Myeloproliferative neoplasms, thrombosis, and COVID-19

Myeloproliferative neoplasms (MPN) are associated with a high prevalence of thrombosis at diagnosis: 28.6% in polycythemia vera (PV), 20.7% in essential thrombocytosis, and 9.5% in myelofibrosis.¹ COVID-19 has also been associated with thrombosis, and there are similarities in the pathophysiology which raise concerns about the elevated risk that COVID-19 poses to patients with MPN.²

On the second day of the Texas Virtual MPN Workshop (TMW) 2020: First Annual Workshop and Meeting, Laura Michaelis, Medical College of Wisconsin² and Brady Stein, Feinberg School of Medicine, Northwestern University,¹ each gave a presentation on COVID-19 and MPN. Here, we are pleased to summarize the key points of their talks.

What do we know about MPN and COVID?

As highlighted by Laura Michaelis, there is little information and limited sources of information regarding general management of MPN in the COVID-19 pandemic. Current knowledge is based on published literature, registries, biological expectations, and expert guidelines.

There are two registries aiming to gather information on COVID-19 in patients with solid tumors/hematological malignancies:

• The COVID-19 & Cancer Consortium (CCC-19) is based on a registry of more than 120 cancer centers and other institutions to collect data about patients with cancer and COVID-19. Currently, of the 928 patients entered into the registry, 22% have hematological malignancies.
• The American Society of Hematology (ASH) has built the Research Collaborative COVID-19 Registry for Hematology, which collects data on patients with a hematologic disease and COVID-19 or patients who experienced a hematologic complication after COVID-19. It has currently collected data on 478 patients. Available data show that the death rate among these patients was 22%, with 36% of these patients requiring hospitalization (data cutoff Aug 15, 2020).

Other studies have demonstrated that having cancer was found to be the highest risk factor for severe events during a COVID-19 infection (OR, 5.3; 95% CI, 1.8–16.2; p = 0.003).² The fatality rate in cancer patients ranged from 5–28%, compared with 2.3% in patients without cancer.² A smaller cohort study at two centers in Wuhan, China conducted by Wenjuan He et al,³ investigated 129 hospitalized patients with hematological malignancies and 226 healthcare providers (HCPs). They found that 10% of patients (n = 13) developed COVID-19 compared to 7% (n = 16) of HCPs. Also, patients with hematological malignancies had an increased disease severity and risk of death compared to 11 hospitalized HCPs with COVID-19 (Table 1).

Table 1. The comparison of outcomes of patients with hematological cancer and hospitalized healthcare workers with COVID-19²

Vulnerability of patients with MPN to COVID-19²

Dr Michaelis discussed the unique vulnerabilities of patients with MPN, noting that they may be more likely to get severe disease upon infection, which may be attributed to older age, a higher rate of comorbid conditions, such as pulmonary hypertension, and higher rates of congestive heart failure, peripheral vascular disease, and stroke. Highlighting that COVID-19 is an infection associated with high rates of clotting, this may aggravate complications in MPN leading to an increased risk in patients who would otherwise have been considered low risk.

MPN-related thrombosis¹

To understand the risk COVID-19 poses to patients with MPN, and potential treatment strategies, Brady Stein emphasized the high rates of thrombosis in patients with MPN.

A study conducted by Malin Hultcrantz et al.⁴ with 9,429 patients with MPN and 35,820 matched controls found that patients with MPN are at higher risk of thrombosis at diagnosis (arterial thrombosis, HR 3.0; venous thrombosis, HR 9.7), though the risk still remains 1 year (HR, 2.0 and 4.7, respectively) and 5 years (HR, 1.5 and 3.2, respectively) after diagnosis. Furthermore, 16.2% of patients with MPN present with arterial thrombosis and 6.2% with venous thrombosis. This study confirmed older age and prior thrombosis as risk factors for thrombosis (HR, 2.4 and 2.7, respectively). It also highlighted that a combination of older age (> 60 years old) and prior thrombosis greatly increased the risk of thrombosis (HR, 7.0).

Thrombosis risk classification varies for different subtypes of MPNs (Table 2).

Table 2. Thrombosis risk groups in MPN subtypes¹

 Other variables, such as blood cell quantity, are also important factors in thrombosis risk.

