Coagulation Studies Research Articles

Hemorrhagic transformation in SARS-CoV-2 infected patients: case reports from Indonesia

Introduction:While initially suggested as a primary respiratory infection, there has been increasing proof that the novel coronavirus disease (COVID-19) also leads to severe neurological manifestation particularly ischemic stroke. The hypercoagulable state observed in COVID-19 patients is thought to contribute to this phenomenon although the exact pathophysiology is still unclear.Case: We are reporting two cases of hemorrhagic transformation after ischemic stroke in COVID-19 patients. Both patients were women presenting with ischemic stroke and bronchopneumonia due to COVID-19. They both experienced prolonged coagulation studies before sudden neurological deterioration. Evaluation CT scan demonstrated the hemorrhagic transformation of infarction. It is still unknown whether the coagulation disruption is primarily caused due to viral activity or secondary due to the inflammatory response. Hemorrhagic transformation is a complication of ischemic stroke, particularly in post-thrombolysis patients. However COVID-19 coagulopathy was thought to induce such event in COVID-19 patients presented with ischemic stroke.Conclusion: Although ischemic stroke has been widely reported in COVID-19 patients, there have been a few reports of hemorrhagic transformation events. This may lead to an increased understanding regarding COVID-19 pathophysiology and cerebrovascular disease.

Are abnormal coagulation studies upon hospital admission in gravidas with COVID-19 associated with adverse outcomes?

Coagulopathies are associated with COVID-19 infection. Given that pregnancy is also a risk factor for thrombosis, we evaluated if coagulation laboratory parameters at the time of hospital admission in pregnant patients with COVID-19 were associated with adverse outcomes.

Case Report on Cellulitis

Introduction: Cellulitis is a bacterial infection that causes an inflammatory condition of the skin that affects the dermis and subcutaneous tissues. 2016 (Lee and Levell). Cellulitis of the lower limbs is a potentially dangerous condition (Halpern et al, 2008). Rubor or erythema, which is warm to the touch and often combined with a degree of localised oedema, is the most common symptom. However, because diagnosis is dependent exclusively on clinical data, it is commonly misdiagnosed [1]. There are a number of different illnesses that have symptoms that are similar to cellulitis. The purpose of this page is to provide information on the clinical symptoms of lower limb cellulitis as well as treatment options ensuring that practitioners are capable of making an accurate diagnosis and developing successful treatment programmes [2].
 Clinical Findings: Fever, pain over right lower leg, wound present right dorsal foot, weariness, malaise, and swelling were the patient’s main complaints.
 Diagnostic Evaluation: Haemoglobin 14.7%,total RBC count 4.77, total WBC count 16100, platelet count 1.56, KFT – UREA -57 CREATININE -2.0 potassium- 4.6, LFT ALKALINE PHOSPHATE -105, ALBUMIN3- 0 TOTAL BILIRUBIN- 1.4 micro report is normal. His liver function and coagulation studies were normal. A diagnostic work-up that includes blood cultures, dengue, malaria smear, typhoid, and other tests. The following tests were sent: leptospirosis, monospot and stool investigations, and Clostridium difficile PCR [3].
 Therapeutic Intervention: Four primary analgesic drugs, antibiotics drug in penicillin.
 Conclusion: My patient, a 65-year-old man, was hospitalised to the Hospital's medicine ward on June12, 2021.Fever, pain over right lower leg, wound present right dorsal foot, fatigue, malaise, and edema were among the symptoms that the patient had. His health improved when he received appropriate treatment. The patient was follow up after 1 weak [4].

O-L04 Peri-operative thrombophilia in patients undergoing liver resection for colorectal metastases

Abstract Background The risk of major haemorrhage during liver surgery has decreased considerably in the modern era. However, there remains reluctance amongst liver surgeons to give routine peri-operative chemical thromboprophylaxis, either because of the perceived risk of bleeding, or transient post-operative abnormalities in conventional coagulation studies. The aim of this study was to ask whether a defined, homogeneous population of patients undergoing liver resection for colorectal metastases (CRM) were at risk from venous thromboembolism (VTE) prior to surgery, and what the impact of liver resection was on that risk. Methods A single-centre prospective observational cohort study comparing pre-, peri- and post-operative haemostasis variables in patients undergoing liver resection for CRM. Patients with cirrhosis, history of VTE or anticoagulated were excluded, as were patients undergoing small wedge, or laparoscopic liver resections. Blood samples for coagulation assays were collected pre-operatively, peri-operatively (after transection) and first post-operative day (13–20 hours post-operatively). Pre- and post-operative Tissue Factor messenger ribonucleic acid (TFmRNA) activation was measured from peripheral blood mononuclear cells (PBMCs) using semi-quantitative polymerase chain reaction (PCR). Patients received peri-operative mechanical thromboprophylaxis until mobile, plus chemical thromboprophylaxis on the first post-operative day, after venesection. Results Of 336 hepatectomies performed October 2017-December 2019, 60 resections in 57 patients were recruited. This included 46.7% major resections, with median (interquartile range [IQR]) blood loss 150.0mls (76.3-263.7), no blood transfusions, post-operative VTE events or deaths. Patients were prothrombotic pre-operatively (high factor VIIIC and thrombin generation velocity index), an effect exacerbated post-hepatectomy. Major hepatectomies had a significantly greater drop in Protein C, rise in Factor VIIIC and von Willebrand Factor, versus minor resections (p = 0.001,0.005,0.001 respectively). Patients with transection times greater than median (40minutes), had significantly increased median (IQR) PMBC-TFmRNA expression [1.65 (0.93-2.70)2ddCt], versus quicker transections [0.99 (0.69-1.28)2ddCt, p = 0.020]. Conclusions These data show the risk of major haemorrhage in elective liver resection in a high volume unit is low and administration of chemical thromboprophylaxis within 13-20 hours of surgery is safe and effective. The study demonstrates that patients with CRM are prothrombotic pre-operatively. Furthermore, this thrombophilia is exacerbated by liver resection, and most marked in patients with longer, more complex operations. These data suggest that chemical thromboprophylaxis should be considered earlier in the patient pathway, and has resulted in a change in practice for the authors.

