The Usefulness of Factor XIII Concentration Assessment in Patients in the Acute Phase of Ischaemic Stroke Treated with Thrombolysis

Round 1

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

Manuscript is generally improved.

2 small suggestions

Results

Table 3  last lane: to be added P for difference within group (see below)

Table 4 last lane to be added P for Me difference within days

Lane 185 Plasmin acts on Fibrin, not fibrinogen

 

 

Author Response

Dear Editor in Chief and Respected Reviewer,

 

We would like to express our gratitude for such a detailed review which helped us to substantially improve our paper. We hope that our answers to all the comments will let our article pass successfully through the reviewing process.  

 

 

Reviewer's note  (1)  Are the results clearly presented?

I made changes to table 3 and 4.

Reviewer's note  (2) Table 3  last lane: to be added P for difference within group 

Table 3. Correlations between the distributions of CRP, D-dimers and fibrinogen concentrations in groups I and II on admission (day 1) and on the day 7.

Reviewer's note  (3) Table 3  last lane: to be added P for difference within group (see below)

 The last row in Table 3 shows the "p" value within the group, which indicates whether the difference between the first and seventh day is statistically significant within the same group.

Table 3. Correlations between the distributions of CRP, D-dimers and fibrinogen concentrations in groups I and II on admission (day 1) and on the day 7.

Variables	Group I  N = 52	Group II  N = 32	P
CRP day 1 [mg/L] Me (Q1–Q3)	1.65 (1.00–3.85)	2.05 (1.35–7.55)	0.06
CRP day 7 [mg/L] Me (Q1–Q3)	4.60 (1.40–12.80)	4.35 (2.00–8.75)	0.98
CRP difference [mg/L] Me (Q1–Q3)	3.30 (-0.30–10.10)	0.20 (-2.70–6.80)	0.16
P for difference between day 1 and day 7	<0.01	0.76
DD day 1 [ngFEU/mL] Me (Q1–Q3)	914.5 (441.5–1248.5)	765.5 (411.0–1430.5)	0.77
DD day 7 [ngFEU/mL] Me (Q1–Q3)	664.5 (437.0–1051.0)	736.00 (295.5–1311.5)	0.91
DD difference [ng FEU/mL] Me (Q1–Q3)	-105.0 (-347.0–128.0)	-14.5 (-201.0–258.5)	0.30
P for difference between day 1 and day 7	0.19	0.98
Fibrinogen day 1 [mg/dL] Me (Q1-Q3)	332.0 (302.5–417.0)	356.0 (306.0–464.0)	0.31
Fibrinogen day 7 [mg/dL] Me (Q1–Q3)	360.0 (285.0–453.5)	377.5 (305.5–431.5)	0.85
Fibrinogen difference [mg/dL] Me (Q1–Q3)	23.5 (-57.0–96.0)	-3.0 (-62.0–83.0)	0.61
p for difference between day 1 and day 7	0.17	0.88

Me - median, Q1 - first quartile, Q3 - third quartile, CRP - acute phase protein, DD -D dimers.

 

Reviewer's note  (4) Table 4 last lane to be added P for Me difference within days

Table 4. Comparison of factor XIII concentrations in relation to stroke aetiology as defined by TOAST scale.

In table 4, I arranged group II, presenting it in the same order as group I, and removed the last column with differences in Me as unnecessary in this table.

 

Table 4. Comparison of factor XIII concentrations in relation to stroke aetiology as defined by TOAST scale.

