JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

Anesth Analg 2007; 105:905-917
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000280481.18570.27
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (22)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mittermayr, M.
Right arrow Articles by Innerhofer, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mittermayr, M.
Right arrow Articles by Innerhofer, P.
Related Collections
Right arrow Cardiovascular
Right arrow Coagulation

CARDIOVASCULAR ANESTHESIOLOGY

Charles W. Hogue Jr. Martin J. London Jerrold H. Levy

Hemostatic Changes After Crystalloid or Colloid Fluid Administration During Major Orthopedic Surgery: The Role of Fibrinogen Administration

Markus Mittermayr, MD*, Werner Streif, MD{dagger}, Thorsten Haas, MD*, Dietmar Fries, MD*, Corinna Velik-Salchner, MD*, Anton Klingler, PhD{ddagger}, Elgar Oswald, MD*, Christian Bach, MD§, Mirjam Schnapka-Koepf, MD||, and Petra Innerhofer, MD*

From the Departments of *Anesthesiology and Critical Care Medicine; {dagger}Pediatrics; {ddagger}Division of Theoretical Surgery; §Department of Orthopaedic Surgery; and ||Central Laboratory, Innsbruck Medical University, Innsbruck, Austria.

Address correspondence and reprint requests to Markus Mittermayr, MD, Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University, Anichstr. 35, A-6020 Innsbruck, Austria. Address e-mail to markus.mittermayr{at}i-med.ac.at.

Abstract

BACKGROUND: To explore whether disturbed fibrin polymerization is the main problem underlying dilutional coagulopathy and can be reversed by fibrinogen administration, we conducted a prospective study using modified thrombelastography (ROTEM®).

METHODS: Sixty-six orthopedic patients randomly received modified gelatin solution, hydroxyethyl starch 130/0.4, or exclusively Ringer lactate solution. ROTEM® analysis was performed, concentrations of coagulation factors and markers of thrombin generation were measured. Fibrinogen concentrate (Hemocomplettan®) was administered (30 mg/kg) when thrombelastographically measured fibrinogen polymerization was critically decreased.

RESULTS: The {alpha} angle, clot firmness, and fibrinogen polymerization (median [min to max]) significantly decreased in the patients receiving hydroxyethyl starch (area under the curve minus baseline (–5 [–9 to –2]), followed by gelatin solution (–3 [–8 to 0]), with the least reductions seen for Ringer lactate solution (–2 [– 4 to 1]) (colloids versus Ringer lactate P < 0.0001). Thirteen patients in the colloid groups but none in the Ringer lactate group needed fibrinogen concentrate to maintain borderline clot firmness. Activity of FVII, FVIII, FIX, and von Willebrand ristocetin activity decreased significantly with colloids. Thrombelastographically measured coagulation time, molecular markers of thrombin generation, and activity of all other coagulation factors were comparable in all groups.

CONCLUSION: Disturbance of fibrinogen/fibrin polymerization is the primary problem triggering dilutional coagulopathy during major orthopedic surgery. The magnitude of clot firmness reduction is determined by the type of fluid used, with hydroxyethyl starch showing the most pronounced effects. These undesirable effects of intravascular volume therapy can be reversed by increasing fibrinogen concentration by administering fibrinogen concentrate, even during continuing blood loss and intravascular volume replacement.

Trauma patients and those undergoing extensive prolonged surgery are prone to develop coagulopathy, even when there is no preoperative coagulopathy or dysfunction of primary hemostasis. This so-called dilutional coagulopathy results from blood loss, consumption of coagulation factors and platelets, and intravascular volume replacement.

A huge number of in vitro and in vivo investigations have clearly demonstrated that natural and artificial colloids impair hemostasis more than crystalloids do (1–5). The result is decreased clot strength. With a greater degree of dilution the reduction in clot firmness is also accompanied by impaired initiation of coagulation, indicating a deficiency of factors needed for thrombin generation.

A previous thrombelastographic study in patients undergoing knee replacement surgery and exhibiting even minor blood loss and intravascular volume replacement already showed that colloid administration reduces final clot strength more than Ringer lactate solution does by impairing fibrinogen polymerization (3). Fibrin formation depends on the concentration of fibrinogen and FXIII, and also on thrombin generation which, in turn, depends on the interaction of platelets and coagulation factors. In addition, the activity of the fibrinolytic system influences fibrin polymerization and total clot strength (6). To further explore whether colloids and crystalloids interfere differently with coagulation factors essential for fibrinogen polymerization, we conducted the present study in orthopedic patients undergoing major surgery of the spine. Functional measurements of hemostasis using modified thrombelastography were performed. Concentrations of coagulation factors and molecular markers of thrombin generation were analyzed. In addition, we tested the hypothesis that administration of fibrinogen concentrate maintains clot strength as long as impairment of fibrin polymerization is the underlying problem during continuing blood loss and intravascular volume replacement.

METHODS

The study protocol was approved by the local University Ethics Committee. Informed written consent was obtained from 66 consecutive patients (ASA I–II, age <80 yr) undergoing surgery of the spine (more than three segments) with an expected duration of surgery of more than 3 h. Exclusion criteria were known allergic reactions to colloid administration, or primary or secondary hemostatic disorders. All patients underwent general anesthesia using propofol, fentanyl, and rocuronium for induction. Anesthesia was maintained with sevoflurane in an oxygen/air mixture supplemented with an infusion of remifentanil. Piritramide was administered at the end of surgery to provide sufficient postoperative analgesia. In addition, standard monitors were used in all patients. Arterial and central venous pressures were measured continuously. In all patients a cell saver collection device (C.A.T.S., Fresenius, Frankfurt, Germany) was used. If the collected volume exceeded 1000 mL the salvaged blood was processed and the resulting red cell concentrate was retransfused.

