Johannes Zipperle

• PhD
• Senior Researcher at Ludwig Boltzmann Institute for Traumatology

With great interest, we read the recent study by Baetu et al [...]

Background: Bleeding guidelines currently recommend use of viscoelastic testing (VET) to direct haemostatic resuscitation in severe haemorrhage. However, VET-derived parameters of clot initiation, such as clotting time (CT) and activated clotting time (ACT), might not adequately reflect a clinically relevant interaction of procoagulant and anticoag...

Background Diagnosis of sepsis at the ICU admission is burdened by uncertainty. There is a need for an accurate identification of patients with sepsis from those with non-infectious, e.g. post-surgical and random trauma. We tested diagnostic utility of a novel biomarker, nucleoside t ⁶ A ( N ⁶ -threonylcarbamoyladenosine) in animal sepsis models an...

Background Human induced pluripotent stem cells represent a scalable source of youthful tissue progenitors and secretomes for regenerative therapies. The aim of our study was to investigate the potential of conditioned medium (CM) from hiPSC-mesenchymal progenitors (hiPSC-MPs) to stimulate osteogenic differentiation of human bone marrow-derived mes...

Extracorporeal membrane oxygenation (ECMO) provides critical support for patients with severe cardiopulmonary dysfunction. Unfractionated heparin (UFH) is used for anticoagulation to maintain circuit patency and avoid thrombotic complications, but it increases the risk of bleeding. Extracellular vesicles (EVs), nano-sized subcellular spheres with p...

Background: Bleeding guidelines currently recommend use of viscoelastic testing (VET) to direct haemostatic resuscitation in severe haemorrhage. However, VET-derived parameters of clot initiation, such as clotting time (CT) and activated clotting time (ACT), might not adequately reflect a clinically relevant interaction of procoagulant and anticoag...

Fibrinogen is a coagulation factor in human blood and the first one to reach critical levels in major bleeding. Hypofibrinogenemia (a too low fibrinogen concentration in blood) poses great challenges to first responders, clinicians, and healthcare providers since it represents a risk factor for exsanguination and massive transfusion requirements. T...

Background: Viscoelastic hemostatic assays (VHAs) have become an integral diagnostic tool in guiding hemostatic therapy, offering new opportunities in personalized hemostatic resuscitation. This study aims to assess the interchangeability of ClotPro® and ROTEM® delta in the unique context of parturient women. Methods: Blood samples from 217 parturi...

Purpose of review Stress hyperglycaemia occur often in critically injured patients. To gain new consideration about it, this review compile current as well as known immunological and biochemical findings about causes and emergence. Recent findings Glucose is the preferred energy substrate for fending immune cells, reparative tissue and the cardiov...

Extracellular vesicles (EVs) represent nanometer-sized, subcellular spheres, that are released from almost any cell type and carry a wide variety of biologically relevant cargo. In severe cases of coronavirus disease 2019 (COVID-19) and other states of systemic pro-inflammatory activation, EVs, and their cargo can serve as conveyors and indicators...

Purpose of the review The purpose of this review is to consider the clinical value of point-of-care (POC) testing in coagulopathic trauma patients with traumatic brain injury (TBI) and trauma-induced coagulopathy (TIC). Recent findings Patients suffering from severe TBI or TIC are at risk of developing pronounced haemostatic disorders. Standard co...

Purpose Due to a better safety profile, direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. However, little is known about DOAC plasma concentrations in trauma patients upon hospital admission. Thus, we investigated the frequency and extent of DOAC possible over- and underdosing in trauma patients...

Hyperfibrinolysis (HF) frequently occurs after severe systemic hypoperfusion during major trauma and out-of-hospital cardiac arrest (OHCA). In trauma-induced HF, hypoperfusion, the activation of protein C (APC), and the release of tissue plasminogen activator (t-PA) have been identified as the driving elements of premature clot breakdown. The APC p...

Trauma patients admitted to an intensive care unit (ICU) may potentially experience a deficiency of coagulation factor thirteen (FXIII). In this retrospective cohort study conducted at a specialized trauma center, ICU patients were studied to determine the dependency of FXIII activity levels on clinical course and substitution with blood and coagul...

Background: There is an ever-increasing number of hip fracture (HF) patients on direct oral anticoagulants (DOAC). The impact of DOAC plasma level prior to HF surgery on perioperative blood loss and transfusion requirements has not been investigated so far. Materials and methods: In this retrospective study of HF patients on DOACs admitted to th...

Trauma and bleeding are associated with a high mortality, and most of these deaths occur early after injury. Viscoelastic haemostatic tests have gained increasing importance in goal-directed transfusion and bleeding management. A new generation of small-sized and thus portable ultrasound-based viscoelastic analysers have been introduced in clinical...

Platelet dysfunction is a suggested driver of trauma-induced coagulopathy. However, there is still a paucity of data regarding the impact of injury pattern on platelet function and the association of platelet dysfunction on transfusion requirements and mortality. In this retrospective cohort study, patients were grouped into those with isolated sev...

