Acquired Factor VIII Inhibitors: A Case Study.

The physiology of hemostasis is one of high complexity that involves the initiation, amplification, and propagation of the many moving parts of the hemostatic system and its regulatory mechanisms. It is imperative that clinical laboratory professionals have a strong understanding of the many intricacies of the physiology of coagulation and its in vitro testing. An elongated activated partial thromboplastin time can have several causes, and the correct cause must be elucidated in a timely manner for proper treatment. A mixing study with normal pooled plasma should be performed to evaluate for the presence of an inhibitor vs factor deficiency. Factor inhibitors, specifically factor VIII in this case study, should be titered so that the clinician can decide which treatment may work best for the patient. Continued monitoring of factor levels and inhibitor titers should be conducted to follow the resolution or progression of inhibitor presence.

Changes in Coagulation Testing During a National Shortage of Blue-Top Tubes.

OBJECTIVES: Manufacturer recalls and altered supply chains during the coronavirus disease 2019 (COVID-19) pandemic caused a nationwide shortage of blue-top tubes (BTTs). Most non-point-of-care coagulation tests use these tubes, leaving laboratories and health care facilities in short supply. The Department of Pathology and Laboratory Medicine at Cedars-Sinai Medical Center implemented interventions to conserve supply without sacrificing patient safety. METHODS: In a retrospective quality improvement analysis, we examined coagulation testing and BTT utilization over the 3-month interval during which our interventions were applied. Our study assessed the interventions' effectiveness by evaluating changes in BTT utilization, coagulation testing volume, and patient impact. RESULTS: Average daily use (ADU) of BTT before and after the intervention were 476 and 403, respectively-a 15.2% reduction. Notably, the Emergency Department had a reduction in ADU of 43.3%. Average daily volumes of coagulation assays performed decreased from 949 to 783-a 17.5% reduction. No adverse events from the Pharmacy Department were identified during the study period. CONCLUSIONS: Interventions resulting in significant reductions were in divisions with effective management and supervision. Success in navigating the BTT shortage stemmed from timely announcements, action, and effective communication. Our recommendations established more effective coagulation assay utilization, decreased overall BTT use, and prevented patients with coagulopathic disorders from experiencing adverse consequences.

D-dimer testing: A narrative review.

D-dimer containing species are soluble fibrin degradation products derived from plasmin-mediated degradation of cross-linked fibrin, i.e., 'D-dimer'. D-dimer can hence be considered a biomarker of in vivo activation of both coagulation and fibrinolysis, the leading clinical application in daily practice of which is ruling out venous thromboembolism (VTE). D-dimer has been further evaluated for assessing the risk of VTE recurrence and helping define optimal duration of anticoagulation treatment in VTE, for diagnosing disseminated intravascular coagulation (DIC), and for screening those at enhanced risk of VTE. D-dimer assays should however be performed as intended by regulatory agencies, as their use outside these indications might make them a laboratory-developed test (LDT). This narrative review is aimed at: (1) reviewing the definition of D-dimer, (2) discussing preanalytical variables affecting D-dimer measurement, (3) reviewing and comparing the assays performance and some postanalytical variables (e.g., different units and age-adjusted cutoffs), and (4) discussing the interest of D-dimer measurement across different clinical settings, including pregnancy, cancer, and coronavirus disease 2019 (COVID-19).

Time Course of Coagulopathy Evaluated with Rotational Thromboelastometry in Patients with Severe Coronavirus Disease 2019.

Objectives Coronavirus disease 2019 (COVID-19) reportedly causes thromboembolic complications due to coagulopathy with hypercoagulability and a hypofibrinolytic state. We evaluated the time-course of coagulopathy in patients with severe COVID-19 from admission to discharge from our intensive-care unit (ICU). Methods We conducted a retrospective study of adults with severe COVID-19 admitted to our ICU between January 20, 2021, and March 31, 2022. We obtained clinical information, laboratory data, and rotational thromboelastometry (ROTEM) parameters at admission and discharge. Results Fifteen patients were included. Fibrinogen and D-dimer values did not change significantly but were above the normal ranges at admission and discharge. Regarding ROTEM parameters, the maximum clot firmness in fibrinogen function (FIBTEM), a marker of hypercoagulability, did not change significantly but was above the normal range at admission and discharge [median (interquartile range), admission vs. discharge: 31 (25-34) mm vs. 31 (27-32) mm, p=0.589]. The maximum lysis at 60 minutes in the extrinsic coagulation pathway (EXTEM) and intrinsic coagulation pathway (INTEM), as markers of the fibrinolytic function, were both significantly lower at discharge than at admission [median (interquartile range), admission vs. discharge: EXTEM, 3 (2-4) vs. 1 (0-2), p=0.011; INTEM, 3 (1-6) vs. 1 (0-2), p=0.008]. Conclusion This study revealed a persistent hypercoagulable state at ICU discharge and a worse hypofibrinolytic state at discharge than at admission. These results may contribute to a better understanding of coagulopathies in the acute to subacute phases of severe COVID-19.

