Use of Thromboelastography in Evaluation of Effects of Crystalloid Solutions on

Many studies on the effects of crystalloid solutions on human coagulation have been done diluting plasma without taking into account that when blood clots, it occurs as whole blood without separation into individual components. Perhaps, this was due to difficulties in methods of analysis that has been solved by Thromboelastography.

It had initially thought that crystalloids have no inherent effects on coagulation apart from plasma haemodilution of coagulation factors which led to use of normal saline as a comparator. However, Ruttmann (1996) using thrombelastography demonstrated for the first time that haemodilution with isotonic saline induces a hypercoagulable state indicating its intrinsic properties on whole blood coagulation. The same author later on used various isotonic fluids and arrived at the same conclusion and commented that crystalloid haemodilution is procoagulant

irrespective of pH, osmolality or type of solutes (Thomas G. Ruttmann, Montoya-Pelaez, & James, 2007). The proposition was not supported by empirical evidence, and could only be true for isotonic solutions.

For a long time it has been thought that calcium in some balanced salt solutions such as ‘Ringer’s lactate’ (RL) or ‘Hartmanns’ solutions may lead to clot activation when blood transfusion are administered through the same filters concurrently. However, this concern does not appear significant since in a study that compared the rate of clot formation in transfusion filters did not find any difference between normal saline and RL (Cull, Lally, & Murphy, 1991). Similarly, no significant differences on coagulation have been demonstrated between them in plasma coagulation tests (Timothy John Coats & Heron, 2004; Ekseth, Abildgaard, Vegfors, Berg-Johnsen, & Engdahl, 2002). Whereas RL contains calcium, a known coagulation factor which is absent in normal saline, the presence of calcium at this concentration plays very little role on coagulation effects (T. J. Coats, Brazil, & Heron, 2006). This probably casts doubt on the role of calcium in coagulation at concentrations normally found in many resuscitation fluids.

In comparative studies using Thrombelastography, it was demonstrated that RL is more hypercoagulable than NS (Boldt, Haisch, Suttner, Kumle, & Schellhase, 2002; Anthony M. Roche, James, Bennett-Guerrero, & Mythen, 2006a). RL is hypotonic compared to NS, has Na and Cl lower (130 and 109 mMol/l compared to 154 and 154 mMol), respectively for the two solutions. Although the osmolality for NS and RL are 295 and 280 mOsm respectively, the marked difference in composition is chloride ions. The difference in Na+ is only 9 mMol, while it is 35 mMol for chloride ions. These data suggest that increase in solute concentration

especially ionised ones may impair whole blood clotting. The greater chloride concentration may account for the differences in parameters but controlled laboratory investigations have not been done.

Magnesium is a divalent cation present in some resuscitation fluids such as ‘Hartmans’ solution that is expected to compete with calcium in coagulation reactions, and probably procoagulant owing to increased thrombin generation (Ravn, Lassen, Bergenhem, & Kristensen, 2001). Clinical experience in which magnesium sulphate was infused for other indications showed that clotting time as well as clot formation time were increased with concomitant decrease in alpha angle and clot firmness in keeping with hypocoagulability (Ames, McDonnell, & Potter, 1999)(Thomas G. Ruttmann et al., 2007; Na, Chung, Hwang, & Do, 2012; Na, Shin, Kang, Hwang, & Do, 2014) in contrast to another study which showed hypercoagulability (Choi, Lee, & Park, 2005). But these were in vivo studies where multiple factors may be at play, especially release of vasopressin from hypothalamus and osmotic activity on endothelium. The tests that demonstrated hypercoagulability were done in very sick liver transplant patients and therefore not a true reflection of its physiological effects on clotting factors.

Unlike in vivo studies, in vitro haemodilution with magnesium solutions have consistently demonstrated hypocoagulability (Jankun et al.., 2013) in keeping with its infusion in healthy volunteers. However, due to inconsistency of study findings and in view of high concentrations administered in volunteers, it is still doubtful whether the effects were due to hyperosmolality, or sulphate anion which is a kosmotrope on the Hofmeister series. Furthermore, no investigations have been done with magnesium chloride solutions

Studies on the effects of Crystalloid osmolality on coagulation have recorded mixed results. Whereas Tan et al (Tan, Tan, Ng, & Loh, 2002) found 7.5% HTS impaired all TEG parameters at dilution of 10% and above in contrast to isotonic saline (Ruttmann, 2003; Ruttmann et al., 2007, 2006, 2002, 2001, 1996). These studies provided strong indication that increased saline concentrations induce hypocoagulability in vitro, and demonstrated clearly that coagulation outcomes may not simply be accounted for on the basis of haemodilution of clotting factors. However, the reasons to account for the difference in NaCl concentration on coagulation and the mechanisms remain unknown to date.

In a study comparing effects of different concentrations of saline with hypertonic mannitol in vitro, it was found that the two molecules produced different results. While hypertonic mannitol was associated with increased ROTEM clotting time as well as clot formation time with concurrent reduction in MCF and alpha angle, changes produced by iso-osmolar NaCl concentration were much less. In the same study isotonic saline was associated with hypercoagulability (Luostarinen, Niiya, Schramko, Rosenberg, & Niemi, 2011). This reinforced previous finding that haemodilution with mannitol or its combination with Ringers acetate or hydroxyethyl starch inhibited whole blood coagulation (Lindroos, Schramko, Tanskanen, & Niemi, 2010). The mechanism for discordance in effects between NaCl and mannitol has not been established.

Even though diabetes mellitus is considered a hypercoagulable state, thromboelastographic evaluation of type II diabetes failed to show enhanced whole blood coagulability (Yürekli et al., 2006a). Acute complications of diabetes are always associated with many electrolyte imbalances

which could confound the picture and mask coagulation effects of glucose. Furthermore, many metabolic products in association with long term diabetic complications are often at play and it is difficult to distinguish coagulation effects of diabetes in this scenario. However, unlike mannitol, no study has been conducted in vitro to define the effects of dextrose on coagulation per se using thromboelastography.

With the findings that antithrombin levels were reduced proportional to extent of dilution, many authors have used this to explain the haemodilution induced hypercoagulability (Nielsen et al., 2004; T. G. Ruttmann et al., 2001, 2006; Szlam et al., 2008). However, when either thrombin or fibrinogen concentrates were added to haemodiluted blood samples, TEG parameters were not restored to predilution levels (Schols, Heemskerk, & van Pampus, 2010). This suggested the inadequacy of antithrombin hypothesis in explaining hypercoagulability, and probably another factor was at play. However, this has not been identified to date