A case of antiphospholipid syndrome presenting cryptogenically as Budd-Chiari syndrome, then fulminantly as Libman-Sacks endocarditis

Abstract

A 58 year-old left-handed woman was transferred to our hospital with an evolving left middle cerebral artery stroke, severe thrombocytopenia and elevated inflammatory markers. She had a history of chronic Budd-Chiari syndrome (BCS) 16 months prior, attributed to a calcified web in the inferior vena cava that was stented. No thrombophilia testing was performed at that time. The current presentation demonstrated dense right-sided facial and arm paresis and neglect. Erythrocyte sedimentation rate and C-reactive protein were elevated, an autoimmune workup was consistent with a new diagnosis of systemic lupus erythematosus and triple-positive antiphospholipid antibodies. A transesophageal echocardiogram demonstrated a vegetation consistent with Libman-Sacks endocarditis (LSE), thought to have embolised to the brain. The patient was treated acutely with steroids, intravenous immunoglobulin and clopidogrel. This case demonstrates an atypical constellation of the antiphospholipid syndrome, with a novel presentation of BCS and LSE, and reinforces the importance of hypercoagulability screening in this population.

Background

Antiphospholipid (APL) syndrome (APS) is a condition whereby autoantibodies target prothrombotic antigens on plasma proteins, platelets or vascular endothelium, leading to thrombotic events in arteries or veins, as well as pregnancy complications. The characteristic antibodies include lupus anticoagulant (LAC), anticardiolipin antibody (aCL) and anti-beta-2-glycoprotein-I antibody (B2GPI). The majority of cases are idiopathic, but some are secondary to autoimmune diseases, with the most common being systemic lupus erythematosus (SLE) in 36% of cases.¹ APS typically presents as recurrent thrombotic events or pregnancy complications, or non-thrombotic manifestations including thrombocytopenia or livedo reticularis, or rarely with catastrophic multiorgan failure.²

Budd-Chiari syndrome (BCS) is characterised by obstruction to hepatic venous outflow. Aetiologies include primary venous processes, which encompass several hypercoagulable conditions (most commonly myeloproliferative neoplasms) or membranous webs, and secondary causes, such as extravascular compression of the posthepatic venous system, by tumours.³ Libman-Sacks endocarditis (LSE) is a thrombotic process whereby non-infectious vegetations develop on cardiac valves and has a prevalence of 11% in patients with SLE.⁴

BCS and LSE are rare manifestations of APS. In one large cohort of 1000 APS patients, fewer than 1% had hepatic involvement from hepatic vein thrombosis, and fewer than 3% had LSE vegetations (though valve thickening was 12% prevalent).¹ In the largest series of 43 patients with BCS secondary to APS, no patients had a concurrent diagnosis of LSE.⁵ Additionally, in this case series, the aetiologies of the BCS were distal inferior vena cava (IVC) or hepatic vein thrombi, and none of the cases were attributed to a calcified venous web.

This case report highlights an unusual combination of BCS and LSE in a patient with a first presentation of APS secondary to SLE.

Case presentation

This patient is a 58-year-old left-handed woman. She lived alone independently, working as a clinical secretary. She smoked five cigarettes per day, without alcohol use. She had no contributing medical history and no previous pregnancies or miscarriages.

Sixteen months prior to this presentation of stroke, she was admitted to a community hospital with abdominal pain and acute liver injury (liver enzymes 100–400 U/L, bilirubin 98 µmol/L, international normalized ratio (INR) 1.6 and platelets 38 x 10⁹/L). Comprehensive investigations were unremarkable apart from an antinuclear antibody (ANA) titre of 1:640, and magnetic resonance of the liver showed irregular enhancement of the liver parenchyma thought due to altered venous pressures, in addition to possibly underlying mild diffuse hepatocellular injury. Ultrasound and contrast-CT demonstrated patent hepatic veins and IVC. A liver biopsy demonstrated moderate areas of congestion and necrosis involving portal tracts, including arterioles and venules, and lobules. The necrosis was patchy in distribution and chronicity, with some regions showing acute necrosis and others showing fibrosis. The possible aetiologies included autoimmune hepatitis, BCS and drug reaction. She was initially treated with 60 mg of prednisone for 2 weeks for possible autoimmune hepatitis. However, at multidisciplinary rounds with pathologists, it was felt that this was more likely BCS versus drug-induced versus cryptogenic hepatitis, and the prednisone was tapered. Her symptoms and liver function normalised with supportive management, and she was discharged home, though 2 months later she returned to hospital with abdominal pain and cholestasis. A conventional venogram revealed a focus of stenosis at the right atrial-IVC junction likely secondary to the presence of a partially calcified web, supporting a diagnosis of BCS. She underwent dilatation of the IVC, and her symptoms resolved. No anticoagulation was administered. She remained asymptomatic for 12 months. Her only other medical condition was chronic thrombocytopenia in the 60 000 range, of unclear aetiology.

