Mild bleeding disorders (MBDs) are the most common bleeding disorders in the general population.1 In contrast to more severe disorders such as severe haemophilia, MBDs are often difficult to diagnose.1–4 A heterogenous group of hereditary diseases are included under this broad classification and their characteristics differ widely. They include von Willebrand disease (VWD), platelet function disorders, mild haemophilia and rare coagulation defects.1,2,5 Some authors even consider MBD to include acquired disorders associated with a bleeding tendency such as anticoagulant treatment or systemic disorders.3 Patients with a MBD suffer from fewer but different bleeding symptoms when compared with those with haemophilia.2,3,6 Often MBDs come to light when bleeding complicates an operation, childbirth or a tooth extraction.2,3,6,7 In contrast to severe haemophilia, MBDs usually become apparent in adulthood and the distinction between MBD and healthy individuals based on clinical criteria alone can be difficult. In addition, the association between laboratory values and bleeding symptoms can be weak.3,8 However, diagnosing an MBD is important in order to recognise an increased peri-operative bleeding risk, to manage appropriately and avoid unnecessary treatment with blood products.
Visco-elastic methods such as thromboelastometry analysis (ROTEM) have promise in overcoming the limitations of conventional laboratory assays in patients with haemostatic disorders, particularly in the peri-operative setting.3,8 Major European guidelines emphasise their potential and even consider thromboelastometry as a replacement for conventional assays.9,10 Modified thromboelastometric techniques have also been employed in patients with haemophilia, in whom distinctive patterns of derived ROTEM variables have been demonstrated,11 and adapted thromboelastographic variables have correlated with bleeding phenotype in children with haemophilia.12 Several authors have also explored using thromboelastometry or thromboelastography (TEG) monitoring of bypassing agents in haemophilia patients.13–15 An association of bleeding phenotype and modified TEG results has been reported in patients with rare bleeding disorders.16 Two authors have studied the diagnostic value of ROTEM, TEG and modified TEG for the diagnosis of VWD but with conflicting results.17,18 Of note, the concentration of tissue factor was much lower in these investigations than in standard reagents. In addition, several authors emphasise that platelet activity contributes to the clot strength of ROTEM/ and TEG.19 The sensitivity of standard thromboelastometry or TEG analysis for the diagnosis of platelet function disorders has not been systematically studied to date.20 In summary, the diagnostic accuracy of visco-elastic methods for the presence of MBD is unclear, which is a major limitation.
To address this, we carried out a prospective cohort study in consecutive patients suspected to have a (mild) bleeding disorder and investigated the sensitivity of thromboelastometry for the diagnosis of MBD. We did not aim to predict bleeding in patients with MBD.
Materials and methods
Study design, setting and patients
This prospective cohort study was approved by the local ethical committee (Kantonale Ethikkomission Luzern; #11001) and all patients signed informed consent. Consecutive patients referred between January 2011 and September 2013 to our centre for a suspected bleeding disorder were included. No restrictions with regard to the type or severity of disease were applied. It is expected that all patients with a bleeding tendency would be referred to our hospital, Luzerner Kantonsspital, which serves as a tertiary centre for the population of Central Switzerland covering both urban areas and many rural communities. Its haematology laboratory is the only laboratory providing specialised haemostasis tests in the region. Patients were referred because of a bleeding tendency, a positive family history of a bleeding disorder or a prolonged prothrombin time (PT)/activated partial thromboplastin time (aPTT).
