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1.
BMC Pediatr ; 22(1): 397, 2022 07 07.
Article in English | MEDLINE | ID: covidwho-1923533

ABSTRACT

BACKGROUND: Multisystem Inflammatory Syndrome in Neonates (MIS-N) can occur following antenatal COVID- 19 infection in the mother. Here we report a rare case of a neonate with Hemophilia A and MIS-N. CASE PRESENTATION: A 2-day-old baby presented with an intramuscular hematoma, neonatal seizures, and isolated activated partial thromboplastin time (APTT) prolongation. The neurosonogram showed a subdural hematoma. A diagnosis of Hemophilia A was made and was confirmed by factor 8 assay and genetic analysis. Supportive measures and Factor 8 replacement was initiated. A rising trend of inflammatory markers and an ongoing need for mechanical ventilation were noted. As there was a history of COVID-19 in the mother in the third trimester, MIS-N was diagnosed. The baby was treated with intravenous immunoglobulin (IVIG) and steroids, and there was an improvement in the clinical and laboratory markers. However, the baby developed seizures on day 16. There was an increase in the subdural hemorrhage and a further rise in inflammatory markers. A craniostomy and hematoma evacuation was done and the baby improved. CONCLUSION: The concurrent occurrence of hemophilia A with intracranial bleed, and MIS-N in a neonate is a diagnostic challenge. It is important to have a high index of suspicion to ensure timely diagnosis and treatment of MIS-N in this pandemic era.


Subject(s)
COVID-19 , Hemophilia A , Factor VIII , Female , Hematoma/complications , Hematoma/etiology , Hematoma, Subdural/diagnosis , Hematoma, Subdural/etiology , Hemophilia A/complications , Hemophilia A/diagnosis , Humans , Infant, Newborn , Pregnancy , Seizures/complications , Systemic Inflammatory Response Syndrome/complications , Systemic Inflammatory Response Syndrome/diagnosis
2.
Am J Hematol ; 97(7): 915-923, 2022 07.
Article in English | MEDLINE | ID: covidwho-1888602

ABSTRACT

Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU µg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42-2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.


Subject(s)
COVID-19 , Thrombophilia , Adult , COVID-19/complications , COVID-19 Vaccines , Factor VIII , Female , Humans , Inflammation , Intercellular Adhesion Molecule-1 , Male , SARS-CoV-2 , Thrombin , Thrombophilia/etiology , von Willebrand Factor
3.
Cells ; 11(7)2022 04 06.
Article in English | MEDLINE | ID: covidwho-1776141

ABSTRACT

COVID-19, a recently emerged disease caused by SARS-CoV-2 infection, can present with different degrees of severity and a large variety of signs and symptoms. The oral manifestations of COVID-19 often involve the tongue, with loss of taste being one of the most common symptoms of the disease. This study aimed to detect SARS-CoV-2 RNA and assess possible morphological and immunopathological alterations in the lingual tissue of patients who died with a history of SARS-CoV-2 infection. Sixteen cadavers from 8 SARS-CoV-2 positive (COVID-19+) and 8 negative (COVID-19-) subjects provided 16 tongues, that were biopsied. Samples underwent molecular analysis through Real-Time RT-PCR for the detection of SARS-CoV-2 RNA. Lingual papillae were harvested and processed for histological analysis and for immunohistochemical evaluation for ACE2, IFN-γ and factor VIII. Real-Time RT-PCR revealed the presence of SARS-CoV-2 RNA in filiform, foliate, and circumvallate papillae in 6 out of 8 COVID-19+ subjects while all COVID-19- samples resulted negative. Histology showed a severe inflammation of COVID-19+ papillae with destruction of the taste buds. ACE2 and IFN-γ resulted downregulated in COVID-19+ and no differences were evidenced for factor VIII between the two groups. The virus was detectable in most COVID-19+ tongues. An inflammatory damage to the lingual papillae, putatively mediated by ACE2 and IFN-γ in tongues from COVID-19+ cadavers, was observed. Further investigations are needed to confirm these findings and deepen the association between taste disorders and inflammation in SARS-CoV-2 infection.


