Could platelet mass index (PMI) be a new prognostic biomarker for COVID-19?

Aim: Although most patients with COVID-19 experience respiratory tract infections, severe reactions to the virus may cause coagulation abnormalities that mimic other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation and thrombotic microangiopathy. Fluctuations in platelet markers, which are an indicator of the acute phase response for COVID-19, are of clinical importance. The aim of this study is to evaluate the relationship between disease severity and Platelet Mass Index (MPI) parameters in COVID-19 patients. Material(s) and Method(s): This retrospective observational study was conducted with patients who were diagnosed with COVID-19 in a tertiary hospital. The study was continued with the remaining 280 patients. All laboratory data were scanned retrospectively from patient files and hospital information system. Result(s): A very high positive correlation was found between PMI and PLT. The PMI value in women was significantly higher than in men. It was observed that PMI did not differ significantly in terms of mortality, intubation, CPAP and comorbidity. PMI vs. Pneumonia Ct Severity Score, biochemistry parameters (AST, CRP), hemogram parameters (WBC, HGB, HCT, MCV, LYM, MPV EO) and coagulation factors (aPTT and FIB) at various levels of positive/negative, weak and strong, and significant relationship was found. There was no significant relationship between hormone and D-dimer when compared with PMI. Discussion(s): Although platelet count alone does not provide information about the prognosis of the disease, PMI may guide the clinician as an indicator of lung damage in seriously ill patients.Copyright © 2022, Derman Medical Publishing. All rights reserved.

Blood derivative therapy

There are three main components manufactured from whole blood: red blood cells (RBCs), plasma, and platelets. Plasma contains a multitude of different proteins, peptides, and biologic substances. Approximately 53 million liters of plasma was collected in the United States in 2019. Following collection, plasma is frozen and manufactured into plasma-derived medicinal products (PDMPs). During the manufacture process, several thousand plasma units are pooled for Cohn fractionation, which is based upon cold ethanol precipitation of proteins. The PDMPs are further prepared using ion exchange or affinity chromatography and additional steps to inactivate and remove infectious diseases such as viruses. Almost 20 different therapeutic plasma proteins are purified from plasma via these multi-step manufacturing processes. Interestingly, the demand for pharmaceutical plasma products, particularly intravenous immunoglobulin (IVIG) products, has been increasing. The manufacture and therapeutic role of blood derivatives particularly immunoglobulin therapy, Rh immunoglobulin (RhIG), COVID-19 convalescent plasma (CCP) and hyperimmune globulins, albumin, clotting factors, fibrin sealants, and platelet rich plasma will be described.Copyright © 2022 AME Publishing Company. All Rights Reserved.

Association of polymorphic variants in human genome with the COVID-2019 severity and post-COVID syndrome development

Background/Objectives: Despite intensive research of the novel coronavirus SARS-CoV-2 and COVID-2019 caused by it, factors affecting the severity of the disease remains poorly understood. Clinical manifestations of COVID-2019 may vary from asymptomatic form to pneumonia, acute respiratory distress syndrome (ARDS) and multiorgan failure. Features of individual genetic landscape of patients can play an important role in development of the pathological process of COVID-19. In this regard the purpose of this study was to investigate the influence of polymorphic variants in genes (ADD1, CAT, IL17F, IL23R, NOS3, IFNL3, IL6, F2, F13A1, ITGB3, HIF1A, MMP12, VEGFA), associated with cardiovascular, respiratory and autoimmune pathologies, on the severity of COVID-19 and post-COVID syndrome in patients from Russia. Method(s): The study included 200 patients recovered from COVID-19. Two groups of patients were formed in accordance with clinical manifestations: with mild and moderate forms of the disease. The polymorphic variants were analysed with real-time PCR using commercial kits (Syntol). Result(s): 13 SNPs (rs4961;rs1001179;rs612242;rs11209026;rs2070744;rs8099917;rs1800795;rs1799963;rs5985;rs5918;rs11549465;rs652438;rs699947) were genotyped and comparative analysis of allele frequency distribution was carried out in two groups of patients recovered from COVID-2019. Conclusion(s): Identification of polymorphic variants in genome associated with severity of pathological processes in patients infected with SARS-CoV-2 can contribute to the identification of individuals with an increased risk of severe infection process and can also serve as a basis for developing personalized therapeutic approaches to the treatment of post-COVID syndrome.

