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Thrombotic thrombocytopenic purpura in chronic myelogenous leukemia

Published:February 18, 2020DOI:https://doi.org/10.1016/j.jcjo.2020.01.003
      Thrombotic thrombocytopenic purpura (TTP) is a rare disease characterized by the pentad of microangiopathic hemolytic anemia, thrombocytopenia with purpura, acute kidney injury, neurologic abnormality with fluctuating mental status, and fever.
      • Percival S.P.
      Ocular findings in thrombotic thrombocytopenic purpura (Moschcowitz's disease).
      ,
      • Said A.
      • Haddad R.Y.
      • Stein R.
      • Lerma E.
      Thrombotic thrombocytopenic purpura.
      It has an incidence ranging from 3.7 to 11 cases per million and risk factors that include female gender, Afro-Caribbean ancestry, and obesity.
      • Said A.
      • Haddad R.Y.
      • Stein R.
      • Lerma E.
      Thrombotic thrombocytopenic purpura.
      The prevailing pathophysiologic theory for TTP asserts that patients have a deficiency or defect in A disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13), a protease that cleaves large multimers of von Willebrand factor.
      • Tsai H.M.
      Pathophysiology of thrombotic thrombocytopenic purpura.
      When these multimers are not cleaved, they build up disproportionately to normal von Willebrand factor in the blood stream and trigger platelet-rich microthrombi formation and subsequent mechanical hemolysis.
      • Tsai H.M.
      Pathophysiology of thrombotic thrombocytopenic purpura.
      ,
      • Zhao C.
      • Qu Y.
      • Sui R.
      • et al.
      Delayed visual recovery in pregnancy-associated thrombotic thrombocytopenic purpura with bilateral serous retinal detachment.
      This process is usually caused by a genetic mutation in the ADAMTS13 gene or by an autoimmune process; however, it may also be triggered by infection,
      • Tsai H.M.
      Pathophysiology of thrombotic thrombocytopenic purpura.
      pregnancy,
      • Tsai H.M.
      Pathophysiology of thrombotic thrombocytopenic purpura.
      ,
      • Zhao C.
      • Qu Y.
      • Sui R.
      • et al.
      Delayed visual recovery in pregnancy-associated thrombotic thrombocytopenic purpura with bilateral serous retinal detachment.
      or medications.
      • Demirsoy E.T.
      • Mehtap O.
      • Atesoglu E.B.
      • et al.
      Dasatinib-induced immune mediated-thrombotic thrombocytopenic purpura.
      Although pieces of the classic pentad are the most common presentation for TTP, ophthalmologic manifestations also rarely occur. We present a case of TTP secondary to dasatinib therapy with the ocular manifestation of papilledema.
      A 33-year-old African American male presented with a chief complaint of throbbing, bilateral headache for several days in both his forehead and occipital region with associated intermittent arm numbness and blurry vision. His medical history was significant for chronic myelogenous leukemia (CML) in molecular remission, hypertension, stage II chronic kidney disease, and syphilis, for which he received penicillin treatment 14 years ago. His family history was significant for hypertension and type II diabetes. His surgical, ocular, and social history was unremarkable. The patient's current medications included valsartan/hydrochlorothiazide and dasatinib 50 mg daily, a chemotherapeutic agent for his CML. Physical examination showed ecchymoses over his lateral chest and right lower extremity. Ocular examination showed a best-corrected visual acuity measured at 20/25 OD (right eye) and 20/20 OS (left eye). Pupils were 4 mm in the dark and 3 mm in the light in both eyes (OU). Extraocular motility was full without any deficit. External and slit-lamp examinations were normal. On fundus examination, he had bilateral Frisen grade 1 papilledema, along with peripapillary angioid streaks. Humphrey visual field testing was normal, and optical coherence tomography global thickness of the retinal nerve fibre layer was 138 OD and 129 OS (Fig. 1), consistent with disc edema OU. Laboratory studies revealed a hemoglobin level of 8.7 g/dL, platelet count of 22 000/μL, elevated lactic acid dehydrogenase, elevated reticulocyte count, and schistocytes on blood smear. Due to bicytopenia, waxing and waning neurologic complaints, and current use of dasatinib, there was high suspicion for TTP confirmed by positive ADAMTS13 activity assay. He was started on high-dose prednisone therapy and plasmapheresis treatment. Owing to the presence of papilledema, magnetic resonance imaging (MRI) of the brain and orbit was performed, revealing a partially empty sella (Fig. 2). Magnetic resonance venography (MRV) demonstrated moderate focal stenosis of the distal right transverse sinus (Fig. 3) without evidence of thrombosis confirmed by computed tomography venogram (CTV). Lumbar puncture revealed an elevated opening pressure of 50 cm of H2O and otherwise normal cerebrospinal fluid. Repeat rapid plasma reagin testing was negative. A diagnosis of increased intracranial pressure (ICP) secondary to TTP and co-existing anemia was made. The asymmetry demonstrated by the MRV could be explained by a physiologic left transverse sinus dominance or a component of transverse sinus stenosis contributing to the increased ICP. This could be further elucidated if the asymmetry were to remain constant on repeat MRV. His hemoglobin and platelet counts normalized with the prednisone and plasmapheresis therapy, and the patient was started on Diamox 1000 mg daily to treat his elevated ICP. This dose was deemed appropriate despite his decreased kidney function, as his creatinine clearance was estimated to be greater than 50 mL/min, at which point dose modification may be considered. At 1 month of follow-up, his creatinine remained within normal limits at 1.26 mmol/L.