Subject(s)
COVID-19 , Tongue , Angiotensin-Converting Enzyme 2 , COVID-19/immunology , COVID-19/pathology , Cadaver , Factor VIII , Humans , Inflammation , RNA, Viral , SARS-CoV-2 , Tongue/pathology , Tongue/virology
6.
BMJ Case Rep ; 15(3)2022 Mar 09.
Article in English | MEDLINE | ID: covidwho-1736044

ABSTRACT

Acquired haemophilia A (AHA) is a rare bleeding disorder with high morbidity and mortality, but it is eminently treatable if diagnosis and treatment are prompt. We report a case of AHA in Southeast Asia following the administration of the Pfizer-BioNTech COVID-19 vaccine. A man in his 80s developed multiple bruises 2 weeks after his first dose of the COVID-19 vaccine. Diagnosis was delayed due to his cognitive impairment and low clinical suspicion. This led to a representation with worsening ecchymosis, a left thigh haematoma and symptomatic anaemia. Laboratory testing was notable for an isolated prolongation of the activated partial thromboplastin time, which remained uncorrected in the mixing test. Further testing confirmed the presence of factor VIII (FVIII) inhibitors and low FVIII titres of 6.7%. He responded to treatment with intravenous methylprednisolone and recombinant activated FVII. Screening for autoimmune diseases and malignancies was negative.


Subject(s)
COVID-19 , Hemophilia A , Asia, Southeastern , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Factor VIII/therapeutic use , Hemophilia A/diagnosis , Hemophilia A/drug therapy , Hemophilia A/etiology , Humans , Male , SARS-CoV-2
7.
Nature ; 607(7917): 97-103, 2022 07.
Article in English | MEDLINE | ID: covidwho-1730298

ABSTRACT

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.


Subject(s)
COVID-19 , Critical Illness , Genome, Human , Host-Pathogen Interactions , Whole Genome Sequencing , ATP-Binding Cassette Transporters , COVID-19/genetics , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Cell Adhesion Molecules , Critical Care , Critical Illness/mortality , E-Selectin , Factor VIII , Fucosyltransferases , Genome, Human/genetics , Genome-Wide Association Study , Host-Pathogen Interactions/genetics , Humans , Interleukin-10 Receptor beta Subunit , Lectins, C-Type , Mucin-1 , Nerve Tissue Proteins , Phospholipid Transfer Proteins , Receptors, Cell Surface , Repressor Proteins , SARS-CoV-2/pathogenicity
8.
Artif Organs ; 46(7): 1328-1333, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1685202

ABSTRACT

BACKGROUND: Patients with COVID-19 infection are at increased risk of thrombosis. We wished to determine whether this was is due to an increase in prothrombotic or reduction in anticoagulant factors and whether heparin would be an appropriate anticoagulant. METHODS: We measured routine coagulation and prothrombotic factors in dialysis patients after a positive COVID-19 test between March 2020 -April 2021. RESULTS: Routine coagulation tests were measured in 227 dialysis patients, 148 males (65.2%), median age 67.5 (53.8-77.0) years. The international normalized ratio was prolonged in 11.5%, activated partial thromboplastin time in 48.5%, thrombin time in 57%. Factor VIII was increased in 59.1%, fibrinogen 73.8%, and D-dimer 95.5%. Protein C was reduced in 15.3%, protein S 28%, and antithrombin (AT) in 12.1%. Two patients were Lupus anticoagulant positive, and two Factor VLeiden positive. Factor VIII levels increased with clinical disease; outpatients 159 (136-179) IU/dl, hospitalized but not ventilated 228 (167-311) IU, ventilated 432 (368-488) IU/dl (p < 0.01). Overall 75% had an AT level ≥ 88 IU/dl (reference range 79-106), but only 11.7% of non-hospitalized patients compared to 45% of those who died, p < 0.01, fibrinogen, D-dimers, and protein S or C did not differ with clinical disease severity, whether patients required hospital admission or not and between survivors and those who died. CONCLUSION: COVID-19 dialysis patients have increased levels of fibrinogen and D-Dimers, but only factor VIII levels in the clotting profile increased with clinical disease severity increasing systemic hypercoagulability. AT concentrations are maintained and as such should not compromise anticoagulation with heparins.


