Hemoglobin-Based Oxygen Carriers: Brief History, Pharmacology and Design Strategies, Review of the Major Products in Clinical Trials, On-Going Studies, and Coagulation Concerns

Transfusion of erythrocytes (RBC) to treat acute or chronic anemia has significant drawbacks, given the risks of transfusion, volunteer donor requirements, limited supply with increasing demand, especially during a pandemic such as COVID-19, and erythrocytes are often unavailable in emergency situations or where blood is not an option. Significant research has been undertaken for almost 100 years to attempt to replicate the functions of RBCs with oxygen carriers/oxygen therapeutics based on hemoglobin. Oxygen carriers that have been evaluated are hemoglobin-based oxygen carriers (HBOCs). HBOCs utilize hemoglobin (Hb) to transport oxygen around the body. Blood transfusion may be critical therapy in hemorrhagic trauma, various pathologies both acute and chronic, and surgical interventions. It has some important goals: the first and most important is to recover oxygen delivery to organs, additionally, when restoration of circulating blood volume is achieved, maintenance of adequate blood pressure to ensure enough blood flow to deliver the oxygen to the microcirculation and resolving oxygen debt. This chapter will review the history of HBOCs, discuss how HBOCs have been designed and how developed HBOCs differ from each other based on their pharmacology and physiology, highlight all major products to undergo human trials including one extensively studied product approved for human use in two countries (Hemopure), introduce newer products still under development, and finally present translational and clinical trials studying whether or not certain HBOCs may cause coagulation issues. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Green Plasma Has a Superior Hemostatic Profile Compared With Standard Color Plasma.

BACKGROUND: Limitations in available donors have dramatically reduced plasma availability over the past several decades, concurrent with increasing demand for some types of plasma. Plasma from female donors who are pregnant or taking oral contraceptives often has a green appearance, which frequently results in these units being discarded. This pilot study aimed to evaluate the hemostatic potential of green compared to standard-color plasma. MATERIALS AND METHODS: Plasma from twelve blood group-matched female and twelve male donors was obtained from the local blood center. Six of the female and all of the male units of plasma had a normal appearance (STANDARD), while six of the female units were grossly green (GREEN). The hemostatic potential was evaluated by thrombelastography (TEG), calibrated automated thrombogram (CAT), and coagulation factor level measurements. Univariate analysis was performed using Wilcoxon Rank-Sum. RESULTS: GREEN plasma was more procoagulant for all TEG values (r-value, k-time, angle, mA) when compared to STANDARD plasma. Differences were also observed in coagulation factor levels, with GREEN plasma having higher than STANDARD (factors II; VII, IX; X, XI, Protein S, and plasminogen); conversely, GREEN plasma had a longer lag time in CAT. DISCUSSION: This pilot study demonstrates that female donors with green plasma have a superior hemostatic profile than standard plasma. GREEN plasma should be further investigated for its safety profile and hemostatic potential, so if it is found to be a safe and functionally non-inferior product, it should be actively re-introduced for transfusion in bleeding patients.

Serial rotational thromboelastography (ROTEM) in mechanically ventilated patients with COVID-19 demonstrates hypercoagulopathy despite therapeutic heparinization.

Background: Clinical hypercoagulopathy in patients with COVID-19 has been anecdotally described, but there is lack of evidence due to the novelty of this disease. Our study reports the results of rotational thromboelastography (ROTEM) in relation to traditional laboratory coagulation tests and acute phase markers among a cohort of severely ill, mechanically ventilated patients with COVID-19. Methods: Patients with COVID-19 (N=21) with respiratory failure requiring mechanical ventilation were included in this prospective case series. ROTEM was serially obtained for all patients on three different days during their intensive care unit (ICU) stay and analyzed using repeated measures analysis. Demographic variables, symptoms at the time of presentation, ROTEM values, laboratory values for traditionally measured coagulation profiles, and acute phase reactants were analyzed, in addition to the use of anticoagulation and clinical hypercoagulopathic complications. Results: The average age of our cohort was 57.9 years old (SD=14.4) and 76.2% were male. The mortality rate was 14.3% (3 of 21). Two patients (12.5%) were identified to have new-onset deep vein thrombosis, two patients (12.5%) were found to have ≥3 episodes of central venous catheter thrombosis, and three patients (18.7%) had confirmed stroke. ROTEM demonstrated elevated EXTEM and INTEM clotting times, including elevated FIBTEM maximum clot firmness (MCFFIB). All patients treated with therapeutic anticoagulation still demonstrated hypercoagulopathy within the MCFFIB tests. Discussion: Repeated measure ROTEMs were able to detect hypercoagulopathy in ICU patients with COVID-19 despite therapeutic anticoagulation with heparin. Level of evidence: III.

Global haemostatic tests demonstrate the absence of parameters of hypercoagulability in non-hypoxic mild COVID-19 patients: a prospective matched study.

