Thrombophilia and Polycythemia in a Woman With Budd-Chiari Syndrome

Question: A 31-year-old woman had a 1-month history of ascites with abdominal distension. She was diagnosed with Budd-Chiari syndrome and transferred to our hospital after the failure of hepatic vein recanalization in another hospital. She denied fever, hematemesis, melena, rash, oral ulcers, hair loss, arthritis, photosensitivity, Raynaud’s phenomenon, disturbance of consciousness, visual disturbance, impaired motility, or pregnancy. The patient had no remarkable medical history. She denied drug abuse. The patient lived in the plains in a nonendemic area. She delivered a child uneventfully 2 years ago, without any adverse pregnancy outcome. Physical examination revealed tachycardia, abdominal distention, and abdominal wall varices in the lateral area. Laboratory findings indicated persistent hyperhemoglobinemia (16.1–20.9 g/dL; reference range, 11.5–15.0 g/dL), increased hematocrit (51%–61%; reference range, 35%–45%), and thrombocytopenia (11–30 × 109/L; reference range, 100–300 × 109/L). She had refractory hyponatremia (115.8–123.5 mmol/L; reference range, 137.0–147.0 mmol/L) and hyperkalemia (5.9–7.9 mmol/L; reference range, 3.5–5.3 mmol/L). Liver function tests revealed increased liver enzymes, including alanine transaminase (up to 61 IU/L; reference range, <40 IU/L), aspartate aminotransferase (up to 130 IU/L; reference range, <35 IU/L), alkaline phosphatase (up to 155 IU/L; reference range, 35–100 IU/L), and glutamate transpeptidase (up to 57 IU/L; reference range, <45 IU/L), and gradually deteriorated total bilirubin (4.08–6.57 mg/dL; reference range, 0.29–1.64 mg/dL). Renal function tests showed slightly elevated urea nitrogen (up to 9.6 mmol/L; reference range, 2.6–7.5 mmol/L) and creatinine (up to 87 μmol/L; reference range, 48–79 μmol/L). Coagulation tests showed elevated international normalized ratios (1.54–3.28; reference range, 0.88–1.15) and low antithrombin III activity (21.3%–49.3%; reference range, 75%–125%). Carbohydrate antigen 125 increased to 494 U/mL (reference range, <47 U/mL), and the remaining tumor markers were unremarkable. Peripheral blood cell morphology showed 9.2% polychromatophilic red blood cells and 0.4% schistocytes. The ascites fluid appeared yellow and cloudy. Pyocytes (250 cells per high power field) were observed in ascites, and the serum ascites albumin gradient was 34.1 g/L (ascitic fluid total protein, 4.9 g/L). The levels of glucose (6.69 mmol/L), lactate dehydrogenase (45 IU/L), and adenosine deaminase (0.4 IU/L) were unremarkable in ascites. Computed tomography indicated obstruction of all 3 hepatic veins with clots in the inferior vena cava (Figure A, B), renal infarction (Figure C), and pulmonary embolism (Figure D). Doppler ultrasound suggested deep vein thrombosis (right subclavian vein, right axillary vein, and right brachial vein). The results for anticardiolipin antibodies (immunoglobulin [Ig] A, IgG, IgM), anti-β2 glycoprotein Ⅰ antibodies (IgA, IgG, IgM), lupus anticoagulant, antinuclear antibodies, antineutrophil cytoplasmic antibodies, liver-related autoantibodies, antiplatelet antibodies, rheumatoid factors, IgG4, ceruloplasmin, serum protein electrophoresis, cardiac function, and human chorionic gonadotropin hormone were unremarkable. Infections such as tuberculosis, toxoplasma, rubella, cytomegalovirus, herpes, human immunodeficiency virus, Epstein‒Barr virus, hepatitis virus, syphilis, fungi, and parasites were excluded. With thrombophilia and persistent polycythemia, myeloproliferative neoplasms, especially polycythemia vera, could not be excluded. Therefore, phlebotomy, ascites drainage, antibiotics, and other supportive therapies were applied. However, the patient’s condition deteriorated, and hyperhemoglobinemia, thrombocytopenia, hyperkalemia, and hyponatremia persisted. Then, bone marrow smears showed poor generation of platelets from megakaryocytes. However, the bone marrow biopsy was unremarkable. Flow cytometry analyses of bone marrow were normal. Multigene panel testing for myeloproliferative neoplasms, including but not limited to JAK2 V617F, JAK2 exon 12, CALR, MPL, DNMT3A, TET2, ASXL1, CBL, SF3B1, EZH2, SRSF2, USAF1, IDH1/2, GATA2, ATM, RUNX1, CHEK2, and TP53 mutations, assessed using next-generation sequencing was negative. Erythropoietin was elevated to 42.8 mIU/mL (reference range, 3.7–29.5 mIU/mL), inconsistent with polycythemia vera. What tests will you do next to establish the etiology of Budd-Chiari syndrome? See the Gastroenterology website (www.gastrojournal.org) for more information on submitting to Gastro Curbside Consult. Then, the case was presented at a multidisciplinary expert meeting. Because the patient had rapid multiorgan thrombotic and thromboembolic events, catastrophic antiphospholipid syndrome was highly suspected. Subsequently, the