Management of Acquired von Willebrand Syndrome During Prolonged VV-ECMO

Acquired von Willebrand syndrome (AVWS) contributes to bleeding during extracorporeal membrane oxygenation (ECMO) support. Although it is recognized that AVWS rapidly resolves after ECMO decannulation, this approach may often be clinically unsuitable. In such cases, optimal AVWS management during ECMO support is not well established. We report our approach to managing AVWS in a patient on veno-venous (VV) ECMO for 59 days. A 19-year-old male developed hypoxemic respiratory failure from SARS-CoV-2 pneumonia. Following intubation, he progressed to VV-ECMO support for refractory hypoxemia and was started on bivalirudin for systemic anticoagulation. Two days later, he developed refractory gastrointestinal and oro-nasopharyngeal bleeding despite blood product transfusions and discontinuing bivalirudin. He was started on pantoprazole along with infusions of octreotide and aminocaproic acid. Upper endoscopy on ECMO day 5 revealed an ulcerative bleeding vessel in the duodenum that was clipped. Recurrent mucosal bleeding precluded resumption of systemic anticoagulation. On ECMO day 23, AVWS was diagnosed based on elevated von Willebrand factor (VWF) activity (207%, normal 55-189%) and antigen (234%, normal 50-210%) levels with abnormally low VWF high-molecular-weight multimers. Factor VIII complex was administered twice over the following week. Between doses, the ECMO circuit was exchanged to empirically mitigate suspected shear-related VWF consumption from the fibrin burden, and a repeat endoscopy controlled additional intestinal bleeding with local hemostatic agents. He received 36 units of red blood cells, 2 units of platelets, 2 units of plasma, and 7 pooled units of cryoprecipitate over 31 days leading into these combined interventions. In the 28 days afterwards, he received 3 units of red blood cells, 3.5 pooled units of cryoprecipitate, and no additional platelets or plasma. Our patient was maintained off systemic anticoagulation for 54 of 59 days of VV-ECMO support without any thrombotic complications occurring. With no subsequent clinical evidence of bleeding, repeat VWF testing was done two months post-decannulation and showed near-normal VWF activity (54%) and normal multimer distribution. Our patient rehabilitated well without any neurologic deficits and on discharge was requiring supplemental oxygen with sleep and strenuous activity. Avoiding systemic anticoagulation, repleting VWF, maintaining circuit integrity, and providing local hemostasis, when possible, may be a safe and effective management strategy of AVWS on ECMO support when decannulation is not a viable option.

Molecular genetics and genomics of the ABO blood group system

The A and B oligosaccharide antigens of the ABO blood group system are produced from the common precursor, H substance, by enzymatic reactions catalyzed by A and B glycosyltransferases (AT and BT) encoded by functional A and B alleles at the ABO genetic locus, respectively. In 1990, my research team cloned human A, B, and O allelic cDNAs. We then demonstrated this central dogma of ABO and opened a new era of molecular genetics. We identified four amino acid substitutions between AT and BT and inactivating mutations in the O alleles, clarifying the allelic basis of ABO. We became the first to achieve successful ABO genotyping, discriminating between AA and AO genotypes and between BB and BO, which was impossible using immunohematological/serological methods. We also identified mutations in several subgroup alleles and also in the cis-AB and B(A) alleles that specify the expression of the A and B antigens by single alleles. Later, other scientists interested in the ABO system characterized many additional ABO alleles. However, the situation has changed drastically in the last decade, due to rapid advances in next-generation sequencing (NGS) technology, which has allowed the sequencing of several thousand genes and even the entire genome in individual experiments. Genome sequencing has revealed not only the exome but also transcription/translation regulatory elements. RNA sequencing determines which genes and spliced transcripts are expressed. Because more than 500,000 human genomes have been sequenced and deposited in sequence databases, bioinformaticians can retrieve and analyze this data without generating it. Now, in this era of genomics, we can harness the vast sequence information to unravel the molecular mechanisms responsible for important biological phenomena associated with the ABO polymorphism. Two examples are presented in this review: the delineation of the ABO gene evolution in a variety of species and the association of single nucleotide variant (SNV) sites in the ABO gene with diseases and biological parameters through genome-wide association studies (GWAS).Copyright © Annals of Blood. All rights reserved.

Atrio-Ventricular Conduction Abnormalities in Multisystem Inflammatory Syndrome in Children

