Anticoagulation for general patients with venous thromboembolism (VTE) is quite effective in preventing recurrent VTE. However, recurrent VTE on warfarin or a direct oral anticoagulant occurs in approximately 2 percent of general VTE patients.1
Prior to diagnosing “anticoagulation failure,” one must determine whether the anticoagulated VTE patient who presents with new extremity or respiratory symptoms truly has a recurrent VTE. Doppler ultrasound and chest computed tomography angiography results may have to be reviewed with the radiologist and compared with prior studies to better determine if the thrombosis is acute or chronic. A D-dimer assay can also be helpful, as a positive result is supportive evidence for a recurrent clot, while a negative D-dimer makes new thrombosis less likely. A common cause of subtherapeutic anticoagulation is suboptimal medication adherence, occurring in 83 percent, 62 percent, and 31 percent of patients on warfarin at three, six, and 12 months, respectively.2 Unsurprisingly, subtherapeutic anticoagulation increases risk for recurrent VTE while “on” anticoagulation.3,4 It can be difficult to determine suboptimal adherence.
Causes of Anticoagulation Failure
| Pseudofailure . | True Failure . |
|---|---|
| Misinterpretation of Doppler ultrasound or chest computed tomography angiography | Cancer10,11 |
| Subtherapeutic anticoagulation (due to suboptimal adherence; inappropriate dosing; drug interactions lowering efficacy of direct oral anticoagulants)2-4 | Antiphospholipid syndrome12,13 |
| Established myeloproliferative neoplasm7 | |
| JAK2 V617F mutation positivity without established myeloproliferative neoplasm (lanotto et al) | |
| Heparin-induced thrombocytopenia in the patient on heparin or with recent heparin exposure | |
| Unexplained |
| Pseudofailure . | True Failure . |
|---|---|
| Misinterpretation of Doppler ultrasound or chest computed tomography angiography | Cancer10,11 |
| Subtherapeutic anticoagulation (due to suboptimal adherence; inappropriate dosing; drug interactions lowering efficacy of direct oral anticoagulants)2-4 | Antiphospholipid syndrome12,13 |
| Established myeloproliferative neoplasm7 | |
| JAK2 V617F mutation positivity without established myeloproliferative neoplasm (lanotto et al) | |
| Heparin-induced thrombocytopenia in the patient on heparin or with recent heparin exposure | |
| Unexplained |
The Table lists the causes of anticoagulation failure that clinicians should consider. Thrombophilias, other than antiphospholipid syndrome (APS), are not associated with a higher risk of recurrent VTE during warfarin therapy.5 Patients with established myeloproliferative neoplasms (MPNs) have a high rate of anticoagulation failure.6 Failure of vitamin K antagonist therapy is seen in 4.2 percent of patients with an established MPN per year.7 With regard to which patients with anticoagulation failure should be screened for JAK2 V617F or CALR mutations, no previous study has reported the prevalence of JAK2 V617F or CALR mutations in unselected patients with anticoagulation failure. Therefore, the present exploratory study was undertaken.
The article by Dr. Jean-Christophe Ianotto and colleagues reports the results of a single-center observational prospective cohort of 787 patients with unprovoked VTE enrolled between the years 2000 and 2013. JAK2 V617F and CALR mutation analyses were performed retrospectively on stored blood samples. The present analysis is from the first half (n = 372) of these patients. Of 372 patients, 138 (37.1%) had isolated leg deep vein thrombosis (DVT), and 234 (62.9%) had a pulmonary embolism with or without DVT.
The main findings of this study include prevalence of the JAK2 V617F and CALR mutations, rates of recurrent VTE on and off anticoagulation, and presence of an overt MPN. In the overall cohort, 10 patients (2.7%) were carrying the JAK2 V617F mutation, and none had a CALR mutation, nineteen patients (5.1 %) had a recurrent VTE on therapeutic anticoagulation. The key finding is that four (21 %) of these 19 individuals had the JAK2 V617F mutation, compared to six (1.7%) of 353 patients who did not have VTE recurrence on anticoagulation (p<0.001). In one of the four JAK2 V617F–positive patients with anticoagulation failure, an MPN was diagnosed within six months of the recurrence, but the remaining three did not develop an overt MPN during the follow-up period (length of follow-up in these 3 patients was not reported). Finally, 16 patients (4.3%) in the overall cohort developed a VTE recurrence within four weeks of having stopped anticoagulation. None of them carried the JAK2 V617F mutation.
The authors concluded that screening for the JAK2 V617F mutation in VTE patients with anticoagulation failure may be warranted, as the prevalence is high, reaching 21 percent; that the prevalence of CALR mutations in patients with anticoagulation failure is low (0%); and that systematic screening for JAK2 V617F and CALR mutations cannot be recommended for patients with recurrent VTE off anticoagulation.
In Brief
How do these study findings impact our practice? In patients with recurrent VTE on anticoagulation but without established MPN, we consider JAK2 V617F testing, but not CALR testing. However, we acknowledge that it is not known whether mutation testing in this situation is beneficial, nor whether an overt MPN will develop.8,9 It may be sufficient to serially monitor CBCs, as only elevations in hematocrit or platelet count would merit cytoreduction in the present treatment paradigms for MPN.
References
Competing Interests
Dr. Moll and Dr. Reeves indicated no relevant conflicts of interest.