Protocol for patients with bleeding symptoms
The investigation of referred patients was set out in a detailed protocol. The history of bleeding events was assessed by the ISTH bleeding score (ISTH BAT),4,21 and all operations, interventions, tooth extractions, obstetric history and detailed family history were documented. Anti-aggregant drugs were stopped 10 days before assessment and the drug history was recorded. Patients were physically examined for petechiae, haematoma, signs of amyloidosis, telangiectasia and joint hyper-flexibility. Menorrhagia was recorded with the help of a visual assessment tool.22 Laboratory tests were performed in a stepwise manner. The first step included a full blood count, including measurement of mean platelet volume, PT, aPTT, thrombin time (TT), fibrinogen concentration (Clauss’ method), coagulometric determination of factor II, factor V, factor VII, factor X, factor VIII, factor IX, factor XI and factor XIII, von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), α2-antiplasmin and ABO blood type. Platelet function was assessed with the platelet function analyser (PFA-100). The following laboratory tests were conducted as second step according to the type of abnormality found: chromogenic factor VIII, factor XII, VWF multimer analysis, VWF - factor VIII binding capacity and euglobulin lysis time. Platelet function disorders were considered in case of a significant bleeding history (ISTH BAT ≥ 4 in men and ISTH BAT ≥ 6 in women) and normal step-one laboratory tests and patients were referred for light transmission aggregometry (LTA) and platelet flow cytometry. These were conducted and interpreted following recommendations previously described.23,24 LTA was performed with increasing concentrations of ADP (4, 6 and 10 μmol l−1 for male patients; 3, 4 and 6 μmol l−1 for female patients), collagen (1.5, 3 and 4 μg ml−1), arachidonic acid (2 mmol l−1) and ristocetin (1.5 and 0.5 mg ml−1). Platelet-rich plasma was prepared by centrifugation at 150g for 15 min and platelet count was adjusted to 250 × 109 l−1. Surface glycoproteins were analysed by flow cytometry using the following antihuman antibodies: CD42b-PE (Ibα; Dako, Basel, Switzerland), CD41-FITC (IIb; Becton Dickinson, Allschwil, Switzerland), CD61-FITC (IIIa, Becton Dickinson) and CD62P-PE (P-selectin; Becton Dickinson). Baseline activation of the fibrinogen receptor was measured using PAC-1-FITC (Becton Dickinson). Platelet reactivity was tested by adding increasing concentrations of ADP (0.5, 5.0 and 50 μmol l−1), convulxin (5, 50 and 500 ng ml−1) and thrombin (0.05, 0.5 and 5 nmol l−1) and measuring anti-CD62P as well as PAC1. Dense granule content was measured by loading the platelets with mepacrine (0.17 and 1.7 μmol l−1) and secretion was analysed after adding Thrombin (5 nmol l−1).
Whole blood samples were collected using citrated plastic tubes containing 1 ml trisodium citrate (0.106 mol l−1) for 9 ml of blood (Monovette, Sarstedt, Nümbrecht, Germany). A standardised protocol was applied to guarantee appropriate pre-analytic conditions. The first syringe was discarded. Thromboelastometry analysis was conducted within 15 min according to manufacturer's instructions using a ROTEM analyser (ROTEM delta; Tem International GmbH, Munich, Germany) as previously described.25 The INTEM, EXTEM and FIBTEM tests were carried out. The technicians performing the ROTEM tests were unaware of other test results.
Definition of diagnosis
MBD was defined as the presence of a hereditary bleeding disorder or bleeding disorder of undefined cause (BUC) defined as follows (Fig. 1b). Diagnoses of bleeding disorders were based on bleeding history and laboratory results according to current guidelines. Definite VWD type 1 was diagnosed with von vWF:RCo levels of 0.05–0.40 U ml−1 and vWF:Ag of 0.05 to 0.40 U ml−1 on two occasions, a ratio of vWF:RCo/vWF:Ag of more than 0.70, a normal multimer pattern and a compatible bleeding history.26–30 Possible VWD type 1 was defined as abnormal VWF:RCo/VWF:Ag on one occasion only or without a significant bleeding history.27,29,31,32 VWD type 2 was classified according to ISTH criteria.28 Acquired von Willebrand syndrome was considered following a new bleeding tendency and laboratory criteria mentioned above, an abnormal vWF:RCo/vWF:Ag ratio of less than 0.60 and an abnormal multimer pattern.26,28,33,34 Patients with low values of VWF:RCo or VWF:Ag (≤ 0.5 U ml−1) not meeting the criteria above, and associated with blood group O were classified as ‘low VWF’.1 Single factor deficiencies and haemophilia were diagnosed according to current definitions.35,36 Platelet function disorders were diagnosed in patients with a clear bleeding tendency according to a bleeding assessment tool (ISTH BAT ≥ 4 in men and ISTH BAT ≥ 6 in women) with normal PT, aPTT and also VWF:RCo/VWF:Ag and pathological LTA on two occasions with a delay of several weeks, together with flow cytometry.20,37–40 We diagnosed possible platelet function disorders in patients in whom not all tests were done. BUC was defined as an abnormal ISTH BAT (men ≥ 4 points; women ≥ 6 points) when all tests mentioned in the diagnostic work-up were normal and no bleeding disorder was identified.5,41,42 Patients with systemic disorders associated with bleeding symptoms (e.g. Crohn's disease) but without a haemostatic disorder were categorised as ‘systemic disorders’. Physicians making the final diagnosis were not aware of ROTEM results.
