What blood disorders are comorbid with Budd-Chiari syndrome in a patient with a positive Antinuclear Antibody (ANA) test and negative Antiphospholipid (aPL) antibodies?

Blood Disorders Comorbid with Budd-Chiari Syndrome

Myeloproliferative neoplasms (MPNs) are the dominant blood disorder associated with Budd-Chiari syndrome, present in approximately 49% of cases, followed by inherited thrombophilias (21%) and paroxysmal nocturnal hemoglobinuria (19%). 1

Primary Hematologic Disorders

Myeloproliferative Neoplasms (Most Common)

• MPNs represent the single most important blood disorder comorbidity, accounting for nearly half of all Budd-Chiari cases 1
• The JAK2V617F mutation is detected in approximately 29% of Budd-Chiari patients, serving as a molecular marker for underlying MPN 1
• Specific MPN subtypes include:
  • Polycythemia vera (most frequently associated) 1, 2
  • Essential thrombocythemia 3, 4
  • Other Philadelphia-negative MPNs 1

Critical diagnostic pitfall: Peripheral blood counts may appear normal in Budd-Chiari patients with MPN due to concurrent hypersplenism, hemodilution from ascites, or occult gastrointestinal bleeding—this can mask the characteristic thrombocytosis and erythrocytosis 1

Inherited Thrombophilias (21% prevalence)

• Factor V Leiden mutation: 7-32% prevalence in Budd-Chiari, conferring 4-11 fold increased risk 1, 3
• Prothrombin G20210A gene variant: More common in portal vein thrombosis but also present in Budd-Chiari with 2-fold increased risk 1, 3
• Protein C deficiency: Variable prevalence in Budd-Chiari syndrome 1
• Protein S deficiency: Present in a subset of cases 1
• Antithrombin deficiency: 0-5% prevalence 1

Multiple thrombophilic factors frequently coexist—patients may have both inherited thrombophilias and acquired disorders simultaneously, creating synergistic thrombotic risk 3, 2

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• PNH is present in 19% of Budd-Chiari cases, making it a substantial comorbidity 1
• This diagnosis has critical treatment implications, as long-term eculizumab therapy may be indicated 1
• PNH should be specifically tested for in all Budd-Chiari patients 1

Acquired Thrombophilias (44% prevalence)

• Antiphospholipid antibodies: Estimated 5-15% prevalence in Budd-Chiari syndrome 1
• Confirmation requires repeat testing after 12 weeks per current diagnostic criteria 1

Important context for your patient: With positive ANA but negative antiphospholipid antibodies, autoimmune disorders remain a consideration, but the negative aPL testing makes antiphospholipid syndrome less likely as the primary thrombophilic mechanism 1

Rare Hematologic Associations

• Acute promyelocytic leukemia: Rarely presents with Budd-Chiari as initial manifestation due to hyperleukocytosis and disseminated intravascular coagulation 5
• Other acute myeloid leukemias with associated coagulopathy 5

Mandatory Diagnostic Workup

All Budd-Chiari patients require comprehensive thrombophilia screening 1:

1. For inherited thrombophilias: Protein S, protein C, antithrombin levels, Factor V Leiden mutation, prothrombin G20210A gene variant 1
2. For MPNs: JAK2V617F mutation testing in all patients regardless of blood counts; if negative, proceed to calreticulin mutation screening; if both negative, consider bone marrow histology with hematology referral 1
3. For PNH: Flow cytometry testing 1
4. For antiphospholipid syndrome: Anticardiolipin antibodies and lupus anticoagulant, with repeat testing at 12 weeks if positive 1

Identification of one risk factor should never stop the search for additional factors—multiple prothrombotic conditions frequently coexist and compound thrombotic risk 1, 3

Treatment Implications Based on Underlying Disorder

If MPN is Identified

• Indefinite anticoagulation with vitamin K antagonist is mandatory (INR 2.0-3.0) 1
• Cytoreductive therapy with hydroxyurea or interferon-alpha to normalize blood counts 1
• Target hematocrit <45% in polycythemia vera patients 1
• Aspirin is typically used in MPN patients, though evidence for adding it to anticoagulation in Budd-Chiari is limited 1

If PNH is Identified

• Long-term eculizumab therapy should be considered 1
• Indefinite anticoagulation 1

If Only Inherited Thrombophilia

• Duration of anticoagulation remains controversial 1
• Major thrombophilic defects (homozygous Factor V Leiden, combined defects) warrant long-term anticoagulation 1
• Mild or single thrombophilic disorders have uncertain predictive value for recurrence 1

Approximately 15% of Budd-Chiari patients have simultaneous portal vein thrombosis, which worsens prognosis and requires aggressive management 1, 6