Subject(s)
Anticoagulants , COVID-19 , Aged , Anticoagulants/therapeutic use , COVID-19/complications , Factor VIII , Heparin/adverse effects , Humans , Male , Protein S , Renal Dialysis/adverse effects
10.
Br J Haematol ; 196(4): 902-922, 2022 02.
Article in English | MEDLINE | ID: covidwho-1566272

ABSTRACT

In 145 previously healthy non-critically ill young adults, coronavirus disease 2019 (COVID-19)-related symptoms, risk factors for thrombosis, coagulation and inflammatory parameters were compared, with 29 patients reporting unusual thrombotic events (UTEs) and 116 not having thrombotic events. The inflammatory indices, coagulation and prothrombotic platelet phenotype (PTPP) were significantly higher in patients with UTEs versus those without. Patients with UTEs were categorised according to detection of thrombophilic genes (TGs), coagulation and inflammatory markers to the non-TG and TG subcohort. A total of 38 UTEs were identified, which included splanchnic vein thrombosis (SVT; 11), stroke (six), cerebral vein thrombosis (five), thrombotic microangiopathy (four), limb ischaemia and inferior vena cava thrombosis (three each), ST-segment elevation myocardial infarction (two), superior vena cava thrombosis (two), upper limb deep venous thrombosis and retinal vein thrombosis, one each. We found a 55% prevalence of TGs mainly heterozygous coagulation factor II, thrombin (FII)-G20210A, Janus kinase 2 (JAK2)-V617F, protein-S, and antithrombin III deficiency with a high (76·9%) prevalence of venous UTEs, multiple vessels thrombosis, and recurrence rate among the TG versus non-TG subcohort. The presence of JAK2-V617F, and FII-G20210A mutations was linked with SVT. Thrombosis in the non-TG subcohort was associated with more haemorrhagic problems, thrombosis progression and a significantly higher level of inflammatory markers, PTPP, mean platelet volume, von Willebrand factor, and factor VIII, which remained high for up to 6 months, as well as elevated D-dimer. Acquired and inherited thrombophilia with endotheliopathy appeared to be a relevant mechanism to explain the occurrence of UTEs that are not correlated to COVID-19 severity.


Subject(s)
COVID-19/complications , Thrombophilia/diagnosis , Thrombosis/diagnosis , Blood Platelets/pathology , COVID-19/diagnosis , Factor VIII/analysis , Female , Humans , Longitudinal Studies , Male , Prospective Studies , Thrombophilia/etiology , Thrombosis/etiology , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/etiology , Young Adult , von Willebrand Factor/analysis
11.
J Thromb Thrombolysis ; 53(3): 646-662, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1439746

ABSTRACT

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


Subject(s)
COVID-19 , Hemostatics , Thrombophilia , Thrombosis , Venous Thromboembolism , Anticoagulants/therapeutic use , COVID-19/complications , Factor VIII , Fibrinogen/analysis , Humans , Prospective Studies , Thrombelastography , Thrombophilia/diagnosis , Thrombophilia/etiology , Thrombosis/drug therapy , Venous Thromboembolism/drug therapy , von Willebrand Factor
12.
Haemophilia ; 27(5): 736-743, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1288288

ABSTRACT

BACKGROUND: Emicizumab, a bispecific monoclonal antibody administered subcutaneously, mimicking the action of activated coagulation factor VIII, has been approved in Europe for use in patients with severe hemophilia of all ages. AIMS: To assess availability, acceptance, adverse events, efficacy and laboratory monitoring of emicizumab and the effect of the coronavirus disease 2019 (COVID-19) pandemic on its use. METHODS: Online questionnaire sent to 144 hemophilia treatment centres (November 2020 to January 2021). RESULTS: Forty-six physicians from 21 countries responded, with a total of 3420 patients with severe HA under their care. Emicizumab was widely available, for 100% of inhibitor patients and 88% of non-inhibitor patients. No major adverse events were reported. Four reported deaths in patients on emicizumab were not thought to be related to emicizumab. An annualized bleeding rate (ABR) of zero was achieved in 73% of inhibitors patients. Haemostasis was satisfactory in the majority of minor (93.7%) and major (90.7%) surgical procedures performed while on emicizumab. Inhibitor titers were monitored in 78.4% of inhibitor patients on emicizumab, but chromogenic FVIII assay was only available in 73% of centres. The COVID-19 pandemic did not have a major impact on the adoption of emicizumab in most centres (64.9%). CONCLUSION: Three years after its rollout in Europe, emicizumab is widely available. Clinical efficacy and safety were evaluated to be very good, keeping in mind the inherent limitations of the study. Unmet needs include establishment of treatment guidelines for surgery and breakthrough bleeding, limited expertise, especially in young children, and availability of laboratory assays.