Purpose of study Since mid-April 2020 in Europe and North America, clusters of pediatric cases with a newly described severe systemic inflammatory response with shock have appeared. Patients had persistent fevers >38.5 C, hypotension, features of myocardial dysfunction, coagulopathy, gastrointestinal symptoms, rash, and elevated inflammatory markers without other causes of infection. The World Health Organization, Centers for Disease Control, and Royal College of Paediatrics associated these symptoms with SARS-CoV-2 as multisystem inflammatory syndrome in children (MIS-C). Cardiac manifestations include coronary artery aneurysms, left ventricular systolic dysfunction evidenced by elevation of troponin-T (TnT) and pro-B-type naturietic peptide (proBNP), and electrocardiogram (ECG) abnormalities. We report the clinical course of three children with MIS-C while focusing on the unique atrioventricular (AV) conduction abnormalities. Case #1:19-year-old previously healthy Hispanic male presented with abdominal pain, fever, and non-bloody diarrhea for three days. He was febrile and hypotensive (80/47 mmHg) requiring fluid resuscitation. Symptoms, lab findings, and a positive COVID-19 antibody test were consistent with MIS-C. Methylprednisolone, intravenous immunoglobulin (IVIG), and enoxaparin were started. He required epinephrine for shock and high flow nasal cannula for respiratory distress. Initial echocardiogram demonstrated a left ventricular ejection fraction (LVEF) of 40% with normal appearing coronaries. Troponin and proBNP were 0.41 ng/mL and proBNP 15,301 pg/mL respectively. ECG showed an incomplete right bundle branch block. He eventually became bradycardic to the 30s-50s and cardiac tracing revealed a complete AV block (figure 1a). Isoproterenol, a B1 receptor agonist, supported the severe bradycardia until the patient progressed to a type 2 second degree AV block (figure 1b). A second dose of IVIG was administered improving the rhythm to a type 1 second degree AV block. An IL-6 inhibitor, tocilizumab was given as the rhythm would not improve, and the patient soon converted to a first-degree AV block. Cardiac magnetic resonance imaging showed septal predominant left ventricular hypertrophy and subepicardial enhancement along the basal inferior/anteroseptal walls typical for myocarditis. Case #2: 9-year-old previously healthy Hispanic male presented after three days of daily fevers, headaches, myalgias, diffuse abdominal pain, and ageusia. He was febrile, tachycardic, and hypotensive (68/39 mmHg). Hypotension of 50s/20s mmHg required 3 normal saline boluses of 20 ml/kg and initiation of an epinephrine drip. Severe hypoxia required endotracheal intubation. After the MIS-C diagnosis was made, he was treated with IVIG, mehtylprednisolone, enoxaparin, aspirin, and ceftriaxone. Due to elevated inflammatory markers by day 4 and patient's illness severity, a 7-day course of anakinra was initiated. Initial echocardiogram showed mild tricuspid and mitral regurgitation with a LVEF of 35-40%. Despite anti-inflammatory therapy, troponin and proBNP were 0.33 ng/mL and BNP of 25,335 pg/mL. A second echocardiogram confirmed poor function so milrinone was started. Only, after two doses of anakinra, LVEF soon normalized. Despite that, he progressively became bradycardic to the 50's. QTc was prolonged to 545 ms and worsened to a max of 592 ms. The aforementioned therapies were continued, and the bradycardia and QTc improved to 405 ms. Patient #3: 9-year-old African American male presented with four days of right sided abdominal pain, constipation, and non-bilious non-bloody emesis. He had a negative COVID test and unremarkable ultrasound of the appendix days prior. His history, elevated inflammatory markers, and positive COVID- 19 antibody were indicative of MIS-C. He was started on the appropriate medication regimen. Initial ECG showed sinus rhythm with normal intervals and echocardiogram was unremarkable. Repeat imaging by day three showed a decreased LVEF of 50%. ECG had since changed to a right bundle branch block. Anakinra as started and steroid dosing was increased. By day 5, he became bradycardic to the 50s and progressed to a junctional cardiac rhythm. Cardiac function normalized by day 7, and anakinra was subsequently stopped. Thereafter, heart rates ranged from 38-48 bpm requiring transfer to the pediatric cardiac intensive care unit for better monitoring and potential isoproterenol infusion. He remained well perfused, with continued medical management, heart rates improved. Methods used Retrospective Chart Review. Summary of results Non-specific T-wave, ST segment changes, and premature atrial or ventricular beats are the most often noted ECG anomalies. All patients initially had normal ECGs but developed bradycardia followed by either PR prolongation or QTc elongation. Two had mild LVEF dysfunction prior to developing third degree heart block and/or a junctional escape rhythm;one had moderate LVEF dysfunction that normalized before developing a prolonged QTc. Inflammatory and cardiac markers along with coagulation factors were the highest early in disease course, peak BNP occurred at approximately hospital day 3-4, and patient's typically had their lowest LVEF at day 5-6. Initial ECGs were benign with PR intervals below 200 milliseconds (ms). Collectively the length of time from initial symptom presentation till when ECG abnormalities began tended to be at day 8-9. Patients similarly developed increased QTc intervals later in the hospitalization. When comparing with the CRP and BNP trends, it appeared that the ECG changes (including PR and QTc elongation) occurred after the initial hyperinflammatory response. Conclusions Although the mechanism for COVID-19 induced heart block continues to be studied, it is suspected to be secondary to inflammation and edema of the conduction tissue. Insufficiency of the coronary arterial supply to the AV node and rest of the conduction system also seems to play a role. Although our patients had normal ECG findings, two developed bundle branch blocks prior to more complex rhythms near the peak of inflammatory marker values. Based on the premise that MIS-C is a hyperinflammatory response likely affecting conduction tissue, our group was treated with different regimens of IVIG, steroids, anakinra, and/or tocilizumab. Anakinra, being an IL-1 inhibitor, has been reported to dampen inflammation in viral myocarditis and tocilizumab has improved LVEF in rheumatoid arthritis patients. Based on our small case series, patient's with MISC can have AV nodal conduction abnormalities. The usual cocktail of IVIG and steroids helps;however, when there are more serious cases of cardiac inflammation, adjuvant immunosuppresants like anakinra and toculizumab can be beneficial. (Figure Presented).

