Therapeutic plasma exchange is feasible and tolerable in severely injured patients with trauma-induced coagulopathy.

Objectives: Trauma-induced coagulopathy (TIC) occurs in a subset of severely injured trauma patients. Despite having achieved surgical hemostasis, these individuals can have persistent bleeding, clotting, or both in conjunction with deranged coagulation parameters and typically require transfusion support with plasma, platelets, and/or cryoprecipitate. Due to the multifactorial nature of TIC, targeted interventions usually do not have significant clinical benefits. Therapeutic plasma exchange (TPE) is a non-specific modality of removing and replacing a patient's plasma in a euvolemic manner that can temporarily normalize coagulation parameters and remove deleterious substances, and may be beneficial in such patients with TIC. Methods: In a prospective case series, TPE was performed in severely injured trauma patients diagnosed with TIC and transfusion requirement. These individuals all underwent a series of at least 3 TPE procedures performed once daily with plasma as the exclusive replacement fluid. Demographic, injury, laboratory, TPE, and outcome data were collected and analyzed. Results: In total, 7 patients received 23 TPE procedures. All patients had marked improvements in routine coagulation parameters, platelet counts, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activities, inflammatory markers including interleukin-6 concentrations, and organ system injuries after completion of their TPE treatments. All-cause mortality rates at 1 day, 7 days, and 30 days were 0%, 0%, and 43%, respectively, and all patients for whom TPE was initiated within 24 hours after injury survived to the 30-day timepoint. Surgical, critical care, and apheresis nursing personnel who were surveyed were universally positive about the utilization of TPE in this patient population. These procedures were tolerated well with the most common adverse event being laboratory-diagnosed hypocalcemia. Conclusion: TPE is feasible and tolerable in severely injured trauma patients with TIC. However, many questions remain regarding the application of TPE for these critically ill patients including identification of the optimal injured population, ideal time of treatment initiation, appropriate treatment intensity, and concurrent use of adjunctive treatments. Level of evidence: Level V.

Cerebral venous sinus thrombosis associated with SRA-negative heparin-induced thrombocytopenia: case report.

BACKGROUND: There are very few documented reports in literature of cerebral venous sinus thrombosis (CVST) caused by immune-mediated heparin-induced thrombocytopenia (HIT). Further, there are very few reports of false negative serotonin release assays (SRAs) when testing for immune-mediated HIT. CASE PRESENTATION: We present a case of a 60- year-old male with recent unfractionated heparin administration for venous thromboembolism prophylaxis, an elevated 4T score of 5 and acute CVST in which immune-mediated HIT was suspected. The enzyme-linked immunosorbent assay (ELISA) screening assay was positive for PF4 antibodies and subsequent reflexive SRA testing was negative. However, given the clinical picture, a false-negative SRA was suspected (and eventually confirmed), prompting use of the alternative PF4-dependent p-selectin expression assay (PEA) which was confirmed to be positive. The patient was successfully managed with a bivalirudin infusion and eventually transitioned to apixaban. CONCLUSION: It is uncommon for immune-mediated HIT with thrombosis to manifest as CVST. Similarly, false-negative SRA is uncommon in immune-mediated HIT. Take-away lessons from our case report include considering HIT in CVST patients with an elevated 4T score and considering the entire clinical picture and degree of suspicion for HIT when interpreting negative HIT testing results. The PEA, in conjunction with the 4Ts score, may be considered as an alternate diagnostic assay for HIT.

Reduced Time to Procedure for Gastrointestinal Bleeding After Warfarin Reversal With Four-Factor Complex Concentrate as Compared to Plasma.

