Abstract
Classically, antiphospholipid antibody syndrome (APS) presents with recurrent episodes of vascular thrombosis and abortions. For APS to present as fever of unknown origin (FUO) is a rare phenomenon. We present an interesting case of FUO who on workup was found to have primary APS with right atrial thrombus and chronic pulmonary thromboembolism (PTE). Fever resolved completely with anticoagulation therapy and surgical removal of the intra-cardiac thrombus. Although rare, APS should be considered in any case of FUO with prolonged activated partial thromboplastin time and/or thrombocytopenia. We also take this opportunity to briefly review 28 cases of APS with intra-cardiac thrombus reported to date in the medical literature.
<Learning objective: Primary antiphospholipid antibody syndrome (APS) presenting as fever of unknown origin (FUO) is rare. APS should be kept in the differential diagnosis in any case of FUO with prolonged activated partial thromboplastin time or thrombocytopenia. Intra-cardiac thrombus is more frequently associated with primary APS as compared to secondary APS.>
Keywords: Antiphospholipid antibody syndrome, Fever of unknown origin, Intra-cardiac thrombus
Introduction
Antiphospholipid antibody syndrome (APS) commonly presents with thrombotic events, pregnancy morbidity, and recurrent pregnancy loss [1]. APS presenting as fever of unknown origin (FUO) is rare. To date, there are only a few case reports that have described FUO as presenting manifestation of APS [2]. Intra-cardiac thrombus and pulmonary thromboembolism (PTE) are life-threatening thrombotic events of APS, but asymptomatic presentation of intra-cardiac thrombus with PTE is rare [3].
Case report
A 41-year-old man presented with 4-months history of high-grade fever, 38.8–40 °C, associated with chills and rigor, 1–2 episodes per month. Each episode used to last for 1–2 days followed by spontaneous resolution of symptoms. During this time, he also had significant loss of appetite with weight loss of ∼15 kg. There was no other history to suggest localization. On evaluation he was febrile, normotensive with tachycardia (heart rate – 100/min) no tachypnea, and was maintaining room air oxygen saturation of 97%. He had average build (body mass index – 21.70 kg/m2), grade-I pan-digital clubbing and there was no palpable lymph node or hepatosplenomegaly. Cardiovascular examinations revealed a systolic click at 3rd inter-costal space, near left parasternal area with no appreciable variation of intensity during respiration and there was no definitive thrill or murmur. Other systemic examinations were essentially normal. Clinically, differential diagnosis of sub-acute bacterial endocarditis, tuberculosis, human immunodeficiency virus (HIV) infection, occult malignancy, lymphoma, or any autoimmune phenomena were considered. Investigations revealed thrombocytopenia (25 × 109/L) with normal hemoglobin (Hb-13.5 g/dL) and total leucocytes count (TLC-7 × 109/L). Blood and urine cultures were sterile multiple times. Chest X-ray showed mild broncho-vascular prominence on the right side and montoux skin test was not reactive. Tests for HIV, hepatitis B virus surface antigen and anti-hepatitis C virus core immunoglobulin M were also negative. Serum procalcitonin, galactomannan, β-d-glucan were not elevated and fungal serology was negative. Coagulogram suggested persistently elevated activated partial thromboplastin time (aPTT) (55–59 s). Electrocardiography showed sinus tachycardia with S1Q3T3 pattern and right ventricular hypertrophy. Trans-thoracic followed by trans-esophageal echocardiography (TEE) showed no evidence of infective endocarditis, but incidentally detected a right atrial (RA) mass of 3.2 cm × 2.0 cm, attached to inter-atrial septum (IAS) by a stalk, prolapsing into the right ventricle (RV) causing tricuspid regurgitation (TR) (Fig. 1A and Supp. Video 1). RA was dilated with raised RV systolic pressure (RVSP) of 85 mmHg and normal left ventricular (LV) function. Subsequently contrast-enhanced computed tomography of the chest and abdomen was done which showed chronic PTE involving bilateral descending pulmonary artery (PA) and a hypodense filling defect in RA with central calcification suggestive of myxoma or thrombus. In addition there was a patchy peripheral opacity at the right upper lobe lung suggestive of infarct. In the view of unprovoked PTE and prolonged aPTT with no evidence of malignancy and infection, a strong possibility of APS was considered. Subsequently he was found to be positive for lupus anticoagulant (LA). IgG anti-cardiolipin antibody (aCL) and IgG anti-β2 glycoprotein I (aβ2GP I) were elevated in high titers, 119 GPLU/ml and 97 U/ml respectively by enzyme-linked immunosorbent assay method. Tests for antinuclear antibody (ANA) and anti-dsDNA were negative; C3 and C4 were normal. Hemolytic workup, direct Coomb test and paroxysmal nocturnal hemoglobinuria (PNH) workup were also negative.
Fig. 1.
(A) Trans-esophageal echocardiography showing a single large right atrial (RA) mass (3.2 cm × 2.0 cm) attached to inter-atrial septum by a stalk. (B) Post-operative picture of the excised RA mass.