COVID-19 convalescent plasma: Mechanisms of action and rationale for use: A narrative review

The use of convalescent plasma (CP) transfusions for patients with coronavirus disease 2019 (COVID-19) has gained great interest during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. This review aims at summarizing the literature on the potential mechanisms of action of COVID-19 CP (CCP) and the rationale for use. A narrative review of the literature was conducted using PubMed, Google Scholar, and the Cochrane Database through October 2020. The rationale of CCP deployment was based on historical use in other outbreaks and pandemics and the emergent need at the time of lack of proven therapies and vaccines. There are many proposed mechanisms of action including direct neutralization and suppression of viremia, antibody-dependent cellular cytotoxicity, modification of the inflammatory response, restoration of the coagulation factors, immunomodulation of the hypercoagulable state and the potential role of ABO naturally occurring iso-agglutinins. Many donor, product, and patient factors can impact the response to CCP, such as antibody titer in the CCP product, CCP dose, frequency of administration, the severity of underlying illness, and the timing of administration from time of disease onset. Based on current evidence, CCP appears to be safe. However, it remains unknown whether it impacts the improvement of clinical symptoms, time to death, and all-cause mortality. In conclusion, the use of CCP offers quick access as an empirical therapy when specific therapies are not available or under development. Ongoing clinical trials are expected to add to the breadth of knowledge on the safety and efficacy of CCP use in patients with COVID-19.Copyright © 2021 AME Publishing Company.

Acquired hemophilia A and deep vein thrombosis attributable to the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine-case report

Background: Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder that occurs in a sporadic, nonhereditary pattern. It is caused by circulating autoantibodies against clotting factor VIII that are triggered by several conditions. Moreover, AHA is clinically distinct from the inherited form of hemophilia A, with a different natural history and management approach, necessitating a high-index of suspicion in at-risk patients. Coronavirus disease 2019 (COVID-19) has emerged as a multisystemic disease whose manifestations are continuously being evaluated. There are few case reports of AHA associated with COVID-19 infection, while one case of AHA has been associated with COVID-19 vaccination. Similarly, deep venous thrombosis (DVT) frequently complicates COVID-19 infection, but two cases of DVT have been reported following COVID-19 vaccination. We report the occurrence of both AHA and DVT in a 63-year-old male patient within one week of receiving his first dose of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine. Case Description: Patient is a 63-year-old male who presented with a 3-day history of left lower extremity (LLE) swelling and pain. He was hemodynamically stable, but examination showed exquisite tenderness, ecchymosis, and pitting edema at the calf of the LLE. He had normal platelet counts at presentation but had mild anemia (11.9 g/dL) and elevated activated partial thromboplastin time (APTT) of 68.0 seconds. Venous Doppler ultrasound showed acute DVT in the left popliteal vein, necessitating commencement on heparin drip. He developed progressively worsening hematomas, symptomatic anemia that required red cell transfusions, and persistently elevated APTT despite stopping the heparin drip. Work up for pulmonary embolism, malignancy, and disseminated intravascular coagulopathy (DIC) were negative. Antiphospholipid antibodies and lupus anticoagulant were also negative. He had low factor VIII levels, tested positive for factor VIII inhibitor, and PTT mixing studies were consistent with acquired factor inhibitor. Treatment involved administration of Factor Eight Inhibitor Bypassing Activity (FEIBA) as well as intravenous methylprednisolone and cyclophosphamide. Following resolution of active bleeding with evidence of stable hemoglobin concentration, he was discharged home on oral prednisone and cyclophosphamide. Conclusion(s): This case report highlights the possibility of AHA and DVT as rare, potentially life-threatening adverse events that could occur following COVID-19 vaccination, which is currently the most effective tool employed in controlling the COVID-19 pandemic.Copyright © Annals of Blood. All rights reserved.

