diphosphate(FDP) is widely used in the treatment of patients with a variety of diseases and is highly effective. However, we have seen very few reports on the toxicity or adverse effects of this drug, and we know even less about the effects of this drug on the coagulation system. The results of our previous study showed that the drug had a significant effect on the four coagulation parameters (prothrombin time, PT; activated partial thromboplastin time, aPTT; fibrinogen, FBG; and thrombin time, TT) and platelet aggregation function. In the present study, it was found that FDP significantly prolonged the coagulation reaction time (R), a parameter routinely detected by thromboelastogram (TEG) testing systems produced by three different manufacturers, in vitro experiments. Further studies revealed that the drug had a significant inhibitory effect on the activity of coagulation factors V, VII, IX, Ⅺ, and Ⅻ, whereas it had no effect on the activity of factors II, VIII, and X. We conclude that FDP has a significant inhibitory effect on coagulation factors V, VII, IX, Ⅺ and Ⅻ activity, and thus it may really affect the function of our coagulation system.

Health sciences/Medical research/Pre clinical studies

Health sciences/Risk factors

Biological sciences/Drug discovery/Drug safety

Sodium fructose diphosphate (fructose-1, 6-diphosphate ,FDP) is an intermediate product of intracellular glycolytic metabolism with regulatory function of key enzyme activities of glucose metabolism¹; Exogenous FDP enters the cell through the cell membrane to activate phosphofructokinase and pyruvate kinase to increase the concentration of adenosine triphosphate and phosphocreatine in the cell, and promote the inward flow of potassium and calcium ions, which is beneficial to the energy metabolism of the cell and glucose utilization under the state of ischemia and hypoxia², so as to make the ischemic tissue cells to reduce the damage, and to further improve the activity and function of the cells^3,4. The drug began to be used in clinical practice in the 1980s, and subsequently, it has been widely used in the treatment of a variety of diseases, such as angina pectoris, acute myocardial infarction, heart failure, arrhythmia, myocardial injury, acute adult respiratory distress syndrome, dilated cardiomyopathy, parenteral nutrition, cardiac surgical extracorporeal circulation, digestive gastrointestinal disease postoperative, chronic hepatitis, anemia, chronic obstructive pulmonary disease, renal insufficiency and so on^3,4. FDP has a wide range of pharmacological effects, from the molecular level to participate in the regulation of a variety of intracellular metabolic processes, thereby improving cellular energy metabolism, increasing energy utilization, inhibiting the generation of free radicals, maintaining cell membrane stability, accelerating tissue repair, and maintaining organ function^4,5. A large number of studies have confirmed that FDP can be used individually or adjunctively in the treatment of various causes of tissue ischemia, hypoxia and organ damage⁵, exogenous FDP has almost no toxic side effects in the process of drug administration, and there is almost no contraindication, can be administered orally or intravenously, and has been widely used in the clinical environment, which has shown good social and economic benefits.

Although a large number of studies have shown that the use of FDP in the treatment of many diseases is efficacious and has few toxic side effects, the side effects of this drug are still not well understood and have only been sporadically reported, and so far, even less is known about whether this drug has any effect on the coagulation process. Thromboelastography (TEG) is a sensitive test used to reflect the coagulation process in whole blood, allowing a comprehensive assessment of platelet function, plasma factor activity, fibrin polymerization and fibrinolysis^6,7. In this article, we further explored and clarified whether FDP has an effect on the coagulation process and on the activities of coagulation factors (II, V, VII, VIII, IX, X, Ⅺ, Ⅻ) through in vitro experiments using TEG and coagulation factor activity monitoring.

For the first time, we confirmed in vitro with experimental results that FDP in blood had a significant inhibitory effect on the activities of coagulation factors V, VII, IX, Ⅺ, and Ⅻ, whereas no inhibitory effect has been shown on the activities of coagulation factors II, VIII, and X.

Correlation between the results of TEG tests and FDP concentration. Correlation analysis showed that the results of TEG routine testing coagulation reaction time (R, min) was positively correlated with FDP concentration. The correlation coefficients between R and FDP concentration were 0.988, 0.999, and 0.996 for the thrombelastography testing systems provided by three different manufacturers, namely, Makotian, Lepu, and Dinrun, while no significant correlation was observed for coagulation formation time (K, min), coagulation angle (α-Angle), and maximal amplitude (MA, mm); the correlation results were as shown in Table 1, Fig. 1,2and3.