For persistence of thrombocytopenia manual platelet count was done, which showed giant platelets. Bone marrow biopsy showed normo-cellular to slightly hyper-cellular marrow with intense megakaryocytic hyperplasia and focal clustering, with no lymphoid aggregates, granulomas, or metastatic deposit. Its culture was sterile for bacteria, mycobacterium, and fungus. We concluded that primary APS with PTE and RA mass with immune thrombocytopenia was the cause of FUO. For immune thrombocytopenia oral prednisolone was started at 1 mg/kg/day. Platelet count gradually improved and anticoagulation was started with fondaparinux 7.5 mg/day once platelet count increased to >50 × 109/L. As RA mass was prolapsing into the RV, there was high chance of outflow obstruction. Hence, he underwent surgical excision to prevent life-threatening complications. During the surgery it was found that there were two large, firm to hard masses, 3 cm × 3 cm each in RA, arising from IAS and RA wall one each, with multiple vegetations over the tricuspid valve leaflets (Fig. 1, Fig. 2). Histopathological examination (HPE) confirmed thrombus with central calcification (Supp. Fig. S1) and cultures were sterile. Post-operatively, the patient was continued with moderate intensity anticoagulation (international normalized ratio of 2–3) with warfarin, steroid was gradually tapered off as thrombocytopenia resolved and sildenafil was added for pulmonary arterial hypertension (PAH). IgG aCL and IgG aβ2GP I were persistently elevated in high titer even after 12 weeks, thereby fulfilling the criteria for APS. Repeat 2D echocardiography after 2 months and 6 months showed no recurrence of thrombus with RVSP of 52 mmHg and there was no recurrence of fever.
Fig. 2.
(A) Intra-operative picture of the right atrial mass arising from the inter atrial septum. (B) Intra-operative picture of the multiple vegetations over the tricuspid valve leaflets.
Discussion
APS is diagnosed in the presence of persistently elevated one or more antiphospholipid (APL) antibody (LA, aCL, aβ2GP I) on two or more occasions at least 12 weeks apart along with presence of one or more episodes of vascular thrombosis or recurrent pregnancy loss [4]. Our patient had vascular thrombosis in the form of PTE and RA thrombus in the presence of persistently elevated high titer of IgG aCL and IgG β2GP I, which were reconfirmed 12 weeks later. There was no evidence of secondary causes of APS such as systemic lupus erythematosus (SLE), autoimmune hemolytic anemia (AIHA), and PNH. There is increased risk of intra-cardiac thrombosis in APS with SLE, LA and high levels of aCL antibody [5]. In a retrospective study it has been shown that venous thrombosis with PTE is more frequent with positive LA activity; however, coronary, cerebrovascular, and peripheral arterial events are more common with elevated levels of aCL antibody [6]. Recurrent thrombotic events are well known in APS. A 5-year prospective study showed that the median time to a recurrent thrombotic event is shorter in patients with high titer of aCL antibody and intra-cardiac thrombus [7].
It is difficult to differentiate intra-atrial thrombus from atrial myxoma [8], [9]. Both can occur in right or left atrium. Both can be attached to the IAS, free cardiac wall with stalk, can be mobile, and have calcification [10]. There is no established association between cardiac myxoma and APS except few case reports [11]. It was hypothesized that interleukin-6 produced by the myxoma can trigger an immunological reaction leading to the APS [12]. Various imaging modalities such as echocardiographic contrast perfusion imaging [13], dual energy cardiac computed tomography scan [14], and contrast cardiac magnetic resonance imaging [15] have been tried but they are not sensitive and specific enough to differentiate intra-atrial thrombus from atrial myxoma. Surgical excision and HPE is the definitive mode of diagnosis as well as to prevent life-threatening complications. Fever was because of recurrent thromboembolic events due to APS as the patient never had febrile episodes after starting anticoagulation. The exact pathophysiology of fever in thrombotic events is not clear. It may be due to inflammatory response to the recurrent infarct and secondary to infection of the infarct or development of pneumonitis in pulmonary infarct [16], [17], [18], [19].
We did a Medline search with MeSH terms such as “APS and intra-cardiac thrombus”. In total we reviewed all the indexed 28 published cases of APS with intra-cardiac thrombus (Table 1). None of those cases presented with FUO. Most of the cases are primary APS as compared to a few cases of secondary APS. Amongst those rare cases of secondary APS, SLE was found to be the most common association. As expected, females (59%) are more commonly affected compared to males (41%). Upon analyzing APL antibody positivity, dual positivity for LA and aCL was most common followed by isolated anti-β2GP-I positivity and rarely triple positivity for all 3 APL antibodies. Although such intra-cardiac thrombus in APS can be seen in any chamber, our review suggested that RA was most frequently involved followed by RV. PTE was frequently seen in APS with intra-cardiac thrombus and more commonly associated with right sided intra-cardiac thrombus. So we concluded that primary APS presenting as FUO is rare. APS should be kept in the differential diagnosis in any case of FUO with prolonged aPTT or thrombocytopenia. Intra-cardiac thrombus is more frequently associated with primary APS compared to secondary APS.
Table 1.