Descriptive statistics were used to characterise the study population; [number (%) or median [IQR] as appropriate]. Mean differences of thromboelastometry variables were reported between patients with and without MBD. Paired t-tests were used to test hypotheses of differences between MBD. No adjustments for multiple measurements were applied and P-values were plainly reported. Analyses were performed using the Stata 14.2 statistics software package. (StataCorp. 2014. Stata Statistical Software: Release 14; StataCorp LP, College Station, Texas, USA), and Figures were created using Prism 6 (GraphPad Software, Inc., La Jolla, California, USA). This manuscript adheres to the STROBE guideline.
Two hundred and seventeen consecutive patients were referred to our hospital and included in the study cohort. The flow of the patients is shown in Fig. 1a. The median [IQR] age was 39 years [28 to 57]; 151 patients were women (70%). The reason for referral was a positive bleeding history in 170 (78%), a positive family history in 24 (11%), an abnormal coagulation test in 11 (5.1%) or verification of a known haemostatic disorder (re-evaluation) in 12 (5.5%). Fifty patients were treated with antiaggregants (23%; stopped 10 days before assessment) and three received anticoagulant treatment (3%; vitamin K antagonists). An abnormal ISTH BAT was observed in 44 women (≥ 4 points; 29%) and in 21 men (≥ 6 points; 32%). The detailed patient characteristics are presented in Table 1.
Type of bleeding disorders
Ninety-seven patients were classified as having MBD (45%), whereas 100 were not (46%; Fig. 1b). Twenty patients were classified as having a systemic disorder (9%). Among patients with MBD, the most frequent disorder was definite or possible platelet function disorder (n = 50; 23.0%), followed by definite or possible VWD or low VWF associated with blood group 0 (n = 37; 17%). Mild haemophilia A was present in four (4%) and mild factor XI deficiency in two (2%). BUC was diagnosed in four (2%). Among patients with a systemic disorder, five received anticoagulation treatment (2%; vitamin K antagonists).
In patients with mild haemophilia A, median [IQR] factor VIII level was 0.28 U ml−1 [0.19 to 0.37]. In two patients with mild factor XI deficiency, factor XI levels were 0.45 and 0.48 U ml−1. In patients with definite or possible VWD type 1, median [IQR] vWF:Ag levels were 0.31 U ml−1 [0.27 to 0.38], and vWF:RCo levels were 0.32 U ml−1 [0.28 to 0.40]. In three patients with VWD typ 2, vWF:Ag levels varied between 0.35 and 0.74 U ml−1 and vWF:RCo between 0.19 and 0.30 U ml−1. The following defects were observed in patients with a definite platelet function disorder: aspirin-like defects in four patients (40%; severely impaired aggregation induced by arachidonic acid; impaired aggregation induced by collagen; unspecific secretion deficits in flow cytometry analysis), impaired dense granule content or secretion in three patients (30%; varying extent of aggregation deficits induced by ADP, collagen, and arachidonic acid; decreased expression of mepacrine and/or meparine secretion after adding thrombin in flow cytometry), decrease in α-granule secretion in one patient (10%; decreased aggregation after stimulation with collagen; decreased expression of p-selectin after adding ADP, convulxin and thrombin), impaired activation of fibrinogen receptor in one patient (10%; impaired aggregation following collagen; severely impaired activation of PAC-1 after adding ADP, convulxin and thrombin), and a complex defect in one patient (10%; decreased aggregation following collagen and ADP; impaired activation of PAC1-1 after adding ADP and convulxin). In patients with a possible platelet function disorder, a variety of nonspecific LTA results were observed that could not be properly characterised by repeated LTA and flow cytometry (the LTA and flow cytometry results did not fit, and/or patients refused another appointment to repeat measurements). Table S1 (supplemental material, http://links.lww.com/EJA/A195) summarises results of laboratory tests of patients with BUC.