Comparison of Perindopril vs. Losartan With Regard to Pro-Coagulation Factors in Adipocytes Exposed to Sars-Cov-2 Spike Protein

Background: Obesity is a strong risk factor for more severe Covid-19 infection as adipocytes play an important role in intermediating the spreading, replication, and release of SARS-COV-2. An increase in pro-coagulation factors (tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)) was observed in Covid-19 patients with moderate to severe symptoms and is reported to be associated with Angiotensin-converting enzyme 2 (ACE2) overexpression. Cardiovascular medications affecting ACE2, such as Perindopril and Losartan, are hypothesized to have an effect on Covid-19 infection-related coagulopathy. This study aims to identify and compare the effect of perindopril and losartan on TF and PAI-1 levels in adipocytes exposed to SARS-COV-2 spike protein. Method(s): Adipocytes were isolated enzymatically from adipose tissue obtained from an obese male donor. Adipocytes were then exposed to SARS-COV-2 S1 spike protein for 24 hours. After exposure, perindopril and losartan were added to the culture medium. ACE2, TF, and PAI-1expression were measured 2 hours later using ELISA. Result(s): SARS-CoV-2 spike protein exposure increased ACE2, TF, and PAI-1 expression. Perindopril addition discernible reduced the tissue factor (TF) expression (4.843 +/- 0.396) compared to a positive control (6.857 +/- 0.228) (p=0.005) but not losartan (5.624 +/- 0.606) (p=0.111). Perindopril was also able to lower PAI-1 expressions (3.484 +/- 0.252) compared to a positive control (4.865 +/- 0.115) (p=0.001), but the losartan did so more effectively (2.633 +/- 0.269) (p=0.000). Conclusion(s): Losartan and perindopril both have the ability to lower pro-coagulation factors, proving the value of ACEIs/ARBs in preventing thrombotic complications in Covid-19 patients.Copyright © 2023

Myocardial infarction with non-obstructive coronary arteries (MINOCA) complicating myocarditis

Myocarditis can lead to myocardial infarction in the absence of coronary artery obstruction. We report a case of probable myocarditis, complicated by myocardial infarction with non-obstructive coronary arteries. A 19-year-old man presented with chest pain typical of myocarditis. He was a smoker but was otherwise well. Electrocardiogram revealed diffuse ST-elevation and echocardiography revealed a thin, akinetic apex. Troponin-T levels on admission were raised leading to an initial diagnosis of myocarditis being made. However, late gadolinium enhancement study on cardiac magnetic resonance imaging demonstrated transmural enhancement typical of ischaemia. Coronary angiogram was normal, leading to a likely diagnosis of myocardial infarction with non-obstructive coronary arteries. It is important to highlight that coronary assessment remains important when working up for myocarditis, as myocardial infarction with non-obstructive coronary arteries can often complicate myocarditis in cases of normal angiography. Another important lesson was on how cardiac magnetic resonance imaging provided vital evidence to support underlying ischaemia despite normal coronary angiogram, leading to a diagnosis of myocardial infarction with non-obstructive coronary arteries. Myocardial infarction with non-obstructive coronary arteries remains a broad 'umbrella' term and cardiac magnetic resonance imaging, as well as more invasive coronary imaging techniques during angiography, can further assist in its diagnosis. Our case provides a reminder that myocardial infarction with non-obstructive coronary arteries, although increasingly recognised, remains under-diagnosed and can often overlap with peri-myocarditis, highlighting the need to employ multi-modality imaging in guiding management.Copyright © The Author(s) 2021.

Efficacy and safety of garadacimab in patients with severe COVID-19

Introduction: Garadacimab (GAR;CSL312), a fully human IgG4 monoclonal antibody, inhibits the kallikrein-kinin pathway at a key initiator, FXIIa, and may play a protective role in the progression of COVID-19 related respiratory disease. Aims and objectives: This placebo (PL)-controlled study evaluated efficacy and safety of GAR plus standard of care (SOC) vs PL plus SOC in patients (pts) with severe COVID-19. Method(s): Pts were randomised (1:1) to GAR (700 mg IV) or PL plus SOC. Primary endpoint was incidence of endotracheal intubation (TI) or death up to Day 28. Key secondary endpoints included all-cause mortality and safety (reporting of AEs). aPTT, FXII levels and FXIIa-mediated kallikrein activity (FXIIa-mKA) were measured to indicate target activation. Result(s): In the ITT analysis set (N=124), baseline demographics were balanced between study groups (GAR, n=63;PL, n=61). Incidence of TI or death was 22% for GAR vs 26% (P=0.274) for PL. No difference in all-cause mortality was observed (crude rate: GAR 17.5% vs PL 18.0%). GAR was associated with fewer TEAEs (60.3% vs 67.8%) and SAEs (34 vs 45 events) vs PL. No GAR-related deaths or bleeding were reported, despite permitted heparin coadministration. aPTT prolongation and increased FXII levels were observed with GAR vs PL to Day 14, while FXIIa-mKA was suppressed to Day 28. Conclusion(s): In pts with severe COVID-19, GAR did not confer a clinical benefit over PL. Transient aPTT prolongation and suppressed FXIIa-mKA showed target engagement of GAR that was not associated with bleeding even with co-administered heparin. The safety profile of GAR in pts with severe COVID-19 was benign, as reported in pts treated with GAR for hereditary angioedema.