Group	Aetiology	N	XIII-A [%] Me (Q1-Q3) Day 1	XIII-A [%] Me (Q1-Q3) Day 7
I	Cardiovascular thromboembolic	12	114.22 (105.61–27.58)	103.51 (89.20–108.71)
	Unknown aetiology	23	127.89 (114.62 –133.85)	109.32 (99.60–124.51)
	Changes in large blood vessels	10	117.20 (103.26–119.73)	107.00 (96.22–119.72)
	Disease of small blood vessels	7	110.68 (109.20–131.53)	116.79 (111.10–124.16)
	p		0.18	0.25
II	Cardiovascular thromboembolic	12	119.90 (102.05–131.85)	117.30 (110.15–125.80)
	Unknown aetiology	9	98.86 (83.46 –117.90)	89.48 (84.78–110.30)
	Changes in large blood vessels	5	110.00 (106.40–116.90)	112.60 (112.10–117.00)
	Disease of small blood vessels	6	105.40 (95.06–124.00)	107.00 (95.34–117.30)
	p		0.27	0.03

Me - median, Q1 - first quartile, Q3 - third quartile.

 

In the 185 Lane we corrected the part (highlited in red):

4. Discussion

In recent years, factor XIII in thromboembolic conditions has been receiving more attention in the field of research on haemostasis in the context of cardiovascular diseases, including stroke. Factor XIII, as one of the last elements of the coagulation cascade, is involved in the formation of the fibrin clot. Cross-linked fibrin shows greater resistance to mechanical deformation and less susceptibility to fibrinolysis. In contrast, t-Pa (Actilyse) administered to treat the acute phase of IS mimics endogenous t-Pa, activating inactive plasminogen to plasmin, which acts on fibrin to dissolve it, removing clots from the vessels

 

Author Response File: Author Response.docx

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

Dear Authors

I had the pleasure of reading the manuscript entitled "The usefulness of factor XIII concentration assessment in patients in the acute phase of ischaemic stroke treated with thrombolysis". The articles ins treating but there is some space for significant improvement. 

1. Definitely, it is not clear in the Introduction why the authors thought that measuring factors XIII in the acute phase could be useful to clinical practice. This could also be present in the Discussion. Do the authors think that such measurement could modify or guide the inclusion criteria of thrombolysis in ischemic stroke? 

2. Do the authors think they would find the same in results with tenecteplase? Its use is gaining strength and a brief discussion is recommended (doi: 10.1161/STROKEAHA.120.029749). 

3. Do the authors have any information on hemorrhagic transformation? 

4. Do the authors have any information on previous use of anticoagulants at the moment of the index stroke? 

5. Was any subject submitted to the endovascular treatment? 

6. Some important variables that could influence the outcomes as well were missed and it must be included as a limitation. The authors must mention that the lipid profile and the use of statins could also have influenced the outcomes. Moreover, the use of statins also influence the coagulation cascade. These aspects must be mentioned citing a proper reference (doi: 10.1080/01616412.2021.1967677). 

 

Author Response

Dear Editor in Chief and Respected Reviewer,

 

We would like to express our gratitude for such a detailed review which helped us to substantially improve our paper. We hope that our answers to all the comments will let our article pass successfully through the reviewing process. 

 

 

Reviewer's note  (1)  Definitely, it is not clear in the Introduction why the authors thought that measuring factors XIII in the acute phase could be useful to clinical practice. This could also be present in the Discussion. Do the authors think that such measurement could modify or guide the inclusion criteria of thrombolysis in ischemic stroke? 

Thank you for your remark and question, In the introduction, we generally discuss coagulation and the significance of factor XIII in stroke, which is an innovative topic that has been poorly explored so far. On the other hand the discussion suggests that these measurements could be important for understanding stroke severity and prognosis. The text does not indicate that these measurements are currently considered for altering thrombolysis inclusion criteria, but it leaves open the possibility for future clinical applications as more evidence becomes available.  In fact Factor XIII, a blood clotting factor, plays a crucial role in the stabilization of fibrin in clot formation, which is integral to the wound healing process and maintaining vascular integrity. Despite its significant role in coagulation and tissue repair, factor XIII has not been widely adopted or utilized as a prognostic marker in stroke or other thromboembolic disorders. Its measurement and the understanding of its dynamics in the acute phase of ischemic stroke are still not common practices in clinical settings.

Reviewer's note  (2). Do the authors think they would find the same in results with tenecteplase? Its use is gaining strength and a brief discussion is recommended (doi: 10.1161/STROKEAHA.120.029749). 