Thromboelastometry analysis according to the presence of mild bleeding disorder
No statistically significant differences in important thromboelastometry variables were observed in patients with MBD compared with those without (Table 2). Mean differences, confidence intervals and corresponding P-values are shown in Table 2; the distribution of values is illustrated in Fig. 2. A small but significant prolongation of CT EXTEM was observed for patients with systemic disorders. The mean difference was −13.6 s, 95% CI −19.8 to −7.5 s; P < 0.0001).
Thromboelastometry analysis according to type of bleeding disorder
Mean differences of thromboelastometry variables between patients with and without individual disorders including CIs and corresponding P-values are summarised in Table 3. Very few statistically significant results were observed, and we did not correct for multiple testing.
Thromboelastometry analysis according to bleeding score
No statistically significant changes in thromboelastometry variables were observed with increasing scores of the ISTH BAT (Table 4). Distribution of CT EXTEM, MCF EXTEM, CT INTEM, MCF INTEM and MCF FIBTEM results are illustrated in Fig. 3. There was no obvious trend in patients with higher bleeding scores.
MBD was diagnosed in one of every two patients assessed for suspected bleeding disorder; a platelet function disorder was considered in 52%, VWD/low VWF in 38%, a mild haemophilia A or factor XI deficiency in 6%, and BUC in 4%. Presence of MBD was not associated with significant differences in important thromboelastometry variables. In addition, no significant differences were observed regarding various categories of the ISTH BAT, or severity of bleeding. Only minor differences were observed for some variables and individual disorders.
We are not aware of previous investigations studying the utility of thromboelastometry or TEG analysis prospectively neither in consecutive patients with a broad range of MBD nor in platelet function disorders. Previous investigations using nonstandard reagents with much lower tissue factor concentrations have concentrated on severe bleeding disorders and the investigators found some differences in thromboelastometry variables. However, the most significant changes were shown with derived variables only. Zia et al.16 studied TEG variables in children with rare bleeding disorders and in healthy controls retrospectively. Although an association between diagnosis of rare bleeding disorders and derived TEG variables was found, varying results were observed with routine variables. Several authors applied thromboelastometric techniques to patients with haemophilia. Sorensen et al.11 identified particular patterns of derived thromboelastometry variables in haemophilia. Changes in TEG variables have been associated with bleeding phenotypes in children with haemophilia.12 Others demonstrated particular changes in TEG and ROTEM variables during treatment of bypassing agents, derived variables in particular.13–15 Conflicting results have been demonstrated with regard to von Willebrand's disease using ROTEM, TEG and modified TEG.17,18
Our investigation has several strengths. First, this was a prospective investigation and all clinical data as well as laboratory tests have been conducted and recorded prospectively. Thus, we assume a high quality of data. Second, consecutive patients were included, resulting in a low risk of selection bias. Third, our hospital is the only haemostasis laboratory in central Switzerland and again a selection bias was unlikely. The most important limitation of our study was the limited number of patients with particular diseases and we are not able to draw firm conclusions with regard to the individual disorders. In particular, our cohort does not contain any patient with a congenital fibrinogen disorder. Previous investigations in these patients report changes in thromboelastometry variables44,45 and ROTEM might be used for monitoring fibrinogen replacement.46 In addition, the assessment of platelet function disorders was not done at our hospital and patients were referred to a specialised laboratory. This resulted in a high number of patients with a suspected platelet function disorder. In contrast to other studies, we found a relatively small number of patients with BUC.5 One possible explanation is that an important fraction of patients with ‘possible’ PFD or VWD are not truly diseased patients. However, this would not influence the study results because these patients would be classified as BUC and counted as MBD. In addition, we did not record the blood group in all patients but determined it in those with low VWF only.
