Management and Treatment of Bleeding and Thrombotic Complications of Congenital Afibrinogenemia during Chemotherapy and Bone Marrow Transplant for B-ALL

Background

Inherited quantitative disorders of fibrinogen are rare and congenital afibrinogenemia (CA) is reported to affect approximately 1:1,000,000 persons worldwide. CA is a clinically heterogenous disease that may involve thrombotic events (TE), bleeding events (BE), or be asymptomatic. Given its prevalence, there is a paucity of evidence-based guidelines for management of affected patients. BE are often with fibrinogen concentrate (FC) and TE are often managed with low-molecular-weight heparin. Here, we present a 30-year-old male with CA diagnosed with acute B-cell lymphoblastic leukemia (B-ALL) and successfully managed from induction through allogeneic stem cell transplant (HSCT) who also developed a symptomatic line-associated TE treated with a direct-oral anticoagulant.

Methods:

Management was by a multispecialty team of classical and malignant hematology at the Medical University of South Carolina. He never had PK-based FC dosing. A peripherally inserted central venous catheter (PICC) was placed for blinatumomab administration. A daily fibrinogen level (FCo) of 100 mg/dl was targeted and 150-200 mg/dl during BE until hemostasis was achieved. The FC manufacturer-recommended formula was used to calculate all doses and the same FC product was used for all doses: its half-life was 60-102 hours. Informed consent was obtained.

Results:

Our patient was diagnosed with CA in infancy after a bleeding evaluation for prolonged bleeding after a circumcision. His parents are known nonconsanguineous carriers so genetic testing was not performed. BE were infrequent until early adolescence. Between 2006-2009 he had 65 BE treated with on-demand (OD) CP then transitioned to FC every 1-2 weeks to treat BE.

In November 2023 he was diagnosed with COVID-19 after developing persistent daily fevers, chills, and bone pain. He re-presented a few weeks later for evaluation of persistent symptoms. His Hgb was 8 g/dl (normally 15 g/dl) and he had 5% circulating blasts and hyponatremia (Na 125 mmol/L). A bone marrow evaluation demonstrated 83.3%, CD19⁺, CD34⁺ and CD45⁺ lymphoblasts, and ~45% of cells had a partial loss of 4q, 6p, 8q, 9p (with homozygous loss of CDKN2A), 14q and 18q, and loss of heterozygosity of 12q. He was diagnosed with B-ALL at age 28 and underwent induction chemotherapy per CALGB 10403.

His baseline fibrinogen is < 60 mg/dl. During induction we recommended a FCo of 100mg/dl (4000 mg/4 vials) of FC for prophylaxis (PR) every 3 days based on his PK and 150-200mg/dl (6000mg/6 vials) on days of procedures or OD. Prophylactic enoxaparin was administered daily for 2.5 weeks after PEGasparaginase. His platelet count was never < 50,000/µL and his course was uncomplicated except for mild peripheral neuropathy attributed to vincristine. He had evidence of molecular residual disease at the end of induction.

Day 14 post discharge, he developed iatrogenic intracranial hypotension syndrome after a LP. Brain imaging demonstrated prior microhemorrhages but no acute bleed. He had a successful blood patch with OD FC dosing. The next day he developed progressive right upper extremity swelling and discomfort in the arm with the PICC line. By day 2, the PICC line was non-functional. Doppler study demonstrated an acute proximal deep vein thrombosis in the right internal jugular, subclavian and axillary veins attributed to the presence of the PICC, malignancy, and congenital afibrinogenemia/FC therapy. Following removal of the PICC line, he was treated with therapeutic apixaban, and a repeat Doppler study showed thrombus resolution after 3 months of anticoagulation. He experienced no adverse events, continued the FC regimen, and was bridged to HSCT with blinatumomab after placement of a new PICC.

In March 2024 he had an HSCT after myeloablative conditioning using the same FC regimen. On recovery of his platelets on day 15 we decreased the FCo goal to 70mg/dl. At last follow-up, day 150 post-transplant, he remained in remission with 100% peripheral blood donor chimerism. His PICC line was removed, and he is not interested in spacing out FC dosing to every week: this discussion is ongoing.

Discussion/Conclusion:

There are limited evidence-based guidelines for managing CA, much less in the setting of marrow suppressive chemotherapy. This case contributes to the collective knowledge of management of rare bleeding disorders complicated chemotherapy, bone marrow transplant, bleeding and thrombosis.

Youkhana:HEMA Biologics: Honoraria. Bergmann:Novo Nordisk: Honoraria.