Patients were actively warmed with fluid warmers and a convective warming system. All patients received enoxaparin subcutaneously (Lovenox®) 12 h before surgery and a second-generation cephalosporin after induction of anesthesia.

Using a computer-generated randomization list, patients were assigned to receive modified gelatin solution (4% Gelofusin®, B. Braun, Maria Enzersdorf, Austria) or medium molecular-weight medium-substituted hydroxyethyl starch (6% Voluven® 130/0.4, Fresenius, Pharma Austria GmbH, Graz, Austria) in addition to a basic infusion of Ringer lactate solution (Ringer Laktat®, Fresenius Pharma Austria GmbH, Graz, Austria) or exclusively Ringer lactate solution throughout the intraoperative study period. The volume regimen was based on the assumption that gelatin solution, hydroxyethyl starch, and Ringer lactate solution show different volume effects considered to be 70%, 100%, and 30%, respectively. The basic Ringer lactate solution infusion consisted of 5 mL · kg–1 · h–1 to cover fluid deficit from the starving period and basal fluid requirements. In addition and according to randomization, patients in the gelatin solution, hydroxyethyl starch, and Ringer lactate solution groups received gelatin solution (8–11 mL · kg–1 · h–1), hydroxyethyl starch (6–8 mL · kg–1 · h–1), or Ringer lactate solution (13–15 mL · kg–1 · h–1), respectively, to maintain normovolemia. In the case of suspected hypovolemia, additional group-specific fluid was administered. A hemoglobin value below 8 mg/dL and/or physiological signs of anemia triggered transfusion of leukocyte-filtered red cells. From our previous results with impaired fibrinogen polymerization with colloids we set a bedside thrombelastographically measured fibrin clot strength (FIBTEM-MCF) of <7 mm (–25% the lower normal value) as the threshold for administering 30 mg/kg fibrinogen concentrate (Hemocomplettan®, ZLB Behring GmbH, Marburg, Germany) to maintain a serum fibrinogen of about 150 mg/dL. Furthermore, fresh frozen plasma (FFP) would be administered in cases with prolonged thrombelastographically measured coagulation time unresponsive to prothrombin complex administration, and platelets would be transfused when total clot strength remained below 45 mm after correction of fibrinogen deficiency.

Modified thrombelastography (ROTEM®, Pentapharm GmbH, Munich, Germany), which is based on the thrombelastograph® system after Hartert (7), was performed bedside in citrated whole blood using the intrinsically activated tests (INTEM test: 20 µL CaCl2 0.2 M, 20 µL thromboplastin-phospholipid, 300 µL blood) and the extrinsically activated tests (EXTEM test: 20 µL CaCl2 0.2 M, 20 µL tissue factor, 300 µL blood). In addition, the polymerized fibrinogen/fibrin was measured using the platelet-inactivating test (FIBTEM test: 20 µL CaCl2 0.2 M plus cytochalasin D, 20 µL tissue factor, 300 µL blood). The variables of ROTEM® analysis are "coagulation time," "clot formation time," {alpha} angle, "maximum clot firmness," and lysis index at 30 min (LI30). A typical ROTEM® tracing and its interpretation is given in Figure 1. In each case the ROTEM® device was checked for proper functioning according to the manufacturer's recommendation using a control serum (ROTROL®). All reagents were purchased from Pentapharm GmbH.


Figure 14
View larger version (15K):
[in this window]
[in a new window]

  		Figure 1. The ROTEM® technique looks beyond the end points of initial fibrin formation measured by prothrombin time (PT) and activated partial thromboplastin time (aPTT) and also assesses the kinetics of clot formation and the stability or lysis of the formed clot. Initiation of coagulation, measured as coagulation time (CT; s), is a function of the concentration of coagulation factors/inhibitors and shows initial thrombin and fibrin formation. Propagation of clot formation follows when a sufficient thrombin burst has been built up. This propagation is a function of the concentration of coagulation factors/inhibitors and also of the interaction of fibrinogen with platelets. It is measured as clot formation time (CFT; s) and is defined as the time needed to achieve a clot firmness of 20 mm. The {alpha} angle describes the kinetics of clot formation. The final clot strength results from firm aggregation of platelets and formation of a stable fibrin network. Thus, measurement of maximum clot firmness (MCF; mm) depends (besides sufficient thrombingeneration) on count and function of platelets and fibrinogen concentration, and on the activity of coagulation factor XIII. Clinically relevant fibrinolysis can be diagnosed from increased maximum lysis (ML) or lysis index at defined time points (LI30, LI60).

 

In addition to prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin (AT), concentrations of fibrinogen and blood cell count, we also measured concentrations of D-dimer, prothrombin fragment F1/F2 (F1 + 2), thrombin-AT complex, and activity of coagulation factors II, V, VII, VIII, IX, X, XI, XII, XIII (FII, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII), von Willebrand factor antigen, and von Willebrand ristocetin activity (vWF:RiCo).

For analysis of all these variables arterial blood samples were obtained at baseline (before induction of anesthesia [A]), after 60 min and immediately before surgical incision (B) and every 90 min thereafter (C–F). Intraoperative blood loss was recorded as the amount of blood in the suction reservoir (plus weight of sponges, blood on the floor). In addition, perioperative loss of red cell volume until postoperative day 5 was calculated using Nadler and Mercuriali et al.'s formula (8,9):

Calculated total blood volume [mL] = [(0.3669 x height [m3]) + (0.03219 x weight [kg]) + 0.6041] x 1000 in males and [(0.3561 x height [m3]) + (0.03308 x weight [kg]) + 0.1833] x 1000 in females.

Preoperative red cell volume = blood volume x preoperative hematocrit x 0.91.

Postoperative red cell volume = blood volume x postoperative hematocrit x 0.91.

Transfused red cell volume = blood product transfused x hematocrit of the blood product x 0.91.