Four days prior to transfer to our centre, she presented to a community emergency room with several hours of drowsiness, confusion, dysarthria and right-sided weakness since awakening that morning. She was diagnosed with acute ischaemic left middle cerebral artery (MCA) stroke on a non-contrast CT scan. During admission there, her platelets dropped from 25 000 to <10 000 and she had elevated inflammatory markers. She received platelet transfusion, methylprednisolone and clopidogrel, and was referred to our tertiary care hospital due to concern for an intracranial vasculitis.

On our assessment, she was slightly drowsy, haemodynamically stable, in sinus rhythm. Cardiac exam revealed normal heart sounds and no murmurs; respiratory exam demonstrated faint fine crackles. Mental status was euthymic, oriented to person and place, not time. Visual acuity and excursion were intact, but a right hemifield neglect was present. She had a right facial droop with frontalis sparing, dysarthria and dysphagia. Increased tone in her right arm was noted. Motor exam revealed 1/5 right wrist and finger extension, 4/5 right wrist and finger flexion and 5/5 in other movements of the right arm and left arm and legs. Sensation was intact, with right sensory neglect. Reflexes were normal bilaterally. Plantar response was upgoing on the right and equivocal on the left. Coordination was intact, though gait was not tested.

Investigations

Initial investigations were as follows: platelets 40 000, with negative haemolytic markers (normal bilirubin, haptoglobin, no schistocytes), creatinine 117 µmol (normal 22–75), ESR 70 mm/hour (0–10), CRP 16 mg/L (<10), ANA positive at 1:1280 homogeneous, dsDNA 623 IU/mL (<30), C3 0.88 g/L (>0.90), C4 0.08 g/L (>0.10), negative extractable nuclear antigen (ENA), antineutrophil cytoplasmic (ANCA), and anti-cyclic citrullinated peptide (anti-CCP) antibodies, rheumatoid factor (RF), and blood cultures. Liver enzymes, INR and albumin were normal.

A head CT-angiogram demonstrated narrowing of the distal left internal carotid artery and a vascular cut-off in the left proximal MCA, consistent with an evolving MCA-territory stroke and normal parenchyma and vasculature elsewhere.

Differential diagnosis

The differential diagnosis for her large embolic stroke included carotid atheroembolism and cardioembolism secondary to atrial fibrillation, the two most common causes in this patient group. Given the systemic involvement and autoantibodies, vasculitic processes were also suspected, specifically lupus vasculitis or primary central nervous system vasculitis; however, more diffuse intracranial vascular narrowings would be expected. Finally, given the thrombotic event, thrombocytopenia and lupus diagnosis, APS was also a possible hypercoagulable cause of stroke.

APL antibodies returned as follows: aCL 2024 CU, B2GPI >150 CU and positive LAC. A transthoracic echocardiogram was normal. She underwent a transesophageal echocardiogram that demonstrated a 5×6 mm mitral vegetation suggestive of LSE.

After all tests were completed, the diagnoses of APS and SLE were made.

Following these diagnoses, the aetiology of her remote liver injury was reconsidered. In consultation with a thrombosis specialist, her remote calcified IVC web was thought to be a chronic clot. The other, less likely aetiology considered was lupus hepatitis or lupus vasculitis affecting the liver, with the web an incidental finding. The chronic thrombocytopenia was attributed to immune thrombocytopenia purpura (ITP) secondary to SLE.

Treatment

The patient received 500 mg of intravenous methylprednisolone daily for 3 days, and then transitioned to 1 mg/kg of oral prednisone daily. She was given two doses of 1 g/kg intravenous immunoglobulin (IVIG) to treat ITP, with the goal of enabling safe administration of anticoagulation to limit thromboembolisation from the mitral valve vegetation. She was also initiated on hydroxychloroquine for SLE.

Outcome and follow-up

Her neurological deficits recovered significantly, though not completely, in the coming weeks in rehabilitation. She was ultimately relocated to an assisted-living facility.

