key: cord-0767934-crnm9bz9
authors: Al-Samkari, Hanny; Song, Fei; Van Cott, Elizabeth M.; Kuter, David J.; Rosovsky, Rachel P.
title: Evaluation of the Prothrombin Fragment 1.2 in Patients with COVID-19
date: 2020-11-05
journal: Blood
DOI: 10.1182/blood-2020-134605
sha: 0b5ce0bef5e7b10596db67287e871161f65ae75d
doc_id: 767934
cord_uid: crnm9bz9

Introduction: Coronavirus disease 2019 (COVID-19) may cause a hypercoagulable state. The D-dimer is frequently elevated in COVID-19, but other markers of coagulation activation, including the prothrombin fragment 1.2 (PF1.2) are poorly described. Given the near universal D-dimer elevation in critically ill patients with COVID-19, the PF1.2 may be a more specific marker to identify thrombotic complications. Methods: We studied hospitalized adults with COVID-19 and PF1.2 measurement performed at any point during hospitalization. We evaluated the relationship between PF1.2 and synchronously measured D-dimer. We utilized receiver operating characteristic (ROC) analysis to evaluate optimal thresholds for diagnosing thrombosis and multivariable logistic regression to evaluate association with thrombosis. Thresholds for each assay for multivariable regression were determined from ROC analysis. To avoid confounding of therapeutic anticoagulation on PF1.2 or D-dimer measurement, patients receiving therapeutic anticoagulation at the time of assay measurement were excluded from these analyses. Results: Patients and Thrombotic Events. 115 hospitalized patients with COVID-19 were included [110 (95.7%) critically ill], encompassing 3318 patient-days (474 patient-weeks) analyzed for thrombotic and critical illness complications. At the data cutoff date, 74 patients (64.3%) had been discharged from the hospital alive, 24 patients (20.9%) died in the hospital, and 17 patients (14.8%) remained hospitalized, having been hospitalized for a median of 44 (range, 30-62) days. Over a median follow-up of 29 (range, 2-62) hospital days, 26 patients developed radiographically-confirmed VTE (22.6%, a rate of 5.49 per 100 patient-weeks); including arterial, extracorporeal circuit, and recurrent line thrombosis, 56 patients (48.7%) developed a thrombotic complication. At the time of PF1.2 and synchronous D-dimer measurement, 37 patients (32.1%) were receiving therapeutic anticoagulation, 77 patients (67.0%) were receiving prophylactic anticoagulation, and 1 patient (0.9%) was not receiving pharmacologic thromboprophylaxis. Association of PF1.2 with D-dimer. Synchronously measured PF1.2 and D-dimer were moderately positively correlated (r=0.542, P<0.001, Figure 1) but significant discordance was observed in elevation of each marker above the laboratory reference range (59.0% patients with elevated PF1.2 vs. 98.5% elevated D-dimer). Association of PF1.2 with Hypercoagulability. Median PF1.2 levels were higher in patients with thrombosis than those without (611 vs. 374 pmol/L, P=0.006, Figure 2). Therapeutic anticoagulation suppressed median PF1.2 levels: median (IQR) PF1.2 in patients not receiving therapeutic anticoagulation (N=29) was 611 pmol/L (333-1148 pmol/L), significantly higher than the median (IQR) PF1.2 in patients receiving therapeutic anticoagulation (N=27) of 347 pmol/L (195-506 pmol/L), P=0.0017. ROC and Multivariable Regression Analyses. In ROC analysis, PF1.2 had superior specificity and conferred a higher positive likelihood ratio in identifying patients with thrombosis than did the D-dimer (PF1.2 threshold of >523 pmol/L: 69.2% sensitivity, 67.7% specificity; >924 pmol/L: 37.9% sensitivity, 87.8% specificity, Figure 3). In multivariable analysis controlling for age, sex, and BMI, a PF1.2 >500 pmol/L was significantly associated with VTE [adjusted odds ratio (OR) 4.26, 95% CI, 1.12-16.21, P=0.034] and any thrombotic manifestation (adjusted OR 3.85, 95% CI, 1.39-10.65, P=0.010); conversely, synchronously measured D-dimer >2,500 ng/mL was not significantly associated with VTE (OR 5.91, 95% CI, 0.69-50.56, P=0.11) or any thrombotic manifestation (OR 2.47, 95% CI, 0.78-7.78, P=0.12). The vast majority (90.6%) of patients with a non-elevated PF1.2 result did not develop VTE and 75% did not develop any thrombotic complication. Conclusions: When measured at any point during hospitalization in patients not receiving therapeutic anticoagulation, PF1.2 was more specific than synchronously measured D-dimer in identifying patients who experienced thrombosis and was significantly associated with thrombotic manifestations in multivariable analyses while the D-dimer was not. PF1.2 may be a useful assay, and potentially more discriminant than D-dimer, in identifying thrombotic manifestations in hospitalized patients with COVID-19. Disclosures Al-Samkari: Rigel: Consultancy; Agios: Consultancy, Research Funding; Argenx: Consultancy; Amgen: Research Funding; Dova: Consultancy, Research Funding. Kuter: Caremark: Consultancy, Honoraria; Immunovant: Other: Travel Expenses, Research Funding; CRICO: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Shionogi: Consultancy; Protalix Biotherapeutics: Consultancy; Principia: Consultancy, Research Funding; Protalex: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Kezar Life Sciences, Inc: Other, Research Funding; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Dova: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding. Rosovsky: Bristol-Myers Squibb, Dova, Janssen, Portola: Consultancy; Bristol-Myers Squibb, Janssen: Research Funding.