Background: Bleeding is a serious adverse effect of vitamin K antagonists (VKAs). Anticoagulation reversal is required in some acute cases. This is usually accomplished by plasma transfusion or four-factor prothrombin complex concentrate (4F-PCC). The aim of this study was to gain insight into the clinical course of patients with gastrointestinal (GI) bleeding who require VKA reversal. Methods: Medical records were collected from two centers from patients who presented to the emergency department (ED) for GI bleeding and received 4F-PCC or plasma for VKA reversal between January 2015 and December 2020. ED, hospital, intensive care unit (ICU) length of stay (LOS) as well as time from admission to GI procedure were determined. Results: 4F-PCC patients (n = 49) as compared to plasma (n = 63) patients were found to have a greater number of comorbidities (average of 4.2 vs. 2.7 comorbidities/patient) and more ICU admissions (47% vs. 21%). Time to GI procedure was significantly decreased in the 4F-PCC group (median (interquartile range (IQR)) 19.47 (9.23 - 30.25) vs. 27.88 (21.38 - 45.00) h; P = 0.01). When adjusting for comorbidities, differences in time to GI procedures were also significant in favor of 4F-PCC regardless of any comorbidities (P = 0.014), in atrial fibrillation (P = 0.045) and in hypertension (P = 0.02). The 4F-PCC patients had shorter LOS in the ED and ICU. Conclusions: Our study demonstrated that compared to plasma, 4F-PCC was utilized in more acutely ill patients with higher rates of comorbidities and ICU admission. Nevertheless, the patients who received 4F-PCC had faster access to GI procedure and shorter ED and ICU LOS.

Cost-Effective Use of the Protein S Algorithm in Thrombophilia Testing.

BACKGROUND: One of the most complex risk factors for the laboratory assessment of thrombophilia is Protein S (PS). The testing algorithm for PS employs the plasma-based assays of free PS antigen, total PS antigen, and PS activity creating a complex diagnostic scheme that can lead to misdiagnosis if incorrectly used, and a potential waste of resources and money. CONTENT: This paper compares the recently published evidence-based algorithm from the International Society for Hemostasis and Thrombosis (ISTH) with several commonly performed nonevidence-based testing schemes, to demonstrate the efficiency of the evidence-based algorithm for diagnostic efficiency with improved patient care and increased cost savings for the laboratory. SUMMARY: Significant savings (31%-60%) can be realized when the evidence-based algorithm is used in place of other testing modalities of initial PS activity testing (31%) or testing with all 3 assays simultaneously (60%). This study utilizing the PS testing evidence-based algorithm as part of a thrombophilia evaluation demonstrates that the appropriate testing methods can be used to limit wasteful practices while achieving the maximum level of information in this time of limited resources and need for increase monetary savings.

Guidance for establishing a factor VIII testing protocol for the myriad of factor VIII products.

INTRODUCTION: Management of hemophilia A has changed significantly in the past few years with the expansion of new and/or modified products as treatment options. Unfortunately, many of the standard factor VIII assays do not always accurately measure all available treatment products; therefore, the laboratory must investigate various assay algorithms to ensure the reporting of the correct results. METHODS: Requirements for factor testing, diagnosis and severity levels, product testing, factor VIII inhibitor detection and titers, are evaluated, and potential algorithms are created for optimal assessment of patients with hemophilia A. RESULTS: The potential for inaccurate result reporting for patients with hemophilia A or those being treated with the myriad of products has left many laboratories uncertain as to which assay algorithm to implement to ensure reporting the correct results for all products used in their hemophilia program. Algorithms for using either One-stage Clotting assays or Chromogenic assays or a combination of both types of assays are presented for each laboratory to implement based on their clinical situation. CONCLUSIONS: Several algorithms are considered based on the needs of the clinical providers and their patients. Each laboratory must select a testing algorithm that is cost-effective and within available resources, yet that encompasses the needs of their providers and patients. Laboratory personnel must consider all assay uses (factor VIII levels, different products, interfering products, and inhibitor titers) in determining the best algorithm for their laboratory. This paper is a starting guide for developing the best factor VIII testing assays and protocols for your laboratory.

Reduced cleavage of von willebrand factor by ADAMTS13 is associated with microangiopathic acute kidney injury following trauma.

