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Blood Clotting Complications in the Myeloproliferative Neoplasms

Blood Clotting Complications in the Myeloproliferative Neoplasms. Tampa MPN Patient Symposium Brady L. Stein, MD MHS April 3, 2014. A case from the hematology clinic. 27 year-old, recentl y pregnant woman with pain under her R rib cage R emoval of her gallbladder 3 weeks prior

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Blood Clotting Complications in the Myeloproliferative Neoplasms

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  1. Blood Clotting Complications in the MyeloproliferativeNeoplasms Tampa MPN Patient Symposium Brady L. Stein, MD MHS April 3, 2014

  2. A case from the hematology clinic • 27 year-old, recently pregnant woman with pain under her R rib cage • Removal of her gallbladder 3 weeks prior • Enlarged liver and spleen noted during her surgery • Review of her records: • Intermittently high white blood cell and platelet counts for ~5 years

  3. A Case from the clinic • Medical testing revealed extensive blood clots occluding the large vein that drains the liver • Complete Blood Count • White blood cell and platelet number normal • Diagnosed with the “Budd Chiari Syndrome” and found to have increased blood pressure in the abdominal system along with an enlarged spleen

  4. Additional evaluation • No evidence of an inherited blood clotting tendency • Bone marrow biopsy • No specific abnormalities-not diagnostic of a specific entity • JAK2 V617F Mutation: • Positive, confirming that she has an MPN

  5. Classical MyeloproliferativeNeoplasms: Shared Clinical Features Blood clotting complications -Epidemiology -Signs and symptoms -Risk factors -Treatment strategies -Chicago Roundtable Research Splenomegaly Marrow fibrosis Disease acceleration/ transformation ET PV MF

  6. Epidemiology—How common are arterial or venous blood clotting complications in MPN? Elliot, MA Seminars in Thrombosis and Hemostasis 2007; Barbui, T Blood 2010; Elliot Haematologica 2010

  7. Clotting Manifestations: “Small Vessel” Disturbances Disrupt Quality but not Quantity of Life • Headache, Dizziness, Transient Visual Disturbances, Numbness/Tingling, Color changes or Pain in the digits • Often responsive to aspirin Erythromelalgia: Redness, swelling, and pain of the extremities Picture from the Erythromelalgia Association Website

  8. Clotting Manifestations: “Large Vessel” Disturbances • Stroke • Transient or prolonged weakness, numbness, difficulty with speech, vision, drooping of the face • Heart Attack • Chest pain, neck/jaw, or arm pain, sweating, nausea, shortness of breath • Deep vein thrombosis or Pulmonary Embolism • Swelling, tightness/discomfort, redness of the limb, typically the leg • Chest pain, difficulty breathing, irregular heart beats

  9. Clotting Manifestations: Unusual Locations and “Occult MPN” 41% will have MPN Hepatic Vein Thrombosis: Budd-Chiari 32% will have MPN Portal Vein Thrombosis Splenic Vein Thrombosis Mesenteric Vein Thrombosis ®Stephan Moll, MD As reviewed in Barbui et al, Blood 2013

  10. Thrombosis Risk Factors: Generic, but accepted and consistent: Lower Risk Intermediate Risk High Risk

  11. MPN-specificrisk factors Stem Cells JAK2 mutation linked to blood clotting Progenitors Increased Red blood cell count linked to blood clotting Increased white blood cell count likely linked to blood clotting Increased Platelet count itself NOT linked to blood clotting

  12. A New Player: CALR mutations in ET and MF MF: 88% with CALR ET: 67% with CALR P. Vera CALR mutated patients appeared to have a lower Hgb and leukocyte count, higher platelet count, and lower rate of thrombosis Klampflet al, Late Breaking Abstracts and Klampfl, T et al. NEJM 2013

  13. Revised Classification for ET: IPSET • Age > 60: 1 point • History of blood clot: 2 points • Cardiovascular Risk factors: 1 point • JAK2 V617F: 2 points Low Risk: < 2 points Intermediate Risk: 2 points High Risk: > 2 points Barbui et al Blood 2012

  14. Managing Thrombosis Risk Lower Risk Intermediate Risk High Risk Lifestyle Modification Aspirin in PV, JAK2+ ET, or small vessel disturbance “Cytoreduction” This is a generic approach rather than personalized!

