Acquired Factor VII Deficiency Associated With Chronic Myeloid Leukemia Blast Crisis

Abstract

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count.

Case Presentation

A 49-year-old female presented to an outside hospital with generalized weakness, abdominal pain, and back pain. She noted the onset of weakness 1 month prior to her presentation and abdominal fullness for a year. Physical exam was notable for marked splenomegaly. On admission, her hemoglobin was 9 (11.6-15.0 g/dL), platelet count was 40 × 10⁹/L (157-371 × 10⁹/L), and white blood cell (WBC) count was 45 (3.4-9.6 × 10⁹/L) with 17% blasts. Bone marrow core biopsy was 100% cellular with marked myeloid predominance and 30% to 40% blasts. Chromosome analysis identified 2 related abnormal clones. One contained a complex 4-way rearrangement between the long arm of chromosomes 1, 11, 9, and 22, generating a BCR-ABL rearrangement and a deletion in the long arm of chromosome 14. The second abnormal clone contained a translocation between the short arm of chromosomes 7 and 12. Fluorescence in situ hybridization (FISH) also confirmed the BCR-ABL1 gene rearrangement in 62% of cells. Next-generation sequencing was negative for ASXL1, DNMT3A, FLT3, IDH1, IDH2, NPM1, RUNX1, TET2, TP53, and Wt1. The bone marrow biopsy and cytogenetic studies suggested either de novo BCR-ABL positive acute myeloid leukemia (AML) or chronic myeloid leukemia with blast crisis (CML-BC). It was felt that the overall picture was more suggestive of CML-BC given the marked splenomegaly and 1-year history of abdominal fullness.

She was treated with induction chemotherapy with cytarabine plus daunorubicin (7 + 3) and subsequently started on dasatinib 140 mg twice daily. Follow-up bone marrow biopsy confirmed complete morphologic remission. Chromosomal analysis showed a normal female karyotype, and FISH was negative for BCR-ABL translocation, indicative of complete cytogenetic remission. She was referred to our institution for an allogeneic hematopoietic stem cell transplant (SCT) and underwent a matched related donor SCT. She received myeloablative conditioning with fludarabine and busulfan.

She had a stable course until day +81 when she was noted to have a new leukocytosis with increased blast count. Upon admission to the hospital, laboratory tests were notable for hemoglobin of 11.7 (11.6-15.0 g/dL), platelet count of 20 (157-371 × 10⁹/L), WBC of 39 (3.4-9.6 × 10⁹/L) with 10% peripheral blasts, prothrombin time (PT) 18 (9.4-12.5 seconds), internationalized normal ratio (INR) 1.6 (0.9-1.1), activated partial thromboplastin time (aPTT) 26 (25-37 seconds), fibrinogen 456 (200-393 mg/dL), and negative soluble fibrin monomers. On hospital day 2, she developed a fever of 38.4 °C and hypotension, concerning for sepsis. Blood cultures showed no growth. Computed tomography (CT) scan of the abdomen and pelvis showed evidence of colitis. Stool testing was positive for Clostridioides difficile. Peripheral blast count rapidly increased from 10% on admission to 41% on day 4 of hospitalization. Bone marrow aspirate and core biopsy performed on hospital day 3 revealed nearly 100% cellular marrow with absent erythroids and megakaryocytes, 85% to 90% blasts, consistent with relapse of CML-BC (Figure 1). Fluorescence in situ hybridization analysis of peripheral blood confirmed BCR-ABL1 fusion in 54% of nuclei.

Figure 1.

(A) Bone marrow core biopsy (H&E, 40×) demonstrating packed bone marrow with 85% to 90% blasts, absent erythroids and megakaryocytes, consistent with relapsed CML-BC. (B) Immunohistochemistry with blast cells staining positive for CD34.

Throughout hospitalization, patient was found to have a worsening coagulopathy. Complete blood count (CBC) revealed worsening anemia and thrombocytopenia with hemoglobin of 6.4 (11.6-15.0 g/dL), hematocrit of 19.2 (35.5%-44.9%), and platelet count of 9 (157-371 × 10⁹/L). Internationalized normal ratio increased rapidly from 1.6 on admission to 4.1 on hospital day 2, corresponding with an increase in peripheral blast count (Figure 2). Prothrombin time was markedly elevated to 52.7 seconds, which mostly corrected when mixed 50:50 with normal pulled plasma, consistent with factor deficiency or presence of a weak inhibitor. Factor VII (FVII) activity was found to be markedly decreased at 3% (65%-180%). Factor II activity was 55% (Ref: 75%-145%), Factor X activity was 57% (Ref: 70%-150%), and Factor V activity was 77% (Ref: 70%-165%). Oral vitamin K 5 mg was administered without any improvement in INR or factor levels. Patient was noted to have a decreased level of responsiveness, prompting transfer to intensive care unit. A CT scan of the head ruled out intracranial hemorrhage. There was no further evidence of bleeding at that time. On hospital day 5, she was started on chemotherapy regimen for relapsed disease with cladribine 5 mg/m² IV on days 1 to 5, cytarabine 20 mg subcutaneous twice daily on days 1 to 10, and venetoclax for 21 days. With cancer directed therapy, she showed clinical improvement and was transferred back to the hematology ward after 2 days. Upon regaining consciousness, she was able to communicate and expressed concerns for vision loss. A dilated fundus exam showed severe bilateral retinal hemorrhages. The coagulopathy rapidly improved after initiation of chemotherapy and correlated with decline in peripheral blast count (Figure 2). Ultimately FVII activity improved to 63% (Ref: 65%-180%) 2 weeks after initiation of chemotherapy. At time of hospital discharge, patient reported improvement of her blurry vision.

