Utilization of lysis percentage via thromboelastography for tissue plasminogen activator-induced symptomatic intracranial hemorrhage

Journal logoUnlabelled imageAmerican Journal of Emergency Medicine 43 (2021) 31-34

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Utilization of lysis percentage via thromboelastography for tissue plasminogen activator-induced symptomatic intracranial hemorrhage

Brian W. Gilbert, PharmD, BCPS a,?, J. Spencer Dingman, PharmD b,

Joel B. Huffman, PharmD a

a Emergency Medicine Clinical Pharmacy Specialist Wesley Medical Center, Wichita, KS, United States of America

b Neurocritical care Clinical Pharmacy Specialist Wesley Medical Center, Wichita, KS, United States of America

  1. Background

Alteplase, the only FDA approved tissue plasminogen activator , remains one of the cornerstones of acute ischemic stroke manage- ment. JustaswithendogenoustPA, recombinanttPApromotestheactiva- tion of plasmin and the subsequent degradation of cross-linked fibrin to fibrin byproducts [1]. The most feared complication of recombinant tPA administration is the development of symptomatic intracranial hemor- rhage (sICH), which occurs in approximately 5.6% of tPA administrations, utilizing the European Cooperative Acute Stroke Study definition, with roughly half of these cases resulting in death [2]. The half-life of recombi- nant tPA is short, lasting approximately 7.5 min, however a sustained fi- brinolytic effect has been well described in previous reports [3]. While there have been many documented risk factors for the development of sICH, there remains a paucity of literature on its management [4].

Risk of hemorrhage expansion once sICH has occurred is an ill- defined area and recommendations on detecting the presence of tPA-associated coagulopathy are lacking. Early Fibrinogen levels should be obtained once the sICH is identified, but these static mea- surements are unable to identify if the patient is experiencing ongo- ing fibrinolysis placing them at risk for Hematoma expansion. However, clinically relevant hemorrhage expansion consistently oc- curred in 30 to 40% of patients diagnosed with sICH across these studies [4]. The American Heart and American Stroke Associations guidelines on Hemorrhagic transformation after tPA recommend the administration of cryoprecipitate and/or antifibrinolytic agents such as Tranexamic acid (TXA) or aminocaproic acid in select pa- tients with sICH, with minimal guidance regarding specific patient selection or timing of administration [4]. While there have been some documented cases of extended tPA-associated fibrinolysis documented within the literature the majority of cases of sICH occur within four hours post-administration. Reflexive administra- tion of theoretical antidotes to all patients with sICH may increase the risk of medication-related adverse events, while application of patient-specific coagulation data could allow for improved blood product stewardship and Cost Avoidance. Here we report the

* Corresponding author.

E-mail addresses: [email protected] (B.W. Gilbert), [email protected] (J.S. Dingman), [email protected] (J.B. Huffman).

possible utility of a viscoelastic test, Thromboelastography , in the management of sICH after tPA.

    1. Viscoelastography

Viscoelastographic tests, such as TEG, are able to measure the pro- cess of clot formation and dissolution. Specifically, TEG is one of the few tests that can accurately predict fibrinolysis and has been used in different critically ill patient populations to guide resuscitation [5]. A TEG tracing (Fig. 1) has the ability to detect and measure clotting distur- bances related to clotting factors, fibrinogen, platelets, and clot break- down or fibrinolysis. Table 1 list the components of a standard TEG tracing, their clinical significance, and the associated normal values. The most pertinent clinical parameter related to tPA-associated coagu- lopathy is the lysis percentage at 30 min (Ly30%) which measures the extent of fibrinolysis over time. The Ly30% has been able to guide resus- citation at our institution, specifically as it relates to reversal agents, such as TXA or blood products, by defining patients with normal phys- iological fibrinolysis (0.8-3%), hyperfibrinolysis (HF; >3%), or fibrino- lytic shutdown (FS; <0.8%). Inadvertent administration of TXA to patients with FS as assessed by Ly30% has been proposed to cause harm in the trauma patient population, and it would not be unreason- able to consider the same detriment plausible in the AIS population when given inappropriately, although this has not been described in the literature [6].

The utility of TEG in AIS has been previously described, with var- iability in post-tPA Ly30% reported between 15 and 95% [7]. This var- iability is likely secondary to clot composition, which deserves further study as a potential risk factor to predict tPA-associated sICH. Previous studies of TEG in the AIS cohort have been unable to predict Clinical response to tPA, but to our knowledge there is no data on the utility of Ly30% in the guidance of tPA-associated coagu- lopathy post-sICH development as it relates to risk for hematoma ex- pansion [8]. The majority of sICH occur within six to eight hours after tPA administration, however tPA may have sustained effects lasting up to 24 h or longer post administration [4]. It is not unreasonable to administer cryoprecipitate early to a sICH patient with a fibrino- gen level of <150-200 mg/dL given that this is a risk factor for hema- toma expansion, however if the value is normal this does not preclude the need for resuscitation with agents like TXA given that fi- brinogen is known to be an acute phase reactant [4]. If a patient has a


0735-6757/(C) 2021

Image of Fig. 1

Fig. 1. Thromboelastography normal tracing R: clotting factor function; K: clot kinetics; ?: fibrinogen activity; MA: platelet activity; A30; fibrinolytic activity.

normal fibrinogen content but has a Ly30% consistent with HF, the patient may still be at risk for hematoma expansion and TXA admin- istration would not be unreasonable rather than using serial CTs or fibrinogen levels to guide resuscitation [4]. Additionally, other por- tions of the TEG tracing may be able to identify disturbances in plate- let function (via maximum amplitude) or fibrinogen content (via ?-angle) for a complete hemostatic evaluation of the sICH patient. Given that a Ly30% takes approximately 30 min to report, clinicians could make real-time decisions in the resuscitation of tPA- associated coagulopathy.

