The challenges in diagnosing pediatric primary antiphospholipid syndrome

Abstract

Pediatric primary antiphospholipid syndrome (APS) is a very rare disease with significant distinctions from the APS in adults. Herein, we present our experience in the diagnosis and treatment of six pediatric primary APS patients, who met the updated Sapporo criteria for the APS diagnosis. One of them was also diagnosed as having probable catastrophic APS (CAPS) due to the involvement of three different organ systems simultaneously. Besides vascular involvement, four patients had thrombocytopenia, one had psychiatric disorder, and one had chorea and valvular heart disease. All patients received immunosuppressive treatment along with long-term anticoagulation therapy. Specific neurologic and hematologic manifestations that are not part of the classification criteria can be seen in children with primary APS. Therefore, using the adult criteria for diagnosing pediatric APS may result in missed or delayed diagnoses in children.

Keywords

Pediatric Antiphospholipid Syndrome Primary Antiphospholipid Syndrome Nonthrombotic Manifestations in Antiphospholipid Syndrome

Key messages

1. Pediatric primary antiphospholipid syndrome is a very rare disease with significant distinctions from the APS in adults.

2. The updated Sapporo APS criteria may lack sensitivity for pediatric APS.

3. Specific neurologic and hematologic manifestations that are not part of the updated Sapporo APS criteria can be seen common in children with APS.

4. International collaborative studies are required to better define pediatric APS and revise classification criteria specific to pediatric patients.

Introduction

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic events and/or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies (aPLs).¹ Although APS is a rare disease in childhood, it is associated with significant morbidity and mortality.² APS could be either primary or secondary. Secondary APS is associated with another connective tissue disease, most commonly systemic lupus erythematosus (SLE), or it can be triggered by infections or medications. If there is no underlying disease, APS is defined as primary APS.

The classification of APS is based on the updated Sapporo criteria, also known as Sydney criteria, which require the presence of at least one clinical event and one persistently (over 12 weeks) positive aPL.¹ Although the updated Sapporo criteria were primarily developed for adult patients, these were also used for pediatric patients, excluding pregnancy morbidity.² However, the diagnosis is more challenging in childhood and requires a high level of suspicion in all children presenting with thrombosis. Moreover, specific neurologic and hematologic manifestations that are not part of the classification criteria can be seen more commonly in children with APS.³ Since the prognosis is significantly improved with timely treatment, early diagnosis should be the primary concern in children. Unfortunately, we lack classification criteria specific for pediatric primary APS patients.

We herein present our experience of pediatric primary APS patients in our center. We report the clinical characteristics, treatment, and outcomes of six pediatric primary APS patients.

Patients

Among the 20 patients with pediatric APS followed in our center between January 2012 and January 2021, six (F/M = 1) were diagnosed with primary APS. All patients met the updated Sapporo criteria for the APS diagnosis.¹ One of them was also diagnosed as having probable catastrophic APS (CAPS) since three different organ systems were involved concurrently. None of them had features suggesting an underlying autoimmune disease. The antiphospholipid antibody positivity within medium and high titers (Lupus anticoagulant (LA) dRVVT>45 and/or confirm ratio>1.4, anticardiolipin (aCL) antibody and anti-b2glycoprotein-I antibody of IgG and/or IgM (>20 U, or >the 99th percentile)) were confirmed after 12 weeks for each patient. The antiphospholipid antibody tests were performed on fresh samples. All patients were investigated for an additional prothrombotic condition by checking protein C, protein S, factor V Leiden R506Q mutation, plasminogen activator inhibitor (PAI-1) mutation, prothrombin G20210A mutation, methylenetetrahydrofolate reductase (MTHFR) gene mutation, and plasma homocysteine levels. Two hadMTHFR, and two had PAI-1 heterozygote mutation. In addition, one had both MTHFR and PAI-1 heterozygote mutation. One patient did not have any additional prothrombotic risk factors. The median age at symptom onset was 16(10–17) years. The median (min-max) follow-up time (from the time of APS diagnosis to the last visit) was 32 (6-77) months.

