Myeloproliferative Neoplasms (MPNs): Diagnosis, Treatment ...
Blood Clotting Complications in the Myeloproliferative Neoplasms
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Transcript of Blood Clotting Complications in the Myeloproliferative Neoplasms
Northwestern University Feinberg School of Medicine
Blood Clotting Complications in the Myeloproliferative Neoplasms
Tampa MPN Patient SymposiumBrady L. Stein, MD MHSApril 3, 2014
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
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
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
Classical Myeloproliferative Neoplasms:Shared Clinical Features
ET
PV
MF
Blood clotting complications-Epidemiology-Signs and symptoms-Risk factors-Treatment strategies-Chicago Roundtable Research
SplenomegalyMarrow fibrosisDisease acceleration/ transformation
Epidemiology—How common are arterial or venous blood clotting complications in MPN?
At diagnosis Follow-up0
5
10
15
20
25
30
35
40
10-29%
34-39%
8 to 31%8 to 19%~13%
~10%
ETPVMF
Elliot, MA Seminars in Thrombosis and Hemostasis 2007; Barbui, T Blood 2010; Elliot Haematologica 2010
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
Picture from the Erythromelalgia Association Website
Erythromelalgia: Redness, swelling, and pain of the extremities
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
Clotting Manifestations: Unusual Locations and “Occult MPN”
®Stephan Moll, MD
Portal Vein Thrombosis
Mesenteric Vein
Thrombosis
Hepatic Vein Thrombosis: Budd-Chiari
Splenic Vein Thrombosis
32% will have MPN
41% will have MPN
As reviewed in Barbui et al, Blood 2013
Thrombosis Risk Factors: Generic, but accepted and consistent:
Age less than 60No clotting
history
High blood pressureDiabetes
↑CholesterolSmoking
Age over 60Prior blood clot
Lower Risk Intermediate Risk High Risk
MPN-specific risk factors
JAK2 mutation linked to blood clotting
Stem Cells
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
A New Player: CALR mutations in ET and MF
Klampfl et al, Late Breaking Abstracts and Klampfl, T et al. NEJM 201312
P. Vera ET: 67% with CALR MF: 88% with CALR
CALR mutated patients appeared to have a lower Hgb and leukocyte count, higher platelet count, and lower rate of thrombosis
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
Managing Thrombosis Risk
Age less than 60No clotting
history
High blood pressureDiabetes
↑CholesterolSmoking
Age over 60Prior blood clot
Lower Risk Intermediate Risk High Risk
Aspirin in PV, JAK2+ ET, or small vessel disturbance
Lifestyle Modification “Cytoreduction”
This is a generic approach rather than personalized!
Managing MPN-specific Risk Factors
JAK2:JAK inhibitorsInterferonInvestigational agents
Stem Cells
Progenitors
Phlebotomy for PV:Hematocrit lowering<45%
HydroxyureaJAK2 inhibitorsInterferons
RBC WBC
Platelet count alone should not dictate therapy unless > 1.5 million
Plts
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 2013Spivak NEJM 2013
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
Chicago RoundtableLaura MichaelisOlatoyosi OdenikeDamiano RondelliJamile ShammoBrady Stein
Are younger MPN patients at low risk for blood clotting complications?
Informal Case Discussion Research Question
Draft proposal, submit to each institution’s review board
Medical Chart Review
6 monthly “dinner rounds to attract community providers
Our ResultsCharacteristic Younger PV
Patients (≤ 45 yrs)N=120
Older PV PatientsN=84 (≥ 65 yrs)
% Women 76 55% MPN Family History 10 11Avg Disease Duration 8 years 4.5 yearsAvg white blood cell count (x 109/L)
9.2 13.4
JAK2 mutation, % 98 95JAK2 Burden, % 51 66
No real differences in Aspirin, Phlebotomy, or Hydroxyurea Use
Stein et al Leuk Lymphoma 2013
Our Results
02468
1012141618
Age > 65 (N=84) Age < 45 (N=120)
Overall rate of blood clotting:27% vs. 31% (Younger vs. Older)
Stein et al Leuk Lymphoma 2013
How do our results compare to other studies?
Portal Vein Thrombosis
Mesenteric Vein
Thrombosis
Hepatic Vein Thrombosis: Budd-Chiari
Splenic Vein Thrombosis
Pieri et al, ASH Abstract 2013
• 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
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
Many factors can influence MPN-thrombosis
MPN-associated thrombosisAdvanced Age
Prior history of blood clotting
Type of mutation, burdenJAK2 > CALR
JAK2 allele burden
InflammationGenderBlood cell membrane
fragments(Microparticles)
Activated Platelets
Increased white cell count and activated WBC’s
Activation of the blood vessel lining
Increased Hematocrit/Blood viscosity
Adapted from McMahon and Stein, Seminars in Thrombosis and Hemostasis 2012“Masked PV:” ASH abstract 1581 (Barbui et al)
Type of MPNPV, “masked PV”Prefibrotic MF, ET
MF
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?
Thank you for your attention