  15. Managing MPN-specific Risk Factors JAK2:JAK inhibitors Interferon Investigational agents Stem Cells Progenitors Plts RBC WBC Phlebotomy for PV: Hematocrit lowering <45% Hydroxyurea JAK2 inhibitors Interferons Platelet count alone should not dictate therapy unless > 1.5 million

  16. The “lowly hematocrit” • Target hematocrit (Hct) for patients with PV debated for decades • 365 patients with PV, randomized to low Hct (< 45%) vs. high Hct (45-50%) • Four-fold lower rate of serious cardiovascular complications in low Hct (4.4%) vs. high Hct (10.9%) group • But…white cell count remained higher in the high Hct group • Going forward, phlebotomy target to goal Hct < 45% Marchioli et al NEJM 2013 Spivak NEJM 2013

  17. Is Anagrelide Coming back?ANAHYDRET • PT-1 study suggested hydroxyurea/aspirin was superior to anagrelide/aspirin in ET patients in the prevention of arterial blood clots • 259 ET patients, randomized to hydroxyurea or anagrelide • No difference between the 2 drugs in the following: • Major or minor arterial or venous blood clots • Severe bleeding • Discontinuation rates • Myelofibrosis or leukemia not seen • Conclusion: Anagrelide does not appear to be inferior to Hydroxyurea in the prevention of blood clotting Gissingler et al Blood 2013

  18. Are younger MPN patients at low risk for blood clotting complications? Research Question Informal Case Discussion Draft proposal, submit to each institution’s review board • Chicago Roundtable • Laura Michaelis • Olatoyosi Odenike • Damiano Rondelli • Jamile Shammo • Brady Stein Medical Chart Review 6 monthly “dinner rounds to attract community providers

  19. Our Results No real differences in Aspirin, Phlebotomy, or Hydroxyurea Use Stein et al Leuk Lymphoma 2013

  20. Our Results Overall rate of blood clotting: 27% vs. 31% (Younger vs. Older) Stein et al Leuk Lymphoma 2013

  21. How do our results compare to other studies? Portal Vein Thrombosis • 475 cases reviewed of abd vein clotting • Majority (88-93%) JAK2 V617F positive • Typically younger (44 yrs) women (61%) • 22% presented ~40 mos before an official MPN diagnosis! • Clinical trials evaluating Ruxolitinib and Peg-interferon in this patient population Mesenteric Vein Thrombosis Splenic Vein Thrombosis Hepatic Vein Thrombosis: Budd-Chiari Pieri et al, ASH Abstract 2013

  22. Our study: conclusions • Overall clotting complications similar by age group, but the locations differ • Younger women particularly at risk for clotting of the abdominal veins • These clotting complications can be quite serious • Our patient required a procedure to lower the pressure in the abdominal blood pressure system • Likely to require blood thinners indefinitely • Our understanding of the mechanisms of blood clotting in the MPN is incomplete

  23. Many factors can influence MPN-thrombosis Increased Hematocrit/Blood viscosity Increased white cell count and activated WBC’s Type of mutation, burden JAK2 > CALR JAK2 allele burden MPN-associated thrombosis Advanced Age Prior history of blood clotting Type of MPN PV, “masked PV” Prefibrotic MF, ET MF Activated Platelets Activation of the blood vessel lining Blood cell membrane fragments (Microparticles) Gender Inflammation Adapted from McMahon and Stein, Seminars in Thrombosis and Hemostasis 2012 “Masked PV:” ASH abstract 1581 (Barbui et al)

  24. Questions and Goals for the Future…. • How do we personalize the risk classification to avoid over or under-treatment? • Develop reproducible assays to measure JAK2 burden, markers of blood cell/vessel activation, microparticles • What is the ideal blood thinning agent? • Warfarin for those with venous clotting, but for how long (limited or indefinite (abdominal veins)) • Injected blood thinners? “Target Specific” blood thinners? • Is there a role for twice daily Aspirin or Aspirin/Clopidogrel? • Will JAK inhibitors impact clotting rates?

  25. Thank you for your attention

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