All six patients presented with vascular involvement. And, three patients had venous, two arterial, and one had both arterial and venous involvement. Four patients had thrombocytopenia, one had psychiatric disorders, and one had chorea and valvular heart disease at the time of APS diagnosis. All patients received enoxaparin as long-term anticoagulation therapy (1 mg/kg/dose subcutaneous every 12 hours) and for the prophylaxis of thrombosis (0.5 mg/kg/dose subcutaneous every 12 hours). However, factor Xa levels were not monitored. Corticosteroids (500 mg/day for 1-3 days pulse intravenous (IV) methylprednisolone and followed by oral prednisolone at a dose of 1 mg/kg/day (maximum 60 mg/day) for 1 month, 0.5 mg/kg/day for 1 month, and 0.2 mg/kg/day for 1-2 months) were given for non-thrombotic manifestations. Corticosteroid treatment was initiated at the time of diagnosis, tapered rapidly after disease control, and continued for about three to six months. All patients presented with severe manifestations and thus were also given immunosuppressive drugs including rituximab (n = 4) (375 mg/m² for four weekly doses), or cyclophosphamide (n = 2) (monthly at a dose of 500 mg/m²/day, maximum 500 mg/dose, for three to six doses), and mycophenolate mofetil (n = 2) (1200 mg/m²/day; maximum 1000 mg/day), and/or azathioprine (n = 2) ) (1–3 mg/kg/day; maximum 150 mg/day). Two patients had recurrent thrombosis at follow-up, and one patient died six years later than the diagnosis. Written informed consents were obtained from the patients. The clinical and laboratory features of the patients are summarized in Table 1.

Table 1.

The clinical and demographic characteristics of children with primary antiphospholipid syndrome (APS)

	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5	Patient 6
Age at APS diagnosis (years)	16	16	11	15	10	17
Gender	Male	Male	Female	Female	Male	Female
Thrombotic manifestations	Sinus venous Thrombosis	Acute ischemic lesions in acute and subacute embolic pattern in both internal carotid arteries border zones	Left femoral and popliteal vein thrombosis	Bilateral periventricular cortical and subcortical ischemic lesions	Chronic thrombosis in inferior vena cava and bilateral iliac veins	-Thrombus in right hepatic vein -Acute ischemic lesions in bilateral cerebellar hemispheres and right caudate nucleus -Intracardiac thrombus
Non-thrombotic manifestations	Thrombocytopenia	Thrombocytopenia Psychiatric disorders	None	Chorea Valvular heart disease	Thrombocytopenia	Thrombocytopenia
APL pattern (at APS diagnosis) Lupus anticoagulant Anti beta2 GPI IgG Anti beta2 GPI IgM Anti-cardiolipin IgG Anti-cardiolipin IgM	Triple Positive Positive Positive Negative Positive Negative	Triple Positive Positive Positive Positive Positive Positive	Double positive Positive Negative Negative Positive Positive	Triple Positive Positive Positive Negative Positive Negative	Triple Positive Positive Positive Positive Positive Positive	Triple Positive Positive Positive Negative Positive Negative
Anticoagulation	LMWH	LMWH	LMWH	LMWH	LMWH	i.v. heparinization followed by LMWH
Immunosuppression	Pulse MP, RTX	Pulse MP, CYC, MMF	Oral steroid and AZA	Pulse MP, RTX	Pulse MP followed by oral prednisolone and AZA	Pulse MP, IVIG, plasma exchange, surgical thrombus removal, RTX
Recurrence	No	No	Yes--Thrombus in ICA, -Thrombus in pulmonary artery	No	Yes- Sinus venous thrombosis	No
Treatment in recurrence			Pulse MP, CYC, Heparin, plasmapheresis, IVIG		Pulse MP, RTX, LMWH

APS: Antiphospholipid Syndrome, Anti beta2 GPI: Anti beta 2 Glycoprotein I, LMWH: Low molecular weight heparin, MP: Methyl Prednisolone, RTX: Rituximab, CYC: Cyclophosphamide, MMF: Mycophenolate mofetil, AZA: Azathioprine, IVIG: intravenous immunoglobulin, ICA: internal carotid artery.

Patient 1

A sixteen-year-old boy was admitted to our Pediatric Emergency Service with complaints of headache and numbness in both hands. He had mild thrombocytopenia (103.000/mm³). He developed a generalized tonic-clonic seizure in the emergency service, and cranial MR venography showed an occlusive sagittal vein thrombosis. Anti-beta 2 glycoprotein IgG, anti-cardiolipin (anti-CL) IgG, and lupus anticoagulant (LA) were elevated within medium and high titers. An autoimmune study revealed negative anti-nuclear antibody (ANA), anti-double-stranded DNA (anti-ds-DNA), anti-Sm, anti-RNP, and normal levels of complements. He responded to anticoagulant therapy with low molecular weight heparin (LMWH), pulse methylprednisolone (MP) followed by oral prednisolone, and rituximab therapy. In the 4^th month of treatment, MR venography revealed that superior sagittal sinus was recanalized. Oral steroid therapy ceased at the 6^th month. After four years, he was still on hydroxychloroquine and antiaggregant treatment without any recurrence.