Possible immune reaction to COVID-19 vaccination - a case report

Introduction Side effects may occur after vaccination against COVID-19. Temporary reactions such as redness, swelling and pain at the injection site, high temperature, fever, tiredness, etc. may be signs of the body's response to the vaccine. Such reactions usually develop within two days after vaccination and last for a few days. With the growing number of vaccinations against SARSCoV- 2 a rising number of reports also showed serious side effects. In some of the most severe cases, life-threatening thrombotic events may develop. We present a case that shows further symptoms that may be due to an immune reaction to the vaccine. Method In this case report a 67 male smoker presented to our outpatient clinic in April 2022. A few days after vaccination against SARS-CoV-2 with an mRNA vaccine the patient developed pain at all finger tips. The clinical examination showed cool and livid discoloration of all fingers to different degrees;toes were not involved. The symptoms developed progressively over the following weeks into a severe form with progressive fingertip skin necrosis. Results The blood test showed a CRP of 9.18 mg/l (reference range: 0-3 mg/l) as well as an increased fibrinogen and factor VIII activity. D-dimers were only slightly increased to 290 ng/ml (reference range: < 230 ng/ml) during initial examination. Cold agglutinins, cryoglobulin and cryofibrinogen were tested negative. Angiologic examination revealed small multiple thrombi in the ulnar and digital arteries. Furthermore, the resting ECG showed no dilated ventricles and no indication of a hemodynamically relevant defect. The assessment revealed a good cardiac function overall with no evidence of embolism. Therapy was started with Nifidipine (gold standard in Raynaud's disease), Eliquis 5 mg 1-0-1, and diclofenac following hospital admission. In the further course, the therapy regimen was changed to Ilomedin IV for 4 days once a month. After two weeks, symptoms significantly improved and the signs of necrosis at the fingers disappeared. Conclusion In summary, a circulatory perfusion disorder associated with microthrombotic events may be a possible side effect of SARS CoV-2 vaccination. A combination of Nifidipine, DOAC and pain therapy has been shown to be an effective treatment of "COVID-fingers" in this case report.

Abnormal postpartum uterine bleeding in adolescence associated with SARS-CoV-2 infection

Background: With a prevalence of 1-3 cases per million, acquired haemophilia A (AHA) is a rare autoimmune bleeding disorder caused by the presence of neutralizing antibodies against factor VIII. Even though diagnosis of this bleeding disorder is rarely established among children and adolescents, AHA may lead to severe, life-threatening hemorrhage in this age group, and therefore it requires special caution. Case report: 19 year old primigravida with confirmed SARS-CoV-2 infection was admitted to hospital due to prolonged vaginal bleeding six weeks postpartum. All gynaecological causes of uterine bleeding were excluded, Foley catheter was placed, but the bleeding still persisted. Coagulation tests revealed isolated deranged aPTT values. Further haematology evaluation demonstrated factor VIII deficiency, presence of factor VIII inhibiting factors, and the diagnosis of AHA was proposed. The anti-inhibitor coagulant complex drug was introduced and patient has responded positively to the treatment. Conclusion(s): Due to disturbance of immune system, pregnancy and postpartum period represent predilection time for AHA development. Furthermore, viral infection in pregnancy, such as COVID-19, might be considered as an additional risk factor for AHA development and several reported cases of AHA after COVID-19 infection support this hypothesis. Even though AHA is a rare disease, due to its high mortality rate of more than 20%, it should be considered in all cases of unusual bleeding of unknown cause in all age groups. Publication of this case report is approved by Institutional Review Board.Copyright © 2023

Acquired hemophilia in a patient with SARS-CoV-2 infection, a case report

Acquired hemophilia (AH) is a potentially life-threatening hemorrhagic disorder. We report the second confirmed case of COVID-19-associated AH in a 45-year-old female which, unfortunately, expired as her treatment failed. She presented to the emergency department with abnormal bleeding and spontaneous hemoptysis about ten days after a removal surgery of her epiglottis tumor. Aggregation tests, such as partial thromboplastin time (PTT), are recommended in patients with COVID-19 infection that have bleeding episodes.Copyright © 2022 The Author(s);Published by Society of Diabetic Nephropathy Prevention.

