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

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

Low incidence of venous thrombosis but high incidence of arterial thrombotic complications among critically ill COVID-19 patients in Singapore.

BACKGROUND: Arterial and venous thrombosis are reported to be common in critically ill COVID-19 patients. METHOD AND RESULTS: This is a national multicenter retrospective observational study involving all consecutive adult COVID-19 patients who required intensive care units (ICU) admission between 23 January 2020 and 30 April 2020 in Singapore. One hundred eleven patients were included and the venous and arterial thrombotic rates in ICU were 1.8% (n = 2) and 9.9% (n = 11), respectively. Major bleeding rate was 14.8% (n = 16). CONCLUSIONS: Critically ill COVID-19 patients in Singapore have lower venous thromboembolism but higher arterial thrombosis rates and bleeding manifestations than other reported cohorts.

COVID-19 associated coagulopathy in critically ill patients: A hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis.

Patients with COVID-19 are known to be at risk of developing both venous, arterial and microvascular thrombosis, due to an excessive immuno-thrombogenic response to the SARS-CoV-2 infection. Overlapping syndromes of COVID-19 associated coagulopathy with consumptive coagulopathy and microangiopathy can be seen in critically ill patients as well. Blood was collected from 12 Intensive Care Unit (ICU) patients with severe COVID-19 who were on either mechanical ventilation or on high flow oxygen with a PaO2/FiO2 ratio of <300 mmHg. Laboratory tests were performed for parameters of haemostasis, clot waveform analysis and anti-phospholipid antibodies. CWA parameters were raised with elevated aPTT median Min1 (clot velocity) 9.3%/s (IQR 7.1-9.9%/s), elevated PT median Min1 10.3%/s (IQR 7.1-11.1%/s), elevated aPTT median Min2 (clot acceleration) 1.5%/s2 (IQR 1.0-1.6%/s2), elevated PT median Min2 5.2%/s2 (3.6-5.7%/s2), elevated aPTT median Max2 (clot deceleration) 1.3%/s2 (IQR 0.8-1.4%/s2) elevated PT median Max2 3.8%/s2 (IQR 2.6-4.2%/s2), increased aPTT median Delta change (decreased light transmission due to increased clot formation) 87.8% (IQR 70.2-91.8%) and PT median Delta change 33.0%. This together with raised median Factor VIII levels of 262.5%, hyperfibrinogenemia (median fibrinogen levels 7.5 g/L), increased median von Willebrand factor antigen levels 320% and elevated median D-dimer levels 1.7 µg/dl support the diagnosis of COVID-19 associated coagulopathy. A lupus anticoagulant was present in 50% of patients. Our laboratory findings further support the view that severe SARS-CoV-2 infection is associated with a state of hypercoagulability.

Tolerability of Daratumumab Amongst Asian Patients with Plasma Cell Dyscrasias - A Single Centre Experience.

Daratumumab is increasingly incorporated into the standard treatment regimens for patients with plasma cell dyscrasias in Asia, especially with cost-containment measures implemented by various regional health authorities. This analysis aimed to study daratumumab's tolerability amongst Asian patients. This is a retrospective medical records review of patients who received daratumumab between November 2016 and August 2021 as part of routine clinical care. Sixty-two patients were included in the study: 62.9% had renal impairment, and 27.4% had creatinine clearance (CrCl) \<30ml/min. Forty-five patients (72.6%) received daratumumab combination therapy, with a median 1 line of prior therapy. The median duration of follow-up was 12.4 months, and the median duration patients were on treatment with daratumumab was 12.3 months. Twenty-one of 62 (33.9%) patients experienced infusion-related reactions (IRRs) after the first dose of intravenous daratumumab. Seven developed mostly grades 1 and 2 respiratory events, and 14 showed grades 1 and 2 non-respiratory IRRs. Only one patient experienced a grade 1 IRR with the second infusion, with none developing any IRRs in the third or subsequent infusions. Eight (12.9%) patients were affected by hematological adverse events (AEs), mostly grades 2 and 3, with one experiencing grade-4 neutropenia without sepsis. Six (9.7%) patients experienced non-hematological AEs, the commonest being pneumonia and other infections, with one developing Nocardia pneumonia (grade 4) 14 months after the initiation of daratumumab. In conclusion, daratumumab is tolerable amongst Asian patients, including the elderly, and patients with severe renal impairment and chronic lung diseases.