The Choice between Plasma-Based Common Coagulation Tests and Cell-Based Viscoelastic Tests in Monitoring Hemostatic Competence: Not an either-or Proposition.

There has been a significant interest in the last decade in the use of viscoelastic tests (VETs) to determine the hemostatic competence of bleeding patients. Previously, common coagulation tests (CCTs) such as the prothrombin time (PT) and partial thromboplastin time (PTT) were used to assist in the guidance of blood component and hemostatic adjunctive therapy for these patients. However, the experience of decades of VET use in liver failure with transplantation, cardiac surgery, and trauma has now spread to obstetrical hemorrhage and congenital and acquired coagulopathies. Since CCTs measure only 5 to 10% of the lifespan of a clot, these assays have been found to be of limited use for acute surgical and medical conditions, whereby rapid results are required. However, there are medical indications for the PT/PTT that cannot be supplanted by VETs. Therefore, the choice of whether to use a CCT or a VET to guide blood component therapy or hemostatic adjunctive therapy may often require consideration of both methodologies. In this review, we provide examples of the relative indications for CCTs and VETs in monitoring hemostatic competence of bleeding patients.

Inference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC).

Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVIDpos) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVIDneg) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVIDneg patients at the time of diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVIDpos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVIDpos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.

Clinical Application of Thromboelastography in Acute Ischemic Stroke.

Acute ischemic stroke (AIS), characterized by high morbidity and mortality, has imposed a considerable burden on society. Despite rapid development in the treatment of AIS, there is still a high risk of recurrence. Furthermore, there is a time delay in waiting for the results of conventional coagulation tests in candidate patients for intravenous thrombolysis therapy. Heterogeneous responses to antiplatelet, intravascular thrombolysis, and endovascular therapies also worsen the situation. Thromboelastography (TEG), as a global and portable detection method for hemostasis, facilitates clinicians in disease monitoring, treatment evaluation, and prognosis prediction in AIS. In this narrative review, we provided a comprehensive summary of the clinical application of TEG in ischemic stroke and gave insights to further studies.

Impaired fibrinolysis in severe Covid-19 infection is detectable in early stages of the disease.

BACKGROUND: A significant degree of mortality and morbidity in Covid-19 is due to thromboembolic disease. Coagulopathy has been well described in critically unwell patients on ICU. There is less clear evidence regarding these changes at the time of presentation to the Emergency Department and the progression of disease over time. OBJECTIVE: We sought to investigate whether coagulation markers can predict severity and how they change over the disease course. METHODS: Patients presenting to a single University Teaching Hospital were recruited and followed up if PCR was positive. Alongside routine blood testing, Rotational Thromboelastometry (ROTEM) was performed. Outcome data was recorded for all patients, and ROTEM values were compared across outcome groups. RESULTS: Extem and Intem Maximum Lysis were significantly reduced in those who died or required an ICU admission, indicating a reduced ability to break down clot mass in the most critically unwell patients. CONCLUSION: Comparisons between groups demonstrated that one distinguishing feature between those who require ICU admission or die of Covid-19 compared with those who survive a hospital stay to discharge was the extent to which fibrinolysis could occur. Mortality and morbidity in Covid-19 infection appears in part driven by an inability to break down clot mass.

The problem with coagulopathy .

Coagulopathy is inextricably linked to the field of hemostasis and thrombosis. In the same manner hemostasis and thrombosis may deal with bleeding and clot formation, coagulopathy also may be connected to bleeding or thrombosis, depending on the circumstances. However, when the same designation, "coagulopathy," may represent two clinically distinct presentations, it can create confusion. It is our obligation as hemostasis and thrombosis specialists to scotch this dubiety and direct the correct usage of coagulopathy.

Rotational thromboelastometry in patients with type 2 diabetes and mild COVID-19 pneumonia: A pilot prospective study.

