Early thrombotic events and preemptive systemic anticoagulation following splenectomy for myelofibrosis
Authors: Mythri Mudireddy, Naseema Gangat, Terra L. Lasho, Christy Finke, Curtis A. Hanson, Rhett P. Ketterling, Aneel A. Ashrani, Animesh Pardanani, David M. Nagorney, Ayalew Tefferi
Journal: American Journal of Hematology (2018)

With the exception of allogenic hematopoietic stem cell transplant, current treatment modalities in myelofibrosis (MF) remain mostly palliative and employ drugs such as JAK2 inhibitors, red blood cell transfusions, involved field radiotherapy and splenectomy. Indications for splenectomy in MF include drug-refractory symptomatic splenomegaly, frequent red cell transfusions, refractory thrombocytopenia and symptoms of portal hypertension, including recurrent upper gastrointestinal (UGI) bleeding and ascites. In our original report of 223 patients with MF who underwent splenectomy between 1976 and 1996, perioperative mortality was 9% and 30% of the patients experienced perioperative complications including 15% bleeding, 9% infections and 7% thrombosis.1 The latter mostly involved splanchnic veins and was often complicated by portal hypertension, ascites, UGI bleeds and recurrent thrombosis. Based on these historical observations, some of the hematologists and general surgeons at our institution have adopted the practice of preemptive full therapeutic dose or low dose systemic heparinization, starting within a week of surgery, as long as hemostasis was secured. The main objective of this study was to retrospectively examine the value of such proactive systemic anticoagulation on the occurrence of early thrombotic events following splenectomy in MF. This study was approved by the Mayo Clinic institutional review board. Patients with MF who underwent splenectomy in the last 15 years were identified from institutional databases. Diagnosis of MF, including primary myelofibrosis (PMF) and postpolycythemia vera (postPV) or essential thrombocythemia (postET), was according to World Health Organization criteria.2 All surgical procedures were performed at our institution. Only major arterial or venous thrombosis was considered; the former included acute myocardial infarction, angina pectoris, ischemic stroke, transient ischemic attack, or peripheral arterial thrombosis; the latter included pulmonary embolism and deep vein thrombosis (DVT), including splanchnic vein thrombosis. Thrombotic episodes were confirmed by diagnostic imaging. For the purposes of this study, major bleeding was defined as symptomatic hemorrhage in a critical organ or bleeding resulting in red cell transfusions or a drop in hemoglobin level of >2 g/dL. Early thrombotic events constituted those occurring in the first 2 months of splenectomy. The decision to institute preemptive anticoagulant treatment and the selection of heparin dose were primarily based on the discretion of the treating physician and acknowledged if documented in the first 2 weeks of splenectomy, prior to an event. Statistical analyses considered clinical and laboratory data collected at time of splenectomy. Survival was computed from the day of splenectomy. Non-parametric statistics was used to determine significance of differences among groups, in the distribution of continuous or nominal variables. The Stat View (SAS Institute, Cary, NC, USA) statistical package was used for all calculations. Between 2001 and 2016, therapeutic splenectomies were performed on 123 consecutive patients with MF; 120 were evaluable for the occurrence of post-splenectomy thrombotic events. Indications for splenectomy included increasing frequency of red cell transfusions (n = 55), mechanical splenic discomfort (n = 29), refractory thrombocytopenia (n = 18), complications of portal hypertension (n = 7) and other reasons (n = 11). Median time between initial MF diagnosis and date of splenectomy was 3.2 years. Median age at time of splenectomy was 66 years (range 43-84) and 58% were males. MF variants were PMF 76%, postPV MF 18% and postET MF 6%. Risk distribution at the time of splenectomy, according to the dynamic international prognostic scoring system3 was 21% high, 55% intermediate-2, 21% intermediate-1 and 3% low. Spleen size measurement at time of splenectomy revealed palpable distance from the left costal margin of >30 cm in 31 (26%) patients, 20-30 cm in 74 (62%), and < 20 cm in 15 (12%). History of thrombosis prior to splenectomy was documented in 26 (22%) patients and included both arterial (15%) and venous (8%) events. Additional clinical and laboratory data at the time of splenectomy are detailed in Table 1. DIPSS-plus risk stratification “N” evaluable = 96 (80%) Driver mutation status “N” evaluable = 89 (74%) Karyotype “N” evaluable = 96 (80%) At a median post-splenectomy follow-up time of 1.3 years (range 0.02-8.5), 34 (28%) patients experienced post-splenectomy thrombosis in the first 2 months of surgery (median 7 days; range 1-60), including 91% venous and 9% arterial only events; venous events included 13 instances of portal vein thrombosis, 12 of splenic vein thrombosis, 3 of mesenteric vein thrombosis, and other less frequent venous episodes including DVT. During a comprehensive analysis of clinical and laboratory variables, post-splenectomy thrombosis was significantly associated with pre-splenectomy history of venous thrombosis (P = .02) and higher platelet count at time of splenectomy (P = .03). Preemptive systemic anticoagulation, within 2 weeks of surgery and a minimum treatment duration of 3 consecutive days, was instituted in 77 (62%) patients and included full (n = 17; 14%) or low (n = 58; 48%) systemic heparinization or continued warfarin therapy in 2 patients with pre-splenectomy thrombosis history. Post-splenectomy thrombosis occurred in none (0%) of the 17 patients receiving preemptive full systemic heparinization; by contrast, the particular complication occurred in 15 (26%) of 58 patients receiving low systemic heparinization and 17 (40%) of 43 patients receiving no systemic anticoagulation (P = .002). Of note, there was no difference, among the different treatment groups, in age (P = .35) and sex (P = .12) distribution, presence or absence of pre-splenectomy thrombosis history (P = .52), platelet (P = .26) or leukocyte (P = .8) counts or major hemorrhagic events prior or after the institution of anticoagulant therapy (Table 1). At the time of this writing, 95 (79%) deaths and 30 (25%) leukemic transformations were documented; postsplenectomy overall and leukemia-free survivals were not affected by either thrombosis history before splenectomy or the occurrence of early thrombotic event following splenectomy (P > .2 in all instances). This study provides evidence that suggests the antithrombotic superiority of full therapeutic dose heparin therapy, compared to treatment with lower dose heparin or no systemic anticoagulation, in preventing early thrombotic complications, following splenectomy in MF. The fact that >90% of these incidents constituted venous thrombosis is in line with consistent with the observation regarding the most optimal treatment strategy; furthermore, it is possible that the procoagulant nature of the underlying disease (ie, myeloproliferative neoplasm often associated with JAK2 mutation) might have contributed to the need for higher heparin dose. A similar argument can be made to explain the difference in the incidence of postsplenectomy thrombosis between patients receiving low-dose heparin and those not receiving systemic anticoagulation. The retrospective nature of our study dictates that our observations should be considered preliminary but worthy of further perusal in a controlled setting. The authors declare that they have no conflicts of interest with the contents of this article.