Angela Sauaia

Viscoelastic measurements of platelet function, not fibrinogen function, predicts sensitivity to tissue-type plasminogen activator in trauma patients.

Systemic hyperfibrinolysis is a lethal phenotype of trauma‐induced coagulopathy. Its pathogenesis is poorly understood. Recent studies have support a central role of platelets in hemostasis and in fibrinolysis regulation, implying that platelet impairment is integral to the development of postinjury systemic hyperfibrinolysis.

Rationale for the selective administration of tranexamic acid to inhibit fibrinolysis in the severely injured patient.

Postinjury fibrinolysis can manifest as three distinguishable phenotypes: 1) hyperfibrinolysis, 2) physiologic, and 3) hypofibrinolysis (shutdown). Hyperfibrinolysis is associated with uncontrolled bleeding due to clot dissolution; whereas, fibrinolysis shutdown is associated with organ dysfunction due to microvascular occlusion. The incidence of fibrinolysis phenotypes at hospital arrival in severely injured patients is: 1) hyperfibrinolysis 18%, physiologic 18%, and shutdown 64%. The mechanisms responsible for dysregulated fibrinolysis following injury remain uncertain. Animal work suggests hypoperfusion promotes fibrinolysis, while tissue injury inhibits fibrinolysis. Clinical experience is consistent with these observations. The predominant mediator of postinjury hyperfibrinolysis appears to be tissue plasminogen activator (tPA) released from ischemic endothelium. The effects of tPA are accentuated by impaired hepatic clearance. Fibrinolysis shutdown, on the other hand, may occur from inhibition of circulating tPA, enhanced clot strength impairing the binding of tPA and plasminogen to fibrin, or the inhibition of plasmin. Plasminogen activator inhibitor ‐1 (PAI‐1) binding of circulating tPA appears to be a major mechanism for postinjury shutdown. The sources of PAI‐1 include endothelium, platelets, and organ parenchyma. The laboratory identification of fibrinolysis phenotype, at this moment, is best determined with viscoelastic hemostatic assays (TEG, ROTEM). While D‐dimer and plasmin antiplasmin (PAP) levels corroborate fibrinolysis, they do not provide real‐time assessment of the circulating blood capacity. Our clinical studies indicate that fibrinolysis is a very dynamic process and our experimental work suggests plasma first resuscitation reverses hyperfibrinolysis. Collectively, we believe recent clinical and experimental work suggest antifibrinolytic therapy should be employed selectively in the acutely injured patient, and optimally guided by TEG or ROTEM.

Activated clotting time of thrombelastography (T-ACT) predicts early postinjury blood component transfusion beyond plasma

INTRODUCTIONnRapid thrombelastography (rTEG) has been advocated as a point-of-care test to manage trauma-induced coagulopathy. rTEG activated clotting time (T-ACT) results become available much sooner than other rTEG values, thus offering an attractive tool to guide blood component transfusion in a hemorrhagic shock. We hypothesize that patients with a prolonged T-ACT require replacement of platelets (Plts) and cryoprecipitate (Cryo) in addition to plasma to correct trauma-induced coagulopathy.nnnMETHODSnA prospective trauma registry was reviewed for patients with an r-TEG available within 3xa0hours of injury. Blood was collected via a standardized protocol for rTEG. Patients were stratified into quartiles: low (T-ACT <113xa0seconds), mild (T-ACT 113-120xa0seconds), moderate (T-ACT 121-140xa0seconds), and severe (T-ACT >140xa0seconds). Transfusion requirements were evaluated during the first 6xa0hours after injury.nnnRESULTSnA total of 114 patients were included. Median age was 39xa0years, injury severity score 20, base-deficit 10, and mortality rate 13%. T-ACT cohorts had similar age (Pxa0=xa0.11), injury severity score (Pxa0=xa0.55), and base deficit (Pxa0=xa0.38). An T-ACT >140xa0seconds predicted a lower angle (median 57 vs 70, Pxa0<xa0.000) and maximum amplitude (46 vs 60, Pxa0=xa0.002), and patients received more Cryo (0.5 vs 0, Pxa0≤xa0.000) and Plts (1 vs 0, Pxa0=xa0.006).nnnCONCLUSIONnInjured patients requiring resuscitation with blood transfusion that have a T-ACT >140xa0seconds are polycoagulopathic and may benefit from early Cryo and Plts.

Fatality and Severity of Firearm Injuries in a Denver Trauma Center, 2000-2013

This study uses trauma center registry data to describe the severity and mortality of gunshot wounds seen at a Colorado trauma center and its catchment area between 2000 and 2013.