Preexisting Ventricular Shunts Are Associated with Failed Evacuation of Acute Subdural Hematomas: Single-Institution Case Series of Complications and Management Strategies

The effect of ventricular shunts on radiographic outcomes after evacuation of acute subdural hematomas (aSDHs) has not yet been established. We studied a series of patients who had undergone craniotomy for aSDH, exploring a possible relationship between the occurrence of a postoperative extra-axial collection (EAC) and the presence of a ventricular shunt. We reviewed all craniotomies for convexity aSDH performed between July 2015 and June 2020. The medical record review included perioperative coagulation studies, platelet counts, and antiplatelet and anticoagulation agent use. Univariate and multivariate analyses were conducted to identify the factors associated with postoperative EACs and reevacuation. A total of 58 patients had undergone craniotomy for aSDHs, including 9 with ventricular shunts. The median age was 67 years (interquartile range, 54-78 years), and 40% of the patients were women. Of the 58 patients, 16 were taking antiplatelet agents, and 6 were taking anticoagulation agents. Ten patients had developed perioperative thrombocytopenia (platelet count, <100,000/μL). Twelve patients had perioperative coagulopathy (international normalized ratio, ≥1.5). A postoperative EAC >10 mm occurred in 17 patients (29.3%). Eight patients (13.8%) had undergone reevacuation. The presence of a shunt and an increasing preoperative aSDH size were independently associated with an EAC >10 mm (P= 0.013 and P= 0.003, respectively). Only the presence of a shunt predicted for the need for reevacuation (P= 0.001). The shunts were explanted (n= 3) or valves were adjusted (n= 3) in all but 3 cases. We found that a lack of brain reexpansion after aSDH evacuation worsens radiographic outcomes and was more common in patients with shunts. Increasing shunt valve resistance might help prevent the formation of large EACs after aSDH evacuation.

Human Granulocytic Anaplasmosis as a COVID-19 Mimicker.

IntroductionHuman granulocytic anaplasmosis (HGA) is a tick-borne illness caused by the bacterium Anaplasma phagocytophilum. HGA has a widely variable clinical presentation and can be life-threatening.Case descriptionA 77-year-old man was transferred from an outside facility with altered mental status, a fever of up to 40.5°C, and shortness of breath. Laboratory analysis revealed a progressively worsening pro-inflammatory state and abnormalities in the patient’s coagulation studies. With clinical and laboratory evidence concerning for potential COVID-19 infection, the patient was placed in isolation as a precaution. The results of two COVID-19 tests, given approximately 24 hours apart, were negative. The patient’s spouse confirmed a bug bite to his upper extremity while working outdoors. His symptoms resolved completely after a 10-day course of empiric doxycycline.DiscussionThe diverse clinical presentations of HGA necessitate a broad differential diagnosis, including viral, bacterial and non-infectious aetiologies. In severe cases, a cytokine-mediated immune cascade can occur (namely, cytokine storm) leading to devastating downstream effects. This cytokine storm can be seen in many other diseases, but most recently it has been demonstrated in the novel coronavirus disease 2019 (COVID-19).ConclusionHere we present a case of HGA in which diagnosis was delayed due to mimicry of COVID-19 infection. This case highlights the importance of taking clinical and social histories, seasonality and geography into account during diagnosis, and maintaining a broad differential with non-specific symptoms. Despite the current COVID-19 pandemic, we recommend that HGA remains in the differential diagnosis of a pro-inflammatory state with an atypical respiratory presentation.LEARNING POINTSHuman granulocytic anaplasmosis (HGA) has a widely variable clinical presentation and can be life-threatening.When presented with non-specific symptoms, it is critical to consider clinical and social histories, seasonality and geography while maintaining a broad differential.Cytokine storm can be seen in HGA and other diseases, but most recently it has been observed in the novel COVID-19. However, despite the prevalence of COVID-19, we recommend that HGA remain in the differential diagnosis of a pro-inflammatory state with an atypical respiratory presentation.

