Year : 2012 | Volume
: 23 | Issue : 1 | Page : 110--113
Catastrophic antiphospholipid syndrome presenting as fever of unknown origin
Fatma I Al-Beladi
Department of Medicine, King Abdul Aziz University Hospital, Jeddah, Saudi Arabia
Fatma I Al-Beladi
Assistant Professor, Consultant Nephrologist, Department of Medicine, King Abdul Aziz University Hospital, Jeddah
Antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies with characteristic clinical manifestation, which include venous, arterial thrombosis, thrombotic microangiopathy, and recurrent fetal loss. The syndrome can be secondary to many causes including systemic lupus erythematosus (SLE) or «DQ»primary«DQ» antiphospholipid syndrome (APLS). We report a case of a man with catastrophic antiphospholipid syndrome (CAPS), which occurs when three or more organ systems are affected by thrombosis in less than a week. Catastrophic antiphospholipid syndrome is uncommon but often fatal. The patient received a successful treatment that controlled this disease and included intravenous heparin, antiplatelet, intravenous corticosteroid, and plasmapheresis.
|How to cite this article:|
Al-Beladi FI. Catastrophic antiphospholipid syndrome presenting as fever of unknown origin.Saudi J Kidney Dis Transpl 2012;23:110-113
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Al-Beladi FI. Catastrophic antiphospholipid syndrome presenting as fever of unknown origin. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2019 Aug 19 ];23:110-113
Available from: http://www.sjkdt.org/text.asp?2012/23/1/110/91313
Antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies with characteristic clinical manifestations, which include venous and arterial thrombosis, thrombotic microangiopathy, and recurrent fetal loss. The syndrome can be secondary to many causes including systemic lupus erythematosus (SLE) or "primary" antiphospholipid syndrome (APLS).
Catastrophic antiphospholipid syndrome occurs when three or more organ systems are affected by thrombosis in less than a week. Catastrophic antiphospholipid syndrome is uncommon but often fatal. It occurs in 1% of APLS patients and is associated with a mortality rate of up to 50%.Treatment should include intravenous heparin, antiplatelet therapy, intravenous corticosteroid, and plasmapheresis. Awareness of this rare, rapidly fatal, medical condition prompts vital, early intervention to improve patients' survival.
A 30-year-old Saudi male patient was admitted to another hospital with fever and rigor of 1-month duration. He had no history of arthralgia, skin rash, mouth ulcers, or family history of a similar disease. He had a history of drinking raw milk six months earlier. Physical examination and laboratory investigations were all within normal limits, except for brucella serology, which was positive (titer not available). A diagnosis of brucellosis was made and he was treated with rifampacin and doxycycline, and he was discharged within five days in a stable condition. Five days later, he developed vomiting and diarrhea in addition to fever and rigor, but with no other complaints. He was again admitted to another hospital for further investigations. His physical examination and lab investigations were all within normal limits. Repeated brucella serology was negative. The patient was discharged with no definite diagnosis, but was advised to stop all medications.
One month later, the patient presented to our hospital complaining of high-grade fever, rigors, repeated vomiting, night sweats, and weight loss of 10 Kg. He had no symptoms related to respiratory, neurological, thyroid, or connective tissue disease and he denied any contact with TB patients. The patient was not known to be hypertensive, diabetic, or dyslipidemic. He denied smoking cigarettes or using illicit drugs.
At time of admission, the patient's physical examination revealed the following: pulse 100/min, blood pressure 104/62 mmHg, respiration rate 20/min, and body temperature 40°C. The patient was not jaundiced and he had no palpable lymph nodes or skin lesions. Chest, heart, abdomen, and CNS examination was unremarkable. A differential diagnosis of chronic infections, autoimmune disorder, or malignancy was considered.
Results of laboratory tests were as follows: hemoglobin 9.3 g/dL, white blood cell count 6.1 k/μL, platelet count 164 K/μL, C- reactive protein 60.4, erythrocyte sedimentation rate 104 mm/h, prothrombin time (PT) 16/12 seconds, activated partial thromboplastin time (APTT) 37/34 seconds, international normalized ratio 1.5, serum creatinine 143 μmol/L (normal up to 115 μmol/L), total protein 82 g/L, serum albumin 26 g/L (normal 34-50 g/L), alkaline phosphate (ALK) 187 μ/L, and total bilirubin 10 μmol/L. Levels of aspartate aminotransferase (74 μ/L) and GGT (97 μ/L) were high. Levels of ALT (55 μ/L), lactate dehydrogenase, and amylase were normal. Urine analysis showed protein +2 and blood +2.24-hour urinary protein excretion was 1.4 g/day.
