Efficacy and tolerability of human fibrinogen concentrate

Transcription

1 ORIGINAL PAPER Vox Sanguinis (2008) 94, Journal compilation 2008 Blackwell Publishing Ltd. DOI: /j x Efficacy and tolerability of human fibrinogen concentrate Blackwell Publishing Ltd administration to patients with acquired fibrinogen deficiency and active or in high-risk severe bleeding A. Farriols Danés, 1 L. Gallur Cuenca, 2 S. Rodríguez Bueno, 2 L. Mendarte Barrenechea 1 & J. Bruno Montoro Ronsano 1 1 Pharmacy Service, 2 Haematology Service, Hospital Universitario Vall d Hebron, Barcelona, Spain Received: 13 August 2007, revised 26 November 2007, accepted 26 November 2007, published online 4 January 2008 Background and Objectives Fibrinogen deficiency is a cause for massive haemorrhage whose management in emergency situations is the subject of debate. Plasma-derived fibrinogen concentrates are indicated for reversing the haemorrhagic diathesis found in congenital and acquired deficiencies. Materials and Methods We report on the results of an observational study that evaluated the effects of fibrinogen concentrates in patients suffering from various forms of acquired severe hypofibrinogenaemia with life-threatening consumptive thrombo-haemorrhagic disorders (surgery, trauma and digestive haemorrhage), or underlying disease states that limit fibrinogen synthesis (hepatic dysfunction, haematological malignancies). Results Sixty-nine patients were identified and included, in whom most of the processes (62%) corresponded to consumptive hypofibrinogenaemia. After a median dose of 4 g, a mean absolute increase of 1 09 g/l in plasma fibrinogen was measured and coagulation parameters were significantly improved (P < 0 001). Mortality rates of 32 3% and 44 2% were reported after 24 h and 72 h, respectively. Conclusion We conclude that the administration of fibrinogen concentrates in unresponsive, life-threatening haemorrhage with acquired hypofibrinogenaemia improves laboratory measures of coagulation, and may also be life saving. Although observational in nature, our data indicate a direct relationship between plasma fibrinogen levels and survival in acquired fibrinogen deficiency. Further studies are warranted to ascertain a clear relationship between fibrinogen levels and survival. Key words: fibrinogen concentrate, fibrinogen deficiency, severe bleeding. Introduction Fibrinogen is a plasma-soluble protein with a molecular weight of 340 kda, consisting of three pairs of polypeptide chains (Aα, Bβ and γ) [1]. It is the key substrate for the Correspondence: J. B. M. Ronsano, Pharmacy Service, Hospital Universitario Vall d Hebron, P Vall d Hebron , Barcelona 08035, Spain bmontoro@vhebron.net Authorship: A. Farriols, designed research, performed research; L. Gallur, designed research, performed research; S. Rodriguez, contributed vital new reagents or analytical tools; L. Mendarte designed research, performed research; and J. Bruno Montoro designed research, analysed data and wrote the paper. plasmatic blood coagulation and fibrinolysis, and interferes with the processes of cellular and matrix interactions, the inflammatory response wound healing and neoplasia. The plasma concentration of fibrinogen in healthy subjects ranges from 2 0 to 4 5 g/l; nevertheless, in patients with various congenital or acquired conditions, fibrinogen is markedly reduced and sometimes even undetectable with current methods of determination. Fibrinogen deficiency is a cause of bleeding and can lead to massive haemorrhage. The critical fibrinogen plasma limit varies between 0 5 and 1 g/l, and values ranging between 1 and 1 5 g/l are considered desirable in patients at risk of haemorrhage or to cease bleeding processes [2]. Congenital severe abnormalities of fibrinogen that result in bleeding 221

2 222 A. Farriols Danés et al. diatheses are rare, thus, acquired afibrinogenaemia is responsible for most cases of fibrinogen-related severe bleeding. Generally, acquired hypofibrinogenaemia is related to consumption and dilutional processes, like disseminated intravascular coagulation, or occurs as a consequence of an underlying disease that limits fibrinogen synthesis. Isolated acquired fibrinogen deficiency is unknown; in most cases, a complex coagulation disturbance is present [3]. Patients with obstetric syndromes, metastatic malignancies, massive trauma and bacterial sepsis, on one hand, and patients with liver disease, hepatic failure, acquired immune deficiency syndrome (AIDS), or lymphoproliferative disorders, on the other hand, are treated with a variety of blood-derived products to replace