Engineered properties of polyurethane laden with beetroot and cerium oxide for cardiac patch application

The cardiac patch provides appropriate physicochemical properties and mechanical strength for the regeneration of damaged heart tissues. In this work, for the first-time, beetroot (BR) is blended with cerium oxide (CeO2) to produce nanofibrous polyurethane (PU) composite patch using electrospinning. The objective of this work is to fabricate the composite and examine its feasibility for cardiac patch applications. Morphological analysis revealed a dramatic reduction of fiber diameter of PU/BR (233 ± 175 nm) and PU/BR/CeO2 (331 ± 176 mm) compared to the pristine PU (994 ± 113 mm). Fourier transform infrared analysis (FTIR) analysis indicated functional peak intensities of the newly formed composite PU/BR and PU/BR/CeO2 were not similar to PU. The addition of beetroot rendered PU/BR hydrophilic (86° ± 2), whereas PU/BR/CeO2exhibited hydrophobic nature (99° ± 3). Atomic force microscopy (AFM) analysis depicted the reduced surface roughness of the PU/BR (312 ± 12 nm) and PU/BR/CeO2 (390 ± 125 nm) than the pristine PU (854 ± 32 nm). The incorporation of beetroot and CeO2 into PU enhanced the tensile strength compared with the pristine PU. The blood clotting time of PU/BR (APTT-204 ± 3 s and PT-103 ± 2 s) and PU/BR/CeO2 (APTT-205 ± 3 s and PT-105 ± 2s) were delayed significantly than the pristine PU(APTT-176 ± 2 s and PT-94 ± 2 s) as revealed in the coagulation study. Further, hemolysis assay showed the less toxic nature of the fabricated composites than the pristine PU. Hence, it can be inferred that the advanced physicochemical and blood compatible properties of electrospun PU/BR and PU/BR/CeO2 nanocomposite can be engineered successfully for cardiac patch applications.

302. Using Antiphospholipid Antibody Presence as an Additional Biomarker to Identify COVID-19 Positive Patients with High Risk for Thrombosis

BackgroundPatients who are hospitalized with Coronavirus 2019 (COVID-19) are known to have increased risk for thrombosis. Several mechanisms have been proposed for increased thrombogenesis, including antiphospholipid antibodies (APLs). We sought to better understand the relationship between a commonly used marker of thrombosis, D-dimer, and antiphospholipid antibodies in relation to thrombosis in COVID-19. MethodsThis was a single-center prospective cohort study. Participants were adults admitted to the hospital with COVID-19 between March and December of 2020. Included patients required a positive COVID-19 nasopharyngeal nucleic acid amplification testing (NAAT), coagulation studies, and regular assessment of D-dimer levels. Patients who were excluded were pregnant adults, use of oral anticoagulants prior to admission, and absence of a positive COVID-19 nasopharyngeal NAAT. We tested 52 patients for antiphospholipid antibodies (APLs), including lupus anticoagulant (LA), anti-beta-2 glycoprotein antibodies (B2GP), and anti-cardiolipin antibodies (aCL). The endpoint for analysis was hospital discharge or development of a confirmed thrombosis. ResultsTwenty-nine of fifty-two patients (55.7%) with COVID-19 had non-negative APLs. Of these patients, twenty-seven (93.1%) had non-negative aCLs, the majority of which were IgM antibodies. There was a total of 7 thrombotic events in our cohort. The sensitivity of D-dimer alone was 85% and the sensitivity of APLs alone was 71%. In patients with an intermediate D-dimer level (i.e., greater than 2 milligrams per liter (mg/L) but less than 5 mg/L), the addition of non-negative APLs increased the sensitivity of D-dimer to 100%. In patients with a high D-dimer (i.e., greater than 5), the combined sensitivity of D-dimer and APLs was 60%. Out of the 7 thrombotic events in our cohort, two patients had negative APLs, however both patients had a D-dimer of greater than 5 mg/L. ConclusionThe use of APLs can assist in risk-stratifying patients in an intermediate-risk D-dimer group to consider prophylactic anticoagulation if APLs are negative and to consider therapeutic anticoagulation if APLs are non-negative. In the high-risk group (i.e., a D-dimer greater than 5 mg/dL), a therapeutic anticoagulation approach may be more appropriate. Disclosures All Authors: No reported disclosures

Diagnostic challenges of an incidental finding: case report of definitely-congenital glioblastoma multiforme in a very preterm infant