The APL antibody tests were repeated 20 weeks following the initial tests, with the following results: aCL >2024 CU, B2GPI >148 CU and positive LAC. This confirmed the diagnosis of APS.⁶

Her platelet count recovered transiently with IVIG and steroids, to a maximum of 90 000, and warfarin was initiated. However, within weeks the platelet count dropped once again, ranging between 15 000 and 33 000 over months. Consultation with thrombosis and neurology experts regarding the safety of anticoagulation acutely was sought. The acute/subacute bleeding risk was deemed to be too high to initiate full anticoagulation in the setting of a large territory cerebral infarct due to risk of haemorrhagic transformation. In subsequent weeks, she was initiated on rituximab, in addition to dexamethasone, producing slow recovery of her platelet count. Over the follow-up course, intermediate doses of anticoagulation with low-molecular weight heparin were introduced, with careful monitoring of bleeding events, and gradual titration to therapeutic anticoagulation.

Discussion

This case highlights a constellation of highly infrequent manifestations of APS, initially presenting as liver failure in the form of BCS and a calcified IVC web, and a year later as an acute embolic stroke secondary to LSE.

Given the rarity of BCS, guidelines recommend that all patients with BCS be investigated for hypercoagulable disorders.³ In our patient, these investigations were forgone after discovery of the venous web, though we present here, for the first time, that the two entities may coexist.

In a series of 43 patients with BCS in the setting of APS, the mean age was 30.8 years, and 19% had SLE. In 65% of these patients, BCS was the first presentation of APS, as with our patient.⁵ No patients had evidence of a calcified venous web on imaging, and no occlusions were located in the proximal IVC; rather, the majority (77%) had occlusions in hepatic veins, and 49% had occlusion of the hepatic portion of the distal IVC. In our patient, there was no radiographic evidence of thrombus at these locations on conventional venography. Of 20 patients with liver biopsy in that study, sinusoidal dilation was present in 50%, and centrilobular necrosis and congestion in 35% and 25%, respectively. In our patient, there were no sinusoidal changes; however, necrosis and congestion were observed.

The odd finding in our patient with APS, was a vena cava membranous web. Membranous webs are a rare cause of BCS, mainly in patients of Asian or African descent.⁷ The pathophysiology is uncertain; initially thought a sequela of thrombosis, recent literature has supported a theory of bacterial infection-induced thrombophlebitis related to poor hygiene.⁷ Hypercoagulable conditions are not thought to cause vena cava webs, given that they are consistently ruled out in every membranous web case series, and interventional treatments are much more effective for treating the lesion and resolution of hepatic dysfunction compared with anticoagulation.⁸ There is only one case in the literature of a patient with membranous obstruction of the IVC and extensive bone marrow necrosis in a patient with catastrophic APS⁹; however, our patient did not have catastrophic APS, but rather her’s was isolated to one organ (cardiac valves). In our patient, angioplasty was effective in reversing the hepatic dysfunction, as is reported. However, she had no other epidemiological risks and was not known for prior significant bacterial illnesses. According to Shrestha, once formed, the web is thought to serve as a nucleus for future acute exacerbations.⁷ Perhaps, her APS facilitated clot formation on a previously existing web, that formed from a remote bacterial infection; though no web was seen on imaging during her admission 2 months prior. The other theory to offer is that APS might, in fact, be the primary aetiology for her membranous web, making this the first recorded case of such a process.

Finally, the irregular liver enhancement with histological congestion and necrosis suggest she may have had a component of autoimmune hepatitis or vasculitis contributing to hepatic failure. While the clinical diagnosis was BCS secondary to the web, it is not possible to delineate the relative contributions of BCS versus intrahepatic inflammation to the overall injury. Regardless, the overlap of these processes, both thought to be potentially contributing to her hepatic failure, is unique in the literature.

In conclusion, this case highlights a unique presentation of the APS, and it urges medical practitioners to have a high index of suspicion for it in patients with unusual site thrombotic complications.

Learning points.

• Any patient with a thrombotic event and evidence of a systemic inflammatory disease process, especially without classic risk factors, should be tested for the antiphospholipid syndrome (APS).

• Budd-Chiari syndrome (BCS) has a broad differential diagnosis that requires diligent biochemical and radiological investigation.

• Vena cava membranous webs are a rare cause of BCS, and are not generally described in patients with hypercoagulable disorders; however, our clinical case questions this assumption, and suggests that these patients may warrant a hypercoagulability workup.

• Hepatic failure in a patient with APS secondary to systemic lupus erythematosus might present with features of both BCS and hepatic parenchymal inflammation.