Acute kidney injury (AKI) is common after trauma, but contributory factors are incompletely understood. Increases in plasma von Willebrand Factor (vWF) with concurrent decreases in ADAMTS13 are associated with renal microvascular thrombosis in other disease states, but similar findings have not been shown in trauma. We hypothesized that molecular changes in circulating vWF and ADAMTS13 promote AKI following traumatic injury. VWF antigen, vWF multimer composition and ADAMTS13 levels were compared in plasma samples from 16 trauma patients with and without trauma-induced AKI, obtained from the Prehospital Air Medical Plasma (PAMPer) biorepository. Renal histopathology and function, vWF and ADAMTS13 levels were assessed in parallel in a murine model of polytrauma and haemorrhage. VWF antigen was higher in trauma patients when compared with healthy controls [314% (253-349) vs. 100% (87-117)] [median (IQR)], while ADAMTS13 activity was lower [36.0% (30.1-44.7) vs. 100.0% (83.1-121.0)]. Patients who developed AKI showed significantly higher levels of high molecular weight multimeric vWF at 72-h when compared with non-AKI counterparts [32.9% (30.4-35.3) vs. 27.8% (24.6-30.8)]. Murine plasma cystatin C and vWF were elevated postpolytrauma model in mice, with associated decreases in ADAMTS13, and immunohistologic analysis demonstrated renal injury with small vessel plugs positive for fibrinogen and vWF. Following traumatic injury, the vWF-ADAMTS13 axis shifted towards a prothrombotic state in both trauma patients and a murine model. We further demonstrated that vWF-containing, microangiopathic deposits were concurrently produced as the prothrombotic changes were sustained during the days following trauma, potentially contributing to AKI development.

Guidance on the critical shortage of sodium citrate coagulation tubes for hemostasis testing.

Recent manufacturing problems and increased utilization has created a shortage of 3.2% sodium citrate blood collection tubes used for coagulation testing, causing stakeholders such as hospitals, clinics and laboratories, to find suitable alternatives. Considerations for in-house citrate blood collection tube preparations or purchasing commercial products from unknown manufacturing sources is of particular concern to laboratories that perform coagulation testing. It is well recognized that variability exists between citrate blood collection tube manufacturers, thereby making any transition to new blood collection methods more challenging than simply switching to a new source. This document provides provisional guidance for validating alternative sources of sodium citrate blood collection tubes (commercial or in-house preparations) prior to clinical implementation.

Evaluation of 4Ts score inter-rater agreement in patients undergoing evaluation for heparin-induced thrombocytopenia.

The American Society of Hematology and American College of Chest Physicians heparin-induced thrombocytopenia guidelines recommend calculation of a pretest probability score prior to performing laboratory testing, and the 4Ts score is commonly used. Inter-rater agreement of the 4Ts score has been evaluated, but limited data are available regarding the reliability of the 4Ts score when performed by nonexpert clinicians. The purpose of this study was to Compare 4Ts scores calculated by medical teams to an expert. A single-center observational study was conducted in patients evaluated for heparin-induced thrombocytopenia over 24 months. The primary outcome was difference in mean 4Ts score calculated by the medical team compared with an expert. Secondary outcomes included inter-rater agreement in risk category assignment and the negative predictive value (NPV) of the 4Ts score. The mean total 4Ts score was significantly higher when calculated by the medical team compared with expert (4.16 ±â€Š1.41 versus 3.42 ±â€Š1.53; P < 0.001). There was slight agreement in risk category assignment (Cohen κ coefficient = 0.164; P = 0.005). The NPV of the 4Ts score was 0.949 (95% confidence interval 0.891-1.000) when calculated by the medical team and 0.927 (95% confidence interval 0.869-0.984) when calculated by expert. Total 4Ts scores calculated by the medical team were significantly higher with only slight inter-rater agreement compared with expert. The NPV of the 4Ts score when calculated by nonexperts may be lower than previously reported. The recommendation to forgo laboratory testing for low 4Ts score patients may need to be revisited.

Recommendations for clinical laboratory testing for protein S deficiency: Communication from the SSC committee plasma coagulation inhibitors of the ISTH.