BackgroundCongenital brain tumors are extremely rare in the neonatal population, and often associated with a poor prognosis. The diagnostic suspicion is often aroused at antenatal scans or postnatally, if clinical signs and symptoms of increased intracranial pressure become evident. We present a case of definitely congenital glioblastoma multiforme incidentally diagnosed in a preterm infant, aiming to raise clinical awareness on this condition and to highlight the challenges of the related diagnostic work-up.Case presentationThis female infant was born at 31 weeks’ gestation after an uneventful pregnancy. No abnormalities were detected at antenatal ultrasound scans and genetic tests. Head circumference at birth was on the 25th centile. A routine brain ultrasound scan performed on day 1 revealed a large, inhomogeneous lesion in the right cerebral hemisphere, with contralateral midline shift, which was confirmed by brain magnetic resonance imaging (MRI). Eye fundus and routine blood exams, including platelets count, coagulation screening and C-reactive protein, were normal.Given the high risk of complications, surgical biopsy of the lesion was temporarily hold and a daily sonographic follow-up was undertaken. Although head circumference growth was steady on the 25th centile, progressive changes of the lesion were detected by cranial ultrasound.The repeat MRI scans showed a significant enlargement of the mass, with contralateral midline shift and signs of intralesional and intraventricular bleeding. In view of this worsening, surgical resection was performed. The histological examination of the lesion biopsy documented a GFAP+ highly cellular neoplasm, with no mutation on SMARCB1 gene. At the molecular analysis, mutations on IDH and H3F3A genes were absent, whereas MGMT promoter was unmethylated. The diagnosis was grade IV glioblastoma IDH wild-type.ConclusionsCongenital glioblastoma multiforme is an extremely rare but highly aggressive neoplasm. Since intralesional biopsy is not often feasible in affected neonates, knowledge of the associated clinical and neuroradiological features is particularly important, as they can also add useful information on the neoplasm behavior. Specimens from open surgical resection allow to perform a definite histological analysis and an extended molecular characterization, with relevant prognostic implications.

Predictive risk factors of adverse perinatal outcomes following blunt abdominal trauma in pregnancy

Background The primary objective was to identify predictive risk factors of preterm delivery following blunt abdominal trauma. The secondary objective was to identify risk factors of other adverse outcomes, Neonatal Intensive Care Unit (NICU) admission, placental abruption, fetal demise, and Cesarean Delivery (CD). Methods This retrospective study included pregnant patients with gestational age (GA) ≥23 weeks who presented after blunt abdominal trauma to Richmond University Medical Center from October 2015 to January 2020. Patients were identified using the following diagnostic International diagnostic classification (ICD-10) codes: O9A.212, O9A.213, and 071.89, and excluded if trauma did not involve the abdomen, penetrating, <23 weeks, or incomplete records. Collected data points included maternal demographic factors, clinical laboratory values, maternal clinical findings at presentation, abdominal ultrasound, results of fetal monitoring, Abbreviated Injury Score (AIS) for abdomen, and Injury Severity Score (ISS). Univariate analyses were compared using the Student’s t-test or Mann-Whitney U-test. Categorical data were compared using the chi-squared test or Fisher’s exact test with P-value < .05 as significant. Results 154 patients were included in the final analysis. The incidence of the primary outcome, preterm delivery before 37 weeks, was 11.0% (17/154). The incidence of secondary outcomes following blunt abdominal trauma were abruption 0% (0/154), fetal demise 0.6% (1/154), CD 44% (68/154), NICU admission 24% (37/154). Maternal demographic factors, presence of uterine contractions, maternal clinical conditions (abdominal pain, abdominal tenderness, vaginal bleeding), hematologic and coagulation studies, ultrasound findings, fetal heart rate tracing category, AIS score for abdomen, and ISS score were not predictive of preterm delivery or other secondary outcomes. Conclusion The incidence of adverse maternal and neonatal outcomes is low following blunt abdominal trauma. Extended monitoring of asymptomatic patients including laboratory tests and coagulation profiles were not predictive of preterm labor or secondary adverse perinatal outcomes. Level of Evidence Therapeutic/Care management, Level III.

Achenbach's Syndrome Revisited: The Paroxysmal Finger Hematoma May Have a Genetic Link.

Achenbach’s syndrome describes the sudden occurrence of bruising, pain and swelling of one or more digits of the hand involving the volar aspect of the proximal and middle phalanges. Also known as the paroxysmal finger hematoma, it presents in dramatic fashion, sometimes with a prodrome of tingling, itching or numbness but despite its dramatic presentation, all investigations are normal. Routine blood investigations, as well as coagulation and thrombophilia screens are all negative as are vascular imaging and echocardiography. The diagnosis is solely clinical. Due to the nature of its presentation, almost all patients are referred for an urgent vascular consultation but the condition resolves spontaneously usually within 2–3 days, although the discoloration may persist for longer. Its appearance usually leads clinicians to start anticoagulation in the belief that it may progress but, in fact, it settles as quickly as it appears. Though there are episodic cases which recur years later, it is generally self-resolving with no complications nor residual morbidity. Although the etiology was previously unknown, there is now a recognized genetic link. Genes related to the acute phase reactive proteins and the coagulation and complement cascades appear to be linked to Achenbach’s syndrome. This evidence may explain why only certain individuals seem prone to this acutely painful, bruising disorder. We review this interesting disorder and compare patients from the tropical Caribbean region with similar cases from the temperate United Kingdom and discuss whether there are climatic variations in presentations.

Utility of the Pediatric Bleeding Questionnaire in Predicting Posttonsillectomy Bleeding.