Even though previous investigations suggested potential value in thromboelastometry analysis in the diagnosis or management with haemophilia and rare bleeding disorders (using modified reagents), our study does not support the implementation of ROTEM for screening, diagnosis or management of patients with MBD. Association between the presence of MBD and thromboelastometry variables is weak and all are within the established reference range of ROTEM. In addition, we were not able to establish an association between thromboelastometry variables and bleeding tendency as determined by the ISTH BAT. Future investigations will be more selective with regard to individual diseases (VWD in particular) to study potential applications.
Associations between the presence of MBD and standard thromboelastometry variables are weak and changes were within the established reference ranges. Our data do not support the application of thromboelastometry analysis for screening, diagnosis or management of patients with MBD.
Acknowledgements relating to this article
Assistance with the study: we thank Johanna A. Kremer Hovinga for helpful discussions and critical review of the manuscript
Funding and sponsorship: we received funding from the Research Fund Haematology Luzerner Kantonsspital, Luzern, Switzerland.
Conflicts of interest: none
Presentation: preliminary results were presented at the XXVI congress of the International Society on Thrombosis and Haemostasis, Berlin, 2017.
1. Boender J, Kruip MJ, Leebeek FW. A diagnostic approach to mild bleeding disorders. J Thromb Haemost
2. de Moerloose P, Levrat E, Fontana P, Boehlen F. Diagnosis of mild bleeding disorders. Swiss Med Wkly
3. Greaves M, Watson HG. Approach to the diagnosis and management of mild bleeding disorders. J Thromb Haemost
2007; 5 (Suppl 1):167–174.
4. Tosetto A, Castaman G, Plug I, et al. Prospective evaluation of the clinical utility of quantitative bleeding severity assessment in patients referred for hemostatic evaluation. J Thromb Haemost
5. Quiroga T, Mezzano D. Is my patient a bleeder? A diagnostic framework for mild bleeding disorders. Hematology Am Soc Hematol Educ Program
6. Rodeghiero F, Tosetto A, Castaman G. How to estimate bleeding risk in mild bleeding disorders. J Thromb Haemost
2007; 5 (Suppl 1):157–166.
7. Leebeek FW, Eikenboom JC. Von Willebrand's disease. N Engl J Med
8. Hans GA, Besser MW. The place of viscoelastic testing in clinical practice. Br J Haematol
9. Kozek-Langenecker SA, Afshari A, Albaladejo P, et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol
10. Rossaint R, Bouillon B, Cerny V, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care
11. Sorensen B, Johansen P, Christiansen K, et al. Whole blood coagulation thrombelastographic profiles employing minimal tissue factor activation. J Thromb Haemost
12. Chitlur M, Warrier I, Rajpurkar M, et al. Thromboelastography in children with coagulation factor deficiencies. Br J Haematol
13. Sorensen B, Ingerslev J. Whole blood clot formation phenotypes in hemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa. J Thromb Haemost
14. Furukawa S, Nogami K, Ogiwara K, et al. Systematic monitoring of hemostatic management in hemophilia A patients with inhibitor in the perioperative period using rotational thromboelastometry. J Thromb Haemost
15. Tran HT, Sorensen B, Bjornsen S, et al. Monitoring bypassing agent therapy: a prospective crossover study comparing thromboelastometry and thrombin generation assay. Haemophilia
16. Zia AN, Chitlur M, Rajpurkar M, et al. Thromboelastography identifies children with rare bleeding disorders and predicts bleeding phenotype. Haemophilia
17. Schmidt DE, Majeed A, Bruzelius M, et al. A prospective diagnostic accuracy study evaluating rotational thromboelastometry and thromboelastography in 100 patients with von Willebrand disease. Haemophilia
18. Topf HG, Weiss D, Lischetzki G, et al. Evaluation of a modified thromboelastography assay for the screening of von Willebrand disease. Thromb Haemost