Correlation of plasma coagulation factor (II, V, VII, VIII, IX, X, Ⅺ, Ⅻ) activities with their plasma FDP concentrations. After the addition of FDP (final concentrations of 0, 1, 2, 3, 4, 5, and 6 mg/mL) to the mixed plasma in vitro, the experimental results showed that V, VII, IX, Ⅺ, and Ⅻ activities decreased dependently with the increase in the concentration of FDP, and that no significant changes in the activities of II, VIII, and X coagulation factors were observed (Table 2, Figs. 4 and 5).

Table 2

Coagulation factor (Ⅱ、Ⅴ、Ⅶ、Ⅷ、Ⅸ、Ⅹ、Ⅺ、Ⅻ) activities(%)of the pooled plasma containing with different concentrations FDP in vitro detected by Sysmex CS5100 coagulation analysis system(x̄ ± s, n = 11);*p<0.000, There is a significant difference in statistical results compared to the control group (0mg/ml FDP).Abbreviations:FDP,Fructose diphosphate.
FDP (mg/mL)	Coagulation factor activities(%)
FDP (mg/mL)	Ⅴ	Ⅶ	Ⅸ	Ⅺ	Ⅻ	II	Ⅷ	Ⅹ
0	125.25 ± 18.96	146.85 ± 26.42	109.35 ± 9.07	75.88 ± 10.15	68.24 ± 7.40	130.05 ± 24.54	112.26 ± 17.50	121.57 ± 17.69
1	123.14 ± 19.33^*	144.94 ± 25.13^*	107.25 ± 8.58^*	74.44 ± 10.08^*	66.85 ± 7.48^*	128.16 ± 22.13	111.47 ± 17.27	120.27 ± 20.73
2	121.99 ± 18.83^*	143.22 ± 24.67^*	104.18 ± 8.31^*	72.42 ± 10.09^*	65.93 ± 7.52^*	126.95 ± 22.12	110.88 ± 17.87	123.57 ± 19.10
3	119.66 ± 17.16^*	141.89 ± 24.15^*	101.83 ± 7.80^*	71.30 ± 10.30^*	64.95 ± 7.25^*	127.66 ± 22.27	112.05 ± 17.60	121.68 ± 20.00
4	118.97 ± 17.29^*	139.80 ± 24.47^*	99.85 ± 7.04^*	70.41 ± 10.05^*	64.25 ± 7.51^*	126.44 ± 23.66	111.01 ± 16.85	123.98 ± 17.98
5	116.26 ± 16.46^*	138.05 ± 23.52^*	98.70 ± 7.00^*	69.07 ± 9.87^*	62.91 ± 7.68^*	127.23 ± 23.57	111.76 ± 18.21	123.12 ± 17.22
6	114.65 ± 16.38^*	136.47 ± 22.38^*	97.29 ± 7.10^*	67.49 ± 9.06^*	61.47 ± 7.35^*	127.05 ± 22.51	109.38 ± 17.13	122.25 ± 17.13
r	-0.995	-0.99	-0.989	-0.997	-0.995	-0.737	-0.630	0.484
Regression equation	Y_result=-1.735X_FDP + 125.19	Y_result=-1.7264X_FDP + 146.78	Y_result=-2.0575X_FDP + 108.81	Y_result=-1.3543X_FDP + 75.636	Y_result=-1.0668X_FDP + 68.143	Y_result=-0.4061X_FDP + 128.87	Y_result=-0.2832X_FDP + 112.11	Y_result=0.2911X_FDP + 121.48
P	<0.000	<0.000	<0.000	<0.000	<0.000	0.059	0.129	0.27

The results of the study showed that in vitro TEG coagulation reaction time (R) was prolonged with the increase of FDP content. Further study revealed that FDP had a significant inhibitory effect on the activity of some coagulation factors (V, VII, IX, Ⅺ, Ⅻ), and the intensity of inhibition was increased in a concentration-dependent way by FDP, whereas no significant change was seen in the activity of factors II, VIII, and X. The TEG R result is the time required for activation of the coagulation system in a blood specimen to initiate to the formation of a clot detectable by the 1st TEG device, reflecting the time of coagulation system initiation. The time it takes for the curve amplitude to reach 2 mm is commonly referred to as the coagulation reaction time R⁸. It provides information on the associated thrombin generation prior to fibrin chain deposition and also reflects the dynamic balance between coagulation factors and coagulation inhibitors.