  1. Application to practice
    1. Patient case 1

A 77 year old male presented to our emergency department with unilateral weakness, difficulty with speech, and confusion with a last known well approximately one hour prior to arrival. After his initial National Institute of Health Stroke Scale score was 22 and after a CT head showed no hemorrhage (ASPECT 9), he was

Table 1

Thromboelastographic components with Kaolin administration

Variable Clinical Relevance Normal Values

deemed a candidate for tPA. He was administered a 0.9 mg/kg dose of tPA and was started on an Intravenous nicardipine drip for blood pressure management. A CT angiogram confirmed a dense right distal M1 occlusion and the patient had a successful endovascular thrombectomy performed, achieving a TICI score of

  1. Approximately four and a half hours after tPA had been adminis- tered the patient exhibited an increase in his NIHSS score of four points. A stat CT head showed an evolving Middle cerebral artery

R Time Prolonged Time – Reduced clotting factor activity

Shortened Time – Increased clotting factor activity

K Time Prolonged Time – Increased time to clot formation

Shortened Time – Reduced time to clot formation

? – angle Angle Approaching 90? – Increased

fibrinogen activity

Angle Approaching 0 – Decreased Fibrinogen Activity

3.8-9.8 min

Image of Fig. 20.7-3.4 min


Maximum Amplitude

Lysis Index at 30 min (Ly30)

Increased Amplitude – Increased platelet count and/or function

Decreased Amplitude – Decreased platelet count and/or function Elevated Value – Increased fibrinolytic activity

Decreased Value – Diminished

fibrinolytic activity

49.7-72.7 mm


a >3% is utilized within trauma literature to identify hyperfibrinolysis. Fig. 2. Patient 1 Pre- and Post-tPA CT head images.

Image of Fig. 2

Fig. 2 (continued).

(MCA) infarct, multiple small hemorrhages along the hyperdensity, a small frontal lobe hemorrhage, and a large intraparenchymal hem- orrhage (IPH) (1.6 x 2.3 cm) within the posterior lobe. Fig. 2 shows the pre and post tPA CT head images. A stat serum fibrinogen was collected and resulted at 180 mg/dL. It was then decided that a rapid TEG would be ordered with parameters for administration of TXA if Ly30% was >3% indicating HF. The initial Ly30% resulted in a value of 0.9% and given the concern of hematoma expansion a subse- quent Ly30% was ordered five hours after, which resulted in a value of 0.7%. A second fibrinogen value was ordered with the repeat Ly30% and showed a slight decrease in fibrinogen to 174 mg/dL. A follow-up CT was performed ~15 h after that showed a stable IPH but evolving MCA infarct. In this instance neither TXA nor cryoprecipitate were administered to the patient and given the evolving ischemia it is not unreasonable to consider cryoprecipitate or TXA could have exacerbated the condition further. The patient was discharged to a rehabilitation center six days after tPA adminis- tration with an NIHSS score of 21.

2.2. Patient case 2

An 81 year old female presented to our emergency department with a sudden onset of confusion, an inability to speak, and an arm drift two hours prior to arrival. Her initial NIHSS score was 6, CT head without con- trast was negative for hemorrhage, and CT angiogram was unremarkable foralargevesselocclusion. Givenherdeficitsshewasdeemedacandidate for tPA, administered a 0.9 mg/kg dose, and started on a continuous nicardipine drip for blood pressure control. Approximately 30 min after tPA completion, the patient began to endorse a headache and markedly increased confusion. A stat CT was performed which showed a new IPH measuring approximately 3.1 x 5.1 cm. A bolus dose of TXA (1 g over 10 min) was promptly administered approximately one hour after tPA

Fig. 3. Patient 2 Pre- and Post-tPA CT head images.

Image of Fig. 3had completed infusing and a stat fibrinogen resulted at 228 mg/dL. Fig. 3 shows the pre- andpost-tPA CT head images. With concern of ongo- ing tPA-associated coagulopathy and hematoma expansion, serial TEG values were performed assessing Ly30% at approximately 5, 11, and 19 h post-TXA administration. The Ly30% values resulted at 1.8, 0.3, and 1.3, which are within the normal physiological fibrinolysis threshold and placed her at a low theoretical risk for hematoma expansion second- ary to sustained fibrinolysis, therefore no pharmacological intervention was deemed necessary. The corresponding fibrinogen values were 215, 194, and 213 mg/dL and a follow-up CT was performed approximately 14 h later and showed a stable IPH without intraventricular extension. Thepatientneverrequiredsubsequent TXAdoses nor cryoprecipitatead- ministration and was ultimately discharged 8 days post-tPA administra- tion with a NIHSS score of 8.

3. Conclusion

Hematoma expansion following tPA-associated sICH can lead to del- eterious outcomes, but Predictive tools and studies are lacking. Utiliza- tion of TEG, particularly Ly30%, to evaluate ongoing fibrinolysis could be an invaluable resource to guide administration of agents like TXA and cryoprecipitate to reduce the incidence of hematoma expansion in this cohort. Protocols on the utilization of TEG post-sICH could be devel- oped and Ly30% cutoff values may need further exploration, as the 3%

Image of Fig. 3

Fig. 3 (continued).

Ly30% threshold for HF is adapted from trauma literature but remains promising. In our cases Ly30% was predictive of fibrinogen degradation within this sICH cohort and hematoma expansion did not occur. While

not mentioned within the guidelines, TEG needs further exploration and could serve a role in the management of tPA-related hemorrhagic complications.

Author statement

All three authors contributed to conceptualization, data curation, and writing (original draft and review/editing).

Declaration of Competing Interest

There are no perceived conflicts of interest or disclosures which would bias this manuscript.


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