Severe COVID-19 patients demonstrate hypercoagulability, necessitating thromboprophylaxis. However, less is known about the haemostatic profile in mild COVID-19 patients. We performed an age and gender-matched prospective study of 10 severe and 10 mild COVID-19 patients. Comprehensive coagulation profiling together with Thromboelastography and Clot Waveform Analysis were performed. FBC, PT, APTT, D-dimer, fibrinogen and CWA were repeated every 3 days for both groups and repeat TEG was performed for severe patients up till 15 days. On recruitment, severe patients had markers reflecting hypercoagulability including raised median D-dimer 1.0 µg/mL (IQR 0.6, 1.4) (p = 0.0004), fibrinogen 5.6 g/L (IQR 4.9, 6.6) (p = 0.002), Factor VIII 206% (IQR 171, 203) and vWF levels 265.5% (IQR 206, 321). Mild patients had normal values of PT, aPTT, fibrinogen and D-dimer, and slightly elevated median Factor VIII and von Willebrand factor (vWF) levels. Repeated 3-day assessments for both groups showed declining trends in D-dimer and Fibrinogen. CWA of severe COVID-19 group demonstrated hypercoagulability with an elevated median values of aPTT delta change 78.8% (IQR 69.8, 85.2) (p = 0.001), aPTT clot velocity (min1) 7.8%/s (IQR 6.7, 8.3) (p = 0.001), PT delta change 22.4% (IQR 19.4, 29.5) (p = 0.004), PT min1 7.1%/s (IQR 6.3, 9.0) (p = 0.02), PT clot acceleration (min 2) 3.6%/s2 (IQR 3.2, 4.5) (p = 0.02) and PT clot deceleration (max2) 2.9%/s2 (IQR 2.5, 3.5) (p = 0.02). TEG of severe patients reflected hypercoagulability with significant increases in the median values of CFF MA 34.6 mm (IQR 27.4,38.6) (p = 0.003), CRT Angle 78.9° (IQR 78.3, 80.0) (p = 0.0006), CRT A10 67.6 mm (IQR 65.8, 69.6) (p = 0.007) and CFF A10 32.0 mm (IQR 26.8, 34.0) (p = 0.003). Mild COVID-19 patients had absent hypercoagulability in both CWA and TEG. 2 severe patients developed thromboembolic events while none occurred in the mild COVID-19 group. Mild COVID-19 patients show absent parameters of hypercoagulability in global haemostatic tests while those with severe COVID-19 demonstrated parameters associated with hypercoagulability on the global haemostatic tests together with raised D-Dimer, fibrinogen, Factor VIII and vWF levels.

The role of rotational thromboelastometry during the COVID-19 pandemic: a narrative review.

The coronavirus disease 2019 (COVID-19) pandemic is currently recognized as a global health crisis. This viral infection is frequently associated with hypercoagulability, with a high incidence of thromboembolic complications that can be fatal. In many situations, the standard coagulation tests (SCT) fail to detect this state of hypercoagulability in patients with COVID-19 since clotting times are either not or only mildly affected. The role of viscoelastic tests such as rotational thromboelastometry (ROTEM®) during this pandemic is explored in this review. COVID-19-associated coagulopathy, as measured using the rotational thromboelastometry parameters, can vary from hypercoagulability due to increased fibrin polymerization and decreased fibrinolysis to bleeding from hypocoagulability. The use of a multimodal diagnostic and monitoring approach, including both rotational thromboelastometry and SCT, such as plasma fibrinogen and D-dimer concentrations, is recommended. Rotational thromboelastometry provides comprehensive information about the full coagulation status of each patient and detects individual variations. Since COVID-19-associated coagulopathy is a very dynamic process, the phenotype can change during the course of infection and in response to anticoagulation therapy. Data from published literature provide evidence that the combination of rotational thromboelastometry and SCT analysis is helpful in detecting hemostasis issues, guiding anticoagulant therapy, and improving outcomes in COVID-19 patients. However, more research is needed to develop evidence-based guidelines and protocols.

Inadequate prophylactic effect of low-molecular weight heparin in critically ill COVID-19 patients.

PURPOSE: The aim of this study was to investigate potential markers of coagulopathy and the effects of thromboprophylaxis with low-molecular-weight heparin (LMWH) on thromboelastography (TEG) and anti-factor Xa in critically ill COVID-19 patients. MATERIAL AND METHODS: We conducted a prospective study in 31 consecutive adult intensive care unit (ICU) patients. TEG with and without heparinase and anti-factor Xa analysis were performed. Standard thromboprophylaxis was given with dalteparin (75-100 IU/kg subcutaneously). RESULTS: Five patients (16%) had symptomatic thromboembolic events. All patients had a maximum amplitude (MA) > 65 mm and 13 (42%) had MA > 72 mm at some point during ICU stay. Anti-factor Xa activity were below the target range in 23% of the patients and above target range in 46% of patients. There was no significant correlation between dalteparin dose and anti-factor Xa activity. CONCLUSIONS: Patients with COVID-19 have hypercoagulability with high MA on TEG. The effect of LMWH on thromboembolic disease, anti-factor Xa activity and TEG was variable and could not be reliably predicted. This indicates that standard prophylactic doses of LMWH may be insufficient. Monitoring coagulation and the LMWH effect is important in patients with COVID-19 but interpreting the results in relation to risk of thromboembolic disease poses difficulties.

Hyper- and hypocoagulability in COVID-19 as assessed by thromboelastometry -two case reports.

BACKGROUND: Coronavirus disease (COVID-19)-associated coagulopathy is most often characterized by elevated D-dimer, interleukin-6, and plasma fibrinogen concentrations as well as hypercoagulability in thromboelastometry with increased clot firmness in the EXTEM, INTEM, and FIBTEM assays. Clinically, it manifests with a very high incidence of thrombosis, particularly in the pulmonary system, whereas bleeding complications are infrequent. CASE: Here, we describe two critically ill patients with COVID-19 admitted to our intensive care unit demonstrating different thromboelastometry and biomarker patterns. One patient presented with hypercoagulability and the other patient with hypocoagulability and fibrinolysis shutdown in thromboelastometry. The pathophysiology and the potential impact on treatment options are discussed. CONCLUSIONS: A combination of biomarkers and thromboelastometry results can be helpful in the future to decide which therapeutic strategy might be most appropriate for critically ill patients with COVID-19. This would be an important step to establish precision medicine in this high-risk patient population.