The reference range for normal adult R is 5–10 min, which is influenced by the most important factors including the relevant coagulation factors in the blood and the anticoagulants used by the patient. Usually, when R is shortened, it indicates that the patient's coagulation system is initiated faster, suggesting that the patient's coagulation factor activity is increased. Conversely, it suggests that the patient has reduced or deficient coagulation factor activity⁹. When serial concentrations of FDP were added to the blood specimens, the R of TEG were all significantly prolonged in a concentration-dependent way, which suggests that FDP may have an inhibitory effect on coagulation factor activity; or it may have an anti-activating effect on coagulation factors. We further tested their coagulation factor activities and found that the activities of coagulation factors V, VII, IX, Ⅺ, and Ⅻ were inhibited in a concentration-dependent manner by FDP. From the experimental results, R prolongation and coagulation factor activity reduction, the two results are mutually verified and coincide with each other, so we have reason to believe that FDP reduces coagulation factor activity or inhibits coagulation factor activation, prolongs the coagulation time of our coagulation system, and thus affects the function of coagulation system. Accordingly, it is reasonable to assume that the clinical use of this drug may prolong the patient's clotting time and even increase the risk of bleeding.

PT, aPTT and TT reflect the function of extrinsic, intrinsic and common coagulation pathways¹⁰. As we have previously reported, in an in vitro assay, the PT, aPTT and TT assays of blood samples were significantly prolonged in a concentration-dependent way as the concentration of FDP increased¹¹. Combined with the results of this experiment, that is, FDP inhibited the activity of coagulation factors (V, VII, IX, Ⅺ, and Ⅻ) or activated anti-coagulation factors (V, VII, IX, Ⅺ, and Ⅻ), it is not difficult to understand and see that, as the samples increased in the concentration of FDP, their coagulation factor activity was reduced, which led to the prolongation of PT, aPTT and TT. The results of the present experiment were mutually verified with the results reported in our last study; accordingly, we have reason to believe that the real reason for the prolongation of PT, aPTT and TT due to FDP is because of the inhibition of coagulation factor activity by FDP, which is a pleasing and meaningful as well as interesting thing to know.

FDP is a biochemically active substance in glucose metabolism and energy metabolism of human tissue cells, which can effectively provide bioenergy, promote the metabolic activity of biological tissue cells, enhance the functional activity of various tissues and organs, and facilitate the repair of damage caused by ischemia and hypoxia in the human heart, brain, liver, kidney and other solid organs and organs or tissue cells, so that clinically the drug has a wide range of uses^2,4,5. The results of our study revealed the effect of FDP on in vitro coagulation assays, and therefore clinical care is required to exclude the effect of FDP combination on coagulation assays and to collect coagulation samples prior to the use of FDP. We have not conducted in vivo trials, and it is unclear whether the drug contributes to the risk of bleeding, but clinicians should be concerned about whether there is an effect on coagulation and should carefully assess coagulation and bleeding trends when using the drug.

Our study has some limitations. We obtained the initial experimental drug concentrations by assuming that the initial experimental drug concentrations were based on the assumed dose used in the drug's instructions for use, which is recommended to be 5–10 g per day for adults, and based on this dose, assuming a body weight of 60 kg, and a human blood percentage of about 7% of body weight, the theoretical expected plasma concentration of FDP blood after intravenous administration is about 1.19 to 2.38 mg/mL. The initial final drug concentration in this experiment was was set at 1 mg/mL for and the maximum concentration was 6 mg/mL, the simulated concentration in vitro, which covers the human blood concentration after intravenous administration. Our study showed that even with a blood concentration of 1 mg/mL, the blood TEG coagulation reaction time R assay was significantly prolonged (p < 0.000) as well as coagulation factors (V, VII, IX, Ⅺ, and Ⅻ) activities were significantly inhibited (p < 0.000). From this, we hypothesized that even the lowest therapeutic amount of FDP is likely to affect our coagulation function, such a conclusion is limited to the in vitro study and is one of the shortcomings of the present study, which requires further in vivo experiments. The purpose of this series of experiments was to validate the correlation between in vitro FDP concentrations and coagulation outcomes, not in vivo administered concentrations; their true in vivo concentrations, which remain to be verified by pharmacokinetic or pharmacodynamic data of the drug. Certainly, potentially useful studies in vitro can help to expose phenomena that may exist in vivo. It would be interesting to know if there is any indication that coagulation changes in treated patients when sodium fructose diphosphate is given. We look forward to the next potentially useful study, which will follow the peak measurements of the pharmacokinetic (PK) study, and further more valuable experimental results from blood samples taken at baseline and after infusion of Sodium fructose diphosphate. In addition, the specimens were obtained from outpatients or hospitalized patients after routine hemagglutination or TEG, such individual samples are extremely easy to have and use in our laboratory, which is also considered as a reuse of the samples that will be thrown away, without the need to recruit additional volunteers, and this specimen selection plan was fully approved by the Ethics Committee of the hospital. At the same time, this practice is also to reduce expenses and save funds, to avoid the recruitment of a large number of volunteers to avoid the consumption and waste of human and financial resources; on the other hand, a single sample is not enough to complete the experiment because the sample size is too small, so multiple individual blood specimens will be mixed together to form a sufficiently large number of mixed samples;Of course, during the experiment, we also considered that the effect of antigen-antibody agglutination reaction after mixing different blood samples might interfere with our experimental results, so we chose to mix samples of the same blood type and prepared mixed plasma or whole blood samples; at the same time, before this experiment, we also randomly selected two volunteers to conduct the same experiments as the mixed samples, and the conclusions of the results were consistent with the results of the mixed samples.