Posttonsillectomy bleeding is a dreadful complication that may be life-threatening. Preoperative coagulation tests have not been shown to be effective in predicting this complication. The Pediatric Bleeding Questionnaire (PBQ) is a validated and sensitive tool in diagnosing children with abnormal hemostatic functions, and the objective of our study was to assess its utility as a preoperative screening tool for predicting posttonsillectomy bleeding. Prospective single-blinded cohort study. Tertiary care hospital system. All children scheduled for tonsil surgery between 2017 and 2019 in the Galilee Medical Center were included. The PBQ was completed by the caregivers prior to surgery, and all children underwent coagulation tests. Each PBQ item is scored on a scale of -1 to 4, and the total score per candidate is based on summation of all items. An overall 272 patients were included in the study with a mean age of 5.2 years; 57.7% were boys. The main finding was that in a multivariable model adjusted to age, a PBQ score of 2 is correlated with increased postoperative bleeding risk (odds ratio, 10.018 [95% CI, 1.20-82.74]; P = .046). The results of the PBQ demonstrated better predictive ability when compared with abnormal coagulation test results (odds ratio, 1.76 [95% CI, 0.63-4.80]; P = .279). Sex was not found to be significant (odds ratio, 1.45 [95% CI, 0.70-3.18]; P = .343). This study demonstrated that a PBQ score ≥2 has a higher yield for detecting children at risk for posttonsil surgery bleeding as compared with coagulation studies.

Acute Kidney Injury and Proteinuria in a Man With Hemoptysis

Acute Kidney Injury and Proteinuria in a Man With Hemoptysis

Use of Preoperative Laboratory Testing Among Low-Risk Patients Undergoing Elective Anorectal Surgery

BackgroundMany low-risk patients receive preoperative laboratory testing (PLT) prior to elective outpatient surgery, with no effect on postoperative outcomes. This has not been studied in patients undergoing anorectal surgery. The aim of this study was to determine if PLT in this population was predictive of perioperative complications. Materials and MethodsThe 2015-2018 National Surgical Quality Improvement Program (NSQIP) databases were queried for elective ambulatory anorectal surgeries. PLT was defined as chemistry, hematology, coagulation, or liver function studies obtained ≤30 days preoperatively. American Society of Anesthesiologists (ASA) class 1 and 2 patients were included who underwent elective, ambulatory, benign anorectal surgery. Patient demographics, comorbidities, and postoperative outcomes were compared between those who did and did not receive PLT. Postoperative outcomes were defined as wound-related, procedure-related, major complications, unplanned readmission, and death occurring within 30 days. Multivariate regression analysis determined patient characteristics predictive of receiving testing. ResultsOf 3309 patients studied, 48.6% received PLT. On multivariate analysis, older age, female sex, Black race, ASA class 2, and comorbidities were predictive of receiving testing. The complication rates were similar between patients who did and did not receive testing (4.3% versus 3.5%, P = 0.22). ConclusionsPLT is performed in over half of low-risk patients receiving elective anorectal surgery. There was no difference in the rate of postoperative complications between patients who received testing or not, nor with normal versus abnormal results. PLT can be used more judiciously in this population.

Hemostasis testing in patients with liver dysfunction: Advantages and caveats.

Due to concomitant changes in pro- and anti-coagulant mechanisms, patients with liver dysfunction have a “rebalanced hemostasis”, which can easily be tipped toward either a hypo- or a hypercoagulable phenotype. Clinicians are often faced with the question whether patients with chronic liver disease undergoing invasive procedures or surgery and those having active bleeding require correction of the hemostasis abnormalities. Conventional coagulation screening tests, such as the prothrombin time/international normalized ratio and the activated partial thromboplastin time have been demonstrated to have numerous limitations in these patients and do not predict the risk of bleeding prior to high-risk procedures. The introduction of global coagulation assays, such as viscoelastic testing (VET), has been an important step forward in the assessment of the overall hemostasis profile. A growing body of evidence now suggests that the use of VET might be of significant clinical utility to prevent unnecessary infusion of blood products and to improve outcomes in numerous settings. The present review discusses the advantages and caveats of both conventional and global coagulation assays to assess the risk of bleeding in patients with chronic liver disease as well as the current role of transfusion and hemostatic agents to prevent or manage bleeding.

The evolution of clot strength in critically-ill COVID-19 patients: a prospective observational thromboelastography study

BackgroundFew studies detail the evolution of COVID-19 associated coagulopathy. We performed serial thromboelastography (TEG) and laboratory coagulation studies in 40 critically-ill, mechanically ventilated COVID-19 patients over a 14-day period and analysed differences between 30-day survivors and non-survivors.MethodsSingle-center prospective, observational study including 40 patients with severe COVID-19 pneumonia admitted to the intensive care unit (ICU) for mechanical ventilation. TEG analysis was performed on days 1, 7 and 14 of ICU admission and laboratory coagulation studies were performed on days 1 and 14. Coagulation variables were evaluated for change over the 14-day observation period. Differences between survivors and non-survivors at 30-days were analysed and compared.ResultsOn admission, TEG maximum amplitude (MA) with heparinase correction was above the upper limit of the reference range in 32 (80%) patients while 33 (82.5%) presented with absent clot lysis at 30 min. The functional fibrinogen MA was also elevated above the upper limit of the reference range in 37 (92.5%) patients. All patients had elevated D-dimer and fibrinogen levels, mildly prolonged prothrombin times (PT), normal platelet counts and normal activated partial thromboplastin times (aPTT). The heparinase MA decreased significantly with time and normalised after 14 days (p = < 0.001) while the increased fibrin contribution to clot strength persisted with time (p = 0.113). No significant differences in TEG analysis were noted between 30-day survivors and non-survivors at all time points. No patients developed disseminated intravascular coagulopathy (DIC) after 14-days, however thrombosis and bleeding were each reported in 3 (7.5%) patients.ConclusionCritically-ill patients with COVID-19 present in a hypercoagulable state characterised by an increased clot strength. This state normalises after 14 days despite a persistently increased fibrin contribution to clot strength. We were unable to demonstrate any significant differences in TEG parameters between 30-day survivors and non-survivors at all time points.