Targeting resuscitation to normalization of coagulating status: Hyper and hypocoagulability after severe injury are both associated with increased mortality

INTRODUCTIONnThe prevalence and impact of hypercoagulability (hypo) in severely injured patients early after injury remains unclear. We hypothesize that the predominant phenotype of postinjury coagulopathy is hypercoagulability (hyper) and it is associated with increased mortality.nnnMATERIAL AND METHODSnBlood samples from 141 healthy volunteers assayed with thrombelastography (TEG) were used to identify thresholds of hypo and hypercoagulability (above 95th/below the 5thpercentile) in four TEG indices. These cutoffs were subsequently evaluated in severely injured trauma patients (ISS>15) from two level 1 trauma centers.nnnRESULTSn2540 patients with a median ISS of 25 were analyzed. Normal TEG was present in 36% of patients. Hyper was found in 38% of patients, with mixed (11%) and hypo (15%) being less common. Compared to normal coagulation patients and after controlling for age, sex, blood pressure, and injury hyper (0.013), mixed (pxa0<xa00.001) and hypo (pxa0<xa00.001) were all independent predictors of mortality.nnnCONCLUSIONnThese data support the ongoing need for goal directed resuscitation in trauma patients, it appears the optimal resuscitation strategy should be targeted towards normalization of coagulation status as both early hyper and hypocoagulability are associated with increased mortality.

Freeze-dried plasma enhances clot formation and inhibits fibrinolysis in the presence of tissue plasminogen activator similar to pooled liquid plasma

Systemic hyperfibrinolysis is an integral part of trauma‐induced coagulopathy associated with uncontrolled bleeding. Recent data suggest that plasma‐first resuscitation attenuates hyperfibrinolysis; however, the availability, transport, storage, and administration of plasma in austere environments remain challenging and have limited its use. Freeze‐dried plasma (FDP) is a potential alternative due to ease of storage, longer shelf life, and efficient reconstitution. FDP potentially enhances clot formation and resists breakdown better than normal saline (NS) and albumin and similar to liquid plasma.

Thrombin stimulates increased plasminogen activator inhibitor-1 release from liver compared to lung endothelium

BACKGROUNDnPlasminogen activator inhibitor-1 (PAI-1) is a major regulator of the fibrinolytic system, covalently binding to tissue plasminogen activator and blocking its activity. Fibrinolysis shutdown is evident in the majority of severely injured patients in the first 24xa0h and is thought to be due to PAI-1. The source of this PAI-1 is thought to be predominantly endothelial cells, but there are known organ-specific differences, with higher levels thought to be in the liver. Thrombin generation is also elevated in injured patients and is a potent stimulus for PAI-1 release in human umbilical endothelial cells. We hypothesize that thrombin induces liver endothelial cells to release increased amounts of PAI-1, versus pulmonary endothelium, consisting of both stored PAI-1 and a larger contribution from de novo PAI-1 synthesis.nnnMETHODSnHuman liver sinusoidal endothelial cells (LSECs) and human microvascular lung endothelial cells (HMVECs) were stimulated inxa0vitroxa0±xa0thrombin (1 and 5 IU/mL) for 15-240xa0min, the supernatants were collected, and PAI-1 was measured by enzyme-linked immunosorbent assays. To elucidate the PAI-1 contribution from storage versus de novo synthesis, cycloheximide (10 μg/mL) was added before thrombin in separate experiments.nnnRESULTSnWhile both LSECs and HMVECs rapidly stimulated PAI-1 release, LSECs released more PAI-1 than HMVECs in response to high-dose thrombin, whereas low-dose thrombin did not provoke immediate release. LSECs continued to release PAI-1 over the ensuing 240xa0min, whereas HMVECs did not. Cycloheximide did not inhibit early PAI-1 release from LSECs but did at the later time points (30-240xa0min).nnnCONCLUSIONSnThrombin elicits increased amounts of PAI-1 release from liver endothelium compared with lung, with a small presynthesized stored contribution and a later, larger increase in PAI-1 release via de novo synthesis. This study suggests that the liver may be an important therapeutic target for inhibition of the hypercoagulable surgical patient and the associated complications that result.

Rotational thromboelastometry thresholds for patients at risk for massive transfusion