Patient 2

A 16-year-old boy was referred to our hospital due to visual and auditory hallucinations. He had been admitted to a local hospital with fatigue and weight loss and mild thrombocytopenia (101.000/mm³) a month prior. When he developed psychiatric symptoms, he was referred to our hospital for further evaluation. On physical examination, he was not cooperative and oriented. He still had mild thrombocytopenia and Coombs positive hemolytic anemia. He was evaluated by different departments including child and adolescent psychiatry, pediatric neurology, pediatric hematology, and pediatric rheumatology. Lumbar puncture and bone marrow aspiration were normal. Cerebral MR angiography and venography showed acute ischemic lesions in acute and subacute embolic patterns in both internal carotid artery (ICA) border zones. Autoantibody profiles including ANA, anti-ds-DNA, anti-Sm, anti-RNP were negative. The complement levels were within the normal range. However, LA, anti-CL IgM, and IgG, anti-beta 2 glycoprotein IgM, and IgG were positive at high titers. Our initial diagnosis was SLE and secondary APS since the patient had three clinical (neurological, thrombocytopenia, hemolytic anemia) and one immunologic (aPL positivity) criteria fulfilling the SLICC. Besides anticoagulant treatment, pulse MP for three days, followed by oral prednisolone and iv cyclophosphamide were initiated. Within two weeks, the hallucinations disappeared. After three doses of cyclophosphamide, we continued with mycophenolate mofetil. He never developed other symptoms of SLE or other antibody positivity in spite of persistent aPL positivity. Therefore, we accepted him as having primary APS. He has not experienced any relapse and had received anticoagulant therapy with enoxaparin for around two years. At the end of two years, we continued with antiaggregant therapy since his aPL titers were fluctuating at low titers.

Patient 3

An 11-year-old girl was admitted to our outpatient clinic with a 20-day history of purple discoloration of her left toes. She had no joint pain, swelling, and difficulty in walking. Venous Doppler ultrasonography showed a chronic thrombus in the distal part of the left femoral and popliteal vein. ANA, anti-ds-DNA, anti-Sm, and anti-RNP were negative. The complement levels were within normal limits. LA, anti-CL IgM, and IgG were found positive at high titers. Anticoagulant therapy with LMWH, oral prednisolone, and azathioprine were initiated. However, she was not compliant with any treatment and was lost to follow-up. After three years, she presented with a severe headache, and MRI revealed a thrombus in the right internal carotid artery and parietal cortical acute ischemia. Besides anticoagulant therapy with LMWH, rituximab was initiated for immunosuppression; however, she experienced anaphylaxis with rituximab. Therefore, we administered cyclophosphamide for six doses and continued the immunosuppressive treatment with mycophenolate mofetil. After two years, she presented with massive pulmonary thromboembolism while she was on mycophenolate mofetil, LMWH, and hydroxychloroquine. However, once again she was not compliant with the therapy. She died despite the treatment with heparin, plasmapheresis, intravenous immunoglobulin (IVIG), and pulse MPs.

Patient 4

A 15-year-old girl was referred to our hospital for further evaluation of chorea. She did not have other symptoms of acute rheumatic fever (ARF) and chorea was accepted as a late symptom of ARF. She developed chorea two years before, and she was on antiepileptic therapy and penicillin prophylaxis for chorea and ARF. The physical examination was normal except for the choreiform movements. On echocardiography, vegetations on the mitral valve were determined. Cranial MR revealed acute and subacute bilateral periventricular cortical and subcortical ischemic lesions. Autoantibody profiles including ANA, anti-ds-DNA, anti-Sm, anti-RNP were negative. However, LA, anti-CL IgG, and anti-beta-2 glycoprotein IgG were positive at moderate to high titers. She was given pulse MP and rituximab therapy along with LMWH. The patient was compliant with enoxaparin treatment but factor Xa levels were not monitored. At her last visit, which was three years after the diagnosis, the patient was on hydroxychloroquine and antiaggregant treatment; however, the symptom of chorea persisted.