patients with COVID-19, the PF1.2 may be a more specific marker to identify thrombotic complications.

We studied hospitalized adults with COVID-19 and PF1.2 measurement performed at any point during hospitalization. We evaluated the relationship between PF1.2 and synchronously measured Ddimer. We utilized receiver operating characteristic (ROC) analysis to evaluate optimal thresholds for diagnosing thrombosis and multivariable logistic regression to evaluate association with thrombosis.

Thresholds for each assay for multivariable regression were determined from ROC analysis. To avoid confounding of therapeutic anticoagulation on PF1.2 or D-dimer measurement, patients receiving therapeutic anticoagulation at the time of assay measurement were excluded from these analyses. were receiving prophylactic anticoagulation, and 1 patient (0.9%) was not receiving pharmacologic thromboprophylaxis.

Association of PF1.2 with D-dimer. Synchronously measured PF1.2 and D-dimer were moderately positively correlated (r=0.542, P<0.001, Figure 1 ) but significant discordance was observed in elevation of each marker above the laboratory reference range (59.0% patients with elevated PF1.2 vs. 98.5% elevated D-dimer). 

In ROC analysis, PF1.2 had superior specificity and conferred a higher positive likelihood ratio in identifying patients with thrombosis than did the Ddimer (PF1.2 threshold of >523 pmol/L: 69.2% sensitivity, 67.7% specificity; >924 pmol/L: 37.9% sensitivity, 87.8% specificity, Figure 3 ). In multivariable analysis controlling for age, sex, and BMI, a PF1.2 >500 pmol/L was significantly associated with VTE [adjusted odds ratio (OR) 4.26, 95% CI, 1.12-16.21, P=0.034] and any thrombotic manifestation (adjusted OR 3.85, 95% CI, 1.39-10.65, P=0.010); conversely, synchronously measured D-dimer >2,500 ng/mL was not significantly associated with VTE (OR 5.91, 95% CI, 0.69-50.56, P=0.11) or any thrombotic manifestation (OR 2.47, 95% CI, 0.78-7.78, P=0.12). The vast majority (90.6%) of patients with a non-elevated PF1.2 result did not develop VTE and 75% did not develop any thrombotic complication.

When measured at any point during hospitalization in patients not receiving therapeutic anticoagulation, PF1.2 was more specific than synchronously measured D-dimer in identifying patients who experienced thrombosis and was significantly associated with thrombotic manifestations in

analyses while the D-dimer was not. PF1.2 may be a useful assay, and potentially more discriminant than D-dimer, in identifying thrombotic manifestations in hospitalized patients with COVID-19

Rigel: Consultancy; Agios: Consultancy, Research Funding; Argenx: Consultancy; Amgen: Research Funding; Dova: Consultancy, Research Funding

Immunovant: Other: Travel Expenses, Research Funding; CRICO: Consultancy, Honoraria

Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Shionogi: Consultancy; Protalix Biotherapeutics: Consultancy; Principia: Consultancy, Research Funding

Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses

Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding

Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria

Momenta: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Rigel: Consultancy, Honoraria, Other

Dova: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; Protalex: Consultancy, Honoraria, Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other

* Asterisk with author names denotes non-ASH members.