Given the analogous mechanisms of tenecteplase and alteplase, both of which facilitate the conversion of plasminogen to plasmin leading to fibrin clot degradation, it is scientifically plausible to postulate that the impact on factor XIII would be similar with both agents. Although tenecteplase features enhanced fibrin specificity and a prolonged half-life, which may alter its pharmacodynamic profile, the differences in effects on factor XIII are likely to be minimal. Comprehensive studies are warranted to elucidate any significant variations in factor XIII dynamics between the two thrombolytic therapies in the context of acute ischemic stroke. The current research focus on alteplase has precluded a detailed comparative analysis in this domain. Despite it we updated our article, The current version reads as follows:

It is worth mentioning that we also noted a significant statistical relationship between factor XIII-A levels and ASTRAL scores on the day 1, where a score of more than 31 points means that the prognosis will be poor for more than 50% of the population, but there are no similar reports in other studies. However, it can be hypothesised that factor XIII-A may have prognostic value in patients treated with thrombolytic therapy. Warach et al. (2020) elucidate the pharmacological advantages of tenecteplase in the treatment of acute ischemic stroke, particularly its enhanced fibrin specificity and extended half-life, which facilitate a more efficient administration relative to alteplase. These pharmacodynamic properties suggest that factor XIII could be explored as a prognostic biomarker during tenecteplase therapy, potentially offering insights into patient outcomes based on its modulation during treatment [30].

 

Reviewer's note  (3). Do the authors have any information on hemorrhagic transformation? 

In this study, hemorrhagic transformation of stroke was not analyzed, and therefore it is not addressed in this article.

Reviewer's note  (4). Do the authors have any information on previous use of anticoagulants at the moment of the index stroke? 

Each patient was queried regarding their medication use; however, this data was not further analyzed in the context of hemorrhagic transformation, and therefore, it is not included in this article.

Reviewer's note  (5). Was any subject submitted to the endovascular treatment? 

None of the patients were submitted to the endovascular treatment.

Reviewer's note  (6). Some important variables that could influence the outcomes as well were missed and it must be included as a limitation. The authors must mention that the lipid profile and the use of statins could also have influenced the outcomes. Moreover, the use of statins also influence the coagulation cascade. These aspects must be mentioned citing a proper reference (doi: 10.1080/01616412.2021.1967677). 

Thank you for this important notice. Each patient underwent lipid profiling; however, there were no statistically significant results confirming a relationship between lipid levels and factor XIII. Therefore, this data was not included in this article. The majority of patients were not on statin therapy prior to their stroke.

Nevertheless we updated the article remarking the importance of this research.  The current version reads as follows:

Limitations of the above study may include the relatively small size of the study group, which consisted of 52 people, and the control group of 32 people. Another limitation of the study is the selection of the control group. Patients in the study group who received thrombolytic treatment represented a highly selected patient population with strict inclusion criteria for thrombolytic treatment, while the control group consisted of patients with varying stroke onset (over 4.5 hours), making this group very heterogeneous. Another limitation appears to be the wide disparity in terms of the age of the patients studied, and this makes for a very heterogeneous group, especially in terms of co-morbidities that may affect the coagulation system, including factor XIII. In addition, there was no long-term follow-up of patients in the study, for example, 30- or 90-day follow-up, which could provide an answer as to whether factor XIII-A levels on admission are a predictor of patients' health status in long-term perspective. It seems that more homogeneous groups of patients in terms of age, for example, from 50 to 70 years, could also influence the results obtained for factor XIII-A. Each patient underwent lipid profiling; however, there were no statistically significant results confirming a relationship between lipid levels and factor XIII. Therefore, this data was not included in this article. The majority of patients were not on statin therapy prior to their stroke. Furthermore, the prognostic significance of lipid profiles post-stroke, as detailed in the study by Vitturi and Gagliardi, underscores the potential influence of lipid levels on stroke outcomes, suggesting that lipid management could play a crucial role in secondary stroke prevention. Therefore, the present study suggests the possibility of further research on factor XIII and lipid profiles in ischemic stroke [31].

