Spontaneous splenic rupture in polycythemia vera

Atraumatic spontaneous splenic rupture is rare and occurs in the setting of spleen pathology from a myriad 
of causes, including myeloproliferative disorders. Only four previously reported cases of atraumatic 
spontaneous splenic rupture associated with polycythemia vera exist. We report the fifth case, which also is 
the first with severe thrombocytosis requiring multiple plateletpheresis despite medical therapy and 
excellent long-term control. In addition to reporting the fifth case of spontaneous splenic rupture in a 
polycythemia vera patient, we also review the risks associated with splenectomy in patients with 
polycythemia vera and therapies that can prevent spontaneous splenic rupture.


INTRODUCTION
Polycythemia vera (PV), a myeloproliferative disorder, is characterized by elevated hemoglobin or hematocrit, myeloid hypercellularity, the presence of JAK2 mutation, and low erythropoietin levels.
Seventy-five to ninety percent of patients have the triad of splenomegaly, polycythemia, and ruddy cyanosis. While splenomegaly is common and causes high symptom burden, the spleen is rarely removed due to associated complications post-operatively such as platelet dysfunction and thrombocytosis.
We present (1) a rare case of a patient with PV and splenomegaly who developed atraumatic spontaneous splenic rupture requiring removal and complicated by severe thrombocytosis, (2) a review of atraumatic spontaneous splenic rupture occurring in the setting of PV and associated post-splenectomy complications, and (3) therapies directed at preventing this morbidity.

CASE REPORT
A 69-year-old Caucasian presented to the emergency room with a two-hour history of sharp, left upper quadrant abdominal pain precipitated by bending over while working in the yard. Medical history was significant for polycythemia diagnosed twenty years earlier (JAK2 V617F positive with elevated hemoglobin and hematocrit, splenomegaly, and subnormal erythropoietin; bone marrow procedure declined). He was offered hydroxyurea on initial visit and at subsequent encounters with Hematology and Medical Oncology when he developed thrombocytosis in 2016, but refused due to side effects, and instead accepted a regimen of aspirin (adding anagrelide after developing thrombocytosis) plus therapeutic phlebotomies every 3 months to keep his platelets and hematocrit below 450,000 and 45%, respectively. His splenomegaly progressed to 24 cm in 2017 sonography and was never symptomatic until presentation.
On presentation, our patient appeared uncomfortable and had tachycardia and tachypnea.
Abdominal auscultation revealed a non-distended abdomen with slightly diminished bowel sounds.
Palpation found diffuse tenderness pronounced in the epigastric and left upper quadrant regions without peritoneal signs, and splenomegaly 9 cm below the costal margin.
Computed tomography of the abdomen and pelvis with contrast enhancement demonstrated an enlarged spleen (20 cm X 22 cm) surrounded by fluid with a hypodense focus suggesting rupture ( figure   1). There was no evidence of venous thrombosis.
Surgery was consulted for spontaneous splenic rupture and patient underwent exploratory laparotomy with splenectomy. Post-operative findings were notable for massive splenomegaly with a laceration in the central lateral aspect and subscapular hematoma.
Post-operative course was complicated by mucocutaneous candidiasis, iron deficiency anemia requiring iron infusion, paroxysmal atrial fibrillation managed with beta-blockers, and severe thrombocytosis not responsive to hydroxyurea recommended by in-house Hematology and Medical Oncology. He was transferred to a tertiary center for plateletpheresis to manage his thrombocytosis after platelets reached 3200 K/μL. The patient has been admitted two additional times for repeat plateletpheresis for platelets above 1000 K/μL despite dose-escalated anagrelide and hydroxyurea (table 1).  Table 2. Criteria for diagnosis of polycythemia vera (World Health Organization): all three major criteria or first two major criteria and the minor criterion Major Hemoglobin >16.5 g/dL (men), >16.0 g/dL (women) OR Hematocrit >49% (men), >48% (women) OR increased red cell mass (RCM) >25% mean predicted value Bone marrow biopsy demonstrating hypercellularity for age with trilineage (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size) Presence of JAK2 V617F or JAK2 exon 12 mutation

