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