Perioperatively red cell volume lost = (blood volume x preoperative hematocrit x 0.91) – (blood volume x postoperative hematocrit x 0.91) + transfused red cell volume.

Data are given as median (min to max). Differences in baseline values were analyzed with the Kruskal–Wallis test. To investigate time dependencies a Friedman ANOVA was applied. The area under the curve was calculated after subtracting the baseline values (AUC-BLA-D and AUC-BLA-F) and was analyzed with the Kruskal–Wallis test and post hoc Wilcoxon's ranked sum test for comparison of between-group differences in the intraoperative response profile. Correlations between plasma fibrinogen concentration and fibrinogen polymerization, and between FXIII and intraoperative blood loss, were analyzed by Spearman rank correlation. A P value <0.05 was considered statistically significant. The sample size of 18 per group (excluding drop-outs) was planned to provide 80% power for detection of a difference in the AUC-Baseline of –10 vs –50 (sd: ± 40) with a two-sided significance level of 5%.

RESULTS

Sixty-six patients were recruited. Five patients were excluded from data analysis because of unexpected pathological baseline measurements of fibrinogen and platelets.

Patient demographics were comparable in the gelatin solution, hydroxyethyl starch, and Ringer lactate solution groups (Table 1). There were no significant differences in any of the coagulation variables at baseline. Data on the intraoperative course of all patients are given in Table 2.


View this table:
[in this window]
[in a new window]

  		Table 1. Demographics and Data on Blood Loss, Transfusion Supply, and Fibrinogen Administration in Patients Undergoing Surgery of the Spine and Randomly Receiving Gelatin Solution, Hydroxyethyl Starch, or Ringer Lactate Solution

 

View this table:
[in this window]
[in a new window]

  		Table 2. Data on Volume Supply and Hemodynamics of Patients in the Gelatin Solution, Hydroxyethyl Starch, and Ringer Lactate Solution Groups 60 min After Induction of Anesthesia and Immediately Before Surgical Incision (B) and every 90 min Thereafter (C–F)

 

All coagulation variables changed significantly over time within groups (Friedman ANOVA) with the exception that thrombelastographically measured coagulation time and lysis index at 30 min (LI30) remained unchanged in all groups. To detect between-group differences in changes in coagulation variables the AUC-BLA-D was calculated (n = 61). Data for patients undergoing an unexpected prolongation of surgery were analyzed separately by calculating the AUC-BLA-F (n = 17).

Analysis AUC-BLA-D
Extrinsically activated ROTEM® analysis (Fig. 2) showed unchanged coagulation time in all groups, while clot formation time increased (data not shown). {alpha} angle, maximum clot firmness, and fibrinogen polymerization decreased significantly more in the hydroxyethyl starch group, followed by the gelatin solution group, and were least pronounced in the Ringer lactate solution group (colloids versus Ringer lactate solution P < 0.0001; {alpha} angle, maximum clot firmness, fibrinogen polymerization: gelatin solution versus hydroxyethyl starch P = 0.006, 0.01, 0.03, respectively). Analysis of the intrinsically activated measurements (INTEM test) showed similar results (data not shown). In addition, at baseline a significant correlation was found between fibrinogen concentration and fibrinogen polymerization in all groups. Although this was also true during intravascular volume replacement in the gelatin solution and Ringer lactate solution groups, no intraoperative correlation was found for the hydroxyethyl starch group, showing a lower fibrinogen polymerization at a given fibrinogen concentration than in the gelatin and Ringer lactate groups (Fig. 3). Thrombelastographic tracings showed no signs of increased fibrinolysis (lysis index 30) in any group (data not shown).


Figure 24
View larger version (16K):
[in this window]
[in a new window]

  		Figure 2. Left side: Thrombelastography values for clotting time (EXTEM-CT, normal range <78 s), {alpha} angle (EXTEM-{alpha}, normal range 63°–83°), clot firmness after 30 min (EXTEM-A30, normal range 50–72 mm), and fibrinogen/ fibrin polymerization (FIBTEM-MCF, normal range 9–25 mm) at baseline before induction of anesthesia (A), 60 min later immediately before surgical incision (B), and then every 90 min (C–F) during administration of gelatin solution (GEL), hydroxyethyl starch (HES) or exclusively Ringer lactate solution (RL). Right side: Differences among groups were analyzed by comparing the calculated area under the curve minus baseline from time point A to D and A to F (AUC-BLA-D,A-F). Values are median (min to max). *P < 0.05 as compared to Ringer lactate solution, #P < 0.05 as compared to hydroxyethyl starch.

 

Figure 34
View larger version (10K):
[in this window]
[in a new window]

  		Figure 3. Correlation between concentration of plasma fibrinogen and functional thrombelastographic measurement of fibrinogen/fibrin polymerization (FIBTEM-MCF) at time points A (Fig. 3a), C (Fig. 3b), and D (Fig. 3c).

 

Results of standard coagulation tests and concentrations of coagulation factors are given in Figure 4. The decrease in PT was more pronounced in the gelatin solution group (P = 0.0012), and aPTT measurements increased significantly more for both colloids than for the Ringer lactate solution group (P < 0.0001). Concentrations of fibrinogen and platelets decreased similarly in all groups.


Figure 44
View larger version (15K):
[in this window]
[in a new window]

  		Figure 4. Left side: Measurement of prothrombin time (PT) (normal range 70%–130%), activated partial thromboplastin time (aPTT) (normal range 23–40 s), fibrinogen concentration (normal range 190–380 mg/dL) and platelet numbers (normal range 150– 380 g/L) at baseline before induction of anesthesia (A), 60 min later immediately before surgical incision (B), and then every 90 min (C–F) during administration of gelatin solution (GEL), hydroxyethyl starch (HES), or exclusively Ringer lactate solution (RL). Right side: Differences among groups were analyzed by comparing the calculated area under the curve minus baseline from time point A to D and A to F (AUC-BLA-D,A-F). Values are median (min to max). *P < 0.05 as compared to Ringer lactate solution, #P < 0.05 as compared to hydroxyethyl starch.

