Isolated Factor V Deficiency in Myeloproliferative Neoplasms: A Mayo Clinic Series of 33 Patients

Background: Although the association of acquired isolated factor V (FV) deficiency with myeloproliferative neoplasms (MPN) has been described, it has not been well characterized.

Objective: To characterize the clinical and laboratory features of patients with MPN and isolated FV deficiency.

Methods: After IRB approval, patients with MPN who underwent coagulation profile diagnostic testing from January 1980 to December 2012 were identified via the Mayo Clinic Special Coagulation Laboratory Registry. Medical records of those with MPN and concurrent isolated FV deficiency or those with mild coagulopathy who had at least 20% discordantly lower FV activity were reviewed. Excluded were patients with known inherited bleeding diathesis, clinically significant liver disease, or on concurrent warfarin treatment. Data on patient demographics, clinical features and laboratory data were abstracted.

Results: Thirty three patients met our study criteria (median age 67 years; 55% males; median BMI 25 kg/m²). Twenty one (64%) patients had either primary or post-polycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis; five (15%) had PV; three (9%) had unclassified MPN; two (6%) had ET; and one (3%) each had chronic myeloid leukemia and chronic myelomonocytic leukemia. Majority of these patients had splenomegaly (85%), with a median palpable spleen size of 14.3 cm below the left costal margin. Nearly 40% had hepatomegaly (median 4 cm below the right costal margin). Twelve (36%) patients were being treated with hydroxyurea; nine (27%) with aspirin and seven (21%) with an investigational agent. Nearly two-thirds (n=21; 64%) of these individuals had bleeding episodes, nine (43%) of which were provoked either by a surgical intervention or trauma. Majority of the bleeding episodes (n=15; 71%) were clinically significant/major bleed, as defined by the standard International Society of Thrombosis Haemostasis criteria, of whom eight required red cell transfusion support. Most of the bleeding were from muco-cutaneous surfaces (45%), followed by excessive bleeding from surgical site (24%). Median time from MPN diagnosis to bleeding was 5.4 years (range: 0 – 25). Of note, 42% (n=14) of all patients had thrombotic events (5 ischemic stroke/ TIA; 4 peripheral artery disease; 1 myocardial infarction; 1 splenic artery thrombosis; 3 leg DVT; and 3 splanchnic vein thrombosis) prior to their bleeding episode. Median time from MPN diagnosis to thrombosis was 1.4 years (range: 0.1 – 19.7).

The median (range) leukocyte and platelet count were 17.8 (3.6 – 212.7) x 1000/ mm³ and 315 (16 – 1284) x 1000/ mm³, respectively. The median (range) PT [reference range: 10.3 – 12.8 sec] and aPTT [reference range: 26 – 36 sec.] were 13.3 sec (10.1 – 18.7) and 38 sec (29 – 66), respectively. The median FV activity [reference range: 70 – 165%] was 44% (range: 18% - 60%). Seven of the 18 individuals (39%) tested for von Willebrand syndrome had ristocetin cofactor activity (RCoA)/von Willebrand antigen (vWF Ag) ratio of <0.7, although their vWF Ag and RCoA were within the normal reference range. Seventeen (52%) patients had platelet aggregation studies; all had at least one aggregation abnormality. Abnormal or absent response to epinephrine was the commonest noted abnormality (n=15), followed by an abnormal response to collagen (n=6).

On univariate analysis, there was no significant correlation of FV activity with age, sex, BMI, myelofibrosis, hepatomegaly, splenomegaly, WBC count, platelet count, or use of hydroxyurea or investigational drugs.

Further, on univariate analysis, neither the aforementioned covariates, nor aspirin use, WBC count, platelet count, FV activity, abnormal platelet aggregation, RCoA/vWF Ag ratio < 0.7 were predictive of either overall bleeding, provoked bleeding or clinically significant/major bleed.

Conclusions: Isolated FV deficiency associated with MPN often co-exists with platelet dysfunction and/or an acquired vWF abnormality, which together may contribute to a clinically significant bleeding diathesis. Our experience did not lead to identification of specific risk factors for MPN-associated isolated FV deficiency.