      Fig 1
      Fig. 1Fundus photographs of the right (A) and left (B) fundi demonstrating Frisen grade 1 papilledema and angioid streaks. Optical coherence tomography of the retinal nerve fibre layer consistent with optic disc edema (C).
      Fig 2
      Fig. 2Sagittal T1 (A) and axial T2 (B) magnetic resonance images of the brain and orbit demonstrating empty sella and fluid in the optic nerve sheath, respectively.
      Fig 3
      Fig. 3Magnetic resonance venography demonstrating stenosis of the right transverse sinus.
      Dasatinib is a tyrosine kinase inhibitor that acts on BCR-ABL kinase and is used in the treatment of CML.
      • Demirsoy E.T.
      • Mehtap O.
      • Atesoglu E.B.
      • et al.
      Dasatinib-induced immune mediated-thrombotic thrombocytopenic purpura.
      TTP is a rare disease characterized by the classic pentad of microangiopathic hemolytic anemia, thrombocytopenia with purpura, acute kidney injury, neurologic abnormality with fluctuating mental status, and fever.
      • Percival S.P.
      Ocular findings in thrombotic thrombocytopenic purpura (Moschcowitz's disease).
      ,
      • Said A.
      • Haddad R.Y.
      • Stein R.
      • Lerma E.
      Thrombotic thrombocytopenic purpura.
      Ocular manifestations of this disease are under-recognized and have been reported to occur in 14–20% of cases.
      • Bobbio-Pallavicini E.
      • Porta C.
      • Brocchieri A.
      • Saporiti A.
      • Tacconi F.
      Ocular involvement in acute thrombotic thrombocytopenic purpura.
      We reviewed the literature for the various ophthalmologic manifestations of TTP and found the following reported: both serous
      • Zhao C.
      • Qu Y.
      • Sui R.
      • et al.
      Delayed visual recovery in pregnancy-associated thrombotic thrombocytopenic purpura with bilateral serous retinal detachment.
      and traction
      • Lewellen D.R.
      • Singerman L.J.
      Thrombotic thrombocytopenic purpura with optic disk neovascularization, vitreous hemorrhage, retinal detachment, and optic atrophy.
      retinal detachments, papilledema from malignant hypertension,
      • Bashir T.
      • Alfishawy M.
      • Babigumira M.
      • Bashir T.
      Malignant hypertension and thrombotic thrombocytopenic purpura: false friends.
      • Dunea G.
      • Muehrcke R.C.
      • Nakamoto S.
      • Schwartz F.D.
      Thrombotic thrombocytopenic purpura with acute anuric renal failure.
      • O'Brien J.L.
      • Sibley W.A.
      Neurologic manifestations of thrombotic thrombocytopenic purpura.
      retinal hemorrhages,
      • Hartley K.L.
      • Benz M.S.
      Retinal pigment epithelial tear associated with a serous retinal detachment in a patient with thrombotic thrombocytopenic purpura and hypertension.
      retinal vascular occlusion including central retinal artery occlusion or central retinal vein occlusion,
      • Schwartz S.G.
      • Hickey M.
      • Puliafito C.A.
      Bilateral CRAO and CRVO from thrombotic thrombocytopenic purpura: OCT findings and treatment with triamcinolone acetonide and bevacizumab.
      choroid vasculopathy,
      • Percival S.P.
      Ocular findings in thrombotic thrombocytopenic purpura (Moschcowitz's disease).
      retinal pigment epithelium tear (thought to be owing to increased perfusion pressure secondary to hypertension as well as damage to the choroidal vasculature),
      • Hartley K.L.
      • Benz M.S.