 

FVII (P = 0.0173), FVIII (P = 0.0039), and FIX (P = 0.0005) decreased significantly more in the colloid groups than in the Ringer lactate solution group, vWF:RiCo (P = 0.0023) decreased most in the gelatin solution group (Fig. 5a), whereas the decrease in FII, FV, FX, FXI (Fig. 5b), FXII, FXIII, AT (Fig. 5c) and von Willebrand factor antigen (data not shown) was comparable in all groups. At time points D and E, a significant correlation was found between FXIII and intraoperative blood loss (P < 0.001, P = 0.019, respectively). At time point F, only a weak trend was observed (P = 0.086).


Figure 4
View larger version (16K):
[in this window]
[in a new window]

  		Figure 5. Left side: Measurement of coagulation factors were obtained at baseline before induction of anesthesia (A), 60 min later immediately before surgical incision (B), and then every 90 min (C–F) during administration of gelatin solution (GEL), hydroxyethyl starch (HES) or exclusively Ringer lactate solution (RL). (a) FVII (normal range 70%–120%), FVIII (normal range 70%–150%), FIX (normal range 70%– 120%), and von Willebrand factor ristocetin cofactor activity (vWF: RiCo, normal range 50%–150%), (b) FII (normal range 70%–120%), FV (normal range 70%–120%), FX (normal range 70%–120%), FXI (normal range 70%– 120%), (c) FXII (normal range 70%– 120%), FXIII (normal range 70%–140%), antithrombin (AT, normal range 80%– 120%). Right side: Differences among groups were analyzed by comparing the calculated area under the curve minus baseline from time point A to D and A to F (AUC-BLA-D,A-F). Values are median (min to max). *P < 0.05 as compared to Ringer lactate solution, #P < 0.05 as compared to hydroxyethyl starch.

 


Figure 4
View larger version (16K):
[in this window]
[in a new window]

  		Figure 5. Continued.

 


Figure 4
View larger version (19K):
[in this window]
[in a new window]

  		Figure 5. Continued.

 
Markers of thrombin generation, concentrations of D-D, thrombin-AT complex, and F1 + F2 also increased without intergroup differences (Fig. 6).


Figure 64
View larger version (20K):
[in this window]
[in a new window]

  		Figure 6. Left side: Concentrations of molecular markers of activation of coagulation prothrombin fragment (F1F2) (normal range 0.4–1.1 nmol/L), thrombin-antithrombin complex (TAT) (normal range 1–4.1 µg/L) and D-dimer (D-DIMER) (normal range 0–190 µg/L) at baseline before induction of anesthesia (A), 60 min later immediately before surgical incision (B), and then every 90 min (C–F) during administration of gelatin solution (GEL), hydroxyethyl starch (HES) or exclusively Ringer lactate solution (RL). Right side: Differences among groups were analyzed by comparing the calculated area under the curve minus baseline from time point A to D and A to F (AUC-BLA-D,A-F). Values are median (min to max). *P < 0.05 as compared to Ringer lactate solution, #P < 0.05 as compared to hydroxyethyl starch.

 

Analysis AUC-BLA-F
Only a few other differences were detected when patients undergoing prolonged surgery were analyzed as a separate subgroup. Fibrinogen levels were lower in the gelatin solution group than in the hydroxyethyl starch group (P = 0.0188), and AT levels decreased more with both colloids than with Ringer lactate solution (P = 0.0476). The decrease in FVIII, FIX and vWF:RiCo was no longer significant among groups.

Blood Loss and Transfusion
Data on blood loss, transfusion, and fibrinogen administration are given in Table 1. The calculated loss of red cell volume was comparable in all groups. Patients treated with gelatin solution or hydroxyethyl starch received more units of red cells. However, baseline values of hemoglobin were already significantly lower in the gelatin solution group (13.2 [11.4–16] mg/dL) and in the hydroxyethyl starch group (13.3 [11.6–15] mg/dL) than in the Ringer lactate solution group (14.2 [11–16] mg/dL).

A bedside thrombelastographically measured fibrin clot strength FIBTEM-MCF of <7 mm together with clinical signs of bleeding was set as the threshold for administering fibrinogen concentrate. Only the gelatin and hydroxyethyl starch groups required fibrinogen concentrate, with a total dose of median (min to max) 2 g (2–6 g) to maintain borderline fibrinogen polymerization. No patient received prothrombin complex concentrate, FFP, or platelet transfusion. The postoperative course of all patients was uneventful and no revision surgery was needed.

DISCUSSION

The most striking finding of our study was that colloids influence the speed and quality of clot formation by interfering with fibrinogen concentration and functional measured fibrinogen/fibrin polymerization. Despite dilutional changes associated with spine surgery, we noted that coagulation factors remained above critical thresholds, suggested to be 20%–30% depending on the specific coagulation factor (6,10,11). In clinical practice and according to the recommendations of official societies, PT and aPTT tests are usually used to detect coagulation factor deficiencies and the need for FFP transfusion. As reported by others (12,13), we found that results of these coagulation tests became pathological soon, although no critical reduction in coagulation factors was present and measurements of coagulation time in whole blood remained unchanged and within acceptable limits in all groups.