Factor VIII Level Comparison in Patients with Severe Hemophilia a on Emicizumab with Inhibitors with One Stage, Bovine and Human Chromogenic Assays and the Factor VIII Equivalency of Emicizumab Using In Vivo Global Hemostasis Assays

IntroductionEmicizumab is a recombinant, humanized bispecific monoclonal antibody that mimics the function of factor VIII (FVIII) which results in a significant reduction in the annualized bleeding rate in patients with hemophilia A (HA), however, the degree with which emicizumab corrects the coagulation defect remains unclear. The objective of this study was to compare the current available laboratory methods in clinical practice; one-stage clotting factor assays (OSCA), bovine and human chromogenic FVIII activity (bovCHR and humCHR, respectively) and FVIII Equivalency of Emicizumab by Thrombin Generation (F8EmT).AimsThe aim of this study is to address the differences of FVIII activity with different techniques in patients with severe HA with inhibitors on emicizumab.Materials and MethodsFactor VIII levels are determined with an activated partial thromboplastin time (aPTT), OSCA using SynthASil on the ACL TOP 500 (Instrumentation Laboratory, Bedford, MA). Factor VIII activity is also determined photometrically via the Chromogenix Coatest® SP4 FVIII chromogenic assay kit (bovCHR, Diapharma Group, West Chester, OH) and the Biophen FVIII:C chromogenic assay kit (humCHR, Aniara Diagnostica, West Chester, OH). For F8EmT, linear regression was utilized to model the FVIII levels as a function of the endogenous thrombin potential (ETP) and peak thrombin values for patients with mild/moderate hemophilia. Then, we used the ETP and peak thrombin results of the severe HA patients on emicizumab with the calibration curve to calculate their F8EmT. Association between patient weight and their F8EmT were also examined and evaluated by linear regression.ResultsData is presented for eight patients with severe HA with inhibitors on emicizumab in the non-bleeding state (Table-1). All patients' FVIII levels measured with OSCA are in or above the normal range (94.0-289.1). Bovine chromogenic FVIII activity is in the severe hemophilia range for five out of eight patients, for the rest it is in the moderate hemophilia range. Human chromogenic FVIII activity ranged between 12.5-49.8%. Factor VIII Equivalency of Emicizumab by Thrombin Generation is either in the mild hemophilia or normal range in all participants of the study.ConclusionOne-stage clotting factor assays demonstrated falsely high results as expected since it is activated partial thromboplastin time based. Bovine chromogenic FVIII activity results were consistent with the severe HA range of the patients though a few had results slightly above that level. Previous literature has stated that the humCHR in patients on emicizumab results in FVIII levels of ∼30% when emicizumab is at its therapeutic concentration (∼50 mcg/ml). This study also demonstrated similar results with 5/8 patients having levels 30-50%. F8EMT levels were mostly consistent with the humCHR. In conclusion, understanding the degree to which emicizumab corrects the coagulation defect of is an important goal as it has clinical implications.Certainly, additional studies with higher participant numbers are needed to confirm these findings. [Display omitted] DisclosuresYoung: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding.

Clinical and Molecular Characterization of Qatari Patients with Inherited Dysfibrinogenemia

