Effects of replacement fluids on coagulation system used for therapeutic plasma exchange

1. Background 

Therapeutic apheresis (TA) has been practiced for approximately 25 years. The list of indications for TA has grown very rapidly and motivated estabilishment of apheresis units [1]. Removal of large volumes of plasma (usually 50 ml/kg) requires replacement with a solution to maintain colloid pressure [2]. Initially, the replacement solution used was fresh frozen plasma (FFP), but this was progressively replaced by pasteurized albumin, when patients did not have coagulation problems [3]. More recently, synthetic plasma expanders were used to reduce the cost of therapeutic exchange (TPE) [4]. Hydroxyethyl starch (HES) is a polysaccaride colloid widely used as an agent for plasma volume expansion and for enhancement of granulocyte yields during centrifugation leukapheresis [5]. Its pharmacology [6] and safety [7] have been well studied, particularly when used in recommended doses. When used in moderate amounts in man and animals, HES produces relatively minor changes in coagulation test results, and overt bleeding rarely occurs [8]. The exact mechanism of these changes is unclear, but it has been ascribed, at least in part, to hemodilution. In this study we aimed to compare the effects of several replacement fluids used for TPE on the coagulation profile.

2. Materials and methods 

3. Results 

3.1. Coagulation tests 

There was no significant difference in PT values between the groups (F=0.0968 P=0.43); however, a change in this parameter with time was significant (F=13.579, P=0.000). Without a group effect, the PT values changed significantly with time. There was no significant difference in aPTT values between the groups (F=2.839, P=0.069) nor in the aPTT with time (F=1.445, P=0.223). No significant difference was found in the TT values (F=2.157, P=0.127), but a significant change was found in the TT over time (F=8.011, P=0.000). There was a significant difference in fibrinogen values between groups 1 and 4, 3 and 2, and 3 and 4 (F=4.390, P=0.000) and in the fibrinogen level over time (F=15.093, P=0.000) (Fig. 1). The change in D-dimer between groups 1 and 2, 2 and 3; and 2 and 4 was significant (F=7.902, P=0.02) because one patient’s D dimer level was so high in the FFP group that this significant value was regarded as unimportant (F=18.391, P=0.000). The change in D-dimer levels with time was also significant (F=6.247, P=0.000) (Fig. 2).

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Fig. 1. Time-related change of fibrinogen during TPE.

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Fig. 2. Time-related change of D-dimer during TPE.

4. Discussion 

During plasmaphereis the coagulation system and hemoreology change due to the administration of replacement fluids as observed in various studies. In these studies, the most significant change is on the fibrinogen levels. The predominantly intravascular distribution of fibrinogen would lead one to predict a significant fall in this important coagulant protein with TPE when the replacement fluid does not contain fibrinogen [8]. Keller and Chrinside [9] reported that fibrinogen levels were lowered to 25±1.2% of preapheresis levels and recovered to baseline after two to three days. Chopek and McCullough observed an exponential fall in fibrinogen concentration predicted by the one compartment model to a 75% decrease when 1.5 plasma volumes were exchanged for albumin containing replacement fluid. At between 1.0 and 1.5 plasma volumes the aPTT approached 180 s. The PT also increased above the normal range when 1.0 plasma volume was exchanged, and it increased rapidly when more than 1.5 plasma volumes were exchanged. Following exchange, the plasma fibrinogen concentration recovered with a half time of about 26 h and returned toward baseline between 48 and 72 h after exchange [8]. Orlin and Berkman performed TPE on subjects using intermittent flow equipment. The replacement fluid was 5% albumin in normal saline. They observed that the plasma fibrinogen recovered to 63% of preapheresis levels by 48 h [10]. Wood and Jocobs carried out 100 exchanges of 1.5 plasma volumes on seven patients at biweekly intervals using continuous flow equipment and replacement fluid containing 4% albumin in a balanced electrolyte solution. The median fibrinogen concentration fell by 76% and remained 40% below baseline 24 h postapheresis. The median aPTT increased from 36 s (–40 s) before TPE to 59 s immediately after TPE and then dropped back to 38 s by 24 h after TPE [11]. Domen et al. prospectively studied the hemostatic imbalances produced in 10 patients treated with intensive TPE using 5% albumin in 0.9% saline as the return fluid. The PT was prolonged immediately after TPE, compared to the preapheresisi measurement, in all patients; however, only one measurement was outside the normal range. Similarly, all patients had a prolonged aPTT postapheresis but in only one patient was the aPTT outside the normal range. In any case, all values returned to baseline within 24–72 h. The plasma fibrinogen concentration fell significantly in each patient. Eight of ten had a plasma fibrinogen level below normal after their first exchange; five remained below normal at 24–72 h after the first exchange; and remained below normal at 24–72 h after the first exchange. Seven remained below the lower limit of normal 24–72 h after the fourth exchange [12]. In our study, in patients who did not received FFP, there was a significant decrease in fibrinogen levels. The fibrinogen level decreased to 83% of the base line level after the end of 48 h of therapy. The APTT, PT and TT increased during TPE. However no statistical difference was observed between the groups. No bleeding diatesis was seen in our groups.

In a follow up study, the same group of investigators reported on alterations in specific coagulation factors with daily TPE. Factors VII, VIII, and IX were less affected by TPE, falling to 48±11%, 45±24%, and 62±11% of preapheresisi levels, respectively. Factors V and X both fell to 38±11% of preapheresis levels. The antithrombin activity fell to 40±16% of the pretreatment level, but antithrombin antigen fell only to 68±24% of baseline, suggesting that enzyme inhibitör complexes were formed between antithrombin and the activated clotting factors generated during the procedures. Most clotting factors returned to 85–100% of normal within a day after TPE, and all but factor X and fibrinogen were thus restored within two days [8]. Suttan et al. performed 18 TPEs (1,6 plasma volumes per ex chance), on seven patients with myasthenia gravis. Procedures occured at two or three-day intervals. Factor V, VII, IX, X, XI, and XII fell 71%, 69%, 55%, 84%, 66% and 66%, respectively. All had returned to baseline 48–96 h later when remeasured just prior to a subsequent TPE. Antithrombin antigen fell an average of 84% after TPE, recovering substantially, but not completely to baseline when remeasured [13]. Although we found a significant change in factor levels with time, only the difference in factors IX and XI between the groups was significant (Fig. 3, Fig. 4). In addition, factor levels measured at 48 h were close to the levels measured before apherises.

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Fig. 3. Time-related change of Fac IX during TPE.

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Fig. 4. Time-related change of Fac XI during TPE.

In our study, the time-related change in AT-3 values was significant. As we could not find any report on Protein C and S levels or APC resistance in the literature, we could not compare our results. Time-related changes of Protein S and APCR were not statistical significant but on the other hand, we found a significant difference in AT-III and Protein C values between groups (Fig. 5, Fig. 6).

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Fig. 5. Time-related change of Pr.C during TPE.

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Fig. 6. Time-related change of artithrombin III during TPE.

The side effects of HES on coagulation factors and tests were comparable to those of other replacement fluids. HES can be safely used to perform short-term plasmapheresis in the first two sessions of therapy in patients in whom albumin level are above 3 g/dl. Its low cost makes it favourable. TPE activity in Turkey is increasing gradually. It is still limited when compared to other European countries. The number of TPE procedure per inhabitant in 1998 is 10 times lower than in the developed countries. In order to increase our TPE activity we should collaborate with other disciplines like nephrology, neurology and immunology [14], [15].