Using an in vitro cell-based model for coagulation and various concentrations of procoagulant factors Allen et al. (10) showed that very low levels of coagulation factor activities are associated with sustained thrombin generation. In addition, this model shows that the interaction of procoagulant factors with cellular surfaces, activated platelets, and leukocytes influences thrombin generation. A thrombelastographic study of hemophilic patients showed impaired clot formation to improve nearly linearly with FVIII. At FVIII levels of 30%, a clot firmness and thrombin generation of >90% of normal were already observed (14). Values of coagulation time depend on concentrations of procoagulation factors and AT levels, reflect initial thrombin formation and, using the first derivative of the thrombelastographic curve for calculating total thrombin generation, correlate with thrombin-AT complex (15). Only 5% of thrombin is required for initiation of cagulation, which can be estimated by measuring coagulation time, whereas the other 95% of thrombin generation occurs with clot formation (16). Although coagulation time remained unchanged and measurements of prothrombin, thrombin-AT complex, D-D, and prothrombin fragment F1 + F2 at the various measurement points showed no differences among groups, we cannot exclude that the dynamics of thrombin generation or thrombin's effects on fibrin polymerization or on FXIII activation are especially inhibited, or probably delayed, in a colloid milieu because {alpha} angle, clot formation time, and clot firmness were found to be impaired with colloids.

Two other studies compared the influence of gelatin solution and hydroxyethyl starch 130/0.4 on the hemostatic system of patients undergoing cardiac or abdominal surgery. In contrast to our findings, in cardiac patients (17) coagulation time increased significantly at the end of surgery with both colloids. However, measurements were still within the normal range and patients also received aprotinin, heparin, and protamine, all of which influence coagulation time. In patients with malignant disease showing elevated fibrinogen levels at baseline, undergoing major abdominal surgery and receiving none of these substances, coagulation time did not change from baseline, and clot firmness was maintained with either colloid, probably due to the effects of FFP administration and patient selection (18).

In addition to thrombin generation, the speed of clot formation and its strength and stability depend on the interaction of platelets, fibrinogen/fibrin, FXIII, and the activity of the fibrinolytic system. Numbers of platelets decreased similarly in all groups without reaching critical values. Concentrations of fibrinogen decreased significantly more after colloids were administered at the late measurement points only. No difference in the FXIII decline was observed. However, several patients in the colloid groups needed fibrinogen administration early, thereby influencing not only ROTEM® measurements but also those of fibrinogen concentration and FXIII, because Hemocomplettan® contains small amounts of FXIII (about 50 IU FXIII per 1 g fibrinogen concentrate). A subgroup analysis of patients without fibrinogen replacement showed no significant difference in the decrease in fibrinogen concentrations but a trend to a greater decrease in FXIII (P = 0.0625) for both colloids than for Ringer lactate solution. A nearly linear decrease in clot strength was observed with FXIII <60% in vitro (19). Some clinical data show increased bleeding in surgical patients exhibiting FXIII <60% (20–22). Since some of our patients showed such low levels, we considered the correlation between FXIII and estimated intraoperative blood loss. At time points C and D, a significant correlation was found, suggesting that administration of FXIII might have been beneficial for some of our patients. However, further data are needed to clarify the importance of FXIII during blood loss and colloid administration.

Fibrinolysis might also be altered by the presence of colloids, as shown in vitro in human diluted plasma and that of rabbits after hemodilution with various hydroxyethyl starch solutions (23). However, cardiac patients showed no effect of tranexamic acid used to reverse hydroxyethyl starch-associated impairment of clot strength (24). The present study showed no evidence of systemic fibrinolysis, but local effects of tissue-type plasminogen activator cannot be excluded. Measurement of molecular markers of fibrinolysis and thrombin-activatable fibrinolysis inhibitor might provide more conclusive answers to this question.

The fact that during blood loss fibrinogen is the first factor to become critically reduced and is associated with increased bleeding was noted as early as 1982 by Mannucci et al. and in 1987 by Ciavarella et al. (13,25) and can be explained by the limited increase in fibrinogen synthesis during blood loss. This limited increase cannot compensate for the concomitantly increased fibrinogen breakdown (26). In addition, fibrinogen is needed at concentrations of g/L, namely 1000-fold higher than other coagulation factors, which physiologically show concentrations in the range of mg/L and can be mobilized from the liver, endothelial, and perivascular tissues (27). Hiippala et al. (28) also reported that fibrinogen deficiency develops first at an extrapolated blood loss of 142% (117%–169%). In the present study, no patient lost more than one calculated blood volume. However, many patients showed an early decrease in fibrinogen concentration and impairment of fibrinogen polymerization. However, in the study by Hiippala et al. many patients showed initial fibrinogen levels well above the upper reference limit, a circumstance avoided in our study. Finally, in that study 10 patients also received FFP, and a blood loss of 20% or even 10% (depending on initial hematocrit) was set as the transfusion trigger for red cells. By contrast, the present study protocol tolerated much lower hemoglobin values. Confirming the results of this study, a mathematical model used to estimate the decline in fibrinogen concentration has clearly shown that patients with initial borderline fibrinogen levels and a lower accepted hemoglobin/hematocrit develop fibrinogen deficiency earlier than in the study by Hiippala et al. (29).

We used ROTEM® analysis to guide therapy and not measurements of fibrinogen concentration. Similarly, we used fibrinogen concentrate instead of FFP to maintain clot firmness and a fibrinogen concentration of about 150 mg/dL, although most transfusion algorithms use 70–100 mg/dL as the critical threshold. In an in vitro study using TEG® Nielsen et al. found that at fibrinogen levels <50 mg/dL no clot is formed and at 75 mg/dL only weak clot formation occurs, which improves nearly linearly at concentrations of up to 300 mg/dL (30). Interestingly, patients with high fibrinogen values undergoing cardiac surgery experienced fewer bleeding complications than did patients with low fibrinogen values (31). Confirming our clinical assumption and those of authors who feel that a threshold of 100 mg/dL fibrinogen is too low (32,33) and sometimes difficult to treat, a recently published study in parturitants showed fibrinogen concentrations <200 mg/dL to have a 100% (71%–100%) predictive value for severity of postpartum hemorrhage (34). Although guidelines issued by medical societies state that no clear critical threshold is known for fibrinogen (35,36), it is recommended that cryoprecipitate be administered to counteract fibrinogen deficiency, since transfusion of FFP remains insufficient because of its volume-expanding effect and its physiologically low fibrinogen concentration (32,33,35,37). However, although cryoprecipitate is not available in most European countries, the more purified concentrate is approved for treatment of congenital and acquired fibrinogen deficiency in some, for example, Austria.