 

 

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

Manuscript is generally improved, but the tables remained to be clarified and better presented.

Finally, general presentation of the text should be improved, many typos errors (lack of alignment for instance and may others, biography should be reviewed)

Results

Table 3  last lane: to be added P for difference within group

Table 4 last lane to be added P for Me difference within days

Lane 185 Plasmin acts on Fibrin, not fibrinogen

 

 

Author Response

Dear Editor,

I have improved the text. The table has also changed its appearance - I removed the last column, believing that it is unnecessary because it complicates reading the table. The "p" value is placed and shows whether the differences between group I treated with thrombolysis and II without thrombolytic treatment are significant. However, there is no comparison between the day of admission to hospital and the seventh day within one group. I think that the table is now legible.

You wrote to send it within five days, i.e. by May 4-5, 2024. I will try to do it on May 3, 2024.

I hope, as do all the authors of the work, that the work will be accepted for your journal. We houpe it can inspire other centers that are better equipped to study factor XIII in stroke. On behalf of all authors, I am asking you to accept this article for your journal.

Sinerely yours

Author Response File: Author Response.docx

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

No further comment. 

Author Response

We would like to express our gratitude for such a detailed review which helped us to substantially improve our paper. 

Round 3

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

manuscript is improved

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

There were 5 patients with TACI in group I and 1 with TACI in group II.  The sample sizes are small.  The question is whether such data is sufficient for the conclusion presented in the manuscript.

The patients in group II did not have thrombolysis treatment. Was that because they missed the optimal time window or thrombolysis? What treatment did these patients receive? Were there any effects of the treatment they had on the level of factor XIII?  

XIII-A concentration decreases after t-PA, and the magnitude of this decline varies among different types of stroke. The data did not fully support this conclusion, and a detailed discussion should be given.

The data should be expressed as mean +/- SD. It is better to explain the reason the authors used median (Q1-Q3).

The abbreviation should have its full name when it first appears in the manuscript. 

The numbers in Tables 1, 5, and 6 were shifted. The format for Tables 3 and 4 is different. It is better to use the same format for all tables.

Author Response

Reply to Reviewer I

Dear Reviewer, thank you very much for your valuable comments, which I will take into account when correcting the work together with the magazine's editors (with the proofreading department)

There were 5 patients with TACI in group I and 1 with TACI in group II.  The sample sizes are small.  The question is whether such data is sufficient for the conclusion presented in the manuscript.

Although the number of patients with the most severe TACI stroke was small (both in the group treated with thrombolysis and without thrombolysis), the decrease in factor XIII was the highest in these patients (the highest was in TACI, in those treated with thrombolysis) - that is why I wanted to point it out. Perhaps another researcher would undertake the study of factor XIII in ischemic stroke in a larger number of patients, where they could then pay special attention to patients with TACI type of stroke. In group I, the concentration of XIII A decreased significantly between days 1 and 7 (p < 0.001). In group I, the concentration of XIII-A on day 7 in TACI was significantly lower than in another stroke. Our study could be treated as a pilot study, which might provide an impulse for further research on this issue. I would like to point out that this test is expensive due to the cost of reagents and sophisticated test methodology.

The patients in group II did not have thrombolysis treatment. Was that because they missed the optimal time window or thrombolysis? What treatment did these patients receive? Were there any effects of the treatment they had on the level of factor XIII?  

Patients in group II did not receive thrombolytic therapy because all were outside the time window for intravenous thrombolysis. The patients received aspirin and Clexane in a usually prophylactic dose and intravenous fluids under the control of heart function. In the group I, the concentration of factor XIII-A decreased significantly between the first and seventh day (p < 0.001), which was not observed so clearly in the group II (without trombolysis).

XIII-A concentration decreases after t-PA, and the magnitude of this decline varies among different types of stroke. The data did not fully support this conclusion, and a detailed discussion should be given.