Figure 2.

Line graph demonstrating INR, peripheral blast percentage, and FVII level during hospitalization. Following administration of chemotherapy, INR and blast count decreased, while FVII level increased.

Two months later, a bone marrow aspirate and biopsy showed persistent disease with 70% blasts. At this time, FVII activity decreased again to 14%, and INR was 2.2. She was started on decitabine and venetoclax for refractory disease. FVII level activity remained low at 15% 10 days following initiation of decitabine and venetoclax; however, patient did not experience any bleeding during this time. She achieved a remission after 1 cycle of therapy. Owing to poor functional status, she was deemed not to be a candidate for a second allogeneic hematopoietic stem cell transplantation.

Discussion

Factor VII is a vitamin K-dependent clotting factor that is synthetized by the liver. Factor VII triggers blood clotting by forming a complex with exposed tissue factor on the vascular lumen following injury.^1,2 Factor VII deficiency is suspected when there is elevated PT but normal aPTT. The prolonged PT is corrected in vitro by addition of normal pool plasma. The diagnosis is confirmed by quantifying FVII coagulant activity, and FVII deficiency is typically defined as less than 70%. ²

Clinical manifestations of FVII deficiency can vary in severity from asymptomatic state to life-threatening bleeding, which cannot be predicted based on the FVII activity level. Common bleeding sites in FVII deficiency include epistaxis, bruising, gum bleeding, menorrhagias, hematoma, hematuria, hemarthrosis, gastrointestinal bleeding, and intracranial bleeding. ² It is unknown what the amount of FVII activity is required to prevent bleeding in various clinical settings. In patients with inherited FVII deficiency, patients with FVII level > 20% are considered to be low risk for spontaneous bleeding. ³ Our patient experienced severe bilateral retinal hemorrhage with no other evidence of bleeding. It is unclear whether her bleeding was due to FVII deficiency, severe thrombocytopenia and anemia requiring transfusions, or a combination of all factors. Severe anemia defined as hemoglobin less than 8 g/dL is known to be a risk factor for the development of retinal hemorrhages, while the combination of thrombocytopenia and anemia was associated with even high rates of retinal hemorrhage.^4,5

Factor VII deficiency can be caused by an inherited disorder or acquired from a range of clinical conditions. The most common causes of acquired FVII deficiency are synthetic liver dysfunction, coumadin therapy, vitamin K deficiency, and diffuse intravascular coagulation (DIC). ⁶ Our patient did not have evidence of hepatic impairment. She was not on any form of anticoagulation therapy, and she did not respond to vitamin K supplementation, suggesting against a vitamin K deficiency. Her laboratory evaluation was not consistent with overt disseminated intravascular coagulation (DIC), with normal levels of fibrinogen and no evidence of soluble fibrin monomers. The mechanism of acquired FVII deficiency in leukemia is unknown. The FVII levels decreased as her peripheral blood blasts number increased, and the FVII levels improved with chemotherapy and reduction in peripheral blood blast count, suggesting that the FVII deficiency is acquired secondary to CML-BC (Figure 2). One possible mechanism is selective adsorption of FVII level by the leukemic cells, similar to the mechanism of acquired von Willebrand factor in multiple myeloma with adsorption of won Willebrand factor by plasma cells. ⁷ Finally, it is important to mention that our patient experienced sepsis due to C difficile infection. Sepsis is a known cause of acquired FVII deficiency. Sepsis as the cause of FVII deficiency would not explain the improvement in FVII levels and associated coagulopathy following chemotherapy and reduction in blast count.

Derangements in PT have been associated with CML, especially with progression of the CML phase. ⁸ Factor VII deficiency has been previously reported in the setting of hematologic malignancies, typically occurring within the first 2 weeks following SCT with myeloablative chemotherapy and often associated with other factor deficiencies such as Factor XII or protein C. ⁶ Toor et al report a case of FVII deficiency in a CML patient, which occurred within 2 weeks of allogeneic SCT. ⁶ Anoun et al report a case of isolated acquired FVII deficiency due to the presence of inhibitor which was associated with AML and Pseudomonas aeruginosa bacteremia. ⁹ The patient developed nasal and sinus hematoma on day 8 of chemotherapy and was treated with fresh frozen plasma (FFP) (10 mL/kg for 2 days) but expired due to intracranial hemorrhage on day 25. To the best of our knowledge, our case is the first reported case of a patient with FVII deficiency associated with CML-BC. Unlike other cases, our patient was not diagnosed with FVII deficiency until 83 days following SCT and was not associated with recent myeloablative chemotherapy.

In patients with acute bleeding, recombinant FVIIa is the recommended therapy. While this treatment is highly effective, it is costly and requires frequent administrations due to its short half-life. ² Fresh frozen plasma is a readily available option for management of acutely bleeding patients, but patients must be monitored for evidence of volume overload. ² Our patient did not receive any therapy for FVII deficiency as it was unclear that she was having bleeding complications until she recovered enough to report vision loss. Factor VII activity had recovered appropriately, and there was no worsening vision loss or other bleeding. In our patient’s case, treating the underlying cause of her FVII deficiency with chemotherapy was effective in increasing the FVII levels to normal levels.

Conclusion

We report a rare case of severe FVII deficiency secondary to blast crisis in CML patient. This was complicated by retinal hemorrhages. Providers should be aware of the risk of FVII deficiency in patients with hematologic malignancies with rapidly increasing peripheral blast counts.