      Retinal pigment epithelial tear associated with a serous retinal detachment in a patient with thrombotic thrombocytopenic purpura and hypertension.
      optic disk neovascularization,
      • Lewellen D.R.
      • Singerman L.J.
      Thrombotic thrombocytopenic purpura with optic disk neovascularization, vitreous hemorrhage, retinal detachment, and optic atrophy.
      vitreous hemorrhage,
      • Lewellen D.R.
      • Singerman L.J.
      Thrombotic thrombocytopenic purpura with optic disk neovascularization, vitreous hemorrhage, retinal detachment, and optic atrophy.
      homonymous hemianopia (possibly owing to petechial hemorrhages related to areas of microangiopathy),
      • Percival S.P.
      Ocular findings in thrombotic thrombocytopenic purpura (Moschcowitz's disease).
      ,
      • O'Brien J.L.
      • Sibley W.A.
      Neurologic manifestations of thrombotic thrombocytopenic purpura.
      and various cranial nerve palsies (possibly owing to thrombotic ischemia).
      • Percival S.P.
      Ocular findings in thrombotic thrombocytopenic purpura (Moschcowitz's disease).
      Our patient presented with the ocular finding of papilledema; however, he did not have concomitant malignant hypertension as seen in previous cases.
      • Bashir T.
      • Alfishawy M.
      • Babigumira M.
      • Bashir T.
      Malignant hypertension and thrombotic thrombocytopenic purpura: false friends.
      • Dunea G.
      • Muehrcke R.C.
      • Nakamoto S.
      • Schwartz F.D.
      Thrombotic thrombocytopenic purpura with acute anuric renal failure.
      • O'Brien J.L.
      • Sibley W.A.
      Neurologic manifestations of thrombotic thrombocytopenic purpura.
      After our review, we found no other cases of TTP presenting with papilledema in a patient without malignant hypertension. Additionally, though it has been reported in the literature, microangiopathic hemolytic anemia (MAHA) secondary to tyrosine kinase inhibitor use is very rare. Three cases have been reported after imatinib use,
      • Al Aly Z.
      • Philoctête Ashley J.M.
      • Gellens M.E.
      • González E.A.
      Thrombotic thrombocytopenic purpura in a patient treated with imatinib mesylate: true association or mere coincidence?.
      ,
      • Ojeda-Uribe M.
      • Merieau S.
      • Guillon M.
      • et al.
      Secondary thrombotic microangiopathy in two patients with Philadelphia-positive hematological malignancies treated with imatinib mesylate.
      and to our knowledge, only 2 cases of dasatinib-induced MAHA have been reported in the literature.
      • Demirsoy E.T.
      • Mehtap O.
      • Atesoglu E.B.
      • et al.
      Dasatinib-induced immune mediated-thrombotic thrombocytopenic purpura.
      ,
      • Martino S.
      • Daguindau E.
      • Ferrand C.
      • et al.
      A successful renal transplantation for renal failure after dasatinib-induced thrombotic thrombocytopenic purpura in a patient with imatinib-resistant chronic myelogenous leukaemia on nilotinib.
      We believe that our patient had a side effect of the treatment of the underlying disease, CML (i.e., CML treated with dasatinib leading to TTP, which in turn provoked intracranial hypertension from the underlying anemia and thrombocytopenia).
      To support our hypothesis of increased ICP secondary to TTP and co-existing anemia, we examined alternate etiologies. First, the papilledema could have been secondary to malignant hypertension; however, physical examination showed a normal blood pressure. An MRV and subsequent CTV were then performed to investigate the possibility of venous sinus thrombus, which could have occurred secondary to thrombi from TTP or a hypercoagulable state owing to the patient's underlying malignancy. We also performed MRI of the brain and orbit to assess for any metastases that could have increased ICP directly (by mass effect) or indirectly (through blockade of arachnoid granulations and, thus, cerebrospinal fluid outflow). Additionally, though the patient had a prior negative rapid plasma reagin test, we repeated this test to investigate for neurosyphilis. The MRV and CTV did not show any evidence of thrombus formation, and the MRI did not reveal any metastases. The repeat rapid plasma reagin also returned negative.
      It is our hope that this article increases awareness of the possibility of MAHA occurring in a patient on tyrosine kinase inhibitor therapy and possible ophthalmic and neuro-ophthalmic complications occurring either directly or indirectly from a side effect of the drug after ruling out direct disease progression or metastasis. We also emphasize that ophthalmologic findings in TTP may aid in early diagnosis and treatment.

      Footnotes and Disclosure

      The authors report no conflict of interest and received no financial support or sponsorship.

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