Minor
Subnormal serum erythropoietin level The most common mutation is JAK2 V617F, and it results in clonal erythroid, granulocytic, and megakaryocytic expansion.
Treatment is dependent on disease and patient characteristics. Patients at low risk (younger than 60 years, no history of venous thromboembolism, minimal constitutional symptom burden, and the absence of leukocytosis, thrombocytosis or massive splenomegaly) need therapeutic phlebotomies to maintain hematocrit below 45% and 42% in men and women, respectively, while patients at high risk should begin cytoreductive therapy. 3 Hydroxyurea (hydroxycarbamide, HC) is most commonly used and demonstrates superior outcomes in reducing thrombotic events when compared to phlebotomy but should be used with caution in young patients due to teratogenicity and potential risk of skin cancers. 4 Other side effectsfatigue, hair thinning, and mucocutaneous ulcerationmay not be tolerated well. Interferon (IFN) is preferred for individuals younger than 60 years and premenopausal women. 5 It induces hematological remission with morphological and molecular responses, but its use is limited due to side effects (flu-like symptoms, mood disturbances, deranged liver function tests, and thyroid dysfunction). 5 Patients who fail HC and IFN could treat with ruxolitinib (JAK1/2 inhibitor). 6 It is FDA approved in the treatment of PV and leads to cessation in phlebotomy for almost all of the patients and at least 50% reduction in spleen size in over 70% of patients. 6 The most common adverse events are cytopenias, diarrhea, infections, and nonmelanoma skin cancers. Aspirin may be utilized as an adjunct to therapy; however, caution should be taken to reduce platelet counts first as once thrombocytosis nears one million, secondary von Willebrand deficiency can result in increased risk of bleeding. 3 Complications of PV include thrombotic events and evolution into myelofibrosis or acute leukemia. 1 Atraumatic spontaneous splenic rupture occurs in the setting of abnormal spleen pathology.
Causes include congenital hemolytic anemias, infections (mononucleosis, malaria, endocarditis); infiltrative disorders (amyloidosis, Gaucher's disease); lymphoproliferative disorders; medications (anticoagulants, granulocyte colony-stimulating factor, thrombolytics); myeloproliferative disorders; nonhematologic malignancies; pancreatitis; and portal hypertension. 7 Symptoms are left upper quadrant pain, guarding, hemodynamic instability, and left shoulder pain from diaphragmatic irritation. Confirm with CT or sonographic imaging. Treatment depends on the clinical scenario: patients who are hemodynamically stable without significant blood loss can be managed conservatively while those with hemodynamic instability or significant blood loss need urgent surgical assessment for splenectomy. 8 Splenic rupture is a rare complication of PV. To date, there are only four cases in world literature of atraumatic spontaneous splenic rupture associated with PV, only one of which has been since the revised diagnostic criteria for polycythemia vera (elevated hemoglobin, JAK2 V617F mutation, and subnormal serum erythropoietin). All cases presented with splenomegaly and hemodynamic instability and required an exploratory laparotomy at which time a splenectomy was performed. [9][10][11][12] The only indications in PV for which splenectomy is definitively therapeutic are painful splenomegaly and local compressive symptoms. 13 Complications of PV post-splenectomy include anemia, hyperviscosity and thrombosis (most commonly in porto-mesenteric system of patients with hematological indications), increased risk of cancer, infection (especially encapsulated bacteria), platelet dysfunction, thrombocytosis, portal hypertension, and acquired von Willebrand deficiency (platelets above one million lead to loss of large vWF multimers in plasma and cause bleeding diathesis, which is reversible with desmopressin or platelet reduction). 13 Infections and thromboembolic events cause the most medical morbidity post-splenectomy, they are more common in the immediate postoperative period but persist throughout life. Management includes antibiotics, anticoagulation and antiplatelet therapy as clinically indicated, patient education, and vaccinations. 13 Patients who have good long-term control of hematocrit are less likely to have complications than those with short-term or poor control.
While our patient reported excellent long-term control of his disease and did not meet the criteria for myelofibrosis pre-splenectomy (anemia, constitutional symptoms, leukoerythroblastic peripheral blood smear), he continued to have severe thrombocytosis refractory to antiplatelet and cytoreductive therapies or iron infusions and required repeat plateletpheresis. It is possible that his massive spleen had kept his platelets in-check until it was removed, then his platelet counts worsened from clonal megakaryocyte hyperproliferation, iron deficiency, and post-operative reactive state. Given his age and increased risk of thrombosis with the new diagnosis of atrial fibrillation, it is imperative that he maintain reduced platelets if possible.
Physicians should assess for splenomegaly at follow-up appointments every 3-6 months. An enlarging spleen size should prompt suspicion for myelofibrotic transformation and raise concerns for the risk of splenic rupture. Instruct patients to prevent splenic rupture by avoiding strenuous activities including contact sports capable of abdomen and chest trauma and those with increased intra-abdominal pressure such as weight lifting. 14 In addition, the use of ruxolitinib can reduce spleen size and further risk of rupture. Our patient would have benefitted from these interventions to avoid this situation. The option to use JAK 1/2 inhibitors remains: reports exist of patients with primary myelofibrosis refractory to multiple cytoreductive drugs and compassionate splenectomy free of constitutional symptoms and transfusions following treatment with ruxolitinib. 15 In conclusion, spontaneous splenic rupture is an extremely rare complication of PV. Clinicians should consider this in their differential when a patient with PV presents with new-onset abdominal pain and leukocytosis. They should recognize post-splenectomy complications unique to PV and be proactive in management as well as prevention using excellent disease control. Patients with splenomegaly should be cognizant of the risk of splenic rupture and take necessary precautions to avoid this sequela by reducing disease burden with cytoreductive therapy and splenic size with JAK 1/2 inhibitors.