In the group I, a significantly lower concentration of factor XIII-A was observed in the second collection (on the seventh day) in the case of TACI (Me = 102.81%) compared to non-TACI  (Me = 109.96%, p = 0.04), as also a large decrease in factor XIII-A concentration values ​​on the seventh day compared to the first day in the non-TACI group (however smaller than in the TACI stroke).

The decrease in factor XIII concentration after a stroke is caused by the consumption of this factor in the forming thrombus and the reduction of its activity by the action of proteolytic enzymes, such as plasmin. However, the explanation of the mechanism for reducing the level of factor XIII is not fully understood, and the research results of various authors are contradictory, so I only added that the research results are different.

In our patients in the group  undergoing thrombolytic treatment (group I), there was a statistically significant decrease in the level of factor XIII-A concentration. Massive activation of the coagulation pathway causes the consumption of factor XIII-A, and in TACI there is the most massive coagulation and therefore the level of factor XIII-A. XIII may be lower on 7 day after stroke and t-PA treatment  than in non-TACI strokes (these are milder strokes and the clotting is not as intense).

I present a fragment of the discussion from the article on this topic. I tried to present various results of researchers, but this problem is not fully explained.

”This study confirmed previous findings, according to which the IS patients treated with thrombolysis experience a decrease in factor XIII-A levels [14, 15]. In our patients treated with Actylise up to 4.5 hours after stroke onset, the level of factor XIII-A values on the day 7 after administrating the treatment decreased statistically significantly (p < 0.001). Szekely et al. [14] in a study that included 132 patients with  AIS treated with thrombolysis in the timespan of 4.5 hours showed that factor XIII levels decreased immediately after the Actylise infusion as well as 24 hours after the end of treatment (factor XIII value before thrombolysis equalled 126.6% +/- 36.1%, 24 hours after the end of treatment – 116% +/- 35.0%; p=0.034). The authors try to explain this phenomenon by the mechanism of consumption and the degradation of factor XIII. The decrease in factor XIII concentration after stroke is due to the consumption of this factor into the thrombus that is formed and a decrease in its activity through the action of proteolytic enzymes such as plasmin. However, the mechanism of the reduction in factor XIII levels is not fully understood”

There is little information in the available literature about the influence of thrombolysin on coagulation system parameters, their mutual correlation and the possible predictive value of any of the hemostasis parameters in relation to the patient's neurological condition. A simultaneous decrease in both fibrinogen and factor XIII-A, which also acts as an inhibitory factor, observed after treatment fibrinolysis is evidence of a complex process of hemostasis, including both fibrinogenolysis and activation of the system protecting against excessive fibrinolysis - the antifibrinolytic system.

I tried to present the research results of various authors. I will submit the entire text to the journal for proofreading so that everything is better written in English. I know that the tables need improvement - we will fix them with the help of the journal to make them legible)

The data should be expressed as mean +/- SD. It is better to explain the reason the authors used median (Q1-Q3).

We chose the median and Q1-Q3 values ​​because they are also used in other works. And the statistician confirmed that this statistical tool can be used to present the data.

We chose the median and Q1-Q3 values ​​because they are also used in other works. The median indicates the average value. Q1 -Determines the lower quarter of the data, i.e. the value below which 25% of the data lies. Q3 specifies that 25% of observations are equal to or greater than the third quartile value.

I am also attaching tables that are correct, but somehow got lost in printing and look strange. We will correct them, of course.

The abbreviation should have its full name when it first appears in the manuscript. 

I will do it of course during corection the text.

The numbers in Tables 1, 5, and 6 were shifted. The format for Tables 3 and 4 is different. It is better to use the same format for all tables.

I know that the tables need improvement - we will fix them with the help of the journal to make them legible. I send  you

I am sending the correct tables, which somehow got lost in print, but of course we will correct it, and the entire text will be proofread by the magazine's editorial office.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Your submission is interesting, but the subject could be better covered. Generally speaking, the article lacks clarity.  There also some mistakes to be corrected... English should also be improved

In my opinion, the text is not acceptable in this form

Abstract: lack of clarity

Lane 24: Better formulation “Blood parameters”

Statistics should not appeared in the abstract (described later methods). Lane 29, Lane 31, is this in TACI patients or in group 1 in general

Lane 31 TACI should defined in the abstract as well as ASTRAL, better formulation” in another stroke type”

Lane 36: significant decrease in all groups or in group 1 only?