Three in vitro (5,38,39) and two experimental studies in pigs (40,41) have shown that fibrinogen concentrate restored clot strength, reestablished the architecture of the fibrin meshwork, reduced total blood loss, and also improved survival as compared to placebo. Studies in rabbits receiving various hydroxyethyl starch solutions revealed that impaired clot formation and clot firmness could be best restored by adding fibrinogen concentrate (42,43). Moreover, an observational study showed that various episodes of increased bleeding were stopped in more than 89% of cases by administering fibrinogen concentrate (44). In a case series reporting huge blood loss unresponsive to conventional therapy, fibrinogen concentrate was able to stop catastrophic bleeding (45). In the present study median values of clot firmness remained at the lower normal value until measurement point C (after 150 min), when several patients in the colloid groups already exhibited critically reduced fibrinogen polymerization. Fibrinogen was thus administered according to protocol. If fibrinogen concentrate had not been administered, fibrinogen polymerization would have decreased still further, thus giving an even larger proportion of patients with abnormal readings for fibrinogen polymerization, and total clot firmness, probably reaching values indicative for platelet transfusion. In total, 7 of 21 patients in the gelatin group and 6 of 19 patients in the hydroxyethyl starch group needed fibrinogen administration to maintain a borderline fibrinogen polymerization of >7 mm and a total clot strength of >45 mm. No patient in the Ringer lactate solution group needed fibrinogen concentrate. The dose of 30 mg/kg administered was not intended to achieve baseline values but to prevent development of profound fibrinogen deficiency, which is associated with increased bleeding, and is sometimes difficult to treat (32). Our data also show that administration of fibrinogen concentrate enables fibrin polymerization and clot firmness to be maintained, without the need of FFP and platelet transfusion. Probably as a consequence, estimated intraoperative and calculated perioperative blood losses were comparable in all groups. The interesting finding that measurements of fibrinogen concentration correlated with those of functional polymerizable fibrinogen was not observed in patients treated with hydroxyethyl starch, suggesting that hydroxyethyl starch specifically interferes with fibrin formation through an unknown underlying mechanism. Confirming these findings, two in vitro studies have shown that in the presence of hydroxyethyl starch, even the highest fibrinogen concentration, could not restore clot strength to baseline values (5,39).

In conclusion, this study shows that impairment of the final step of the hemostatic process, fibrinogen polymerization, is the main problem underlying dilutional coagulopathy during orthopedic surgery in otherwise healthy patients. Polymerization of fibrinogen, and thus total clot strength, is significantly more impaired with colloids than with crystalloids, with hydroxyethyl starch showing the most pronounced effects. These effects were already observed at moderate blood loss and infusion of about 1500–2000 mL of colloids. In addition, our data also show that, as long as impaired fibrinogen polymerization is the main reason for impaired speed of clot formation and for reduced clot firmness, administration of fibrinogen concentrate enables clot firmness to be maintained even during continuing blood loss and further colloid administration. From a practical point of view, our results show that, in patients with anticipated considerable blood loss, the initial fibrinogen concentration is of interest. These patients should preferably receive crystalloids and perhaps gelatin solution. Monitoring coagulation status using thrombelastographic techniques is more informative than results of conventional coagulation tests.

Footnotes

Accepted for publication June 20, 2007.

Supported in part by Fresenius, Pharma Austria GmbH, Graz, Austria, and B. Braun, Maria Enzersdorf, Austria.