BACKGROUND: It was repeatedly demonstrated that patients with severe COVID-19 pneumonia, as well as patients with type 2 diabetes (T2D) have higher risk of thromboembolic complications. Rotational thromboelastometry (ROTEM®) is a viscoelastic hemostatic assay which allows complex assessment of hemostasis in whole blood. The aim of this study was to compare changes in hemostasis measured by ROTEM® in diabetic and nondiabetic patients with mild COVID-19 pneumonia. METHODS: We performed a pilot, prospective, observational study and enrolled 33 consecutive patients (14 with T2D and 19 nondiabetic ones) admitted to regular ward with mild COVID-19 pneumonia. The control group consisted from 11 healthy, nondiabetic blood donors. Blood samples were tested with ROTEM® using INTEM® and EXTEM® reagents. RESULTS: We detected significant differences in EXTEM® clotting time (CT), clot formation time (CFT), and maximum clot firmness (MCF) comparing patients with mild COVID-19 pneumonia and healthy donors. However, there were no significant differences in EXTEM®, INTEM®, and HEPTEM® parameters (CT, CFT, and MCF) according to diabetes status. CONCLUSIONS: Our study demonstrated hypercoagulation in patients with mild COVID-19 pneumonia. T2D did not affected ROTEM® parameters in patients with mild COVID-19 pneumonia.

Comparison of Fibrinogen Concentrations Determined by the Clauss Method with Prothrombin-Derived Measurements on an Automated Coagulometer.

BACKGROUND: This research aims to compare fibrinogen results, obtained from the Clauss and PT-derived method on the Cobas t511 analyzer, in patients with specific categories of disease. A second aim was to determine the reference range for these 2 methods. METHODS: We retrospectively compared fibrinogen concentrations of 914 patients obtained by the Clauss and PT-derived methods on the Cobas t511 coagulation analyzer from the laboratory information system. Fibrinogen data was segregated into a healthy outpatient population and those populations with possible fibrinogen abnormalities including pregnancy, chronic illness, liver disease, heart and vascular diseases, and clinical suspicion of COVID-19. All data were analyzed using Passing-Bablok regression and Bland-Altman analysis. Reference ranges were determined from fibrinogen results of the healthy outpatient population who presented for a clinic check-up. RESULTS: All fibrinogen results were grouped and compared according to fibrinogen values (low, normal, and high), international normalized ratio (INR) values (<1.2, 1.2-2.0, and >2.0), and diagnosis. There were statistically significant positive correlations in all groups (P < 0.05), except for low fibrinogen values (P = 0.96). Results with INR value <1.2 had the highest correlation between 2 methods. CONCLUSION: The PT-derived method can be used alone in the Cobas t511 analyzer, especially in patients with an INR <1.2. Reported new reference ranges of the PT-derived method could help to determine and compare the clinical significance of fibrinogen methods. Further studies must be focused on the conditions in which PT-derived fibrinogen results should be directed to the Clauss test.

Assessment of Coagulation Profiles by Rotational Thromboelastometry in COVID 19 Patients.

BACKGROUND: According to recent studies, thrombotic complications frequently occur in Coronavirus Disease-19 (COVID-19) and are associated with increasing disease severity and poor prognosis. However, conventional coagulation assays are unable to identify these patients' hypercoagulable states, raising questions about the appropriate assessment tool. We aimed to evaluate coagulation abnormalities in patients with different severity of CO-VID-19 using viscoelastic tests. METHODS: This was a single center retrospective observational study in a group of 50 adult patients with SARS-COV-2 infection and different severity of pneumonia (20 moderate, 30 severe). Coagulation status was evaluated using rotational thromboelastometry (ROTEM®) in conjunction with conventional coagulation assays (platelet count, PT, aPTT, fibrinogen, and D-dimer levels). RESULTS: Shorter than normal EXTEM CFT, higher than normal A10 and MCF in INTEM, EXTEM, and FIBTEM and higher than normal α-angle were classified as markers of hypercoagulable state. Forty-four (88%) patients had at least two hypercoagulable ROTEM parameters. Seven patients developed thromboembolic complications. All were classified as having severe COVID-19 pneumonia. With increment increases in disease severity, we observed an increase in the number of patients with hypercoagulable parameters and higher INTEM, EXTEM, and FIBTEM MCF but without being statistically significant. On the other hand, we noted a significant decrement of PT (p = 0.039), higher fibrinogen (p = 0.001), higher D dimer (p < 0.001), and shorter CT EXTEM (p < 0.001). CONCLUSIONS: Our findings support the presence of a hypercoagulable state in COVID-19 patients, especially in the severe forms. It also highlights the role of viscoelastic tests in assessing COVID-19 coagulopathy and, therefore, their potential use in thrombophrophylactic management.

Clot Stiffness Measured By Seer Sonorheometry As a Marker Of Poor Prognosis In Hospitalized COVID-19 Patients.