test for non-criteria antiphospholipid antibodies showed that antiphosphatidylethanolamine antibody-IgM and antiprothrombin antibody-IgM were positive. Thus, Budd-Chiari syndrome was considered secondary to non-criteria antiphospholipid syndrome. At present, it is recognized that about three-quarters of patients with Budd-Chiari syndrome have an etiology secondary to a hereditary or acquired hypercoagulable state, and evaluation of its underlying cause is essential for further management and achieving a better prognosis.1Garcia-Pagan J.C. Valla D.C. Primary Budd-Chiari syndrome.N Engl J Med. 2023; 388: 1307-1316Crossref PubMed Scopus (7) Google Scholar Indeed, myeloproliferative neoplasm is reported to cause approximately half of Budd-Chiari syndrome cases.1Garcia-Pagan J.C. Valla D.C. Primary Budd-Chiari syndrome.N Engl J Med. 2023; 388: 1307-1316Crossref PubMed Scopus (7) Google Scholar In our case, persistent hyperhemoglobinemia with thrombophilia suggested myeloproliferative neoplasm. Although the coexistence of antiphospholipid syndrome and polycythemia vera has been reported,2Zahra Ha-ou-Nou F. Boumzebra D. Essaadouni L. Coexistence of renal artery stenosis, primary antiphospholipid syndrome and polycythaemia vera: an exceptional association.Lupus. 2014; 23: 84-87Crossref PubMed Scopus (5) Google Scholar polycythemia and thrombophilias were not caused by the latter in our patient. A previous study suggested that hepatic erythropoietin production could increase in the acute phase of Budd-Chiari syndrome, resulting in polycythemia,3Levy V.G. Ruskone A. Baillou C. Theirman-Duffaud D. Najman A. Boffa G.A. Polycythemia and the Budd-Chiari syndrome: study of serum erythropoietin and bone marrow erythroid progenitors.Hepatology. 1985; 5: 858-861Crossref PubMed Scopus (28) Google Scholar which is consistent with our case. Moreover, polycythemia might also be a result of decreased circulating blood volumes and hemoconcentration due to a large volumes of ascites. Other atypical presentations in this patient included the absence of pregnancy morbidity or any autoimmunologic background, resulting in delayed diagnosis. Although criteria antiphospholipid syndrome is known to cause approximately 10% of Budd-Chiari syndrome,1Garcia-Pagan J.C. Valla D.C. Primary Budd-Chiari syndrome.N Engl J Med. 2023; 388: 1307-1316Crossref PubMed Scopus (7) Google Scholar non-criteria antiphospholipid syndrome as the underlying cause has not been reported before. The characteristics of criteria antiphospholipid syndrome–related Budd-Chiari syndrome are nonspecific, including predominance of females (63%), young age (mean, 24 years old), and oral contraceptive use.4Pelletier S. Landi B. Piette J.C. et al.Antiphospholipid syndrome as the second cause of non-tumorous Budd-Chiari syndrome.J Hepatol. 1994; 21: 76-80Abstract Full Text PDF PubMed Scopus (111) Google Scholar The term non-criteria antiphospholipid syndrome was raised only 20 years ago and is still under heated discussion.5Abreu M.M. Danowski A. Wahl D.G. et al.The relevance of "non-criteria" clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features.Autoimmun Rev. 2015; 14: 401-414Crossref PubMed Scopus (160) Google Scholar,6Pires da Rosa G. Bettencourt P. Rodriguez-Pinto I. Cervera R. Espinosa G. "Non-criteria" antiphospholipid syndrome: a nomenclature proposal.Autoimmun Rev. 2020; 19102689Crossref PubMed Scopus (29) Google Scholar The precise prevalence of non-criteria antiphospholipid syndrome is not clear. Four potential profiles were established: seronegative antiphospholipid syndrome, clinical non-criteria antiphospholipid syndrome, incomplete laboratory antiphospholipid syndrome, and laboratory non-criteria antiphospholipid syndrome.6Pires da Rosa G. Bettencourt P. Rodriguez-Pinto I. Cervera R. Espinosa G. "Non-criteria" antiphospholipid syndrome: a nomenclature proposal.Autoimmun Rev. 2020; 19102689Crossref PubMed Scopus (29) Google Scholar Specifically, for our patient, laboratory non-criteria antiphospholipid syndrome was considered, and it was characterized by clinical criteria (thrombosis and/or obstetric morbidity), with no- or low-titer criteria antiphospholipid antibodies and positivity for some non-criteria antiphospholipid antibodies.6Pires da Rosa G. Bettencourt P. Rodriguez-Pinto I. Cervera R. Espinosa G. "Non-criteria" antiphospholipid syndrome: a nomenclature proposal.Autoimmun Rev. 2020; 19102689Crossref PubMed Scopus (29) Google Scholar As for non-criteria antiphospholipid antibodies, at least there are antiphosphatidylethanolamine antibodies, antibodies to prothrombin and phosphatidylserine/prothrombin, IgA anticardiolipin and IgA anti-β2 glycoprotein I antibodies, anti-β2 glycoprotein I Domain I antibodies, and antiannexin A5 antibodies.7Funke A. Staub H.L. Monticielo O.A. et al.Non-criteria antiphospholipid antibodies: a narrative review.Rev Assoc Med Bras (1992). 