Pregnancy-Related Acquired Haemophilia A: Description of Two Recent Cases

Introduction: Acquired haemophilia A (AHA), characterized by neutralizing autoantibodies against factor VIII (FVIII), is a rare disorder (1.5/million/y). Pregnancy-relatedAHAis an even rarer disorder affecting 0.03/million/y with an incidence of 1 case/350000 births. Aim(s): to describe two pregnancy-related AHA presented at the same year of 2022. Method(s): We evaluate data from two women (patient 1 and 2) with AHA diagnosed within 1 year following childbirth. Result(s): Two women, patient 1 (P1) and P2 with 32 and 33-year old respectively, presented AHA seven (P1) and six (P2) months after delivery. They had no relevant medical history, except for COVID-19 vaccination fifteen days before the development of bleeding in P1, and late-pregnancy COVID-19 infection in P2. They had no complications related to childbirth. The bleeding events in both patients were haematuria and apparently spontaneous hematomas in the upper limb, requiring no haemostatic treatment. Laboratorial investigation, demonstrated in P1 a FVIII activity of 0.026 IU/ml and a FVIII antibody titer of 26 Bethesda Units (BU), and in P2 a FVIII activity of 0.005 IU/ml and a FVIII antibody titer of 34 BU. Concomitant disorders were excluded. The patients started eradication of the inhibitors with prednisone (1mg/kg/day orally). In P1, inhibitor titer was 0 BU and FVIII> 0.5 IU/ml after 8 weeks of immunosuppression. During eradication period, the P2 had a hematoma in right thigh treated with bypassing agent (FEIBA), but the inhibitor titer was 0 BU and FVIII>0.5 IU/ml after 1 month of inhibitor eradication. Curiously, P2 with FVIII< 0.01 IU/ml and a higher inhibitor titer than P1 had a faster response to prednisolone therapy (4 vs. 8 weeks). Currently, prednisone has been completely withdrawn in P1 and the prednisone dosage is being gradually reduced in P2. Discussion/Conclusion: Data from these two women with pregnancyrelated AHA are similar to previously described cases and expand the knowledge about this rare disorder. The peculiarity of this report is due to the emergence of two cases of a disease with markedly low incidence, in the same local and year, raising the question of whether there were new acquired factors (as immunological triggers such as COVID-19 infection or vaccination) that could be involved in the modification of the natural history of the disease. It cannot be excluded the possibility that these two cases were a coincidence.

Complex Regional Pain Syndrome (Crps) in a Hemophilia Child with Inhibitor: A Rare Interactable Cause of Joint Pains

Introduction: Joint bleeding is the main cause of joint pain in hemophilia patients and can lead to chronic joint disease which also happens to be one of the significant causes of disability and joint pain in these patients. Furthermore, ComplexRegional Pain Syndrome (CRPS), despite being a very rare complication, should be considered in cases of persistent intractable pain, especially in the pediatric group. Clinical symptoms in CRPS include severe chronic pain, edema, and decreased range of motion. CRPS management is critical to allowing the function and ability of the joint to restore. Method(s): This study aims to report a hemophilia case with intractable pain and his underlying diagnosis. A 14-year-old severe hemophilia A patient with high titer/responder inhibitor was on on-demand treatment by Bypassing Agents (BPAs). Result(s): During the disease course, his right knee became a target joint due to recurrent bleedings. Consequently, he underwent Radiosynoviorthesis (RSO) and treatment with BPAs. After three days of improving, he got an increasing fever and severe right knee pain. The COVID-19 test result was negative, but Staph. Aureus was found in the synovial fluid, and treatment began with Vancomycin and Rifampin. After several days, his condition and laboratory markers were improved, However, intractable disabling pain remained constant regardless of augmented combination therapy with FEIBA and rFVIIa. Parallelly, morphine was prescribed due to the Pain Management counseling. However, the pain began to rise as the morphine dosage declined. As a result, CRPS proposed to be the leading cause of pain, and after several prolonged special physiotherapy sessions, pain reduced significantly, only one BPA was continued and he was ambulated again. Discussion/Conclusion: The current case indicates that CRPS is a rare complication in patients with bleeding disorders which has been reported rarely till now. Nonetheless, it should be considered a diagnosis in complicated patients with recurrent hemarthrosis due to its debilitating and destructive nature.

Incidences of Adverse Effects of Vaccination against Sars-Cov-2 in Patients with Congenital Coagulopathies

Introduction: Traditionally, the administration of intramuscular vaccination has been avoided in patients with congenital coagulopathies due to its possible deleterious effects, including large hematomas, contractures or fibrosis. However, vaccination against SARS-CoV- 2 received approval from regulatory agencies only for intramuscular administration, since its efficacy by other routes has not been studied, so its administration was generalized by this route in this group of patients. The objective is to evaluate the possible adverse effects secondary to vaccination against COVID-19 in patients diagnosed with congenital coagulopathies in a single center. Method(s): Retrospective, analytical and single-center study documenting the adverse effects of vaccination against COVID-19 in a population diagnosed with congenital coagulopathies in a rural center in Spain. Clinical and epidemiological results were collected. Result(s): Twenty-six patients (61.5% male population) with a median age of 24 years (range 3-79 years) were evaluated. The most frequent congenital coagulopathies were deficiency of factor VII (34.6%), VIII (19.2%) and XI (19.2%). 11.5% received prophylaxis. 20% of the sample was infected during the first wave of the pandemic (pre-vaccination) without the need for hospital admission. The entire sample received vaccination in the complete scheme (3 doses, 57.7% were administered from the Pfizer-Bi brand, the difference from the Moderna-Rec brand) without evidence of significant hemorrhagic or thrombotic complications, presenting the entire sample of humoral immune response. No patient in the sample has required hospital admission secondary to severe COVID-19. Discussion/Conclusion: After completing the vaccination schedule against SARS-CoV-2, it can be inferred that the intramuscular administration of this vaccine does not produce significant hemorrhagic adverse events, being the route of preference at present.