plasma fibrinogen in case of life-threatening bleeding, for example, fresh-frozen plasma (FFP), cryoprecipitate and/or specific plasma concentrate. Plasma is criticized because of its limited efficacy and the risks of transfusion-related infections, immunological reactions [4] and hypervolaemia, because ml/kg of plasma are usually required to achieve haemostasis [5]. Cryoprecipitate preparation, which avoids at least some of the inconveniences associated with plasma, is the only available source of fibrinogen for therapeutic purposes in some countries. Pasteurized human fibrinogen concentrate is an alternative, convenient therapeutic tool for supplementing plasma fibrinogen and achieving haemostatic levels. This product has the advantages of a standardized concentration of fibrinogen and effective virus inactivation. Commercially available fibrinogen concentrate is labelled for reversing the haemorrhagic diathesis found in congenital hypo-, dys-, and afibrinogenaemia and in acquired hypofibrinogenaemia situations, but clinical experience is scarce [6 8]. The efficacy of fibrinogen concentrate in acquired afibrinogenaemia-related bleeding is poorly documented under experimental conditions, because placebo-controlled studies with selective inclusion criteria and fixed follow-up conditions are simply not feasible and/or ethically unacceptable. Observational studies, based on case reports or series of cases, are also currently scarce. In this sense, there is an inadequacy of data on the efficacy and safety of fibrinogen concentrate, not only in the cessation of bleeding but also in terms of short-term survival rates. In the meantime, life-threatening bleeding episodes in acquired hypofibrinogenaemia suffer from the lack of any universally recognized treatment schedule and a specific and concrete therapeutic tool. Simultaneously, an assessment of the efficacy and tolerability of fibrinogen concentrate in clinically relevant bleeding episodes, in patients with acquired severe hypofibrinogenaemia, is still pending. Thus, the aim of the present study is to evaluate the efficacy and safety of fibrinogen concentrate in patients suffering from different forms of acquired afibrinogenaemia, including the management of life-threatening consumptive thrombo-haemorrhagic disorders, or underlying disease states that limit fibrinogen synthesis. Methods Study design An open-label, non-controlled retrospective study was performed in a third-level, 1600-bed general hospital, from June 2002 to June 2005, to evaluate the therapeutic effect of fibrinogen concentrate (Haemocomplettan HS, CSL Behring, Marburg, Germany) in patients with various forms of acquired hypofibrinogenaemia, associated with the presence or high risk of severe bleeding. Patient population Patients were identified from pharmacy-dispensing records. Local guidelines indicate fibrinogen concentrate for patients with plasma fibrinogen levels below 1 g/l and the presence or risk of severe active bleeding. Data were collected from the medical records of bleeding patients treated accordingly with fibrinogen concentrate during the study period. Data were collected from pharmacy service data, and clinical and laboratory records. A direct interview with the patient s responsible physician was conducted to complete or to check the available data. Data were collected as soon as possible after the treatment was initiated to avoid the potential loss of information. Parameters of evaluation For each patient included in the study, the following parameters were collected: age, gender, primary disease (diagnosis/ bleeding cause), fibrinogen dose, plasma fibrinogen level, prothrombin time (PT) and activated partial thromboplastin time (aptt) (previous to, and within 24 and 72 h after fibrinogen concentrate administration) and mortality (all causes, following 24 h and 7 days). Safety was investigated by describing any adverse event documented in clinical records. Patients were included in the study only if data on plasma fibrinogen before and after fibrinogen administration were documented. Patients lacking a full record of fibrinogen plasma levels were excluded. Fibrinogen measurements were performed at baseline, 24 h and 72 h after fibrinogen administration. Mortality was assessed at 24 h and at day 7. Eventually, patients were classified according to the nature of fibrinogen deficiency: those patients whose concentration of fibrinogen with or without other clotting factors was habitually lower, such as patients with hepatic insufficiency or haematological malignancies, arbitrarily called chronic fibrinogen deficiency; and those patients whose fibrinogen concentration was suddenly lowered, mainly by consumption