Subject(s)
Antibodies, Bispecific , Antibodies, Monoclonal, Humanized , Hemophilia A , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Europe , Factor VIII , Hemophilia A/drug therapy , Humans , Pandemics , Surveys and Questionnaires
13.
J Thromb Haemost ; 19(6): 1515-1518, 2021 06.
Article in English | MEDLINE | ID: covidwho-1238450

ABSTRACT

Acquires hemophilia A (AHA) is rare bleeding condition commonly associated with malignancy, autoimmune disease, or pregnancy. We report a case of a 69-year-old gentleman who developed bleeding symptoms after receiving COVID-19 vaccine. Laboratory testing showed isolated prolongation of the activated partial thromboplastin time, and normal von Willebrand factor. Further testing confirmed the presence of factor VIII inhibitor. To date, no cases of AHA have been reported after exposure to COVID-19 vaccine. There have been two cases of AHA following seasonal flu and H1N1 vaccination, as well as two cases of AHA following COVID-19 infection. We present a summary of these cases and review of literature of autoimmune reactions following vaccination.


Subject(s)
COVID-19 , Hemophilia A , Influenza A Virus, H1N1 Subtype , Aged , COVID-19 Vaccines , Factor VIII , Female , Hemophilia A/diagnosis , Humans , Male , Pregnancy , SARS-CoV-2
14.
Haemophilia ; 27(1): 41-48, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1066683

ABSTRACT

INTRODUCTION: The SARS-CoV-2 coronavirus-induced infection (COVID-19) can be associated with a coagulopathy mainly responsible for pulmonary microvasculature thrombosis and systemic thromboembolic manifestations. The pathophysiology and management of the COVID-19 coagulopathy are likely more complex in patients with inherited bleeding diseases such as haemophilia. These individuals might indeed present with both bleeding and thrombotic complications and require simultaneous antithrombotic and haemostatic treatments. OBJECTIVE: We propose practical guidance for the diagnosis and management of COVID-19 coagulopathy in persons with haemophilia. RESULTS: Continuation of regular haemostatic treatment is recommended for ambulatory patients. For patients requiring hospital admission and on replacement therapy with factors VIII or IX concentrates, prophylaxis with concentrates should be intensified according to the risk of bleeding complications and associated with prophylactic doses of LMWH. For patients on nonreplacement therapy, emicizumab should be continued and possibly combined with factor VIII and prophylactic doses of LMWH depending on the risk of bleeding and thrombosis. Dose escalation of LMWH tailored to the risk of thrombosis can be employed but not supported by evidence. CONCLUSIONS: These practical recommendations are based on the current literature on COVID-19 with its impact on haemostasis, indications and modalities for thromboprophylaxis mainly in nonhaemophilic patients and how that is likely to affect persons with haemophilia in different circumstances. They will need to be tailored to each patient's clinical status and validated in future studies.


Subject(s)
COVID-19/complications , Disseminated Intravascular Coagulation/complications , Hemophilia A/complications , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Anticoagulants/therapeutic use , COVID-19/diagnosis , COVID-19/therapy , Disease Management , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/therapy , Factor IX/therapeutic use , Factor VIII/therapeutic use , Hemophilia A/diagnosis , Hemophilia A/therapy , Heparin, Low-Molecular-Weight/therapeutic use , Humans
15.
Blood Coagul Fibrinolysis ; 32(4): 285-289, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1066462

ABSTRACT

Patients with novel coronavirus pneumonia show increased thrombotic risk. Although hemostatic alterations have been described in novel coronavirus pneumonia patients, case-control studies of von Willebrand factor (VWF), factor VIII (FVIII), and a disintegrin-like and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) are lacking. VWF, ADAMTS13, FVIII, d-dimer, C-reactive protein, and routine blood cells and chemistry were measured in 10 novel coronavirus pneumonia patients and 10 non-novel coronavirus pneumonia controls. Hemostatic factors were measured less than 48 h of hospital admission in patients without invasive ventilation. d-Dimer, C-reactive protein, and fibrinogen concentrations, high in both groups, did not differ significantly in novel coronavirus pneumonia vs. non-novel coronavirus pneumonia patients. Median VWF-antigen (324 vs. 153 IU/dl, P < 0.0001), VWF-Rco (342 vs. 133 IU/dl, P < 0.001), and FVIII-activity levels (203 vs. 123 IU/dl, P < 0.0001) were significantly higher in novel coronavirus pneumonia cases vs. controls ADAMTS13-activity was normal in both groups. Coronavirus pneumonia cases vs. non-novel coronavirus pneumonia controls showed marked VWF/FVIII elevation, suggesting specific virus-induced endothelial activation causing VWF/FVIII hypersecretion, which may represent a therapeutic target in novel coronavirus pneumonia.


