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Essential thrombocythemia is associated with a higher risk of thrombosis during COVID-19

Mar 18, 2021
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COVID-19 has been reported to damage multiple organ systems, primarily the respiratory system, which contributes to the high mortality rate among patients. In addition, it causes venous thromboembolism (VTE), arterial thrombosis, and blockage in the microcirculation. The incidence of thromboembolic events may vary among patients; some comorbidities, such as hypertension, obesity, diabetes or cardiovascular disease, chronic respiratory disease, and cancer, may increase the risk of these events in patients with SARS-CoV-2 infection. The estimations of the incidence widely depend on screening for the presence of these events and being treated in an intensive care unit (ICU).

Patients with myeloproliferative neoplasms (MPN) are known to be at a higher risk of experiencing thrombotic complications, along with spontaneous or drug-related bleeding, compared with the general population. This disposition may put patients in a more vulnerable position for thrombotic events.

MPN Hub Steering Committee member Tiziano Barbui and colleagues have conducted the international MPN-COVID study (NCT04385160) to collect related data on COVID-19 and the incidence of thrombosis/bleeding events in patients with MPN, i.e. essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), and to identify associated predictors. The results have recently been published in Blood Cancer Journal,1 and here, we are pleased to summarize key points.

Study design

  • Multicenter, retrospective, cohort study in 38 European hematology units, conducted on behalf of European LeukemiaNet (ELN).
  • Adults (≥18 years of age) with an MPN diagnosis and SARS-CoV-2 infection between February 15, 2020, and May 31, 2020, were eligible.
  • Patients were followed for a minimum of 1 month; the study protocol was amended to follow survivors for an additional 6 months.
  • Related data were collected at:
    • last MPN follow-up visit before COVID-19 onset
    • COVID-19 diagnosis
    • MPN follow-up after COVID-19
    • last visit.
        • Primary outcome: The incidence of pulmonary embolism with or without deep vein thrombosis of the legs confirmed by imaging.
        • Secondary outcomes: The occurrence of any other major thrombosis, major bleeding, and death.
        • Possible risk factors, including comorbidities, MPN type and status, MPN treatments, laboratory parameters at the time of COVID-19 diagnosis, and COVID-19 severity and treatments, were also investigated.

        Results

        The analysis included 162 patients; the incidence and types of thrombosis and bleeding were reported with a median follow-up duration of 50.5 days (interquartile range [IQR], 16.0–69.0) and are presented in Table 1. A total of 22 thrombohemorrhagic events were observed in 19 patients.

        Table 1. Thrombosis and bleeding events by MPN type1

         

        Total
        (N = 162)

        ET
        (n = 48)

        PV
        (n = 42)

        MF
        (n = 56)

        Pre-MF
        (n = 16)

        p value

        Thrombosis

        Patients with thrombosis, n (%)

        14 (8.6)

        8 (16.7)

        2 (4.8)

        3 (5.4)

        1 (6.3)

        0.13

        Thrombotic events, n (%)

        15 (10.0)

        9 (18.8)

        2 (4.8)

        3 (5.4)

        1 (6.3)

        0.35

        Arterial, n (%)
                      AMI
                      Stroke
                      PAT

        3 (1.9)
        1
        1
        1

        1 (2.1)
        0
        1
        0

        0 (0.0)


        1 (1.8)
        1
        0
        0

        1 (6.3)
        0
        0
        1

        0.47


        Venous, n (%)
                      PE
                      DVT + PE
                      SVT

        12 (7.4)
        10
        1
        1

        8 (16.7)
        6
        1
        1

        2 (4.8)
        2
        0
        0

        2 (3.6)
        2
        0
        0

        0 (0.0)


        0.031


        Median time to any thrombosis, days (IQR)

        11.5 (4.0–25.0)

        7.0 (2.5–11.5)

        8.0 (1.0–15.0)

        25.0 (16.0–32.0)

        28.0 (28.0–28.0)

        0.27

        Median time to PE, days (IQR)

        8.0 (0.0–14.0)

        4.0 (0.0–8.0)

        7.0 (0.0–14.0)

        27.5 (24.0–31.0)

        0.097

        Bleeding

        Patients with bleeding, n (%)

        7 (4.3)

        1 (2.1)

        2 (4.9)

        4 (7.1)

        0 (0.0)

        0.51

        Transfusion needed, n (%)

        5 (3.1)

        1 (2.1)

        0 (0.0)

        4 (7.1)

        0.030

        Median time to bleeding, days (IQR)

        16.0 (13.0–24.0)

        14.0 (14.0–14.0)

        23.0 (16.0–30.0)

        17.5 (6.5–23.0)

        0.50

        AMI, acute myocardial infarction; DVT, deep vein thrombosis of the legs; ET, essential thrombocythemia; IQR, interquartile range; MF, myelofibrosis; MPN, myeloproliferative neoplasms; PAT, peripheral arterial thrombosis; PE, pulmonary embolism; pre-PMF; prefibrotic MF; PV, polycythemia vera; SVT, superficial vein thrombosis.
        *Adapted from Barbui et al.1
        Values in bold are statistically significant.

