Viscoelastic Testing and Coagulopathy of Traumatic Brain Injury

Abstract

A unique coagulopathy often manifests following traumatic brain injury, leading the clinician down a difficult decision path on appropriate prophylaxis and therapy. Conventional coagulation assays-such as prothrombin time, partial thromboplastin time, and international normalized ratio-have historically been utilized to assess hemostasis and guide treatment following traumatic brain injury. However, these plasma-based assays alone often lack the sensitivity to diagnose and adequately treat coagulopathy associated with traumatic brain injury. Here, we review the whole blood coagulation assays termed viscoelastic tests and their use in traumatic brain injury. Modified viscoelastic tests with platelet function assays have helped elucidate the underlying pathophysiology and guide clinical decisions in a goal-directed fashion. Platelet dysfunction appears to underlie most coagulopathies in this patient population, particularly at the adenosine diphosphate and/or arachidonic acid receptors. Future research will focus not only on the utility of viscoelastic tests in diagnosing coagulopathy in traumatic brain injury, but also on better defining the use of these tests as evidence-based and/or precision-based tools to improve patient outcomes.

Keywords: adenosine diphosphate; arachidonic acid; blood platelets; brain injuries; cerebral hemorrhage; critical care; fibrinolysis; mortality; resuscitation; thromboelastography; traumatic.

Figure 5

The Multiplate^® multiple electrode impedance aggregometer measures platelet function in diluted anticoagulated whole blood. Each plate uses two sensors containing a pair of silver-coated copper wire electrodes. Over a set duration of time, aggregation of activated platelets on the surface of the electrodes causes a measurable change in impedance, measured in aggregation units (AU, where 8AU ≈ 1 Ω) and area under the AU curve [148].

Figure 1

The TEG^® and ROTEM^® analyzers are each composed of a cup containing a whole blood sample, a pin suspended in the blood sample, a torsion wire, and a transducer. The cup is rotated at a speed of 4.45° per 10 s in TEG^®. In ROTEM^®, the pin is instead rotated, at the same speed of 4.45° per 10 s. In both assays, clotting of the whole blood gradually synchronizes the rotations of the cup and pin, which causes a change in torque on the torsion wire that is measured by the transducer. Various coagulation activators may be used depending on the assay. Intrinsic coagulation activators include kaolin or ellagic acid; extrinsic activation most commonly uses tissue factor [43,106,107].

Figure 2

A typical graphical output of TEG^® (parameters shown in black) and ROTEM^® (parameters shown in red). R (Reaction Time)/CT (Clotting Time) denotes the time taken for blood to begin initiation of enzymatic clotting factor activation (marked by a movement of 2 mm along the y-axis). K/CFT (Clot Formation Time) denotes the time taken for movement of the pin by 20 mm along the y-axis. The α-angle is software-calculated using the slope of the secant line from the split point of the curve to K [111]. Clot kinetics are typically determined by K and α-angle, which together describe clot-strengthening rate and the cleavage of fibrinogen to fibrin by thrombin. Maximum Amplitude (MA) or Maximum Clot Firmness (MCF) denotes the peak of the curve and the point of greatest platelet-fibrin interaction [105,107]. Lysis at 30 min (LY30) is measured 30 min after MA as a percentage dissolution from MA peak. LI30 (Lysis Index at 30min) is measured as the amplitude 30 min after CT. Maximum Lysis (ML) is expressed as a percentage dissolution from MCF peak at the time of evaluation during the performance of the test and is roughly equivalent to the LY30 [43,106,107,108,112].

Figure 3

The analysis of platelet function requires four cups for Modified Thromboelastography with Platelet Mapping (TEG-PM^®). In Cup 1 is a baseline kaolin TEG^® which describes control parameters. In Cups 2–4, heparin is added to neutralize thrombin which allows for isolation of platelet function in the presence of a pure fibrin clot. Reptilase and Factor XIIIa are added to Cups 2-4 to enhance fibrinogen and fibrin formation. Therefore, the additions of ADP in Cup 3 and AA in Cup 4 allow selective and respective activation of isolated ADP and AA receptors which then create an isolated pure fibrinogen/fibrin-platelet clot [109,121].

Figure 4

The TEG^® PlateletMapping assay is composed of four tests, starting with a standard kaolin TEG^® (black line; corresponds to Cup 1 of Figure 3) that depicts maximally activated platelets and full clot strength potential (MA_thrombin). The clot strength of pure fibrin (red line; corresponds to Cup 2 in Figure 3) is isolated after blockage of all thrombin in the second test. Platelets are then activated in the third and fourth tests through either their ADP or AA receptors, and clot strength of platelets activated at either receptor (blue line; corresponds to Cups 3 & 4 in Figure 3) is evaluated by the proximity of the stimulated platelet as a percentage of MA_thrombin [128]. The platelet inhibition in response to the agonist is calculated from platelet aggregation: [(MA_ADP − MA_fibrin)/(MA_thrombin − MA_fibrin) × 100] and % inhibition = (100 − %aggregation) [109].