Subject(s)
COVID-19/blood , Factor VIII/analysis , Pneumonia/blood , SARS-CoV-2/isolation & purification , Thrombophilia/etiology , von Willebrand Factor/analysis , ADAMTS13 Protein/blood , Aged , Biomarkers , Blood Cell Count , C-Reactive Protein/analysis , COVID-19/complications , Case-Control Studies , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrinogen/analysis , Humans , Male , Middle Aged , Pneumonia/virology , Thrombophilia/blood
17.
Haemophilia ; 27(1): 41-48, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-936739

ABSTRACT

INTRODUCTION: The SARS-CoV-2 coronavirus-induced infection (COVID-19) can be associated with a coagulopathy mainly responsible for pulmonary microvasculature thrombosis and systemic thromboembolic manifestations. The pathophysiology and management of the COVID-19 coagulopathy are likely more complex in patients with inherited bleeding diseases such as haemophilia. These individuals might indeed present with both bleeding and thrombotic complications and require simultaneous antithrombotic and haemostatic treatments. OBJECTIVE: We propose practical guidance for the diagnosis and management of COVID-19 coagulopathy in persons with haemophilia. RESULTS: Continuation of regular haemostatic treatment is recommended for ambulatory patients. For patients requiring hospital admission and on replacement therapy with factors VIII or IX concentrates, prophylaxis with concentrates should be intensified according to the risk of bleeding complications and associated with prophylactic doses of LMWH. For patients on nonreplacement therapy, emicizumab should be continued and possibly combined with factor VIII and prophylactic doses of LMWH depending on the risk of bleeding and thrombosis. Dose escalation of LMWH tailored to the risk of thrombosis can be employed but not supported by evidence. CONCLUSIONS: These practical recommendations are based on the current literature on COVID-19 with its impact on haemostasis, indications and modalities for thromboprophylaxis mainly in nonhaemophilic patients and how that is likely to affect persons with haemophilia in different circumstances. They will need to be tailored to each patient's clinical status and validated in future studies.


Subject(s)
COVID-19/complications , Disseminated Intravascular Coagulation/complications , Hemophilia A/complications , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Anticoagulants/therapeutic use , COVID-19/diagnosis , COVID-19/therapy , Disease Management , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/therapy , Factor IX/therapeutic use , Factor VIII/therapeutic use , Hemophilia A/diagnosis , Hemophilia A/therapy , Heparin, Low-Molecular-Weight/therapeutic use , Humans
18.
Am J Case Rep ; 21: e926728, 2020 Oct 30.
Article in English | MEDLINE | ID: covidwho-895721

ABSTRACT

BACKGROUND Coagulation abnormalities are frequently encountered in patients with coronavirus disease 2019 (COVID-19), especially in those with more severe disease. These hematologic abnormalities are suspected to occur in the context of underlying immune dysregulation and endothelial dysfunction. Elevated D-dimer levels, COVID-19-associated coagulopathy (CAC), disseminated intravascular coagulation (DIC), and positive lupus anticoagulants are the most common findings to date. Current guidelines suggest that all patients with COVID-19 should receive pharmacologic thromboprophylaxis. CASE REPORT An 89-year-old man with a medical history of hypertension, type 2 diabetes, and advanced prostate cancer in remission presented with generalized weakness. At our center, a reverse transcription-polymerase chain reaction test was positive for severe acute respiratory syndrome coronavirus 2, but the patient did not have symptoms of COVID-19. He was also found to have a prolonged activated partial thromboplastin time, secondary to both a high titer of factor VIII inhibitor and a lupus anticoagulant. He eventually developed respiratory compromise, during which his disease manifested as a bleeding rather than a prothrombotic state. CONCLUSIONS This report highlights the importance of a comprehensive evaluation of prolonged partial thromboplastin time, rather than making an assumption based on a positive lupus anticoagulant result. In the case presented, the concomitant factor VIII inhibitor caused the patient to have a greater bleeding tendency. It is imperative that physicians balance the risk of bleeding and clotting in patients with COVID-19 because patients seem to have varying presentations based on disease severity and level of immune dysregulation.