Background and Objectives:Inherited Dysfibrinogenemia is a rare functional fibrinogen disorder in which the fibrinogen protein is present but with a reduced function. Fibrinogen is a 340-kDa glycoprotein that is encoded by three genes namely: Fibrinogen Bb (FGB), Aa (FGA), and g (FGG). The disorder is characterized by a wide spectrum of clinical phenotypes, ranging from asymptomatic to mild- to-severe bleeding or thrombotic manifestations and recurrent miscarriages. The mode of inheritance is mostly autosomal dominant manner and frequently as a result of a point mutation in FGA (Arg35) and FGG (Arg301).The laboratory diagnosis is based on discrepancy between fibrinogen antigen (detected by immunoassay or by immuno-turbidimetric assay) and functional assay (detected by Clauss method or other clot-based assays). The disorder is often associated with prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT).Fibrinogen activity is reduced by Clauss method while the antigen assay remains normal.The management is directed towards prevention of bleeding with prophylactic fibrinogen concentrates or cryoprecipitate prior to invasive procedures, surgeries or delivery.Dysfibrinogenemia is a rare disorder yet it is very prevalent in Qatar as a result of high rate of consanguineous marriages. The aim of our study is to describe the clinical phenotype in relation to genotype in this cohort.MethodsWe conducted a retrospective analysis of 23 patients with Inherited Dysfibrinogenemia reported by our center from 2015 to 2020 . Patients with a positive family of history fibrinogen disorder and abnormal coagulation screen, low functional fibrinogen assay (by Clauss method) or normal antigen level by turbidimetry were included. Whole exome sequencing (WES) was performed on the proband case which detected a likely pathogenic mutation that was tested on subsequent cases.We diagnosed our patients with Inherited Dysfibrinogenemia based on both coagulation-based assays and molecular tests. Probable Inherited Dysfibrinogenemia was considered in patients where the molecular test or antigen assay were not performed. To assess the clinical phenotype, data was collected that included; age at diagnosis, gender, bleeding and thrombotic events as well as coagulation screening. (Table 1)Results23 patients who were described in this cohort belong to the same tribe. 74% (17 o/23) were female and only 41% (7/17) reported an obstetric bleeding (postpartum or post abortion) and one reported mild bleeding that occurred in the postmenopausal period and no previous bleeding (case#19). The median age of diagnosis was 28.8 years (5-69) for the females. All male cases in the cohort were detected either during routine screening or prior to surgery with no previous history of bleeding. No thrombotic events were observed in this cohort.Genetic AnalysisFollowing proper genetic counseling and informed consent, whole exome sequencing analysis (WES) was performed on the index case which included testing of the fibrinogen genes FGA, FGB and FGG. WES revealed a likely pathogenic mutation in the FGA gene (p. Arg35His (R35H) (CGT>CAT): c.104 G>A in exon 2)-Located within the cleavage site of fibrinopeptide A by thrombin (The UniProt Consortium, 2017), which is a mutational hotspot.This result is likely consistent with the diagnosis of Dysfibrinogenemia.ConclusionThe FGA R35H mutation is considered a probable recurrent variant in a large tribe in the Qatari population and is associated with late onset mild bleeding manifestations in minority of cases . Despite the fact that the reported tribe is highly consanguineous, the R35H mutation behaved in an autosomal dominant manner rather than recessive in this cohort.Further studies to assess phenotype - genotype correlation of Dysfibrinogenemia is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Geographic Remoteness Is Associated with Increased Blood Product Utilization and Higher Rates of Hospitalization and Deaths in Adults with Immune Thrombocytopenia

INTRODUCTIONImmune thrombocytopenia (ITP) is a hematological disease characterized by immune-mediated destruction of platelets. Prior to starting therapy for ITP it is critical to determine whether it is idiopathic or related to a secondary underlying condition as this informs treatment. There is significant use of blood products and components in patients with chronic ITP for management of thrombocytopenia and bleeding, including intravenous immune globulin (IVIg). Platelet transfusions are generally reserved for life-threatening bleeding or may be used in the preoperative setting in patients unresponsive to other therapies. The aims of this study are to identify gaps in process of care and to examine the impact of geographical remoteness on health service utilization and outcomes in adults with chronic ITP in Alberta.METHODSAdults who received rituximab, splenectomy, or thrombopoietin receptor agonists (TPO-RA) as second-line therapy for ITP during 2012-2019 in the province of Alberta, Canada were identified via the provincial special drug access database. Diagnostic workup including bone marrow biopsy results, abdominal imaging (ultrasound or CT scan), coagulation parameters, viral serologies for hepatitis, human immunodeficiency virus (HIV), serum protein electrophoresis (SPEP), and quantitative immunoglobulins were recorded and rates of completed tests were calculated. Utilization of IVIg, platelets, and packed red blood cells was assessed. Rates of hospitalization, mortality, and ITP-related deaths were calculated and compared according to geographic region.RESULTSOf the 204 patients identified for analysis 106 were female (52%). Most patients (123; 60%) lived within a major centre, whereas 21 (10%) lived over 250 km from a major centre. Review of diagnostic laboratory parameters revealed incomplete coagulation parameters in 117 patients (58%), and no coagulation parameters checked in 16%. Eighty-nine patients (44%) did not have quantitative immunoglobulins tested, and 57 (28%) did not have an SPEP performed. Fifty-three (26%) did not have any abdominal imaging performed to assess for splenomegaly or liver disease. Thirty-five (17%) did not have any viral serologies for hepatitis B, C, or HIV completed. Bone marrow aspirate and biopsy was performed in 110 patients (54%). Eighty-six (77%) of these biopsies yielded a normal result. Eight biopsies (7%) displayed a lymphoproliferative disorder or plasma cell disorder which was suspected or known prior to completing the test.There was significant geographic discrepancy in utilization of blood products and hospitalizations. During 527 patient years of follow up, 83 patients received a total of 343 doses of platelets. Eleven patients (13%) received platelet transfusions for inappropriate indications, and eight (9%) for unclear indications. One hundred twenty-seven patients received IVIg (mean 1290 g) with comparable usage across geographic regions. Compared to patients within 250 km from a major centre, those with geographic remoteness (>250 km from a major centre) utilized more platelets (mean 5.2 vs 1.2 doses; Figure 1) and packed red blood cells (mean 4.3 vs 1.2 units; Figure 2). Those with geographic remoteness also experienced a higher rate of ITP-related hospitalizations (mean 1.5 vs 1.1) and deaths (24% versus 9%). At a median follow-up of 3.42 years from ITP diagnosis, 27 patients (13%) were deceased. Fourteen of these deaths were ITP-related due to bleeding or infection (52%). There appears to be a gradient of rates of both all-cause and ITP-related deaths by distance from a major centre (Figures 3 and 4).DISCUSSIONThis study highlights gaps in quality of care in patients with chronic ITP in Alberta, Canada. A significant number of patients have an incomplete workup for ITP at the time of diagnosis with the most forgotten tests being coagulation studies, SPEP, quantitative immunoglobulins, viral serologies, and abdominal imaging. Additionally, we identified an unexpectedly high rate of bone marrow biopsies performed in our population. Most of these bone marrow examinations did not result in any change in management. Finally, this study identified that geographic remoteness is associated with increased health services utilization and ITP-related deaths. These data can be used to inform further quality improvement initiatives in chronic ITP and help address geographic inequities in healthcare outcomes. [Display omitted] DisclosuresSun: Bayer: Consultancy; Novo Nordisk: Consultancy; Pfizer: Consultancy; Shire: Consultancy; Octapharma: Consultancy, Research Funding.