BACKGROUNDnGoal-directed hemostatic resuscitation based on thrombelastography has a survival benefit compared to conventional coagulation assays. While thrombelastography transfusion thresholds for patients at risk for massive transfusion (MT) have been defined, similar cutoffs do not exist for the other commonly used viscoelastic assay, rotational thromboelastometry (ROTEM). The purpose of this study was to develop ROTEM blood product thresholds in patients at risk for MT.nnnMETHODSnROTEM was assessed in trauma activation patients admitted from 2010 to 2016 (nxa0=xa0222). Receiver operating characteristic curve analyses were performed to test the predictive performance of ROTEM measurements in patients requiring MT. The Youden Index defined optimal thresholds for ROTEM-based resuscitation.nnnRESULTSnPatients who required MT (nxa0=xa037, 17%) were more severely injured. EXTEM clotting time (CT) was longer in patients with MT compared to non-MT (87 versus 64 s, Pxa0<xa00.0001). EXTEM angle was shallower in MT patients compared to non-MT (54° versus 69°, Pxa0<xa00.0001). Clot amplitude after 10 min (CA10) was less in MT compared to non-MT patients (30.5 versus 50xa0mm, Pxa0<xa00.0001). Clot lysis index 60 min (CLI60) was lower in patients who had MT than non-MT (47 versus 94%, Pxa0=xa00.0006). EXTEM CT yielded an area under the receiver operating characteristic curve (AUROC)xa0=xa00.7116 and a cut point of >78.5 s. EXTEM angle had an AUROCxa0=xa00.865 and a cut point of <64.5°. EXTEM CA10 had an AUROCxa0=xa00.858, with a cut point of <40.5xa0mm. CLI60 had an AUROCxa0=xa00.6788 with a cut point at <74%.nnnCONCLUSIONSnWe have identified ROTEM thresholds for transfusion of blood components in severely injured patients requiring an MT. Based on our analysis, we propose plasma transfusion for EXTEM CTxa0>xa078.5 s, fibrinogen for angle <64.5°, platelet transfusion for CA10xa0<xa040.5xa0mm, and antifibrinolytics for CLI60xa0<xa074%.

Defining the criteria for intubation of the patient with thermal burns

OBJECTIVESnRecent studies demonstrate that burn patients are undergoing unnecessary intubations. We sought to determine the clinical criteria that predict intubations with benefit.nnnMETHODSnThis was a retrospective review of intubated adults admitted to our center with thermal burns 2008-2013. Criteria for intubation were defined as traditional criteria (suspected smoke inhalation, oropharynx soot, hoarseness, dysphagia, singed facial hair, oral edema, oral burn, non-full thickness facial burns), or ABA criteria as defined by the 2011 ABA guidelines (full thickness facial burns, stridor, respiratory distress, swelling on laryngoscopy, upper airway trauma, altered mentation, hypoxia/hypercarbia, hemodynamic instability). Patients with <26days free from mechanical ventilation (ventilator-free days (VFD)) out of 28, were deemed indicated long-term intubations. Those with ≥26 VFD were deemed unnecessary short-term intubations.nnnRESULTSnOf 218 patients, 151 had long-term and 67 had short-term intubations. Long-term intubation was strongly associated with ABA criteria (77.5%) compared to traditional criteria (22.5%) (p<0.001). Sensitivity of ABA criteria for long-term intubation was 77% and specificity 46%. Traditional criteria associated with long-term intubation included suspected smoke inhalation (OR 2.45 [95% CI, 1.18-5.11]), and singed facial hair (OR 2.53 [95% CI, 1.25-5.09]). The addition of these to ABA criteria created the Denver criteria, which exhibited an increased sensitivity for long-term intubations (95%), but decreased specificity (24%).nnnCONCLUSIONSnIntubation should be considered for patients displaying the Denver criteria, which includes full thickness facial burns, stridor, respiratory distress, swelling on laryngoscopy, upper airway trauma, altered mentation, hypoxia/hypercarbia, hemodynamic instability, suspected smoke inhalation, and singed facial hair. Patients lacking these criteria should not be intubated.

14-Day thawed plasma retains clot enhancing properties and inhibits tPA-induced fibrinolysis

BACKGROUNDnPlasma-first resuscitation attenuates trauma-induced coagulopathy (TIC); however, the logistics of plasma-first resuscitation require thawed plasma (TP) be readily available due to the obligatory thawing time of fresh frozen plasma (FFP). The current standard is storage of TP for up to 5xa0days at 4°C, based on factor levels at outdate, for use in patients at risk for TIC, but there remains a 2.2% outdated wastage rate. However, the multitude of plasma proteins in attenuating TIC remains unknown. We hypothesize that TP retains the ability to enhance clotting and reduce tPA-induced fibrinolysis at 14-day storage.nnnMETHODSnFFP was thawed and stored at 4°C at the following intervals: 14, 10, 7, 5, 3, and 1-day prior to the experiment. Healthy volunteers underwent blood draws followed by 50% dilution with TP stored at previously mentioned intervals as well as FFP, normal saline (NS), albumin, and whole blood (WB) control. Samples underwent tPA-modified (75xa0ng/mL) thrombelastography (TEG) with analysis of R-time, angle, maximum amplitude (MA), and LY30.nnnRESULTSnTEG properties did not change significantly over the thawed storage. 14-day TP retained the ability to inhibit tPA-induced hyperfibrinolysis (median LY30% 9.6%) similar to FFP (5.6%), WB (14.6%), and superior to albumin (59.3%) and NS (58.1%). 14-day TP also retained faster clot formation (median angle, 66.2°) and superior clot strength (MA, 61.5xa0mm) to albumin (34.8°, 21.6xa0mm) and NS (41.6°, 32.2xa0mm).nnnCONCLUSIONSnTP plasma stored for 14xa0days retains clot-enhancing ability and resistance to clot degradation similar to FFP. A clinical trial is needed to validate these inxa0vitro results.