19. Solomon C, Ranucci M, Hochleitner G, et al. Assessing the methodology for calculating platelet contribution to clot strength (platelet component) in thromboelastometry and thrombelastography. Anesth Analg
20. Harrison P, Mackie I, Mumford A, et al. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol
21. Bowman M, Mundell G, Grabell J, et al. Generation and validation of the Condensed MCMDM-1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost
22. Janssen CA, Scholten PC, Heintz AP. A simple visual assessment technique to discriminate between menorrhagia and normal menstrual blood loss. Obstet Gynecol
23. Daskalakis M, Colucci G, Keller P, et al. Decreased generation of procoagulant platelets detected by flow cytometric analysis in patients with bleeding diathesis. Cytometry B Clin Cytom
24. Cattaneo M, Cerletti C, Harrison P, et al. Recommendations for the standardization of light transmission aggregometry: a consensus of the working party from the Platelet Physiology Subcommittee of SSC/ISTH. J Thromb Haemost
25. Nagler M, ten Cate H, Kathriner S, et al. Consistency of thromboelastometry analysis under scrutiny: results of a systematic evaluation within and between analysers. Thromb Haemost
26. Laffan M, Brown SA, Collins PW, et al. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors’ Organization. Haemophilia
27. Biss TT, Blanchette VS, Clark DS, et al. Quantitation of bleeding symptoms in children with von Willebrand disease: use of a standardized pediatric bleeding questionnaire. J Thromb Haemost
28. Sadler JE, Budde U, Eikenboom JC, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost
29. Sadler JE, Rodeghiero F, Factor ISSovW. Provisional criteria for the diagnosis of VWD type 1. J Thromb Haemost
30. Quiroga T, Goycoolea M, Belmont S, et al. Quantitative impact of using different criteria for the laboratory diagnosis of type 1 von Willebrand disease. J Thromb Haemost
31. Bidlingmaier C, Grote V, Budde U, et al. Prospective evaluation of a pediatric bleeding questionnaire and the ISTH bleeding assessment tool in children and parents in routine clinical practice. J Thromb Haemost
32. Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Blood
33. Tiede A, Rand JH, Budde U, et al. How I treat the acquired von Willebrand syndrome. Blood
34. Mohri H. Acquired von Willebrand syndrome: features and management. Am J Hematol
35. White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost
36. Mumford AD, Ackroyd S, Alikhan R, et al. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors’ Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol
37. Gresele P, Harrison P, Bury L, et al. Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey. J Thromb Haemost
38. Knofler R, Eberl W, Schulze H, et al. [Diagnosis of inherited diseases of platelet function. Interdisciplinary S2K guideline of the Permanent Paediatric Committee of the Society of Thrombosis and Haemostasis Research (GTH e. V.)]. Hamostaseologie
39. Kottke-Marchant K, Corcoran G. The laboratory diagnosis of platelet disorders. Arch Pathol Lab Med
40. Quiroga T, Goycoolea M, Matus V, et al. Diagnosis of mild platelet function disorders. Reliability and usefulness of light transmission platelet aggregation and serotonin secretion assays. Br J Haematol
41. Elbatarny M, Mollah S, Grabell J, et al. Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project. Haemophilia
42. Quiroga T, Goycoolea M, Panes O, et al. High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls. Haematologica
43. Lang T, Bauters A, Braun SL, et al. Multicentre investigation on reference ranges for ROTEM thromboelastometry. Blood Coagul Fibrinolysis
44. Galanakis DK, Neerman-Arbez M, Brennan S, et al. Thromboelastographic phenotypes of fibrinogen and its variants: clinical and nonclinical implications. Thromb Res
45. Trelinski J, Pachniewska K, Matczak J, et al. Assessment of selected ROTEM parameters, kinetics of fibrinogen polymerization and plasmin amidolytic activity in patients with congenital fibrinogen defects. Adv Clin Exp Med
46. Kalina U, Stohr HA, Bickhard H, et al. Rotational thromboelastography for monitoring of fibrinogen concentrate therapy in fibrinogen deficiency. Blood Coagul Fibrinolysis