A Case Series of Acquired Factor Inhibitor Following Sars-COV2-Vaccination

▪Abstract : Autoimmune disorders post viral illness and post vaccination are some of the known complications. COVID 19 is known to cause complement dysregulation and possible reactivation of known autoimmune disorders. New data are emerging on the possible autoimmune reactivation and cases of de novo ITP and vaccine induced immune thrombotic thrombocytopenia are reported. We are presenting two cases of factor deficiencies due to acquired factor inhibitor in patients who had no apparent cause but who had recently received the Moderna COVID-19 vaccine. We hypothesize that just like native COVID 19 infection can be associated with development of acquired inhibitors, so can the COVID 19 vaccination.Cases:An 83 year old Caucasian Male with history of Arrhythmia, Coronary artery disease, H/O heart artery stent and hypertension, had received the second dose of Moderna covid vaccine one month prior to presentation. Presented with new onset headache and noted to have large right sub insular acute intra parenchymal hemorrhage. He was managed conservatively, and this bleed was attributed to his h/o hypertension. Post treatment was discharged to rehab, where he had worsening neurological status and repeat imaging showed slightly expanded size of a parenchymal hemorrhage centered in the right sub insular region and increasing surrounding edema with new tiny right frontal cortical parenchymal hemorrhage. Initial admission labs reveled a prolonged APTT of 70 and PT normal after his readmission from rehab, his PTT remained elevated to 70 and PT became prolonged to 17. PT. APTT mixing studies demonstrated only partial correction of PT and no correction of APTT. All factor levels were normal except Factor IX low at 8% and Factor XI low at 2.4%. Bethesda titer was positive at 11 BU to specific to factor IX. Further work up demonstrated no oncologic or rheumatological etiology for the coagulation inhibitor. The only possible etiology had been his age and patient had received SARS COV2 moderna vaccine. The patient was treated with rituximab, prednisone and cyclophosphamide with improvement in the inhibitor titer.A 77-year-old Caucasian female with history of hypertension, obesity, steroid induced psychosis, and Moderna Covid-19 vaccination four months prior. She presented to the hospital with epigastric pain, hematochezia, hematuria, epistaxis, and significant bruising without trauma. Laboratory studies showed hemoglobin drop from baseline of 13.8 to 11.8 to 8.2 g/dL. Significant coagulopathy, with elevated PT 130 sec, PTT 108.7. All factor levels were normal except Factor X levels low at <2%. Mixing study of the prolonged prothrombin time mainly demonstrates an inhibitory pattern, with incomplete correction. (1:1 mix PT 22.7 sec; normal 9.4-12.5 sec). Bethesda titers could not be demonstrated. No neoplastic or rheumatologic etiology of her inhibitor was found. She was given cryoprecipitate and vitamin K with no improvement in her coagulation studies. She received factor X infusion for 3 doses 2500 units during day 3 of her hospitalization. She was treated with prednisone and weekly rituximab with complete normalization of her Factor X levels at 132%.Discussion:Acquired inhibitors to coagulation factors are rare disorders that can be related to infections, malignancy, autoimmune conditions, and pregnancy and sometimes seen spontaneously in older individuals. There have been several individual case reports of acquired coagulation inhibitors with COVID 19 infection including inhibitors to III, Factor XI, Factor V and Thrombin. To our knowledge there have been no acquired inhibitors described to the COVID vaccine however, it would seem conceptually possible. Acquired factor deficiencies should be suspected when a patient presents with no previous history of bleeding, use of anticoagulation and unexplained prolonged prothrombin, and activated partial thromboplastin time. It is vital to have high index of suspicious for prompt recognition as it can have a high mortality. Treatment would involve resuscitation and eradicating the inhibitor with immunosuppression. It would be interesting to follow this patient long term for any relapse. In the above mentioned cases, no other etiologies could be attributed to the abnormal coagulopathy and could be related to the SARS-COV-2 vaccine. DisclosuresNo relevant conflicts of interest to declare.