A high risk of thrombotic complications has been observed among severely ill COVID-19 patients. Viscoelastic tests (VET) have shown a hypercoagulable profile in these patients, although so far there is no clear evidence on the use of these tools as predictors of risk in the clinical course of patients. In this study we aimed to evaluate the association between Quantra® sonorheometry VET parameters, standard coagulation tests and inflammatory markers in 69 patients with COVID-19 on hospital admission with disease severity and outcome. Inflammatory markers were elevated in a high percentage of patients, as were coagulation-related parameters such as fibrinogen and D-dimer levels. Quantra® sonorheometry analysis revealed increased clot stiffness (CS), especially due to increased fibrinogen contribution (FCS) in 63.7%. Analysis of clot stability to lysis (CSL) on the Quantra showed a value of 100%, suggesting hypofibrinolysis, in 32.4%. Age > 65 years, elevated values of fibrinogen, D-dimer, LDH, increased CS and CSL were significantly associated with worsening disease. The combination of elevated FCS and D-dimer values showed a particularly high prognostic value in distinguishing patients with severe symptomatology. In conclusion, FCS measured by Quantra® system and its combination with D-dimer could be established as a powerful tool to identify poor prognosis in COVID-19 patients on hospital admission.

Thrombotic thrombocytopenic purpura as an acute complication of COVID-19.

Introduction: While disseminated intravascular coagulation (DIC) is a serious complication of COVID-19, a close differential in critically ill patients with thrombocytopenia is Thrombotic thrombocytopenic purpura (TTP). Case Report: We describe the case of a middle-aged lady admitted with COVID-19 pneumonia who developed progressive thrombocytopenia, altered sensorium and renal failure. The absence of coagulation abnormalities alerted to the possibility of TTP, strengthened by presence of schistocytes in peripheral smear. Conclusions: This case highlights the need for high index of suspicion and to pay attention to normal tests as well that might give clues to the diagnosis. New onset thrombocytopenia in COVID-19 need not always indicate DIC. A careful examination of peripheral smear may help diagnosing TTP especially if coagulation profile is normal.

Coagulation profile of human COVID-19 convalescent plasma.

Convalescent plasma is used to treat COVID-19. There are theoretical concerns about the impact of pro-coagulant factors in convalescent plasma on the coagulation cascade particularly among patients with severe COVID-19. The aim of this study was to evaluate the coagulation profile of COVID-19 convalescent plasma. Clotting times and coagulation factor assays were compared between fresh frozen plasma, COVID-19 convalescent plasma, and pathogen-reduced COVID-19 convalescent plasma. Measurements included prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, D-dimer, von Willebrand factor activity, von Willebrand factor antigen, coagulation factors II, V, VII-XII, protein S activity, protein C antigen, and alpha-2 plasmin inhibitor. Clotting times and coagulation factor assays were not different between COVID-19 convalescent plasma and fresh frozen plasma, except for protein C antigen. When compared to fresh frozen plasma and regular convalescent plasma, pathogen reduction treatment increased activated partial thromboplastin time and thrombin time, while reducing fibrinogen, coagulation factor II, V, VIII, IX, X, XI, XII, protein S activity, and alpha-2 plasmin inhibitor. The coagulation profiles of human COVID-19 convalescent plasma and standard fresh frozen plasma are not different. Pathogen reduced COVID-19 convalescent plasma is associated with reduction of coagulation factors and a slight prolongation of coagulation times, as anticipated. A key limitation of the study is that the COVID-19 disease course of the convalesced donors was not characterized.

Comparison of Routine Hematology, Coagulation, and Clinical Chemistry Parameters of Cynomolgus Macaques of Mauritius Origin With Cynomolgus Macaques of Cambodia, China, and Vietnam Origin.

Cynomolgus macaques (Macaca fascicularis) are commonly used in safety assessment and as translational models for drug development. Recent supply chain pressures, exportation bans, and increased demand for drug safety assessment studies exacerbated by the COVID-19 pandemic have prompted the investigation of utilizing macaques of different geographic origin in preclinical toxicity studies. This study compares routine hematology, coagulation, and clinical chemistry endpoints of 3 distinct subpopulations of mainland Asia origin (Cambodia, China, and Vietnam) with Mauritius origin macaques compiling results of 3,225 animals from 123 regulatory toxicology studies conducted at North American and European Union contract research organization facilities between 2016 and 2019. Results were generally similar amongst the subpopulations compared in this study. Few notable differences in hematology test results and several minor differences in serum biochemistry and coagulation test results were identified when 3 distinct subpopulations of mainland Asia origin macaques were compared with Mauritius origin macaques. Our findings support the use of different origin macaques in drug development programs; however, emphasizes the importance of maintaining consistency in geographic origin of animals within a study.