3 Fibrinogen infusion in high-risk severe bleeding 223 (disseminated intravascular coagulation or active severe bleeding), such as patients with severe traumatisms of surgery, sepsis or gynaecological diseases, arbitrarily called acute fibrinogen deficiency. Eighty-one patients were included in the study, of whom 69 (85%) were evaluated in the final follow-up. The main reason for exclusion was lack of a definite pre-treatment fibrinogen measurement. The study population comprised 29 males and 40 females, with a mean age of 52 years [range: 1 89 years; two patients (2 9%) were aged < 18 years]. All patients had plasma fibrinogen values that effectively ruled out congenital deficiency (mean ± standard deviation: 3 6 ± 1 7 g/l). Fibrinogen analysis Fibrinogen analysis was routinely performed according to the standardized operating procedures of our laboratory, as follows: all samples were initially processed for fibrinogen quantification by the so-called derived fibrinogen technique, based on the difference in sample absorbance after the addition of calcium thromboplastin, 5 seconds after the coagulation point was detected. All pathological samples were additionally processed by the Clauss test, where highly concentrated thrombin is added to diluted citrated plasma and clotting time is measured [9]. Efficacy analysis Efficacy was evaluated by means of increases in plasma fibrinogen levels, and changes in PT and aptt at 24 and 72 h. Specifically, measurement of the fibrinogen concentrate performance was achieved by the in vivo recovery. Tolerability of fibrinogen administration and survival of patients at 24 h and after 7 days were also recorded. Statistics For demographic variables, results are expressed as mean and standard deviation. The Student s t-test for paired data was used to evaluate differences before and after administration. To evaluate the association between fibrinogen concentration and 24-h and 7-day patient survival, a logistic regression was performed. In vivo recovery of fibrinogen (real fibrinogen concentration, expected fibrinogen concentration ratio) was also estimated. The paired Student s t-test was used to compare means (Mann Whitney U-test, when necessary). The χ 2 test (Fisher s exact test, when necessary) was used to compare proportions. The influence of the primary disease was investigated together with other potentially influential variables by analysis of variance (Kruskal Wallis test, when necessary). Moreover, the association between plasma fibrinogen and patient survival was also evaluated using the logistic regression method. Statistical analysis was performed using the SPSS version 8 0 (SPSS Inc., Chicago, IL, USA) software package. For single-outcome comparisons, the treatment effect was considered significant, if P values were 0 05 or less. Results The pathological processes that provoked the therapeutic administration of fibrinogen concentrates are shown in Table 1. Most of the processes (62%) corresponded to acute fibrinogen deficiency: mainly surgery/trauma (27 5%) and upper gastrointestinal tract haemorrhage (20 3%). Chronic fibrinogen-deficient representatives were hepatic dysfunction (30 4%) and haematological malignancies (7 2%). The changes in coagulation parameters occurring after the administration of fibrinogen are shown in Table 2. In all Table 1 Effect of fibrinogen administration on plasma fibrinogen and main haemostatic parameters by group of fibrinogen deficiency Group Number of cases (%) Fibrinogen a (g/l) APTT a (ratio) PT a (%) Mortality 24 h 72 h Fibrinogen deficiency acute Sepsis 8 (11 6) 0 49 (0 07) (0 18) 3 4 (4 0) 1 7 (0 6) 24 0 (17 7) (28 1) 3/8 3/8 Upper gastrointestinal tract haemorrhage 14 (20 3) 0 63 (0 23) (0 73) 2 8 (4 6) 0 9 (7 9) 30 1 (18 4) (11 8) 0/14 5/14 Gynaecological diseases 6 (8 7) 1 10 (0 60) (0 43) 2 3 (5 0) 0 8 (3 8) 35 2 (20 3) (17 8) 0/6 0/6 Surgery/trauma 11 (15 9) 0 91 (0 08) (0 62) 2 2 (3 3) 0 4 (1 8) 34 7 (20 0) (14 9) 1/11 1/11 Other 4 (5 8) 0 72 (0 08) (1 33) 4 1 (4 1) 3 2 (4 1) 41 7 (43 1) (59 0) 1/4 1/4 Fibrinogen deficiency chronic Haematological malignancy (AML-M3) 5 (7 2) 0 68 (0 10) (0 27) 1 12 (0 3) 0 1 (0 3) 41 8 (8 8) (11 2) 0/5 0/5 Liver transplantation 11 (15 9) 0 73 (0 25) (0 40) 3 9 (4 9) 1 1 (4 0) 28 1 (17 9) (16 6) 1/11 1/11 Hepatic insufficiency 10 (14 5) 0 90 (0 30) (0 42) 2 2 (2 9) 0 1 (6 5) 28 7 (12 6) (20 1) 2/10 5/10 a Changes of parameters refer to post-24 h. APTT, activated partial thromboplastin time; PT, prothrombin time.