Hereditary deficiencies of protein S (PS) increase the risk of venous thrombosis; however, assessing the plasma levels of PS can be difficult because of its complex physiological interactions in plasma, sample-related preanalytical variables, and numerous acquired disease processes. Reliable laboratory assays are essential for accurate evaluation of PS when diagnosing a congenital deficiency based on the plasma phenotype alone. This report presents the current evidence-based recommendations for clinical PS assays as well as when to test for PS abnormalities.

Impact of a multidisciplinary workflow on safety and management of patients with heparin-induced thrombocytopenia.

PURPOSE: Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin administration. Management strategies are complex and include discontinuing heparin products, initiating alternative anticoagulants, interpreting laboratory test results, documenting heparin allergies, and providing patient education. Medication error reports and a retrospective review conducted at an academic medical center revealed an opportunity for a quality improvement initiative and led to the creation of a multidisciplinary workflow for the management of HIT. In a pre-post study, the impact of the multidisciplinary workflow on the safety and management of HIT was evaluated. METHODS: The preimplementation group consisted of adult patients tested for suspected HIT from April 4, 2014, through May 31, 2016; the postimplementation group consisted of adult patients tested from November 1, 2016, through October 31, 2018. The primary outcome was the incidence of heparin product administration while HIT testing was ongoing. The secondary outcome was the rate of appropriate heparin allergy documentation. RESULTS: The incidence of heparin product administration while HIT testing results were pending was significantly reduced, from 54.2% to 20.0% (P < 0.001), after workflow implementation. The rate of appropriate heparin allergy documentation significantly increased, from 95.0% to 100% (P < 0.001). CONCLUSION: Implementation of a multidisciplinary workflow for the management of HIT significantly reduced the incidence of heparin administration while testing was ongoing and improved the rate of appropriate heparin allergy documentation.

Therapeutic plasma exchange and intravenous immune globulin in the treatment of heparin-induced thrombocytopenia: A systematic review.

BACKGROUND: Immunomodulatory strategies in heparin-induced thrombocytopenia (HIT) include the use of intravenous immune globulin (IVIG) and therapeutic plasma exchange (TPE). The optimal application of these therapies is unknown and outcomes data are limited. We investigated treatment categories and laboratory and clinical outcomes of IVIG and/or TPE in HIT with a systematic literature review. STUDY DESIGN AND METHODS: We searched MEDLINE, Embase, and Web of Science through December 2019 for studies combining controlled vocabulary and keywords related to thrombocytopenia, heparin, TPE, and IVIG. The primary outcome was treatment indication. Secondary outcomes were platelet recovery, HIT laboratory parameters, heparin re-exposure, and post-treatment course. Case-level data were analyzed by qualitative synthesis. RESULTS: After 4241 references were screened, we identified 60 studies with four main categories of IVIG and/or TPE use as follows: (a) treatment of refractory HIT (n = 35; 31%); (b) initial therapy (n = 45; 40%); (c) cardiopulmonary bypass surgery (CPB; n = 30; 27%); and (d) other (n = 2; 2%). IVIG was most commonly used for the treatment of refractory HIT while TPE was primarily used to facilitate heparin exposure during CPB. Both IVIG and TPE were equally used as initial therapy. Heparin re-exposure occurred without thrombotic event in 29 TPE-treated patients and three IVIG-treated patients. CONCLUSION: In patients with HIT, both TPE and IVIG are used for initial therapy or treatment of refractory HIT. However, TPE is more commonly used in patients undergoing CPB. Prospective studies may help clarify which treatment is indicated in HIT population subsets.

Therapeutic plasma exchange taper does not decrease exacerbations in immune thrombotic thrombocytopenic purpura patients.