2020; 66: 1595-1601Crossref PubMed Scopus (4) Google Scholar In our patient, both antiphosphatidylethanolamine antibody-IgM and antiprothrombin antibody-IgM were positive, and all 3 criteria antiphospholipid antibodies were negative. The seronegativity of criteria antiphospholipid antibodies may be caused by antibody consumption in thrombotic events in some patients.5Abreu M.M. Danowski A. Wahl D.G. et al.The relevance of "non-criteria" clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features.Autoimmun Rev. 2015; 14: 401-414Crossref PubMed Scopus (160) Google Scholar Moreover, thrombocytopenia developed in this patient could be identified as one of non-criteria manifestations of antiphospholipid syndrome. Other major non-criteria manifestations include nephropathy, livedo reticularis, chorea, longitudinal myelitis, heart valve disease, and superficial vein thrombosis.6Pires da Rosa G. Bettencourt P. Rodriguez-Pinto I. Cervera R. Espinosa G. "Non-criteria" antiphospholipid syndrome: a nomenclature proposal.Autoimmun Rev. 2020; 19102689Crossref PubMed Scopus (29) Google Scholar As for prognosis, the outcomes between criteria and non-criteria antiphospholipid syndrome were deemed similar.8Pires da Rosa G. Ferreira E. Sousa-Pinto B. et al.Comparison of non-criteria antiphospholipid syndrome with definite antiphospholipid syndrome: a systematic review.Front Immunol. 2022; 13967178Crossref PubMed Scopus (3) Google Scholar Usually, patients have a favorable prognosis with a 10-year survival rate of 90.7%, and the most common cause of death is severe thrombosis (36.5%),9Cervera R. Serrano R. Pons-Estel G.J. et al.Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients.Ann Rheum Dis. 2015; 74: 1011-1018Crossref PubMed Scopus (491) Google Scholar especially when catastrophic antiphospholipid syndrome ensues. Catastrophic antiphospholipid syndrome is very rare, affecting only 1% of patients experiencing criteria antiphospholipid syndrome,10Cervera R. Rodriguez-Pinto I. Espinosa G. The diagnosis and clinical management of the catastrophic antiphospholipid syndrome: a comprehensive review.J Autoimmun. 2018; 92: 1-11Crossref PubMed Scopus (101) Google Scholar which could be even less for non-criteria antiphospholipid syndrome. It is characterized by multiple thromboses with vessel occlusions involving 3 or more organs (especially the lungs, kidneys, liver, brain, and heart) during a very short period of time and is notorious for its life-threatening nature.10Cervera R. Rodriguez-Pinto I. Espinosa G. The diagnosis and clinical management of the catastrophic antiphospholipid syndrome: a comprehensive review.J Autoimmun. 2018; 92: 1-11Crossref PubMed Scopus (101) Google Scholar As seen in this case, thrombocytopenia and scanty schistocytes (unlike the abundant schistocytes in thrombotic thrombocytopenic purpura) are observed in catastrophic antiphospholipid syndrome.10Cervera R. Rodriguez-Pinto I. Espinosa G. The diagnosis and clinical management of the catastrophic antiphospholipid syndrome: a comprehensive review.J Autoimmun. 2018; 92: 1-11Crossref PubMed Scopus (101) Google Scholar The basic treatments include anticoagulation (vitamin K antagonists), glucocorticoids, and targeting identifiable trigger factors such as infection. Apparently, catastrophic antiphospholipid syndrome should be recognized rapidly to prevent lethal outcomes, but the underlying non-criteria antiphospholipid syndrome made this case complicated. Nevertheless, this case highlights that non-criteria antiphospholipid syndrome should be screened after conventional work-up for Budd-Chiari syndrome of undetermined cause, especially in those with multiple thromboemboli and thrombocytopenia, as in this case. A transjugular intrahepatic portal shunt was then performed by puncture of the main right portal branch directly via the inferior vena cava, during which many white thrombi extending from the inferior vena cava to the right side of the heart were observed (Figure E) and removed via endovascular thrombectomy (Figure F). Afterward, her condition was improved using intravenous methylprednisolone combined with low–molecular-weight heparin and warfarin sequential anticoagulant therapy for 2 weeks. Ascites was gradually eliminated. The laboratory parameters, including hemoglobin, hematocrit, platelets, serum electrolytes, and antithrombin III activity, returned to normal, and total bilirubin decreased to 3.16 mg/dL before discharge. Figure G shows the clinical course for this case, emphasizing the changes in hemoglobin, platelet, and antithrombin III activity before and after treatment. The patient, on the waiting list for liver transplantation, was discharged on warfarin and oral methylprednisolone. The patient has sustained remission without recurrence, and follow-up is ongoing.