4 224 A. Farriols Danés et al. Table 2 Main changes in plasma fibrinogen and laboratory coagulation parameters related to fibrinogen administration. Values are mean (standard deviation), except for activated partial thromboplastin time (aptt), which is shown as median (interquartile range) Parameter Previous Post-24 h Post-72 h Fibrinogen (g/l) 0 76 (0 35) 1 86 (0 77) a 2 97 (1 45) a aptt (ratio) 2 09 (2 18) 1 49 (0 74) a 1 19 (0 44) a Prothrombin time (%) 30 7 (18 5) 50 6 (19 2) a 67 3 (22 5) a a P < 0 001, baseline vs. post-treatment. Table 4 Logistic regression of plasma fibrinogen after fibrinogen administration and 7-day patient survival Population Patients (number) Equation and constant Exponent Significance Fibrinogen (1 32) 1 87 (0 76) P = deficiency acute Fibrinogen (0 89) 2 79 (1 60) P = deficiency chronic All (0 84) 0 85 (0 45) P = Value (confidence interval 95%). Table 3 In vivo recovery of the administered fibrinogen Parameter Absolute dose (g) Increase in plasma fibrinogen (g/l) Increase in plasma fibrinogen (g/l/dose) In vivo recovery (%) a Median (range). b Mean (standard deviation). Value 3 52 (0 5 8) a 1 09 (0 68) b 0 28 ( ) a (165 2) b cases (plasma fibrinogen, aptt and PT), the changes were statistically significant. The mortality rate was 32 3% and 44 2%, after 24 h and 72 h, respectively. Table 1 summarizes the effect of fibrinogen administration when stratifying by pathological process. The median administered dose of fibrinogen concentrate was 4 g, as shown in Table 3. As a result, the mean absolute increase in plasma fibrinogen was 1 09 g/l (median increase, 0 45 g/l, normalized by dose). The in vivo recovery was 109 1% of the expected value. Logistic regression, evaluating the relationship between plasma fibrinogen level after fibrinogen concentrate administration and 7-day patient survival, showed a trend (P = 0 073) towards higher levels of plasma fibrinogen among patients surviving. In the acute fibrinogen disease group, there was a statistically significant association (P = 0 014) between the two parameters, whereas in the chronic fibrinogen-deficiency group, only a trend (P = 0 314) was observed. Therefore, higher plasma fibrinogen levels were generally associated with increased survival rate (Table 4). Considering the safety and tolerability, the administration of fibrinogen was well-tolerated: neither local reactions nor thromboembolic events were recorded during the observation period. No severe adverse event attributable to fibrinogen concentrate was recorded. Discussion The management of high-risk severe haemorrhage in emergency situations is the subject of continuous debate [3]. This is particularly true when fibrinogen plasma levels fall below 1 g/l (widely accepted as critical in bleeding patients), as this protein plays a major role in coagulation and platelet function. Current treatment options include the transfusion of FFP or cryoprecipitate, platelet transfusions and administration of specific clotting factor concentrates. The use of FFP is inappropriate in cases of severe fibrinogen deficiency, as it contains insufficient concentrations of fibrinogen. Cryoprecipitate is generally given to replace fibrinogen or factor XIII when purified preparations are not available, but evidence for its efficacy is scarce [10 12]. There are also safety concerns with all plasma-derived products, relating to potential transmission of infectious or pathogenic viruses. Guidelines and recommendations for treating emergency haemorrhage with severe fibrinogen deficiency are based largely on experience/intuition, with few supportive randomized controlled trials [5]. Despite the lack of convincing data [13,14], there is a clear consensus that FFP and cryoprecipitate should not be used when coagulation factors are available as fractionated/specific concentrates [15,16]. Purified preparations have several advantages over crude primary fractions, such as their ease of preparation and use, and stringent quality controls during the manufacturing process [17]. Moreover, purified fibrinogen has improved haemostasis in a variety of models of haemodilution and severe bleeding [18 20]. Currently, there is little scientific evidence regarding the clinical efficacy of fibrinogen concentrate. There are no published randomized controlled clinical trials, and evidencebased recommendations for best clinical practice are limited [21]. The only published study on the use of fibrinogen concentrate in severe bleeding refers to patients with congenital afibrinogenaemia, a rare hereditary disorder. In an open, multicentre, uncontrolled, retrospective study of patients with congenital fibrinogen deficiency, Kreuz et al. showed