REFERENCES

  1. de Jonge E, Levi M. Effects of different plasma substitutes on blood coagulation: a comparative review. Crit Care Med 2001;29:1261–7[Web of Science][Medline]
  2. Fries D, Innerhofer P, Klingler A, Berresheim U, Mittermayr M, Calatzis A, Schobersberger W. The effect of the combined administration of colloids and lactated Ringer's solution on the coagulation system: an in vitro study using thrombelastograph coagulation analysis (ROTEG. Anesth Analg 2002;94:1280–7[Abstract/Free Full Text]
  3. Innerhofer P, Fries D, Margreiter J, Klingler A, Kuhbacher G, Wachter B, Oswald E, Salner E, Frischhut B, Schobersberger W. The effects of perioperatively administered colloids and crystalloids on primary platelet-mediated hemostasis and clot formation. Anesth Analg 2002;95:858–65[Abstract/Free Full Text]
  4. Jones SB, Whitten CW, Despotis GJ, Monk TG. The influence of crystalloid and colloid replacement solutions in acute normovolemic hemodilution: a preliminary survey of hemostatic markers. Anesth Analg 2003;96:363–8[Abstract/Free Full Text]
  5. Nielsen VG. Colloids decrease clot propagation and strength: role of factor XIII-fibrin polymer and thrombin-fibrinogen interactions. Acta Anaesthesiol Scand 2005;49:1163–71[Web of Science][Medline]
  6. Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol 2006;26:41–8[Abstract/Free Full Text]
  7. Mallett SV, Cox DJ. Thrombelastography. Br J Anaesth 1992;69:307–13[Free Full Text]
  8. Nadler S, Hidalgo J, Bloch T. Prediction of blood volume in normal human adults. Surgery 1962;51:224–32[Web of Science]
  9. Mercuriali F, Inghilleri G. Proposal of an algorithm to help the choice of the best transfusion strategy. Curr Med Res Opin 1996;13:465–78[Web of Science][Medline]
  10. Allen GA, Wolberg AS, Oliver JA, Hoffman M, Roberts HR, Monroe DM. Impact of procoagulant concentration on rate, peak and total thrombin generation in a model system. J Thromb Haemost 2004;2:402–13[Web of Science][Medline]
  11. Reiss RF. Hemostatic defects in massive transfusion: rapid diagnosis and management. Am J Crit Care 2000;9:158–65; quiz 66–7[Medline]
  12. Murray DJ, Pennell BJ, Weinstein SL, Olson JD. Packed red cells in acute blood loss: dilutional coagulopathy as a cause of surgical bleeding. Anesth Analg 1995;80:336–42[Abstract]
  13. Ciavarella D, Reed RL, Counts RB, Baron L, Pavlin E, Heimbach DM, Carrico CJ. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. Br J Haematol 1987;67:365–8[Web of Science][Medline]
  14. Bassus S, Wegert W, Krause M, Escuriola-Ettinghausen C, Siegemund A, Petros S, Scholz T, Scharrer I, Kreuz W, Englelmann L, Kirchmaier CM. Platelet-dependent coagulation assays for factor VIII efficacy measurement after substitution therapy in patients with haemophilia A. Platelets 2006;17:378–84[Web of Science][Medline]
  15. Rivard GE, Brummel-Ziedins KE, Mann KG, Fan L, Hofer A, Cohen E. Evaluation of the profile of thrombin generation during the process of whole blood clotting as assessed by thrombelastography. J Thromb Haemost 2005;3:2039–43[Web of Science][Medline]
  16. Brummel KE, Paradis SG, Butenas S, Mann KG. Thrombin functions during tissue factor-induced blood coagulation. Blood 2002;100:148–52[Abstract/Free Full Text]
  17. Haisch G, Boldt J, Krebs C, Suttner S, Lehmann A, Isgro F. Influence of a new hydroxyethylstarch preparation (HES 130/0.4) on coagulation in cardiac surgical patients. J Cardiothorac Vasc Anesth 2001;15:316–21[Web of Science][Medline]
  18. Haisch G, Boldt J, Krebs C, Kumle B, Suttner S, Schulz A. The influence of intravascular volume therapy with a new hydroxyethyl starch preparation (6% HES 130/0.4) on coagulation in patients undergoing major abdominal surgery. Anesth Analg 2001;92:565–71[Abstract/Free Full Text]
  19. Nielsen VG, Gurley WQ Jr, Burch TM. The impact of factor XIII on coagulation kinetics and clot strength determined by thrombelastography. Anesth Analg 2004;99:120–3[Abstract/Free Full Text]
  20. Chandler WL, Patel MA, Gravelle L, Soltow LO, Lewis K, Bishop PD, Spiess BD. Factor XIIIA and clot strength after cardiopulmonary bypass. Blood Coagul Fibrinolysis 2001; 12:101–8[Web of Science][Medline]
  21. Gerlach R, Raabe A, Scharrer I, Meixensberger J, Seifert V. Post-operative hematoma after surgery for intracranial meningiomas: causes, avoidable risk factors and clinical outcome. Neurol Res 2004;26:61–6[Web of Science][Medline]
  22. Wettstein P, Haeberli A, Stutz M, Rohner M, Corbetta C, Gabi K, Schnider T, Korte W. Decreased factor XIII availability for thrombin and early loss of clot firmness in patients with unexplained intraoperative bleeding. Anesth Analg 2004;99:1564–9[Abstract/Free Full Text]
  23. Nielsen VG. Hemodilution modulates the time of onset and rate of fibrinolysis in human and rabbit plasma. J Heart Lung Transplant 2006;25:1344–52[Web of Science][Medline]
  24. Kuitunen AH, Suojaranta-Ylinen RT, Kukkonen SI, Niemi TT. Tranexamic acid does not correct the haemostatic impairment caused by hydroxyethyl starch (200 kDa/0.5) after cardiac surgery. Blood Coagul Fibrinolysis 2006;17:639–45[Web of Science][Medline]
  25. Mannucci PM, Federici AB, Sirchia G. Hemostasis testing during massive blood replacement. A study of 172 cases. Vox Sang 1982;42:113–23[Web of Science][Medline]
  26. Martini WZ, Chinkes DL, Pusateri AE, Holcomb JB, Yu YM, Zhang XJ, Wolfe RR. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs. Am J Physiol Endocrinol Metab 2005;289:E930–4[Abstract/Free Full Text]
  27. Bartels M, Poliwoda H. Gerinnungsanalysen. 6th ed. Stuttgart, New York: Georg Thieme Verlag, 1998
  28. Hiippala ST, Myllyla GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995;81:360–5[Abstract]
  29. Singbartl K, Innerhofer P, Radvan J, Westphalen B, Fries D, Stogbauer R, Van Aken H. Hemostasis and hemodilution: a quantitative mathematical guide for clinical practice. Anesth Analg 2003;96:929–35[Abstract/Free Full Text]
  30. Nielsen VG, Cohen BM, Cohen E. Effects of coagulation factor deficiency on plasma coagulation kinetics determined via thrombelastography: critical roles of fibrinogen and factors II, VII, X and XII. Acta Anaesthesiol Scand 2005;49:222–31[Web of Science][Medline]
  31. Blome M, Isgro F, Kiessling AH, Skuras J, Haubelt H, Hellstern P, Saggau W. Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost 2005;93:1101–7[Web of Science][Medline]
  32. Levy JH. Massive transfusion coagulopathy. Semin Hematol 2006;43:S59–63[Web of Science][Medline]
  33. Erber WN. Massive blood transfusion in the elective surgical setting. Transfus Apher Sci 2002;27:83–92[Medline]
  34. Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H, Sibony O, Mahieu-Caputo D, Hurtaud-Roux MF, Huisse MG, Denninger MH, de Prost D. PPH Study Group. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007;5:266–73[Web of Science][Medline]
  35. O'Shaughnessy DF, Atterbury C, Bolton Maggs P, Murphy M, Thomas D, Yates S, Williamson LM. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004;126:11–28[Web of Science][Medline]
  36. American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology 2006;105:198–208[Web of Science][Medline]
  37. Hedin A, Hahn RG. Volume expansion and plasma protein clearance during intravenous infusion of 5% albumin and autologous plasma. Clin Sci (Lond) 2005;108:217–24[Medline]
  38. Fenger-Eriksen C, Anker-Moller E, Heslop J, Ingerslev J, Sorensen B. Thrombelastographic whole blood clot formation after ex vivo addition of plasma substitutes: improvements of the induced coagulopathy with fibrinogen concentrate. Br J Anaesth 2005;94:324–9[Abstract/Free Full Text]
  39. Fries D, Innerhofer P, Reif C, Streif W, Klingler A, Schobersberger W, Velik-Salchner C, Friesenecker B. The effect of fibrinogen substitution on reversal of dilutional coagulopathy: an in vitro model. Anesth Analg 2006;102:347–51[Abstract/Free Full Text]
  40. Fries D, Krismer A, Klingler A, Streif W, Klima G, Wenzel V, Haas T, Innerhofer P. Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J Anaesth 2005; 95:172–7[Abstract/Free Full Text]
  41. Fries D, Haas T, Klingler A, Streif W, Klima G, Martini J, Wagner-Berger H, Innerhofer P. Efficacy of fibrinogen and prothrombin complex concentrate used to reverse dilutional coagulopathy–a porcine model. Br J Anaesth 2006;97:460–7[Abstract/Free Full Text]
  42. Nielsen VG. Effects of PentaLyte and Voluven hemodilution on plasma coagulation kinetics in the rabbit: role of thrombin-fibrinogen and factor XIII-fibrin polymer interactions. Acta Anaesthesiol Scand 2005;49:1263–71[Web of Science][Medline]
  43. Nielsen VG. Effects of Hextend hemodilution on plasma coagulation kinetics in the rabbit: role of factor XIII-mediated fibrin polymer crosslinking. J Surg Res 2006;132:17–22[Web of Science][Medline]
  44. Bonik K, Rode MD, Broder M. Therapie von Fibrinogenmangelzuständen. Hämostasiologie 1996;16:194–9
  45. Heindl B, Delorenzo C, Spannagl M. High dose fibrinogen administration for acute therapy of coagulopathy during massive perioperative transfusion. Anaesthesist 2005;54:787–90[Web of Science][Medline]