Introduction:

Lane 49 lane better formulation: “two potentially active A sub-units and two carrier B sub-units

Lane 50 at this stage (FXIII A2B2) should be deleted (appropriate after thrombin conversion)

Lane 50 title is lacking:  2. Aim of the study

Methods

Lane 79-80 “CT Scan performed within 20 minutes upon...”

Lane 87: interview for a patient with stroke?

Results

Table 1  figures are not aligned, the legend should mention the type of data expression (it seems to be median and range, to be uniformed with other tables

Table 2 is not referenced in the text (is it possible to combine both tables?)

Data expression is not clear (is it a median and range?), P should be more explicit: the same value for everything?

Table 3 same remark: data expression in the legend not in the table

Tables should inserted in the text

Table 4 same remark and better presentation is needed, messy. A graphic presentation should maybe better

Lane 144 FXIII is determined in citrated plasma, not in serum

Table 5 same remark on data expression in the legend, I do not understand your differences on column 4 (XIII-A % Me Q1-Q3 differences). Again, a graph maybe more explicit

Table 6: redundant with table 5?

Lane 165: mRS is not defined

Table 7 figures not aligned, table not understandable. Again a graph? Alternatively, is it necessary to show this? It could be summarized in one sentence.

Discussion should be clearer and could be shorter, to be revised. Sentences should shorter as well

Lane 187 Blood serum must be replaced by blood circulation

Lane 193 the level of FXIII was significantly decreased

Lane 200 decrease of FXIII could be due

Lane 202 the reduction mechanism

Lane 206=> 207 I don’t understand the “but”

Lane 209 similarly to us

Lane 210 acting on the fibrin trapped into the thrombus? Not clear to me

Lane 216: the group 1 patients, (treatment group)

Lane 224 in the micro-circulation due to inflammation resulting in…

Lane 225: in inflammation, there is an increase in platelet count?

Lane 232 Hur and not Her and this is a repetition

Lane 245 figures should not be repeated,

Lane 263 to delete “those treated by thrombolytics”: say shortly in the treatment group

Lane 272 our results

Conclusions should be improved as well and be coherent to the abstract

 

 

 

 

Comments on the Quality of English Language

sentences too long

language not fluent

 

Author Response

Dear Reviewer,

thank you very much for your valuable comments on the paper ” The usefulness of factor XIII concentration assessment in patients in the acute phase of ischaemic stroke treated with thrombolysis”

The English will be corrected by a translator from the editorial office.

I changed the abstract according to the instructions  of you and I think -  it is more readable now.

I am attaching good tables because they got lost in print.

Lane 29, Lane 31: this is in TACI patients  in group 1   I wrote it exacty  now.

Thank you once again for the valuable comments. I made in the text correction and I hope that the article will now be appreciated by the Reviewer. The English will be corrected by a specialist in the editorial office. I marked the chenges made in yellow.

I crossed out the fragments that needed to be removed and marked them in gray

All tables will be corrected and I am sending them.

Sincerely yours

Author

 

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

You will find here my comments on the reviewed manuscript

Manuscript is generally improved, but the tables remained to be clarified and better presented. In particular, in some of them, it not clear what figures the P value belongs to?

For instance, do not understand the expression ‘Me differences” and how it is calculated? From my point of view, statistical differences between Me is enough with a p value only

In the entire manuscript, I suspect the term correlation is not employed in its real meaning in the text en general- to be replaced by association?

Finally, general presentation of the text should be improved, many typos errors (lack of alignment for instance and may others, biography should be reviewed)

A separated text with responds to my comments could be useful for better comprehension to each other

Abstract

Lane 24: Better formulation “Blood parameters” instead of paremeters

Lane 26 in the blood should be deleted (previously mentioned)

Lane 33 what’s the meaning of <31

Results

Table 1  Median and range instead of mean? Is the population Gaussian? It seems that your statistics methods are non-parametric?