Patient 5

A 10-year-old boy was admitted with a complaint of bilateral leg pain for one month. On physical examination, he had abdominal distention and prominent superficial veins. CT angiography showed massive chronic thrombosis in the inferior vena cava and bilateral iliac veins. In the laboratory investigation, the platelet count was 24.000/mm³. ANA, anti-ds-DNA, anti-Sm were negative. LA, anti-CL IgM, and IgG, anti-beta 2 glycoprotein IgM, and IgG were positive at high titers. Besides anticoagulant treatment with LMWH, pulse MP followed by oral prednisolone and azathioprine were initiated. After six months, he was admitted with severe headache, and cranial MR revealed thrombosis in the right sigmoidal sinus. He was given pulse MP and rituximab along with anticoagulant treatment. He has been stable during the last year under rituximab and LMWH treatment.

Patient 6

A previously healthy 17-year-old girl was presented with headache, abdominal pain, and hematuria. The platelet levels were 58.000/mm^3, and erythrocyte sedimentation rate (ESR) was 40 mm/hour. Hepatic doppler ultrasonography revealed a thrombus in the right hepatic vein. Cranial MR angiography showed acute ischemic lesions in bilateral cerebellar hemispheres and the right caudate nucleus. Echocardiography showed an intracardiac thrombus in the right atrium. She was immediately heparinized. LA, anti-beta 2 glycoprotein IgG, anti-CL IgG were found positive. ANA, anti-ds-DNA, anti-Sm, and complement levels were normal. She met the updated Sapporo criteria for the APS diagnosis and she was also diagnosed with probable catastrophic APS (CAPS) due to the involvement of three different organ systems simultaneously, however, we could not confirm the presence of microscopic thrombi histologically. Pulse MP, plasmapheresis, and IVIG were started along with anticoagulation. She underwent surgical thrombus removal. Despite these interventions, she developed a new intracardiac thrombosis within one month and rituximab was added to the immunosuppressive treatment. She has been stable during the last six months under LMWH, corticosteroid, and rituximab treatments.

Discussion

In this study, we presented the clinical characteristics of six pediatric patients with primary APS and our experience in the management of pediatric primary APS. Since primary APS is very rare in childhood, sharing experience is very valuable.^4,5 Although the mean age of the first presentation of APS in childhood is between 9 and 14 years,⁶ it can present at any age during childhood. In our case series, the median age of the six patients was 16 years.

Currently, there are no APS classification criteria specific for children. Updated Sapporo criteria is used for diagnosing pediatric patients by excluding the item regarding pregnancy morbidity; however, this criteria set is primarily developed for adult patients.⁷ Thus, depending on these criteria may cause missed or delayed diagnosis in children. Due to the rarity of the disease in children, there are no randomized, controlled clinical trials. Most of our knowledge regarding pediatric APS comes from the International pediatric APS registry which included 121 children diagnosed with APS according to the updated Sapporo criteria.² We also lack data on how to treat pediatric patients, especially those with severe presentations. These patients are treated based on recommendations in adults and our experience in SLE.

According to the updated Sapporo criteria, at least one clinical and one laboratory criteria are required for the definitive diagnosis of APS.¹ Clinical criteria include large and small venous and/or arterial thrombosis and obstetric problems. In the pediatric APS registry, venous thrombosis occurred in 51.6%, arterial thrombosis in 45%, and ischemic stroke in 38.3% of the primary APS patients.⁸ Arterial thrombosis and ischemic stroke were significantly more frequent among patients with primary APS than those with secondary APS.⁸ In our small case series, three (50%) patients had venous, two (33.3%) had arterial, and one (16.6%) had both venous and arterial thrombosis, who presented with probable CAPS. CAPS is characterized by thrombotic events in three or more organ systems/tissues that develop in a week, and small-vessel occlusion should be proven histopathologically.^9,10 Since we could not perform a histopathological test, patient 6 was diagnosed as probable CAPS. CAPS is a life-threatening condition with a high mortality and morbidity rate and is more frequent among pediatric APS patients compared to adults and may be the initial manifestation of APS more frequently in children as one of our patients.^11,12