Challenges associated with the identification of germline variants on myeloid malignancy genomic profiling-a Singaporean experience.

Genomic profiling to identify myeloid-malignancy-related gene mutations is routinely performed for patients with suspected or definite myeloid malignancies. The most common specimen types in our experience are peripheral blood and bone marrow aspirates. Although primarily intended to identify somatic mutations, not infrequently, potentially clinically significant germline variants are also identified. Confirmation of the germline status of these variants is typically performed by hair follicle or skin fibroblast testing. If the germline variant is classified as a pathogenic or likely pathogenic variant and occurs in a gene known to be associated with a disease relevant to the patient's phenotype (for example, the identification of a DDX41 pathogenic variant in an individual with acute myeloid leukemia), the management algorithm is typically quite straightforward. Challenging situations may occur such as when the germline variant is classified as a pathogenic or likely pathogenic variant and occurs in a gene not known to be associated with the patient's phenotype/presenting complaint. We have encountered several such challenging cases in which potentially clinically significant germline variants were identified on the initial genomic profiling of peripheral blood or bone marrow aspirate. In this article, we present these cases and discuss the genetic counseling and management approaches.

Real-World Experience of Measurable Residual Disease Response and Prognosis in Acute Myeloid Leukemia Treated with Venetoclax and Azacitidine.

The prognostic value of measurable residual disease (MRD) by flow cytometry in acute myeloid leukemia (AML) patients treated with non-intensive therapy is relatively unexplored. The clinical value of MRD threshold below 0.1% is also unknown after non-intensive therapy. In this study, MRD to a sensitivity of 0.01% was analyzed in sixty-three patients in remission after azacitidine/venetoclax treatment. Multivariable cox regression analysis identified prognostic factors associated with cumulative incidence of relapse (CIR), progression-free survival (PFS) and overall survival (OS). Patients who achieved MRD < 0.1% had a lower relapse rate than those who were MRD ≥ 0.1% at 18 months (13% versus 57%, p = 0.006). Patients who achieved an MRD-negative CR had longer median PFS and OS (not reached and 26.5 months) than those who were MRD-positive (12.6 and 10.3 months, respectively). MRD < 0.1% was an independent predictor for CIR, PFS, and OS, after adjusting for European Leukemia Net (ELN) risk, complex karyotype, and transplant (HR 5.92, 95% CI 1.34−26.09, p = 0.019 for PFS; HR 2.60, 95% CI 1.02−6.63, p = 0.046 for OS). Only an MRD threshold of 0.1%, and not 0.01%, was predictive for OS. Our results validate the recommended ELN MRD cut-off of 0.1% to discriminate between patients with improved CIR, PFS, and OS after azacitidine/venetoclax therapy.

Relationship of JAK2 (V617F) Allelic Burden with Clinico- Haematological Manifestations of Philadelphia-Negative Myeloproliferative Neoplasms.

JAK2 (V617F) allelic burden is the main genetic driver behind and a potential differentiator between individual myeloproliferative neoplasm (MPN) subtypes. This study aimed to explore the relationship between JAK2 (V617F) allelic burden, MPN subtypes and their clinico-haematological manifestations in a Singapore-based cohort. Analysis was performed on a retrospectively collected dataset of 128 patients diagnosed with JAK2 (V617F) positive Philadelphia-negative MPNs between 2016 to 2017 in Singapore. Genomic analysis was conducted on blood samples via DNA extraction and Droplet Digital Polymerase Chain Reaction (ddPCR). The mean age was 62.4 (SD=14.1). 85 out of the 128 (66.4%) patients were male. There was a statistically significant difference in allelic burdens between the different MPN disease subtypes χ2(3) = 9.064, p=0.028, with essential thrombocytosis (ET) patients having the lowest mean JAK2 percentage allelic burden (26.5%). Patients with an allelic burden >50% had higher leukocyte counts (MWU 1016.5, p=0.001), haemoglobin levels (MWU 1287.0, p=0.045), lactate dehydrogenase levels (MWU 611.5, p=0.001), and lower platelet levels (MWU 1164.0, p=0.008). Subgroup analysis revealed none of these correlations was significant in the ET subgroup. The results are largely in concordance with previous research in Asian cohorts demonstrating the association between allelic burden and clinico-haematological manifestations of MPN. However, in the ET subgroup, the JAK2 (V617F) allelic burden do not correlate positively for haematological parameters which is only seen in Asian patients.
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