5 Fibrinogen infusion in high-risk severe bleeding 225 that substitution with pasteurized human fibrinogen concentrate was effective and generally well-tolerated [7]. In our study, we have found that the administration of fibrinogen concentrate to patients with, or at high risk of, severe bleeding, and acquired fibrinogen deficiency below 1 g/l significantly increases the plasma fibrinogen concentration by a mean absolute value of 1 1 g/l (in the following 24 h). Similarly, it significantly increases PT by a mean value of 9 9%, and decreases the aptt ratio by a median value of 0 50 (Table 2). Interestingly, the improvements in haemostatic parameters are not equally distributed among clinical groups: patients with acute fibrinogen deficiencies exhibited major increases of plasma fibrinogen, absolute values ranging between 1 09 and 2 31 g/l; while patients with chronic fibrinogen deficiencies exhibited minor increases ranging between 0 62 and 0 96 g/l. PT and aptt showed similar trends, as can be easily appreciated in Table 1. Related to the administered dose of fibrinogen, the median increase of fibrinogen plasma levels observed was 0 28 g/l per g of fibrinogen concentrate; which represents a recovery of 109%. A predictable fibrinogen recovery of g/l per 1 0 mg/kg infused is foreseen from the data shown here and from the available literature [6]. The mean increase in fibrinogen plasma concentration observed in our study was 2 04 g/l per 1 0 mg/kg of fibrinogen administered. This value is clearly higher than those previously described for patients with congenital deficiencies, but it is consistent with the in vivo recovery value observed. Thus, the increase in fibrinogen plasma concentration, adjusted to patient s weight, has to be considered for a better dosing schedule. The fibrinogen plasma level increase observed after fibrinogen concentrate administration is of paramount importance, because fibrinogen values below the critical threshold, 1 g/l, can be directly responsible for severe haemorrhage. Moreover, adequate plasma fibrinogen is key to the correct function of coagulation and haemostasis. In this sense, it has been shown that recombinant activated factor VII has limited activity when fibrinogen levels are below the 1 g/l threshold [22]. The true role of the plasma fibrinogen level in the management of high-risk severe haemorrhage was assessed in the present study by correlating plasma fibrinogen values with patient survival after 24 and 72 h. Logistic regression showed that plasma fibrinogen levels following administration of the concentrate are related to 24-h patient survival, and especially to 7-day patient survival (P = 0 073). Considering the patients that suffered from acute fibrinogen disease, there was a statistically significant association between plasma fibrinogen level and 7-day patient survival (P = 0 014) (Table 4), whereas this association was only weak and not statistically significant in chronic fibrinogen disease. Our pathophysiological differentiation between acute and chronic fibrinogen disease offers a potential explanation for this discrepancy. In case of pre-existing defects (chronic disease), the effect of fibrinogen supplementation was only transitory and the influence on outcome at day 7 only marginal, whereas in acute cases the effect was sustained. Although based on a limited patient population, the present findings are of paramount importance, because they highlight the importance of early supplementation of plasma fibrinogen in high-risk severe bleeding. In conclusion, the administration of fibrinogen concentrate in unresponsive, life-threatening haemorrhage with acquired hypofibrinogenaemia improves laboratory measures of coagulation, that is, increases plasma fibrinogen concentration and PT, and decreases aptt. It may also be life saving. Although this study was retrospective and limited by not being controlled or randomized, it is worth noting that the effect was appreciable in the case of patients with high-risk severe bleeding, particularly those able to maintain fibrinogen plasma levels after the episode of hypofibrinogenaemia. Our data indicate a direct relationship between fibrinogen levels and improved survival in acquired fibrinogen deficiency states, and may trigger further investigation. Prospective studies are warranted to ascertain a clear relationship between fibrinogen levels and 7-day survival. Acknowledgements We thank Dr José Aznar-Salatti (CSL Behring S.A., Barcelona, Spain) and Dr Michael Thimme (CSL Behring GmbH, Marburg, Germany) for their support and contributions to the study. We also gratefully acknowledge the physicians, nurses and laboratory staff for their help in providing the data reported here. References 1 Mosesson MW: Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3: Levy JH: Massive transfusion coagulopathy. Sem Hematol 2006; 43 (Suppl. 1):S59 S63 3 Fries D, Streif W, Haas T, Kühbachen G: Dilutional coagulopathy, an underestimated problem? Transfus Med Hemother 2004; 31: MacLennan S, Williamson LM: Risks of fresh frozen plasma and platelets. J Trauma 2006; 60 (Suppl. 6):S46 S50 5 Stanworth SJ, Brunskill SJ, Hyde CJ, McClelland DBL, Murphy MF: Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. 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