Published cases of intra-cardiac thrombus with antiphospholipid antibody syndrome.
| Authors | Primary/secondary | Sex | Secondary association | Heart involved | PTE | LA | aCL | Anti-β2GP I |
|---|---|---|---|---|---|---|---|---|
| 1. Lawrence JL, et al. (Am J Med. 1989) | Primary | F | – | RA | − | + | + | − |
| 2. Kjernsmo A, et al. (Tidsskr Nor Laegeforen. 1990) | Primary | F | – | RA | + | + | + | − |
| 3. Hickey SO, et al. (Br Heart J. 1993) | Primary | M | – | RV | + | − | + | − |
| 4. Villani R, et al. Minerva (Cardioangiol. 1994) | Primary | F | – | RA | + | + | + | − |
| 5. Matos V et al. (Acta Medica Portuguesa. 1994) | Primary | F | – | RA | + | + | − | − |
| 6. Bräuninger S, et al. (Dtsch Med Wochenschr. 1995) | Primary | M | – | RV | + | + | + | − |
| 7. Yeghen T, et al. (Am J Hematology. 1995) | Primary | M | – | RA | + | − | + | − |
| 8. Granel B, et al. (Cardiology. 1999) | Primary | F | – | RA | − | + | + | + |
| 9. Aguilar JA, et al. (J Am Soc Echocardiogr. 2000) | Primary | F | – | LV | − | − | + | − |
| 10. Ghirarduzzi A, et al. (Ital Heart J Suppl. 2001) | Primary | F | – | RA | − | + | + | − |
| 11. Philip M, et al. (J Am Soc Echocardiogr. 2002) | Primary | M | LA | − | − | + | − | |
| 12. Latagliata R, et al. (Acta Haematol. 2002) | Secondary | F | AIHA | RA | − | + | + | + |
| 13. Tamura K, et al. (Kyobu Geka. 2002) | Primary | F | – | RA | − | + | − | − |
| 14. Willens HJ, et al. (Echocardiography. 2003) | Secondary | M | SLE | LV | − | − | + | − |
| 15. Lime, et al. (Internal Med J. 2004) | Secondary | F | SLE | RA | + | − | + | − |
| 16. Cristina B, et al. (J Thorac Cardiovasc Surg. 2005) | Primary | F | – | RA | − | + | − | − |
| 17. Bahlmann E, et al. (Heart. 2005) | Primary | M | – | LV | − | + | + | − |
| 18. Morel O, et al. (Thrombosis J. 2005) | Primary | M | – | RA, RV | − | − | + | − |
| 19. Zhong-Xuan Y, et al. (Circ J. 2005) | Primary | F | – | RA | + | − | + | − |
| 20. Duman D, et al. (Heart Surg Forum. 2006) | Primary | M | – | RA | − | − | + | − |
| 21. Guedes-Barbosa LS, et al. (Arthritis Rheum. 2007) | Primary | M | – | RA, LA, RV, LV | − | + | + | − |
| 22. Gomez AII, et al. (Radiologia. 2008) | Primary | F | – | RV | + | + | + | − |
| 23. Tomas FC, et al. (Tex Heart Inst J. 2008) | Secondary | F | SLE | RA | + | + | − | − |
| 24. Jose et al. (Eur Heart J – Cardiovascular Imaging. 2009) | Primary | F | – | RV | − | + | + | − |
| 25. Tomas FC, et al. (Cardiology J. 2009) | Primary | M | – | LV | − | + | − | − |
| 26. Ashish A, et al. (J Am Soc Echocardiogr. 2010) | Primary | F | – | RA | − | − | + | + |
| 27. Rawat SKS, et al. (Ann of Card Anaesthesia. 2010) | Primary | F | – | RA | + | + | − | − |
| 28. Nadine A, et al. (Eur Heart J. 2012) | Primary | M | – | RA, LA, RV, LV | − | − | + | − |
F, female; M, male; RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.
Authors’ contribution
K.K. Sahu was involved in the concept and design of the study. Critical writing was done by D.P. Dhibar. Interpretation of data was done by S. Kumari and Vikas Suri. S. Varma and A.K. Mishra revised the intellectual content. Final approval was given by P. Malhotra. Interpretation of histopathology data was done by Kim Vaiphei. Interpretation of echocardiography data was done by Suraj Khanal. Interpretation of Radiological Imaging was done by Manphool Singhal.
Conflict of interest
None to disclose.
Footnotes
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jccase.2016.07.005.
Appendix A. Supplementary data
Trans-esophageal echocardiogram showing single large mobile right atrial mass arising from the inter atrial septum and prolapsing into the right ventricle.
Supplementary Fig. 1.
(A) The resected specimen composed of firm whitish irregular tissue pieces with multiple brownish areas. It gave areas of gritty sensation on cutting. (B) Medium power photomicrograph of the tissue shows large areas of dystrophic calcification and hyalinization which are intermixed in the background with fibrin and proliferating myofibroblasts (Hematoxylin & Eosin, 250×).
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Associated Data
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Supplementary Materials
Trans-esophageal echocardiogram showing single large mobile right atrial mass arising from the inter atrial septum and prolapsing into the right ventricle.