Reader Responses: Is JAK2 positivity clinically significant in this 28-year-old patient with Budd-Chiari syndrome?

Here’s how readers responded to a You Make the Call question about the clinical significance of JAK2 positivity in a patient with Budd-Chiari syndrome.

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Hepatic vein thrombosis is the only type of venous thrombosis that is specifically associated with JAK2 V617F expression. It also occurs more frequently in young women with PV, while portal vein thrombosis is more common in men with polycythemia vera (PV). JAK2 V617F can be acquired at any time in life and can occur in individuals with no clinical evidence of a myeloproliferative disorder (clonal hematopoiesis of indeterminate potential), though in this situation it predisposes to cardiovascular disease, not hepatic vein thrombosis. The variant allele frequency of 0.06% is too low to be associated with clinical manifestations of a myeloproliferative neoplasm (MPN) and I would not associate it with the hepatic vein thrombosis in this patient, though I am aware of reports of the mutation being discovered years after such an event. Of course, MPN mutations are not mutually exclusive, but I doubt that CALR or MPL mutation would be involved here. Most important would be the evaluation for other forms of thrombophilia such as paroxysmal nocturnal hemoglobinuria, antiphospholipid syndrome, or a hereditary thrombophilia. Equally important is not to fall into the trap of thinking that hydroxyurea is a useful remedy in this situation. It is not, nor are antiplatelet agents.

Jerry Spivak, MD
Baltimore, MD

Yes, allele burden does have a relationship with the spectrum of clinical presentation. The higher the allele burden, the higher the patient’s risk of developing thrombosis.

Israr Ahmed, MBBS
Lahore, Pakistan

Yes, there is a cutoff. No, you shouldn’t attribute the thrombosis to the JAK2 positivity.

Edgar F. Prasthofer, MD
Salt Lake City, UT

Yes. It is clinically relevant and allele frequency, as per my knowledge, is not predictive of clinical course. This should be treated as high-risk PV, particularly if no other risk factors for Budd-Chiari syndrome were present in 2015.

Maryam Khan, MBBS
Rawalpindi, Pakistan

Yes, this patient has a myeloproliferative disorder and should probably be on treatment.

Richard Lind, MD
Asheville, NC

If JAK2 is positive and the patient had a previous thrombosis, I would ignore the quantitative result and treat the clinical finding, the thrombosis, with long-lasting anticoagulation.

Laura Fogliatto, MD, PhD
Porto Alegre, Brazil

I believe that JAK2 mutation is the most likely cause, in the absence of other potential causes, especially if there is PV.

Mohamed Abdelazim, MD
Khartoum, Sudan

Yes, JAK2 mutation can cause Budd-Chiari syndrome.

Mona Grain
Tripoli, Libya

It is highly likely that the episode of thrombosis is related to the JAK2 positivity. Given the patient’s age and the likelihood of recurrence, I would consider him for long-term anticoagulation regardless of the allele burden, which is not universally available, and I am not certain if the test is standardized widely.

I had a similar case with a similarly aged patient who also had an elevated platelet count and required cytoreductive treatment. He remains well controlled and symptom free.

Hussein Baden, MD
Gatley, United Kingdom

Yes, this is clinically significant.

Michel van Gelder, MD, PhD
Maastricht, Netherlands

I think the presence of JAK2 mutation at any burden level, specifically with no other causes of thrombophilia, makes this low percentage the key toward causative pathogenesis.
In a similar case that I have with a low allele burden in the peripheral blood, another sample was taken from bone marrow, which confirmed the presence of JAK2 positivity at a high percentage. You may want to try the same step!

Rehab Al-Ansari, MD
Dammam, Saudi Arabia

The answer to this question remains speculative. There must be 1 to 3% of perfectly healthy people with this much mutated allele load. More importantly, I wouldn’t think cytoreductive treatment is warranted unless the patient has PV or thrombocytosis. I would certainly start him on anticoagulant therapy (warfarin or a direct oral anticoagulant) and monitor his JAK2 allele burden. If he does have thrombocytosis or erythrocytosis, he may be a candidate for interferon treatment. He should be tested for a panel of myeloid genes, such as TET2 and ASXL1, as these mutations sometimes precede the JAK2 V617F.

Aleksandar Mijovic, MBBS, PhD
London, United Kingdom

I have found it very rare for Budd-Chiari syndrome to exist in the absense of thrombophilia. A CT angiogram is needed to search for a local malformation that could favor such condition.

Even if the allele burden of JAK2 is very low, I consider it as pathologic. I recently saw a case of unexplained deep vein thrombosis in a 36-year-old woman who had a JAK2 clone size of around 1%, and a platelet count between 400 and 450×109/L. I would like to know this patient’s platelet counts. Finally, I would propose testing the JAK2 again in three months by an alternative method, like next generation sequencing, before considering him to have a deep vein thrombosis linked to a JAK2 positive myeloproliferative neoplasm. Meanwhile, I would continue anticoagulation therapy and advise the patient to stop smoking if he does so.

Pierre Rohrlich, MD, PhD
Nice, France

Assuming that all other prothrombotic inherited and acquired causes have been excluded, I would consider the JAK2 mutation to be sufficiently significant to manage per PV guidelines. The mutation analysis should be repeated and should again be detected.
We have a similar patient with an unprovoked pulmonary embolism that we have chosen to manage with a venesection target hematocrit of 0.45%. The patient is on lifelong anticoagulation.

The Danish population study by Cordua, et al. (Blood 2019) is probably the best evidence base, accepting that a variant allele frequency greater than 1% was their cutoff for higher blood counts and increased thrombosis.

The biggest challenge is to predict future outcomes for the patient and to advise the young man meaningfully about his likely future medical trajectory.

David Bowen, MD
Leeds, United Kingdom

I would recommend warfarin therapy to reduce the thrombotic risk.

Pietro Accardo, MD
Marsala, Italy

Yes, there is a quantitative cutoff for which the allele burden is considered clinically significant. At least practically, and that cutoff is at 0.1%. Real-time PCR tests (depending on the nature of the design) can yield a ‘positive’ response given enough amplification cycles. So, it is important to judge the very low values according to the test platform that was used to make a call at 0.06%. Many ‘normal’ samples have yielded very low JAK2 variant positives in the past with PCR assays (real-time PCR, TaqMan based PCR, allele-specific PCR, Droplet Digital PCR).

There is not a lot of support to blame the thrombosis on JAK2 V617F variant at this low of a value. There have been many reports of individuals with this low of a variant load being ‘normal.’ The causes of thrombosis should be diagnosed through the various blood tests (complete blood count, coagulation testing) that evaluate clotting factors for that individual.

Scott Reading, PhD
Salt Lake City, UT

The variant allele (JAK2 V617F) seems extremely low (0.06%). Still, if this result is clearly above the cutoff of the quantitative assay method, I would assume that the Budd-Chiari syndrome is related to an early myeloproliferative neoplasm, e.g. polycythemia vera or essential thrombocythemia. Regular follow-up, aspirin, and anticoagulant therapy should be considered.

Bernhard Lämmle, MD
Mainz, Germany