Although the criteria mainly focused on thrombotic events and pregnancy morbidity, there is a broad spectrum of manifestations that are associated with APS, such as livedo reticularis and racemosa, migraine, chorea, epilepsy, valvular heart disease, and nephropathy.³ In our case series, five patients had non-criteria manifestations along with thrombosis. Furthermore, four of our patients had thrombocytopenia and one had hemolytic anemia. In the literature, hematologic disorders, including thrombocytopenia, autoimmune hemolytic anemia, and Evans syndrome are the most frequent non-thrombotic manifestations in pediatric APS, occurring in 30-50% of the patients.³ Both in adult and pediatric APS series, thrombocytopenia is the most frequently reported non-criteria manifestation.¹³

One of our patients had presented with chorea before the thrombotic event and had valvular heart disease, as well. Chorea is a hyperkinetic movement disorder that develops due to basal ganglia damage. Various conditions such as infections, acute rheumatic fever, toxic and metabolic processes, and inborn errors can cause chorea.¹⁴ APS-related chorea is more common in children than adults.^3,15 A prospective study regarding the long-term outcome of 32 patients with chorea and persistent aPL positivity showed that 37.5% of those patients developed arterial thrombosis in the follow-up.¹⁶ Our patient had thrombosis three years later than the diagnosis of chorea. She also had vegetations on the mitral valve, detected on transthoracic echocardiography. Valvular heart disease is most frequently seen in patients with APS secondary to SLE.¹⁷ However, there are also reports of primary APS patients that presented with valvular heart disease.^18,19 Particularly in the pediatric population, the importance of those non-thrombotic manifestations should be extensively investigated to develop more sensitive and specific classification criteria.

Based on the updated Sapporo criteria, APS has been classified in the presence of persistently raised levels within moderate and high titers of the circulating antiphospholipid antibodies, namely LA, anti-CL IgM, and IgG, and anti-β2-glycoprotein I IgM and IgG.¹ In some studies, thromboembolic events were significantly higher in “triple positive” patients.^20–22 Triple positivity is defined as the simultaneous positivity for LA, anti-CL, and anti-β2-glycoprotein I antibodies.²¹ Five of our patients were triple positive.

Management of pediatric APS is mainly based on the results of observational studies and expert opinion. In 2019, the SHARE initiative (Single Hub and Access point for pediatric Rheumatology in Europe) published evidence-based recommendations for the diagnosis and treatment of pediatric APS.²³ However, due to the lack of longitudinal studies, the level of evidence was low in these recommendations. According to the SHARE recommendations, adequate long-term anticoagulant treatment is recommended in both venous and arterial thrombosis.²³ However, particularly non-thrombotic aPL-related clinical problems require immunosuppressive treatment along with anticoagulation.^23–25

The combination of anticoagulation, corticosteroids, and plasma exchange is considered the gold standard treatment for adult CAPS patients based on the data from the CAPS Registry.^26,27 Based on these data, the SHARE Initiative recommends also the same triple therapy with or without IVIG for pediatric APS patients.²³ In our series, all patients were managed by immunosuppressive and anticoagulant treatment concomitantly and patient 6, who was diagnosed as probable CAPS treated successfully with plasma exchange, IVIG, pulse methylprednisolone, iv heparin, and rituximab. In the literature, rituximab is usually preferred over cyclophosphamide in the treatment of APS.^28,29 We used cyclophosphamide in two of our patients. In one of them, at the time of admission APS was considered secondary to SLE . The second patient, on the other hand, experienced anaphylaxis with rituximab. Since the patient had a severe presentation, we switched the immunosuppressive treatment with cyclophosphamide.

In our small case series, three out of six patients had cerebral arterial involvement. For the long-term secondary prevention of stroke in patients with no history of cardioembolic ischemic stroke or transient ischemic attack, treatment with an antiplatelet agent is recommended.³⁰ However, if the cerebral stroke is associated with persistent aPL positivity, long-term anticoagulation or combined anticoagulation and anti-aggregation therapy should be indicated in pediatric APS.²³ Therefore, all of our patients with cerebral arterial involvement received adequate long-term anticoagulation, as well.

In conclusion, although primary APS is very rare in children, the presentation can be severe and it can cause significant morbidity and mortality. In our series, five out of six patients had non-thrombotic manifestations, as well. All were treated with corticosteroids, immunosuppressive drugs, and anticoagulants. International collaborative studies are needed to better define pediatric APS and revise classification criteria specific to pediatric patients. The subsequent step would be to design well-organized studies to guide us in the management and treatment of this rare disease.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Selcan Demir

Erdal Sağ

Ümmüşen Kaya Akca

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