COVID-19 Mortality and the Cytokine Storm: An Added Value for APOE Genotyping

The new COVID-19 presents some comorbidities, such as obesity, Alzheimer's, and coronary risk, among others. We argue that the current understanding of some of these clinical conditions may illuminate the design of future COVID-19 studies to account for a bias that may be the cause of the para-doxical associations between COVID-19 mortality and cytokine storm. Given that we know some of the genetic mechanisms behind these diseases, it is possible to circumscribe these studies to some key genes that help us understand why some patients experience a cytokine storm and what the treatment strategies might be. In this paper, we discuss the role of A2M and APOE genes. A2M encodes a multifaceted protein which is highly expressed in the liver and released to the bloodstream associated with the apolipopro-tein E. This association depends on the APOE genotype. A2M has protease-clearing activity binding of a broad range of proteases, such as thrombin and Factor Xa. It also presents the ability to bind to proin-flammatory ligands, like cytokines. Further, A2M acts as chaperone of misfolded substrates, like beta-amyloid peptide. The last two molecular functions grant it a key role in regulating both inflammatory processes, as well as extracellular protein homeostasis. For these reasons, we conclude that A2M-APOE association will have prophylactic, therapeutic, and prognostic implications;and the proper understanding of the physiological role of APOE and A2M in controlling inflammatory processes can shed further light on the putative treatment of COVID-19-derived cytokine storm.Copyright © 2022 Bentham Science Publishers.

The predictive value of coagulation parameters for the course of disease in COVID-19 patients

Introduction COVID-19 is a systemic disease associated with a high incidence of thrombotic complications. In this study we aimed to identify coagulation parameters as predictors of mortality in hospitalized patients with severe COVID- 19 infection. Method We conducted a non-interventional, national, monocentric observational study of patients treated for COVID infection at the ICU at Frankfurt University Hospital. A total of 410 patients were enrolled in the study between April 1, 2020 and December 31, 2021. Patients had to be 18 years or older and the diagnosis was confirmed by COVID real-time PCR. Coagulation parameters were analysed once on admission to the clinic and 5 to 8 days later. Variables studied included thromboplastin time, aPTT, fibrinogen, D-dimers, antithrombin, hs-troponin, all coagulation factors and vWF antigen, protein C and protein S. Data was also collected on age, sex, comorbidities, medication, and invasive ventilation, ECMO therapy and dialysis. In order to compare patients regarding their general disease status, the SAPS-II and the Horovitz index were determined at the beginning and end of the observation period. Univariate and multivariate logistic regression models were then used to screen coagulation parameters for association with mortality in critically ill COVID patients. Results The arithmetic mean age of patients was 60.9 ( +/- 14.7) years, with 76.1 % being male. Of 410 patients, 259 (63.2 %) received invasive ventilation, 95 (23.2 %) received ECMO therapy and 105 (25.6 %) received renal replacement therapy. The median inpatient length of stay was 16 (IQR: 10-29) days and ICU length of stay was 12 (IQR: 6-25) days. 176 patients (43 %) died because of their COVID disease, 234 (57 %) were discharged home or to other facilities for further treatment. In univariate logistic regression, increased age (OR = 1,029, 95 %-CI [1,013- 1,1,044]), higher SAPS-II (OR = 1,031, 95 %-CI [1,018-1,045]), fibrinogen (OR = 1,002, 95 %-CI [1,001-1,003]), FVIII (OR = 1,004, 95 %-CI [1,001-1,007]) and vWF antigen (OR = 1,005, 95 %-CI [1,003-1,007]) as well as lower antithrombin (OR = 0,981, 95 %-CI [0,971-0,991]), FII (OR = 0,983, 95 %-CI [0,972-0,993]), FXIII (OR = 0,992, 95 %-CI [0,986-0,999]), Horovitz index at admission (OR = 0,994, 95 %-CI [0,990-0,997]) and decreased protein C activity (OR = 0,989, 95 %-CI [0,982-0,996]) were associated with increased mortality. In the final multivariate regression analysis with backward elimination, low antithrombin activity (OR = 0.987, 95 %-CI [0.974-1.000]), high vWF antigen levels (OR = 1.004, 95 %-CI [1.002-1.007]) and a low Horovitz index (OR = 0.993, 95 %-CI [0.989-0.997]) were identified as independent predictive factors for increased mortality. Conclusion In the study of 410 COVID patients requiring intensive care, the Horovitz index, antithrombin activity and vWF antigen on hospital admission were identified as independent predictors of mortality.