Background Trauma-induced coagulopathy in traumatic brain injury (TBI) remains associated with high rates of complications, unfavorable outcomes, and mortality. The underlying mechanisms are largely unknown. Embedded in the prospective multinational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) stu...

Background: Heparan sulfate is an integral component of the glycocalyx that provides an anticoagulant layer close to the endothelium. Hypoperfusion, inflammation and sympathoadrenal activation following major trauma result in glycocalyx shedding and subsequent release of heparan sulfate into the bloodstream. The possible anticoagulant effect of th...

Specific antagonists have been developed for the reversal of direct oral anticoagulants (DOAC). We investigated the impact of these reversal agents on the plasma concentration and visco-elastic test results of dabigatran and factor Xa inhibitors. After baseline measurements of dabigatran, the plasma concentration, and the visco-elastic ClotPro® eca...

Severe bleeding remains a prominent cause of early in-hospital mortality in major trauma patients. Thus, prompt prediction of patients at risk of massive transfusion (MT) is crucial. We investigated the ability of the inflammatory marker interleukin (IL)-6 to forecast MT in severely injured trauma patients. IL-6 plasma levels were measured upon adm...

Introduction Trauma care providers are facing an increasing number of elderly patients on direct oral anticoagulants prior to injury. For dabigatran etexilate (DAB), the specific antagonist idarucizumab (IDA) has been approved since 2015 as a reversal agent. However, only limited data regarding the use of IDA in trauma patients are available. Meth...

As extracellular vesicles (EVs) have become a prominent topic in life sciences, a growing number of studies are published on a regular basis addressing their biological relevance and possible applications. Nevertheless, the fundamental question of the true vesicular nature as well as possible influences on the EV secretion behavior have often been...

In urgent clinical situations, such as trauma, urgent surgery or before thrombolysis, rapid quantification of direct oral anticoagulant plasma drug levels is warranted. Using the ClotPro® analyser, we assessed two novel viscoelastic tests for detection of clinically-relevant plasma drug levels in trauma patients. The ecarin clotting time was used t...

Immunocompromised patients are predisposed to chronically infected wounds. Especially ulcers in the dorsal region often experience secondary polymicrobial infections. However, current wound infection models mostly use single-strain bacteria. To mimic clinically occurring infections caused by fecal contamination in immunocompromised/immobile patient...

Photobiomodulation (PBM), especially in the red wavelength range, has been demonstrated to be an effective treatment option for superficial and chronic wounds. However, ischemia and subsequent reperfusion can further challenge wound healing. Therefore, we investigated the effect of pulsed red LED light at 635 nm on cellular function in an in-vitro...

Background: Many trauma centres have adopted the administration of fixed ratios of packed red blood cells (PRBCs), platelet concentrates and fresh frozen plasma (FFP) for bleeding patients. However, the haemostatic efficacy of this concept is not well proven. Objective: Our objective was to characterise the haemostatic profile of different ratio...

This manuscript emerged from a larger third-party funded project investigating a new poly-trauma model and its influence upon secondary sepsis. The present sub-study compared selected leukocyte subpopulations in the circulation and bone marrow after polytrauma in BALB/c versus CD-1 mice. Animals underwent unilateral femur fracture, splenectomy and...

Aims: As many current approaches for heart regeneration exert unfavorable side-effects, the induction of endogenous repair mechanisms in ischemic heart disease is of particular interest. Recently, exosomes carrying angiogenic miRNAs have been described to improve heart function. However, it remains challenging to stimulate specific release of repa...

Background: Viscoelastic coagulation testing is increasingly used to diagnose trauma-induced coagulopathy. Two fully automated analysers, TEG 6s and ROTEM Sigma, were launched recently. No previous studies have compared these devices in trauma paients. Objective: The aim of this study was to evaluate whether both fully automatic devices deliver...

Background: Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared to crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a th...

Abstract In polytrauma patients, the impact of splenectomy is equivocal, ranging from negative to protective. We investigated the impact of splenectomy on immune responses in the 1st-hit polytrauma alone and on survival in the post-traumatic sepsis (2nd hit). Female BALB/c mice underwent polytrauma (1st hit) consisting of either a) TH: femur fractu...

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains a highly lethal condition in which current tools for early diagnosis and therapeutic decision-making are far from ideal. Extracellular vesicles (EVs), 30 nm to several micrometers in size, are released from cells upon activation a...

INTRODUCTION. EXTEM clotting time (CT) is considered representative of the activation of the coagulation cascade and therefore of the thrombin generation potential. However CT is defined as the time needed to reach 2 mm amplitude on the viscoelastic tracing and it is thus also dependent on fibrinogen concentration. OBJECTIVES. To test the correlati...

Mitochondrial-derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria-targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long-term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3-month-old female CD-1 mice ( n=...

Background: Hemorrhagic shock (HS) followed by resuscitation is often associated with sympatho-adrenal activation (SAA) and endothelial damage (ED). Objective: We aimed to a) evaluate the impact of HS alone on the magnitude of SAA and consecutive ED and b) characterize potential targets for a standardized and reproducible model of HS-induced end...