Malaria film, peripheral blood film, and tests for HCV, HBV, HIV, and brucella were all negative. Thyroid function tests were normal. Levels of anti-nuclear antibody and dsDNA antibody were 1:1280 (NR <1:40) and 128.0 (NR 0-200), respectively. Tests for RNP - Ena, SM - ENA, and SS-BENA were negative. C3, C4 were normal.
Computed tomography (CT) scans of abdomen and pelvis showed thickening of the distal esophagus and the gastric antrum, periportal thickening of the liver parenchyma, and evidence of retroperitoneal fibrosis causing right mild hydronephrosis.
Autoimmune disease and lymphoma were at the top of the list of differential diagnosis. A kidney biopsy was considered, but thought of as unsafe because of the coagulopathy at that time.
The patient underwent UGI endoscopy, which revealed a large esophageal ulcer of nonspecific nature. Histopathology later showed severe acute inflammation, ulceration, and extensive tissue necrosis.
After the endoscopy, the patient did not recover from the sedation. An urgent CT scan of the brain was normal. Fifteen hours later, the patient was fully conscious and oriented but with right-sided weakness. Three hours later, the patient became hypotensive and went into a deep coma requiring intubation and administration of pressor medications. Laboratory investigations showed low levels of hemoglobin (6.2 g/dL), low platelet counts (47 k/μL), and a prolonged APTT of 97 s. PT was 19/12 s and D-Dimer concentration was 3.9 mg/L (normal up to 0.55 mg/L). The patient was treated with broad-spectrum antibiotics and was transferred to the intensive care unit for further management. Within 24 hours, the patient's hemodynamic status had improved and he was taken off pressor medications. However, he developed dry gangrene of the left leg probably secondary to arterial thrombosis.
The results of a septic screen at admission were negative. Hemoglobin concentration and platelet counts continued to decrease to 5.4 g/dL and 9 k/μL, respectively, with progresssive prolongation of PT to 24 s, and APTT to 109 s. However, a 50:50 mixing study was negative. Bilirubin continued to increase along with transaminases and alkaline phosphate (ALK). Peripheral blood film showed no schistocytes but the Coomb's test was positive. The levels of amylase and lipase were 872 μ/L, 3,987 μ/L (NR 23-300), respectively, and they confirmed the diagnosis of acute pancreatitis.
Due to respiratory distress, which was interfering with weaning and extubation, a CT scan with an angiogram of the lungs was done and showed no pulmonary embolism. However, in the intravenous abdominal angiogram, an extensive thrombus was seen in the inferior vena cava, iliac, femoral vein extending down to the popliteal veins and more distal branches. A later MRI scan of the brain showed white matter disease, consistent with vasculitis. The patient also developed acute kidney injury, which was managed with only two hemodialysis sessions as the urine output and the renal function normalized.
The positive Coomb's test, spontaneous thrombosis despite prolonged APTT and PT directed us to think of APLS as a possible diagnosis. Diagnostic Laboratory tests confirmed APLS [anticardiolipin antibody-G was 120 u/mL (NR 0-10) anticardiolipin-M was 2 (NR 0-7) and, B2-glycoprotein-IgG >100 U/ML which is strongly positive]. In view of the patient's clinical state, which was indeed "catastrophic", a diagnosis of CAPS was made on the basis of the laboratory and clinical findings of catastrophic course involving with thrombosis in multiple organs.
The patient was treated with intravenous prednisolone 1 g for three days followed by oral prednisolone (1 mg/kg/day) and azathioprine as a maintenance therapy. In addition, five sessions of plasmapheresis and intravenous immunoglobulin (IVIG) (0.4 mg/kg) was administered on three consecutive days. Aspirin and anticoagulants were administered as a maintenance therapy. The patient responded quickly with complete normalization of platelet count, liver function, kidney function, and pancreatic enzymes. He regained consciousness. Power in the affected limb also improved. Four months later, the patient was seen in the clinic walking; C-reactive protein (CRP) was less than 3 (normal range 1 - 3). Results of laboratory analyses showed anti-nuclear antibody of 1:160 and an erythrocyte sedimentation rate of 6. Renal function ad and urinalysis were normal.
The main characteristic of the catastrophic antiphospholipid syndrome is a widespread coagulopathy that primarily affects small vessels of organs. A minority of patients have features of classic APS with involvement of large veins or cerebral vasculature. Vascular occlusions occur within days to weeks of a "triggering" event or they may occur spontaneously. Serological tests reveal very high levels of antiphospholipid antibodies in more than 50% of patients and often a moderate to severe thrombocytopenia. Results of laboratory tests may provide evidence of disseminated intra-vascular coagulation (DIC); microangiopathic hemolytic anemia (MAHA) may be present. 