Subject(s)
Blood Coagulation Disorders/etiology , COVID-19/complications , Factor VIII/antagonists & inhibitors , Lupus Coagulation Inhibitor/blood , SARS-CoV-2 , Aged, 80 and over , Blood Coagulation Disorders/blood , COVID-19/blood , COVID-19/epidemiology , Humans , Male , Pandemics , Partial Thromboplastin Time
19.
Acta Haematol ; 144(3): 319-321, 2021.
Article in English | MEDLINE | ID: covidwho-802601

ABSTRACT

A 54-year-old man with a long history of severe haemophilia A treated prophylactically with efmoroctocog alpha (3,000 IU twice weekly) was diagnosed with COVID-19 infection. He had multiple risk factors for COVID-19 severity including obesity, diabetes mellitus and hypertension. He required prolonged intensive care unit (ICU) stay due to the severity of respiratory failure until his death on day 24. During his ICU stay, he received a continuous infusion of efmoroctocog alpha in order to maintain factor VIII activity between 80 and 100%, together with therapeutic doses of low-molecular-weight heparin targeting anti-Xa activity above 0.5 IU/mol. He tolerated numerous invasive procedures without bleeding. At post-mortem examination, there was no evidence for thrombosis or haemorrhage in the different organs.


Subject(s)
COVID-19/diagnosis , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Heparin, Low-Molecular-Weight/therapeutic use , Immunoglobulin Fc Fragments/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Blood Coagulation Tests , COVID-19/complications , COVID-19/virology , Hemophilia A/complications , Hemophilia A/pathology , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , Severity of Illness Index
20.
Eur Rev Med Pharmacol Sci ; 24(17): 9161-9168, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-790177

ABSTRACT

OBJECTIVE: Coronavirus Disease-2019 (COVID-19) predisposes patients to thrombosis which underlying mechanisms are still incompletely understood. We sought to investigate the balance between procoagulant factors and natural coagulation inhibitors in the critically ill COVID-19 patient and to evaluate the usefulness of hemostasis parameters to identify patients at risk of venous thromboembolic event (VTE). PATIENTS AND METHODS: We conducted an observational study recording VTEs defined as deep vein thrombosis or pulmonary embolism using lower limb ultrasound (92% of the patients), computed tomography pulmonary angiography (6%) and both tests (2%). We developed a comprehensive analysis of hemostasis. RESULTS: Ninety-two consecutive mechanically ventilated COVID-19 patients (age, 62 years [53-69] (median [25th-75th percentiles]); M/F sex ratio, 2.5; body-mass index, 28 kg/m2 [25-32]; past hypertension (52%) and diabetes mellitus (30%)) admitted to the Intensive Care Unit (ICU) from 03/11/2020 to 5/05/2020, were included. When tested, patients were receiving prophylactic (74%) or therapeutic (26%) anticoagulation. Forty patients (43%) were diagnosed with VTE. Patients displayed inflammatory and prothrombotic profile including markedly elevated plasma fibrinogen (7.7 g/L [6.1-8.6]), D-dimer (3,360 ng/mL [1668-7575]), factor V (166 IU/dL [136-195]) and factor VIII activities (294 IU/dL [223-362]). We evidenced significant discrepant protein C anticoagulant and chromogenic activities, combined with slightly decreased protein S activity. Plasma D-dimer >3,300 ng/mL predicted VTE presence with 78% (95%-confidence interval (95% CI), 62-89) sensitivity, 69% (95% CI, 55-81) specificity, 66% (95% CI, 51-79) positive predictive value and 80% (95% CI, 65-90) negative predictive value [area under the ROC curve, 0.779 (95%CI, 0.681-0.859), p=0.0001]. CONCLUSIONS: Mechanically ventilated COVID-19 patients present with an imbalance between markedly increased factor V/VIII activity and overwhelmed protein C/S pathway. Plasma D-dimer may be a useful biomarker at the bedside for suspicion of VTE.


Subject(s)
Blood Coagulation Factor Inhibitors/metabolism , Blood Coagulation Factors/metabolism , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Aged , Area Under Curve , Betacoronavirus/isolation & purification , Body Mass Index , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/virology , Critical Illness , Factor V/analysis , Factor VIII/analysis , Female , Fibrin Fibrinogen Degradation Products/analysis , Fibrinogen/analysis , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Protein C/analysis , Protein S/analysis , ROC Curve , SARS-CoV-2 , Venous Thromboembolism/complications , Venous Thromboembolism/diagnosis
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