This article has been cited by other articles:


Home page
 Br J AnaesthHome page
N. Rahe-Meyer, M. Pichlmaier, A. Haverich, C. Solomon, M. Winterhalter, S. Piepenbrock, and K. A. Tanaka
Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study
Br. J. Anaesth., June 1, 2009; 102(6): 785 - 792.
[Abstract] [Full Text] [PDF]

Home page
 Br J AnaesthHome page
P. Moor, T. Woolley, M. Midwinter, C. Fenger-Eriksen, J. Ingerslev, and B. Sorensen
Coagulation tests in future studies: what to use?
Br. J. Anaesth., May 1, 2009; 102(5): 716 - 717.
[Full Text] [PDF]

Home page
 Anesth. Analg.Home page
J. Boldt
Modern Rapidly Degradable Hydroxyethyl Starches: Current Concepts
Anesth. Analg., May 1, 2009; 108(5): 1574 - 1582.
[Abstract] [Full Text] [PDF]

Home page
 Ann. Thorac. Surg.Home page
J.-F. Hardy, S. Belisle, and P. Van der Linden
Efficacy and Safety of Recombinant Activated Factor VII to Control Bleeding in Nonhemophiliac Patients: A Review of 17 Randomized Controlled Trials
Ann. Thorac. Surg., September 1, 2008; 86(3): 1038 - 1048.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
T. Haas, D. Fries, C. Velik-Salchner, C. Reif, A. Klingler, and P. Innerhofer
The In Vitro Effects of Fibrinogen Concentrate, Factor XIII and Fresh Frozen Plasma on Impaired Clot Formation After 60% Dilution
Anesth. Analg., May 1, 2008; 106(5): 1360 - 1365.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
S. Kozek-Langenecker and G. Scharbert
Which Hemostatic Changes Determine Clinical Outcome?
Anesth. Analg., May 1, 2008; 106(5): 1588 - 1588.
[Full Text] [PDF]

Home page
 Br J AnaesthHome page
M. Mittermayr, W. Streif, T. Haas, D. Fries, C. Velik-Salchner, A. Klingler, and P. Innerhofer
Effects of colloid and crystalloid solutions on endogenous activation of fibrinolysis and resistance of polymerized fibrin to recombinant tissue plasminogen activator added ex vivo
Br. J. Anaesth., March 1, 2008; 100(3): 307 - 314.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
T. Haas, D. Fries, C. Velik-Salchner, E. Oswald, and P. Innerhofer
Fibrinogen in Craniosynostosis Surgery
Anesth. Analg., March 1, 2008; 106(3): 725 - 731.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
V. G. Nielsen and J. H. Levy
Fibrinogen and Bleeding: Old Molecule New Ideas
Anesth. Analg., October 1, 2007; 105(4): 902 - 903.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (22)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mittermayr, M.
Right arrow Articles by Innerhofer, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mittermayr, M.
Right arrow Articles by Innerhofer, P.
Related Collections
Right arrow Cardiovascular
Right arrow Coagulation

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press