In conclusion, our in vitro study confirmed that FDP has a clear and definite effect on our coagulation assay results, especially coagulation factor activity (V, VII, IX, Ⅺ, and Ⅻ), and whether FDP really affects our body's coagulation function should be of great concern to us.

Instruments and reagents. TEG was performed using test systems from three different manufacturers; the Maiketian Haema TX Thromboelastography Test System and its accompanying reagent (Rapid Kaolin Reagent, Lot 20231101, provided by Shenzhen Maiketian Biomedical Technology Co. Ltd.), LEPU CFMS LEPU-8880 Thromboelastography Analyzer and its accompanying reagent (Thrombelastograph General Cup Test Kit viscosity measuring, Lot 23SH0102, provided by Lepu Medical Technology Co. Ltd.), Dingrun DRNX-Ⅲ Thrombelastograph Analyzer and its supporting reagents (Activated Coagulation Reagent (Coagulation Method), Lot 20230504, provided by Chongqing dingrun Medical Equipment Co. Ltd.). The Sysmex Coagulation Testing System is based on the Sysmex CS5100 Coagulation Analyzer and its corresponding reagents, including Dade Actin Activated Cephaloplastin reagent for aPTT testing (Lot 562729A), Thromborel S for PT (Lot 568182), Coagulation Factor II Deficient Plasma (Lot 503659), Coagulation Factor V Deficient Plasma (Lot: 575712), Coagulation Factor Ⅶ Deficient Plasma (Lot 500776), Coagulation Factor VIII Deficient Plasma (Lot: 560857A), Coagulation Factor IX Deficient Plasma (Lot: 504172B), Coagulation Factor X Deficient Plasma (Lot 504029), Coagulation Factor Ⅺ Deficient Plasma (Lot 503358B), Coagulation Factor Ⅻ Deficient Plasma (Lot 503427), Standard Human Plasma (Lot 563120), CONTROL N (Lot 507936), CONTROL P (Lot 556743), and the reagents were provided by Siemens Medical Diagnostic Products GmbH, Germany. Sodium fructose diphosphate was purchased from Anhui Weilman Pharmaceutical Co., Ltd, China (Lot 20231001).

Sample testing methods and procedures. The following experimental procedures and protocols were approved by the Ethics Review Committee of Anhui No.2 Provincial People's Hospital, China [(R) 2024-037]. Prior to this test, all assay systems, except for normal calibration, were performed using commercially available control samples specified by the manufacturer of each assay system supporting traceability, including normal and abnormal quality control samples. Each sample was then tested on the machine with the assay system under normal conditions.

Preparation and testing of coagulation factor plasma samples. About 2 ml venous blood with normal results of four routine coagulation tests (no history of blood disorders such as platelet and coagulation disorders, and no medication that affects coagulation, such as aspirin, in the past 2 weeks) was randomly collected from outpatients or hospitalized patients with anticoagulation of trisodium citrate at 1.09 mmol/L (blood-to-citric-acid anticoagulation ratio of 9:1), and centrifuged horizontally at 3000 r/min, R = 15 cm, for 10min, 1ml of platelet-poor platelet plasma was prepared.. One mixed plasma(Approx. 5 ml)was obtained by mixing plasma samples from every 6-7persons with the same blood type (A, B, O or AB), and a total of 11 different mixed plasmas were prepared. Take the above 1 mixed plasma sample and 7 graduated plastic centrifuge tubes, add 0.5 ml of mixed plasma into each centrifuge tube, and then add FDP to each tube (weighed accurately with an analytical balance) to give a final concentration of 0 (control tube), 1, 2, 3, 4, 5, and 6 mg/mL, respectively. the same operation was carried out for the other 10 mixed plasma samples as described above. After sufficient mixing, the coagulation factor II, V, VII, VIII, IX, X, Ⅺ, and Ⅻ activity of each sample was measured in a Sysmex CS5100 fully automated blood coagulation detection analyzer.

