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Double the Trouble: Acute Coronary Syndrome and Ischemic Stroke in Polycythemia Vera

      Keywords

      Presentation

      Vague symptoms turned out to be life-threatening conditions. A 50-year-old man with a history of polycythemia vera presented to the hospital with epigastric discomfort and clumsiness of the right hand for 5 days. Polycythemia vera was diagnosed 1 year prior, with good control of hematocrit by intermittent phlebotomy. He did not have any other medical history and was not taking any medications. He denied chest pain, shortness of breath, nausea, headache, vision change, or speech difficulty.

      Assessment

      On examination, he was in no acute distress and the vital signs were unremarkable except for increased heart rate of 119 beats per minute. Cardiovascular examination revealed regular rhythm with normal S1 and S2 sounds without murmur, rubs, or gallops. Lung fields were clear to auscultation. Laboratory investigation revealed white blood cell count of 33 × 109/L, hemoglobin of 13.5 g/dL, and platelet count of 1252 × 109/L. Noncontrast computed tomography of the head did not show intracranial hemorrhage. Troponin was elevated and electrocardiogram showed Q waves in the inferior leads and nonspecific ST-T changes. An echocardiogram showed inferior wall hypokinesis. Antiplatelet therapy was initiated with aspirin, prasugrel, and Integrilin (Merck & Co, Inc, Whitehouse Station, NJ) infusion, and troponin was trended daily. He was also initiated with hydroxyurea to reduce platelet count.
      The patient reported worsening numbness and clumsiness in the right hand on day 5, and magnetic resonance imaging and magnetic resonance angiography were performed on day 7. The images showed multiple foci of cortical diffusion restriction with fluid-attenuated inversion recovery signal abnormality consistent with acute to early subacute infarcts in the bilateral frontal, parietal, and occipital lobes, and in the left cerebellum (Figure 1). The common, internal, and external carotid arteries were patent. Transesophageal echocardiogram did not demonstrate a cardiac source of emboli.
      Figure thumbnail gr1
      Figure 1Magnetic resonance imaging (MRI) scan showing multifocal ischemic stroke. Diffusion-weighted imaging and T2 fluid-attenuated inversion recovery (FLAIR) images of brain MRI show multiple foci of diffusion restriction with FLAIR signal abnormality consistent with acute to early subacute infarcts. There was also an old lacunar infarct in left corona radiate and external capsule.
      On day 10, blood count decreased to white blood cell count of 14.5 × 109/L and platelet of 669 × 109/L. Cardiac catheterization was deemed safe and he underwent coronary angiogram, which showed coronary artery disease without any obstructions.

      Diagnosis

      With electrocardiogram finding, elevated troponin and evidence of hypokinesis in echocardiogram, he was diagnosed with non-ST-segment elevation myocardial infarction on admission. He was also diagnosed with acute to subacute multifocal ischemic stroke from magnetic resonance imaging findings later during the hospital stay.
      Polycythemia vera is one of the myeloproliferative neoplasms characterized by abnormal proliferation of hematopoietic stem cells.
      • Spivak J.L.
      Polycythemia vera: myths, mechanisms, and management.
      Thrombosis in polycythemia vera is not a rare event: the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study revealed that incidence of fatal, major and minor thrombosis was 5.5 events/100 persons per year, with myocardial infarction of 0.32 and stroke of 0.53 events/100 persons per year, respectively.
      • Finazzi G.
      Low-Dose Aspirin in Polycythemia (ECLAP)
      A prospective analysis of thrombotic events in the European collaboration study on low-dose aspirin in polycythemia (ECLAP).
      His presentation was atypical for both myocardial infarction and ischemic stroke, and could have been missed easily. Notably, there is, to our knowledge, no report of simultaneous manifestation of these events during the course of polycythemia vera. The mechanism underlying the hemostatic imbalance in polycythemia vera is not completely understood. Clinical data have implicated that increased hematocrit, increased leukocytes, increased or activated platelets, and increased JAK2V617F allele burden are risk factors for thrombosis in polycythemia vera patients in addition to conventional risks.
      • Marchioli R.
      • Finazzi G.
      • Specchia G.
      • et al.
      Cardiovascular events and intensity of treatment in polycythemia vera.
      • Bonicelli G.
      • Abdulkarim K.
      • Mounier M.
      • et al.
      Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera: a population-based study of 327 patients.
      • Vannucchi A.M.
      • Antonioli E.
      • Guglielmelli P.
      • et al.
      Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden.
      • Dawson A.A.
      • Ogston D.
      The influence of the platelet count on the incidence of thrombotic and haemorrhagic complications in polycythaemia vera.
      • Landolfi R.
      • Ciabattoni G.
      • Patrignani P.
      • et al.
      Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo.
      However, the current consensus on criteria to stratify patients into high-risk category is age >60 years or with a history of thrombosis, or both. These patients are considered to benefit from cytoreduction in addition to phlebotomy, correction of cardiovascular risk factors, and low-dose aspirin.
      • Tefferi A.
      • Barbui T.
      Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management.
      The treatment goal to reduce thrombotic events focuses on maintaining hematocrit <45% based on a randomized clinical trial.
      • Marchioli R.
      • Finazzi G.
      • Specchia G.
      • et al.
      Cardiovascular events and intensity of treatment in polycythemia vera.
      In our case, the patient fit in the low-risk category prior to the events and he was managed by phlebotomy. The hematocrit was well controlled at <45%; however, the platelet and white blood cell count were rising, with platelets exceeding 1000 × 109/L and white blood cell count >25 × 109/L (Figure 2), which, in retrospect, may have contributed to the thrombotic events.
      Figure thumbnail gr2
      Figure 2Hematocrit (HCT) and white blood cell (WBC) count during the course of polycythemia vera. Trend of hematocrit and platelet count (A) and hematocrit and white blood cell count (B) since the patient was diagnosed with polycythemia vera. The patient achieved the goal of hematocrit <45% after 2 months of diagnosis; however, his platelet and white blood cell count were elevated prior to his thrombotic events.