• Platelet count has been associated with bleeding rather than thrombosis.
• Leukocyte number seems to be associated with thrombosis.
• Red cell count seems to be a risk factor for major thrombosis/cardiovascular (CV) death.

As the effect of mutations in patients with MPN is becoming better understood in terms of thrombosis risk, it becomes increasingly clear that mutations matter.

Different mutations result in varying thrombosis, risk depending on the specific MPN. For example, in essential thrombocytosis, CALR mutations have a 10-year cumulative incidence (CI) of thrombosis of 5%, whereas the MPL mutation conveys the highest risk of thrombosis, with a 10-year CI of 19.5%. In myelofibrosis, CALR mutations are the lowest risk but have a 10-year CI of 13.6%, with the JAK2 V617F mutation being the highest risk at a 10-year CI of 18.3%. In patients with PV, thrombosis risk seems to be influenced only by the JAK2 V617F variant allele frequency.¹

In recent studies modelling JAK2 V617F mutations, a pro-thrombotic phenotype has been found to occur due to changes in endothelial expression of P-selectin and β1/β2 integrins, leading to increased neutrophil extracellular traps, which are thought to affect how white blood cells adhere to the endothelium and may increase MPN-associated thrombosis.¹

As Dr Stein highlighted, MPN-related thrombosis is very complex with contributions of multiple factors, including CV risk factors, gender, age, thrombosis history, inflammation (CRP/pentraxin 3), leukocytosis, and erythrocytosis.

COVID-19-associated coagulopathy¹

COVID-19 has a distinct form of coagulopathy which comes with:

• Increased d-dimers
• Mild thrombocytopenia
• Unremarkable prothrombin/prothrombin time
• Increased fibrinogen
• Venous thrombosis
• Arterial thrombosis
• CV accident in the young
• Clotting of catheters or circuits
• Microthrombosis

Possible contributors to COVID-19 thrombosis include platelet activation, thrombin generation, complement activation, antiphospholipid antibodies, and suppression of fibrinolysis following inflammatory stress.  This concept is called ‘thromboinflammation’, suggesting that it is a surge of inflammation which leads to downstream effects causing thrombosis. It is worth noting that this pattern is also seen in MPN.¹

Autopsy studies have shown severe endothelial injury, accompanied by intracellular virus particles, and widespread thrombosis with microangiopathy. This suggests that the thrombosis risk associated with COVID-19 may not only be attributed to thromboinflammation but also to endotheliopathy. Whether this is a cause or consequence of multi-organ failure is still unknown.

Management of patients with MPN and COVID-19

Surveys among treating physicians have shown that the management of hematological disorders, including MPN, was similar following a diagnosis of COVID-19, with mild modifications.

The current recommendations for treatment of patients with MPN in the era of COVID-19, and how these translate to clinical practice, are summarized from both presentations in Table 3.

Table 3. Summary of current recommendations in patients with MPN and with/without COVID-19^1,2

 While ruxolitinib has been associated with improved outcomes after severe COVID-19 infection, it is unclear whether JAK inhibition would also convey a protective effect, and there are trials ongoing to assess ruxolitinib (alone and in combination with other immunomodulatory agents) for the treatment of COVID-19 in various settings. Other agents currently under investigation include tofacitinib and baricitinib. It is worth noting that ruxolitinib treatment should not be stopped in patients with MPN and COVID-19 as there may be some benefit in terms of cytokine protection.²

Conclusion

Laura Michaelis described COVID-19 as a disorder of the blood, leading to thrombotic events which may be amplified in patients with MPN. Furthermore, studies have shown that there is a higher risk for more severe COVID-19 disease and death in patients with MPN. Although there is insufficient data for evidence-based management of COVID-19 in patients with MPN, treatment guidelines have been developed mostly based on expert consensus. It is important to remember that patients are concerned regarding their infection risk and the risk of severe illness. Online sources, such as the ASH COVID-19 resources, provide information for treating clinicians to support the decision-making process. Current studies are ongoing to address the role of JAK inhibition for the treatment of COVID-19. Healthcare professionals are encouraged to register patients with COVID-19 and MPN in online databases such as the ASH COVID-19 Registry or CCC-19 in order to support the clinical learning process.