        Thrombosis

        • The incidence of arterial thrombosis was low (1.9%), while VTE was more common (7.4%).
          • The frequency of VTE events was significantly higher in patients with ET (p = 0.031) compared with PV or MF.
        • All patients (except two with VTE) were on anticoagulation with low or intermediate doses (50%) or therapeutic doses (50%) of low molecular weight heparin.
        • Of all patients with thrombosis (n = 14), seven died. However, only one patient died from a thrombotic event (acute myocardial infarction), while the other death events were attributed to multiorgan failure (n = 4), pneumonia (n = 1), and unknown reasons (n = 1).

        Bleeding

        • Seven patients experienced bleeding events, and five were on anticoagulation, including low molecular weight heparin or apixaban.
        • Four events were reported in patients with MF.
          • All events required blood transfusions.
          • Most patients were >70 years of age.
          • Three events affected the gastrointestinal tract.
          • Severe thrombocytopenia <30 × 109/L was observed in three patients.

          The analysis of cumulative incidence demonstrated the following:

          • Thrombotic events were reported earlier than bleeding events.
          • Median times to thrombosis and bleeding events were 11.5 days (IQR, 4.0–25.0) and 16.0 days (IQR, 13.0–24.0), respectively.
          • The cumulative incidence rates at 10, 20, and 30 days were 4.1%, 5.9%, and 7.1%, respectively, for thrombosis, and 0.6%, 2.4%, and 3.6%, respectively, for bleeding.
          • Mortality reached 26.6% (95% confidence interval [CI], 4.9–13.4%) at Day 60 with most of the fatal events occurring in the first 15 days (20%).
            • The most fatal events overall were pneumonia (37%) and multiorgan failure (41%).
            • Pneumonia as a cause of death was more common in patients with ET (55%) compared with PV (33%) or MF (29%).
            • Deaths due to multiorgan failure did not differ among the MPN phenotypes.
          • The probability of survival was higher in patients with ET who did not experience thrombosis (75.6%; 95% CI, 67.5–82.0%) compared with those with ET and thrombosis (53.6%; 95% CI, 23.3–76.6%; p = 0.052).

          Univariate analysis for the risk of thrombosis

          • In univariate analysis, the risk for thrombosis was significantly higher in patients with ET compared with those with PV or MF (p = 0.018). However, there was no correlation between the occurrence of thrombosis and various variables, including driver mutations, gender, age, history of thrombosis or bleeding, splenomegaly, duration of MPN disease, or exposure to cytoreductive therapy.
          • Interestingly, platelet counts were significantly lower (−23.2%; p < 0.0001) at the time of COVID-19 diagnosis compared with at the last MPN follow-up visit before COVID-19 onset. This difference was more apparent in patients with ET (p ≤ 0.0001) and less apparent in PV (p = 0.1730). Furthermore, this platelet count reduction was associated with a higher mortality rate from pneumonia (p = 0.0051).
          • Inflammation indicators, such as neutrophil/lymphocyte ratio (NLR; p = 0.004), platelet/lymphocyte ratio (p = 0.02), and C-reactive protein (p = 0.019) levels, were significantly higher in patients with thrombosis. For D-dimer levels, no significant correlation was found with thrombosis in the entire patient population. However, D-dimer levels were significantly higher in patients with ET and thrombosis compared with those without thrombosis (p < 0.0001).
          • Further correlations with the risk of thrombosis were found for patients transferred to ICU and those treated with corticosteroids or antibiotics.

          Multivariate analysis for the risk of thrombosis

          Multivariate analysis confirmed the following three markers as independently associated with thrombosis risk:

          • Transfer to ICU (sub-distribution hazard ratio [SHR], 3.73; 95% CI, 1.14–12.23; p = 0.029).
          • NLR (SHR, 1.16; 95% CI, 1.06–1.27; p = 0.001).
          • ET phenotype (SHR, 4.37; 95% CI, 1.51–12.64; p = 0.006).

          Conclusion

          The overall rate of thromboembolic events in patients with MPN and COVID-19 was 8.6% (n = 14). Strikingly, most of these events were VTE, indicating an association of VTE events observed in this study with COVID-19 rather than MPN, where arterial thrombosis is more common. However, patients with ET and COVID-19 experienced significantly more VTEs compared with patients with PV and MF, where the event rate was similar to patients with COVID-19 but without MPN, who were treated on regular wards. Vascular events occurred shortly after hospitalization and were associated with shorter survival. Independent risk factors for thrombosis were an ET phenotype, elevated NLR, and transfer to ICU. While most thrombotic events occurred within 15 days of COVID-19 onset, bleeding events were more frequent ~2 weeks after COVID-19 onset.

          The authors acknowledged that the evaluation of risk factors for thrombohemorrhagic events may be confounded with the low number of patients and the retrospective design.

          1. Barbui T, De Stefano V, Alvarez-Larran A, et al. Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19. Blood Cancer J. 2021;11(2):21. DOI: 1038/s41408-021-00417-3

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