      Management

      The patient was initiated with antiplatelet therapy upon diagnosis of non-ST-segment elevation myocardial infarction. Cardiac catheterization was deferred because elevated blood counts would put him at risk for thrombosis and bleeding complications. Instead, cytoreduction therapy was initiated with hydroxyurea to decrease platelet and white blood cell count prior to coronary angiography. The blood count improved prior to the coronary angiography, and he did not have any complications from the procedure.
      The management of acute-phase thrombotic events in polycythemia vera patients has not reached consensus. As described in an early case report in 1899,
      • Cabot R.C.
      A case of chronic cyanosis without discoverable cause, ending in cerebral hemorrhage.
      polycythemia vera can cause both hemorrhage and thrombosis. In our case also, there was concern for hemorrhagic diathesis, with minimal disturbance in hemostatic balance. Exchange phlebotomy and platelet pheresis is often used to acutely lower red blood cell or platelet count. The safety of anticoagulant and thrombolytic therapy is not fully proven in polycythemia vera. A report showed that heparin, which is usually used in acute-phase myocardial infarction, was ineffective in polycythemia vera patients.
      • Zinn P.
      • Applegate R.J.
      • Walsh R.A.
      Acute total aortic occlusion during cardiac catheterization associated with polycythemia vera.
      Also, arterial catheterization with stent placement in an uncontrolled polycythemia vera patient may precipitate thrombosis.
      • Bacani C.J.
      • Maniaci M.J.
      • Blackshear J.L.
      Subacute stent thrombosis in a patient with polycythemia vera.
      It was notable that the coronary angiogram performed on day 10 did not show any obstruction. We noted that troponin level decreased significantly on day 6 (Figure 3), which may suggest that obstructing thrombus had spontaneously resolved prior to angiogram.
      Figure thumbnail gr3
      Figure 3Trend of troponin and cardiac angiogram. (A) Trend of troponin after admission, which peaked on day 4-5 and significantly decreased on day 6. (B) Cardiac angiogram on day 10 showing nonobstructive coronary artery disease.
      For multifocal ischemic stroke, there was no cardiac source of emboli and it was thought that the infarcts were considered secondary to spontaneous thrombosis. It is known that multifocal ischemic stroke in different vascular territories is significantly more frequent in patients with hematological disorders,
      • Fagniez O.
      • Tertian G.
      • Dreyfus M.
      • Ducreux D.
      • Adams D.
      • Denier C.
      Hematological disorders related cerebral infarctions are mostly multifocal.
      and our patient was not an exception. He was initiated with high-intensity statin therapy for secondary prevention.
      He was discharged the following day of coronary angiography with continuation of hydroxyurea and low-dose aspirin. He also received physical and occupational therapy and recovered with minimal residual deficits. Since discharge, the hemoglobin level was stable, while white blood cell and platelet counts decreased in a short period and stabilized with hydroxyurea (Figure 4).
      Figure thumbnail gr4
      Figure 4Trend of blood cell count after the thrombotic events. White blood cell (WBC) count, hemoglobin, and platelet count after the thrombotic events. Patient began hydroxyurea immediately after admission, and the dose was adjusted according to response. Note that hemoglobin is relatively stable throughout the treatment, whereas platelet and white blood cell counts were reduced.

      Conclusion

      A low threshold to work up for thrombotic events should be kept for a patient with polycythemia vera. Further understanding of pathophysiology of thrombohemorrhagic diathesis, and the discovery of laboratory markers of intrinsic state of platelet or leukocyte activities to predict thrombotic events in addition to the established markers to risk-stratify the patients is awaited.

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