Endothelial cells (ECs) are major modulators of hemostasis by expressing and releasing pro- and anticoagulant mediators into the circulation. Previous studies showed that cultured ECs release procoagulant mediators into cell culture supernatants as evidenced by the reduction of viscoelastic clotting time. This effect was reversed with an anti-tissu...

Background: Platelet dysfunction has been identified as an important contributor of trauma-induced coagulopathy (TIC) but the underlying mechanism still remains to be elucidated. Trauma-associated pro-inflammatory stimuli strongly activate leukocytes, which in turn bind activated platelets. Therefore, we investigated the role of platelet-leukocyte...

Supplementary Fig. 1. Score sheet for a custom-developed mouse clinical assessment scoring system. The well-being of mice is assessed based on six endpoints every 12 hours (beginning at 12h post-CLP); tree severity grades (i.e. 0, 1 or 2 points) are assigned. Euthanasia is indicated when: score ≥8 and/or by inability to trigger the startle reflex a...

The control of bleeding is one of the most important interventions after a traumatic injury. Hemostatic devices delivering blood clotting accelerating agents such as fibrinogen are increasingly used due to their efficacy and their ease of application. In the present study, we describe a method to incorporate the coagulant supplements fibrinogen and...

Background: Platelet concentrates (PCs) are usually stored at room temperature under constant gentle agitation. Risk of bacterial contamination limits maximum storage time to 5 days. The objective of the study was to investigate platelet function with regard to storage time in different reconstituted whole blood (RWB) variants. Methods: Donated...

Introduction: Low-level light therapy (LLLT) is clinically used to attenuate inflammation and improve tissue repair processes. We aimed to evaluate the effects of red LED light on inflammatory response in a whole blood in vitro model as well as in isolated granulocytes. Methods: Human whole blood was stimulated with 1ng/ml LPS for 4 h. Pulsed LE...

Introduction: Leukocyte-platelet aggregates (LPA) are associated with atherosclerosis, SIRS and sepsis. Severely injured patients often develop granulocytosis and present with coagulopathy with prolonged clotting times, impaired clot stability and fibrinolytic activation. Following major trauma, 'capture' of functional platelets on activated granu...

Introduction: In preclinical and clinical setting, severe polytrauma affects the immune system frequently triggering strong immunological deregulation, which predisposes patients for secondary complications. Yet not all body compartments are equally responsive to development of immunosuppression. Methods: Focusing on blood/bone marrow compartmen...

Introduction: Altered mitochondrial function by excessive production of reactive oxygen species (ROS) has been considered an important factor in pathogenesis of organ failure in sepsis. Methods: We investigated effects of two specific mitochondria-targeted antioxidants (SkQ1: lipophilic; MitoTEMPO: hydrophilic) on outcome, inflammatory response...

The concept of haemostatic resuscitation implies early and high-volume plasma transfusion. We investigated the haemostatic profile of reconstituted whole blood prepared in a 1:1:1 ratio of blood, platelets and plasma. This consisted of packed red blood cells, platelet concentrate and four different plasma variants: fresh frozen; solvent-detergent;...

The use of cell-laden hydrogels to engineer soft tissue has been emerging within the past years. Despite, several newly developed and sophisticated techniques to encapsulate different cell types the importance of vascularization of the engineered constructs is often underestimated. As a result, cell death within a construct leads to impaired functi...

Background / Purpose: Fibrin polymerisation may be enhanced depending on the functional fibrinogen polymerisation assay used. Main conclusion: Maximum clot firmness was increased in the FIBTEM and FIBTEM PLUS assays but was decreased in the functional fibrinogen test.

T cells play a central role in host defense. ATP release and autocrine feedback via purinergic receptors has been shown to regulate T cell function. However, the sources of the ATP that drives this process are not known. We found that stimulation of T cells triggers a spike in cellular ATP production that doubles intracellular ATP levels in <30 s a...

Fibrinogen concentrate is increasingly considered as a hemostatic agent for trauma patients experiencing bleeding. Placing a venous access is sometimes challenging during severe hemorrhage. Intraosseous access may be considered instead. Studies of intraosseous infusion of coagulation factor concentrates are limited. We investigated in vivo recovery...

Background: Viscoelastic tests such as functional fibrinogen polymerization assays (FFPAs) in thrombelastography (TEG(®)) or thromboelastometry (ROTEM(®)) measure the elasticity of extrinsically activated clotting under conditions of platelet inhibition. There are no reports on whether components of the FFPAs have any effects on fibrin polymerizat...

Following vascular injury or activation, endothelial cells (ECs) partici-pate in the modulation of haemostasis and fibrinolysis. Viscoelastic tests (VETs) are a potent bedside monitoring tool that reports hae-mostatic parameters in real time. However, VETs neglect the influence of the surrounding endothelium. Our aim was therefore to establish an a...