BACKGROUND: Despite rapid and intensive treatments with therapeutic plasma exchange (TPE) and immunosuppression, immune thrombotic thrombocytopenic purpura (TTP) patients are at risk of disease exacerbation, i.e., early recurrence of TTP within 30 days of achieving treatment response. TPE taper, a practice of performing additional TPE procedures after achieving treatment response, is commonly performed for decreasing exacerbations, although no evidence supports this practice. STUDY DESIGN AND METHODS: In this prospective observational investigation over four years, our center switched its standard of care for treating all TTP patients from not performing TPE taper after achieving treatment response (i.e., no-taper cohort) to performance of TPE taper (i.e., yes-taper cohort) to characterize impacts on exacerbations. Continuous and categorical data were analyzed by Mann-Whitney, Fisher's exact, and log-rank tests; significance was defined as p < 0.05. RESULTS: The two cohorts were well matched and had no significant differences in demographics, presentation laboratory values, or TTP history (p > 0.05 for all). The yes-taper cohort of 26 patients with 29 consecutive episodes did not have a significantly different exacerbation rate from the no-taper cohort of 24 patients with 27 consecutive episodes (exacerbation rates of 37.9% vs. 33.3%, respectively; p = 0.78); however, treatment-related complications directly attributed to the TPE procedures, blood products, or central venous catheters were significantly greater in the yes-taper cohort (nine vs. one events, respectively; p = 0.01). CONCLUSION: Since TPE taper did not reduce exacerbations in our TTP patients, we no longer advocate for TPE taper and have reverted to our original standard of care.

Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness.

The endothelial exocytosis of high-molecular-weight multimeric von Willebrand factor (vWF) may occur in critical illness states, including trauma and sepsis, leading to the sustained elevation and altered composition of plasma vWF. These critical illnesses involve the common process of sympathoadrenal activation and loss of the endothelial glycocalyx. As a prothrombotic and proinflammatory molecule that interacts with the endothelium, the alterations exhibited by vWF in critical illness have been implicated in the development and damaging effects of downstream pathologies, such as disseminated intravascular coagulation and systemic inflammatory response syndrome. Given the role of vWF in these pathologies, there has been a recent push to further understand how the molecule may be involved in the pathophysiology of related diseases, such as trauma-induced coagulopathy and acute renal injury, which are also known to develop secondarily to critical illness states. Elucidation of the role of vWF across the broader spectrum of generalized pathologies may provide a basis for the development of novel preventative and restorative measures, while also bolstering the scaffold of more widely used treatments, such as the administration of plasma-containing blood products.

Traumatic injury results in prolonged circulation of ultralarge von Willebrand factor and a reduction in ADAMTS13 activity.

BACKGROUND: Increases in plasma von Willebrand Factor (VWF) levels, accompanied by decreases in the metalloprotease ADAMTS13, have been demonstrated soon after traumatic injury while downstream effects remain unclear. STUDY DESIGN AND METHODS: A cohort of 37 injured trauma patients from a randomized control trial investigating the use of prehospital plasma transfusion were analyzed for activity and antigen levels of ADAMTS13 and VWF at 0 and 24 hours after admission. Relevant clinical data were abstracted from the medical records. Trauma patient plasma was analyzed via agarose gel electrophoresis to evaluate the effects of injury on VWF multimer composition compared to healthy controls. RESULTS: von Willebrand factor levels were elevated at presentation (189% [110%-263%] vs. 95% [74%-120%]), persisting through 24 hours (213% [146%-257%] vs. 132% [57%-160%]), compared to healthy controls. Ultralarge VWF (UL-VWF) forms were elevated in trauma patients at both 0 and 24 hours, when compared to pooled normal plasma (10.0% [8.9%-14.3%] and 11.3% [9.1%-21.2%], respectively, vs. 0.6%). Circulating plasma ADAMTS13 activity was decreased at 0 hours (66% [47%-86%] vs. 100% [98%-100%]) and at 24 hours (72.5% [56%-87.3%] vs. 103% [103%-103%]) in trauma patients. ADAMTS13 activity independently predicted the development of coagulopathy and correlated with international normalized ratio, thromboelastography values, injury severity, and blood product transfusion. CONCLUSION: Traumatic injury is associated with acute coagulopathy that is characterized by increased UL-VWF multimers and reduction in ADAMTS13, which correlates with blood loss, transfusion requirement, and injury severity. These findings suggest the potential for future trials targeting ADAMTS13 repletion to enhance clearance of VWF multimers.