Anticoagulation doses used in management of COVID-19 patients, stratified by severity: a systematic review and meta-analysis of RCTs.

Since the recognition of the hypercoagulable state in COVID-19 patients, several interim guidance documents have recommended the use of pharmacologic thromboprophylaxis in hospitalized patients with COVID-19. Most of these guidelines recommend the use of unfractionated heparin (UFH) or low molecular weight heparin (LMWH), though the consensus is yet to be reached in the recommendations of standard(low), intermediate or therapeutic (full) dose anticoagulation. We seek to systematically review the available evidence to help guide clinicians weighing up decisions regarding the anticoagulation approach for COVID-19 patients admitted to intensive care units

Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia

Refractory acute myeloid leukemia (AML), defined as failure of two cycles of induction therapy at diagnosis or of one cycle at relapse, represents a subgroup with poor outcomes. Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (fludarabine + cytosine + granulocyte colony-stimulating factor ± idarubicin or mitoxantrone + etoposide) followed by 1-week rest and then reduced-intensity transplant with fludarabine + melphalan. We used the same backbone for this trial (CTRI/2019/02/017505) with the addition of CD56-positive cells from a family donor infused 1 day after the completion of chemotherapy. CD56-positive selection was done using a CliniMACS Prodigy system (Miltenyi Biotec, Bergisch Gladbach, Germany) followed by overnight incubation in autologous plasma with 2 micromolar arsenic trioxide and 500 U/mL of interleukin-2. From February 2019, 14 patients with a median age of 29 years (interquartile range [IQR]: 16.5–38.5) were enrolled in this trial. Six were females. Six had primary refractory AML while eight had relapsed refractory AML. The median CD56-cell dose infused was 46.16 × 106/kg (IQR: 25.06–70.36). One patient withdrew consent after NK cell infusion. Of the 13 patients who proceeded to transplant, five died of immediate post-transplant complications while two did not engraft but were in morphologic leukemia-free state (both subsequently died of infective complications after the second transplant). Of the remaining six patients who engrafted and survived beyond 1 month of the transplant, two developed disease relapse and died. The remaining four patients are alive and relapse free at the last follow-up (mean follow-up duration of surviving patients is 24 months). The 2-year estimated overall survival for the cohort was 28.6% ± 12.1% while the treatment-related mortality (TRM) with this approach was 38.5% ± 13.5%. Haploidentical NK cell therapy as an adjunct to transplant is safe and needs further exploration in patients with AML. For refractory AML, post-transplant NK infusion and strategies to reduce TRM while using pre-transplant NK infusion merit exploration

Biomarkers of coagulation, endothelial, platelet function, and fibrinolysis in patients with COVID-19: a prospective study

Abstract Prospective and sequential evaluation of homeostatic changes leading to thrombosis across COVID 19 disease severity spectrum are limited. In this prospective observational study, haemostasis was evaluated in patients with mild, moderate-severe, and critical COVID-19 infection. Markers of endothelial activation [Soluble thrombomodulin (sTM), von Willebrand Factor (VWF)], platelet activation [Soluble P-selectin, beta-thromboglobulin (BTG)] and global haemostasis [Rotational thromboelastometry (ROTEM)] were evaluated on days 1 and 5 after admission. The study cohort comprised of 100 adult patients (mild = 20, moderate-severe = 22, critical = 58). Sixty-five patients received anticoagulation for 10 (7–14) days. Thrombotic events were seen in 9 patients. In-hospital mortality was 21%. Endothelial activation markers were elevated at baseline in all subgroups, with levels in moderate-severe (sTM = 4.92 ng/ml, VWF = 295 U/dl) [reference-ranges: sTM = 2.26–4.55 ng/ml; Soluble P-selectin = 13.5–31.5 ng/ml; BTG = 0.034–1.99 ng/ml] and critical patients (sTM = 6.07 ng/ml, VWF = 294 U/dl) being significantly higher than in the mild group (sTM = 4.18 ng/ml, VWF = 206 U/dl). In contrast, platelet activation markers were elevated only in critically ill patients at baseline (Soluble P-selectin = 37.3 ng/ml, BTG = 2.51 ng/ml). The critical group had significantly lower fibrinolysis on days 1 and 5 when compared with the moderate-severe arm. COVID-19 infection was associated with graded endothelial activation and lower fibrinolysis that correlated with illness severity

sj-jpg-6-cll-10.1177_09636897231198178 – Supplemental material for Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia

Supplemental material, sj-jpg-6-cll-10.1177_09636897231198178 for Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia by Uday Kulkarni, Arun Kumar Arunachalam, Hamenth Kumar Palani, Reeshma Radhakrishnan Nair, Nithya Balasundaram, Arvind Venkatraman, Anu Korula, Sushil Selvarajan, Sharon Lionel, Poonkuzhali Balasubramanian, Madhavi Maddali, Aby Abraham, Biju George and Vikram Mathews in Cell Transplantation</p

sj-jpg-4-cll-10.1177_09636897231198178 – Supplemental material for Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia

Supplemental material, sj-jpg-4-cll-10.1177_09636897231198178 for Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia by Uday Kulkarni, Arun Kumar Arunachalam, Hamenth Kumar Palani, Reeshma Radhakrishnan Nair, Nithya Balasundaram, Arvind Venkatraman, Anu Korula, Sushil Selvarajan, Sharon Lionel, Poonkuzhali Balasubramanian, Madhavi Maddali, Aby Abraham, Biju George and Vikram Mathews in Cell Transplantation</p

sj-docx-1-cll-10.1177_09636897231198178 – Supplemental material for Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia

Supplemental material, sj-docx-1-cll-10.1177_09636897231198178 for Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia by Uday Kulkarni, Arun Kumar Arunachalam, Hamenth Kumar Palani, Reeshma Radhakrishnan Nair, Nithya Balasundaram, Arvind Venkatraman, Anu Korula, Sushil Selvarajan, Sharon Lionel, Poonkuzhali Balasubramanian, Madhavi Maddali, Aby Abraham, Biju George and Vikram Mathews in Cell Transplantation</p

sj-jpg-3-cll-10.1177_09636897231198178 – Supplemental material for Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia

Supplemental material, sj-jpg-3-cll-10.1177_09636897231198178 for Haploidentical Natural Killer Cell Therapy as an Adjunct to Stem Cell Transplantation for Treatment of Refractory Acute Myeloid Leukemia by Uday Kulkarni, Arun Kumar Arunachalam, Hamenth Kumar Palani, Reeshma Radhakrishnan Nair, Nithya Balasundaram, Arvind Venkatraman, Anu Korula, Sushil Selvarajan, Sharon Lionel, Poonkuzhali Balasubramanian, Madhavi Maddali, Aby Abraham, Biju George and Vikram Mathews in Cell Transplantation</p