Lane 139 “Table 3 and 4 shows the correlations between the factor XIII levels

and CRP, DD and fibrinogen levels on admission-on day 1 and on the day 7”

I don’t see any correlation but rather a distribution?

Lane 142 (Me was 4.6mg/l on day 7 vs.1.65mgl/l on day 1), I suppose this is median, to be expressed as Median and range; 4.6 (…-…), 1.65 (…-…)

Table 3  don’t understand why there are two P values for differences between day 1 and 7?

Me differences should be replaced by a “p value” only (if not possible to insert it in the table-to put it on the legend or/and  in the text)

Presentation on table 4 is more comprehensive…

Table 5 last column: Me differences should be replaced by a “p value” only

Table 6: same remark: it not clear to what figures the P value refers to

Lane 165: mRS is not defined (not corrected)

Not corrected/not clear: Table 7 figures not aligned, table not understandable. Again a graph? Alternatively, is it necessary to show this? It could be summarized in one sentence.

Lane 219 after “lysis of the thrombus by t-PA “

Lane 228: no statistically significant correlation between CRP and FXIII (data not shown? I don’t find real correlations in the results) I suspect the term correlation is not employed in its real meaning in the text en general to be replaced by association?

Lane 247 same remark

 

 

Comments on the Quality of English Language

You will find here my comments on the reviewed manuscript

Manuscript is generally improved, but the tables remained to be clarified and better presented. In particular, in some of them, it not clear what figures the P value belongs to?

For instance, do not understand the expression ‘Me differences” and how it is calculated? From my point of view, statistical differences between Me is enough with a p value only

In the entire manuscript, I suspect the term correlation is not employed in its real meaning in the text en general- to be replaced by association?

Finally, general presentation of the text should be improved, many typos errors (lack of alignment for instance and may others, biography should be reviewed)

A separated text with responds to my comments could be useful for better comprehension to each other

Abstract

Lane 24: Better formulation “Blood parameters” instead of paremeters

Lane 26 in the blood should be deleted (previously mentioned)

Lane 33 what’s the meaning of <31

Results

Table 1  Median and range instead of mean? Is the population Gaussian? It seems that your statistics methods are non-parametric?

Lane 139 “Table 3 and 4 shows the correlations between the factor XIII levels

and CRP, DD and fibrinogen levels on admission-on day 1 and on the day 7”

I don’t see any correlation but rather a distribution?

Lane 142 (Me was 4.6mg/l on day 7 vs.1.65mgl/l on day 1), I suppose this is median, to be expressed as Median and range; 4.6 (…-…), 1.65 (…-…)

Table 3  don’t understand why there are two P values for differences between day 1 and 7?

Me differences should be replaced by a “p value” only (if not possible to insert it in the table-to put it on the legend or/and  in the text)

Presentation on table 4 is more comprehensive…

Table 5 last column: Me differences should be replaced by a “p value” only

Table 6: same remark: it not clear to what figures the P value refers to

Lane 165: mRS is not defined (not corrected)

Not corrected/not clear: Table 7 figures not aligned, table not understandable. Again a graph? Alternatively, is it necessary to show this? It could be summarized in one sentence.

Lane 219 after “lysis of the thrombus by t-PA “

Lane 228: no statistically significant correlation between CRP and FXIII (data not shown? I don’t find real correlations in the results) I suspect the term correlation is not employed in its real meaning in the text en general to be replaced by association?

Lane 247 same remark

 

 

Author Response

Dear, I made corrections again according to the reviewer's suggestions. I improved what I could.   I hope that this article will be able to be published. I think it is interesting from a scientific point of view and maybe it will cause others to become interested in factor XIII and conduct further research in this direction. Please consider this article positively.

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

Concerning the manuscript, responses to comments are generally adequate. Editorial layout of the tables need still to be improved

Comments on the Quality of English Language

no more comments