CAPS is an important clinical entity to consider due to mortality rates up to 50%.  Patients with CAPS and SLE are more likely to be female and young, to have cerebral and pancreatic involvement, to receive corticosteroids and cyclophosphamide, to demonstrate lower prevalence of high anti-cardiolipin immunoglobulin G antibody, and to have a higher risk of death compared with other patients with APL syndrome who do not develop CAPS after adjusting for age, sex, organ involvement, and treatment. 
In a review of 250 cases of CAPS, the main cause of death was found to be cerebral involvement (27.2%) followed by cardiac involvement (19.8%) and infection (19.8%).  The kidney was the organ most involved (70-78 % of the cases) ,
Patients with CAPS and SLE who is treated with a combination of plasmapheresis and corticosteroids have a survival rate of 65%. Our patient fit most of these criteria fairly well. He was young, had pancreatic involvement, and responded well to plasmapheresis, but he was male and presented with SLE-like syndrome (although he did not meet all of the criteria of SLE).
Multi-organ failure following a trigger is the mode of presentation of CAPS. The trigger, which may include infections, trauma, invasive procedures, SLE flares, or warfarin withdrawal,  may be quite minor or several triggers may occur simultaneously. Central nervous system involvement, which occurs in 56% of patients,  presents as confusion, disorientation, drowsiness, seizures, coma, and frank hemiplegias. Our patient displayed many features of CAPS, given that he had an SLE-like syndrome. He had worsening of kidney function, coma, and frank hemiplegia with dermatological involvement in the form of digital ischemia and dry gangrene.
Unusual blood vessels tend to be involved in CAPS, such as scrotal, testicular, esophageal, and gastric vessels. Our patient had large esophageal and gastric ulcers in addition to his acute pancreatitis. Review of the medical literature showed common presentation of pancreastitis, usually of a chronic nature, but four cases were reported as acute pancreatitis.  The hematological manifestations of CAPS in our patient occurred as autoimmune hemolytic anemia (AIHA). Cervera et al , reported that AIHA was seen in 6.6% of 1,000 patients with APLS as DIC in 20% of cases, in addition to severe thrombocytopenia of less than 10 × 103 /L. Thrombocytopenia associated with APLS is usually moderate (greater than 50 × 103 /L).  The literature description of treatment of CAPS is confusing; prospective studies are lacking because of the rarity of the condition. Therefore, treatment with a combination of anticoagulants plus steroid plus plasma exchange and/or IVIG has the highest survival rate (70%).  Other treatments have been described in the literature, such as the use of rituximab, an anti-CD20 monoclonal antibody that acts against B-cells. However, the use of these alternate modalities has been limited to a few small case series. 
Awareness of this rare and rapidly fatal medical condition is vital for prompt diagnosis and early intervention to improve patients' survival. Our patient had a severe form of multi-organ failure and SLE-like syndrome. Fortunately for him, the clinical picture improved after five cycles of plasmapheresis, corticosteroids, immunoglobulin, and azathioprine. However, it is important to retain a high degree of awareness of the CAPS due to its high mortality rate.
|1||Asherson RA, Cervera R. The catastrophic antiphospholipid syndrome. Systemic Lupus Erythematosis. 2004;41:1125-38.|
|2||Vyas A, Kadikoy H, Haque W, Abdellatif A. Catastrophic antiphospholipid syndrome presenting as ischemic pancreatitis in systemic lupus erythematosus. JOP 2009;10(5):566-9.|
|3||Bucciarelli S, Espinosa G, Cervera R, et al. Mortality in the catastrophic antiphospholipid syndrome: Causes of death and prognostic factors in a series of 250 patients. Arthritis Rheumat 2006;54(8):2568-76.|
|4||Asherson RA, Cervera R. Catastrophic anti-phospholipid syndrome. Curr Opin Hematol 2000;7(5):325-9.|
|5||Yeh TS, Wang CR, Lee YT, Chuang CY, Chen CY. Acute pancreatitis related to anti-cardiolipin antibodies in lupus patients visiting an emergency department. Am J Emerg Med 1993;11(3):230-2.|
|6||Cervera R, Piette JC, Font J, et al. Anti-phospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46(4):1019-27.|
|7||Cervera R, Bucciarelli S, Plasín MA, et al Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of a series of 280 patients from the "CAPS Registry". J Autoimmun 2009;32:240-5.|
|8||Uthman I, Godeau B, Taher A, Khamashta M. The hematologic manifestations of the anti-phospholipid syndrome. Blood Rev 2008;22: 187-94.|