Preparation and detection of thromboelastographic samples. Fresh whole blood specimens (Approx. 1.8 ml) with normal TEG test results (no history of blood disorders such as platelet and coagulation disorders, and no medications that affect coagulation, such as aspirin, within the past 2 weeks) 1.09 mmol/L trisodium citrate anticoagulation (blood to citrate, 9:1) were randomly collected from patients who were retained as outpatients or hospitalized. Take the same blood type (type A, B, O or AB) every 5–6 people of the above blood samples mixed to get 1 mixed blood sample((Approx. 9 ml)), a total of 11 different from each other mixed blood samples were prepared. Take any 1 mixed blood sample and 7 graduated plastic centrifuge tubes, add 1 ml of mixed blood sample to each centrifuge tube, and add FDP to each tube (weighed accurately with an analytical balance) so that the final concentration is 0 (control tube), 1, 2, 3, 4, 5, and 6 mg/mL, respectively. The same procedure was performed on the other 10 mixed blood samples, and the coagulation reaction time (R), clotting time (K), α-angle (α-Angle), and maximal amplitude (MA) were measured on the Maiketian, Lepu, and Dingrun thromboelastography systems, respectively.

Statistical analysis. Before testing, each assay system was completed by the manufacturer to validate the performance of the assay system and qualified to pass the performance validation. Each sample was tested in three independent replicates according to the manufacturer's protocol and completed within two hours, with the average of the three assay results used as the basis for calculations. The test results of samples with an FDP concentration of 0 mg/mL were used as control tubes, and the percentage change in the test results of each sample from the control tube was calculated in order to infer, based on the degree of change, whether the drugs had an effect on the results of the coagulation tests and to further assess the presence of concentration-dependent interferences in the coagulation tests. All statistical analyses were performed using Microsoft Excel 2003 (Microsoft Corporation, Redmond, WA, USA), linear regression analyses were performed using Statistical Products and Services Solutions 20.0 (SPSS20.0, IBM, Armonk, USA) statistical software, and the Spearman Correlation coefficients were used to assess the correlation coefficients between the R, K, α-Angle, MA, or coagulation factors II, V, VII, VIII, IX, X, Ⅺ, and Ⅻ. activity measurements of the sample thromboelastograms and the FDP concentration of each analyzed system, respectively, to obtain linear regression equations, and statistical hypothesis tests were performed on the regression coefficients to determine the presence or absence of a linear relationship, and P < 0.05 was used to determine whether there was a significance; plasma or blood with the same FDP concentration for each FDP concentration was used as each comparison group, and plasma or blood with its FDP concentration of 0 was used as its corresponding control group, and was statistically analyzed using a paired t-test, and P < 0.05 was used to determine if significance existed.

Human and Animal Rights All procedures performed in study 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. The study was approved by our Institutional Review Board, Anhui No.2 Provincial People's Hospital, China [(R) 2024-037].

FDP

Sodium fructose diphosphate

Maiketian

Maiketian TX thromboelastography analyzer detection system

Lepu

Lepu CFMS LEPU-8880 thromboelastography analyzer detection system

Dingrun

Dingrun DRNX-III thromboelastography detection system.

Ethical approval The purpose of this study was to investigate the effects of FDP on routine coagulation tests in vitro. This study was conducted in vitro and has no adverse effects on patients’ health, because the samples used were the remaining samples after clinical examination and experimenters did not have direct contact with patients. Demographic and clinical data were collected by a questionnaire. The the Ethical Committees of The Anhui No.2 Provincial People's Hospital approved the study [protocol number :No. [(R) 2024-037] and all the participants provided their written informed consent in accordance with the Declaration of Helsinki.

Acknowledgements. This work was supported by a fund from the Anhui Provincial Health Commission (Health Research Program of Anhui, AHWJ2023BAc20016; and Health Research Program of Anhui, AHWJ2023BAa20021).

Authorship Contributions. Participated in research design: Tongqing Chen and Xingguo Zhong. Conduct experiments: Yalong Zhang and Xingguo Zhong. Contribute new reagents or analytic tools: Lu Chen and Yuan Fang. Perform data analysis: Lin Zhou and Ying Zhang . Wrote or contributed to the writing of the manuscript: Tongqing Chen and Yuan Fang.

Competing interest. The authors declare no competing interests.

Data availability statement. All relevant data are within the manuscript and its Additional files.

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Table 1 is available in the Supplementary Files section.

No competing interests reported.

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The Effects of Sodium Fructose Diphosphate on Coagulation Factor Activity Tests in vitro

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