Antiphospholipid syndrome leading to paradoxical embolus and stroke via secundum atrial septal defect

Abstract

We have presented a case of a 22-year-old man, presenting with cerebral infarct, subsequently found to have antiphospholipid syndrome (APS), deep venous thrombosis, pulmonary embolism and atrial septal defect (ASD), thereby confirming the presence of infarct due to paradoxical embolism in this patient. The importance of ASD in the patients of APS, resulting in paradoxical embolism is debatable, with recent studies undermining its importance. We have demonstrated that it does indeed happen. This would have implications in the risk assessment and management of ASD in such patients. This case report is intended to serve as a reminder of this association and the need to perform further research in this area.

Background

Antiphospholipid syndrome (APS) is an autoimmune condition characterised by arterial and/or venous thrombosis with or without pregnancy morbidity and thrombocytopenia.¹ According to the current consensus criteria, to merit a diagnosis of APS a patient must have several positive lupus anticoagulant assays over 3 months and/or β₂-glycoprotein-I antibodies (a subset of anticardiolipin antibodies) and/or anticardiolipin antibodies with clinical symptoms of thrombosis.² APS can occur as a primary condition or secondary to other systemic autoimmune diseases, most commonly systemic lupus erythematosus. Primary APS is the most common cause of acquired thrombophilia and is said to account for 15%–20% of all episodes of deep vein thrombosis (DVT) with or without pulmonary embolism, one-third of ‘young strokes’ (age <50), and up to 15% of women with recurrent fetal loss.³ Some of these patients can have an atrial septal defect (ASD), it is however debated whether the incidence of strokes increase as a result of paradoxical embolism. Here we aim to contribute to the literature by presenting an interesting case of primary APS leading to paradoxical embolus and stroke in a young male.

Case presentation

A 22-year-old male patient was admitted to the emergency department having been found on the floor by a neighbour. The patient had experienced a right-sided weakness causing his collapse and had attempted to send a text message to his mother which was unintelligible. The message prompted his mother to ask the neighbour to check-in on the patient while she returned from a trip. The patient had a right-sided weakness in upper (power 4/5) and lower limb (power 3/5) on examination with expressive dysphasia but otherwise examination was unremarkable with National Institutes of Health Stroke Scale score 7. CT scan (figure 1) showed a dense left middle cerebral artery (MCA) with a left insular infarct. The patient was then thrombolysed with alteplase as per local protocol. A subsequent CT of the head showed no evidence of haemorrhagic transformation. MRI (figure 2) re-confirmed left MCA infarcts. A CT angiogram of the neck vessels did not reveal any abnormality.

Figure 1.

Initial CT scan. White arrow shows a dense middle cerebral artery within left sylvian fissure suggesting underlying thrombus. Black arrow shows early changes of an acute infarct.

Figure 2.

MRI. (A–C) shows diffusion weighted images and (D–F) shows corresponding apparent diffusion coefficient maps. White arrows show diffusion abnormalities consistent with acute left middle cerebral artery territory infarcts.

On further review by stroke team, the patient described a few days history of unprovoked pain following a long train journey in his right calf and shortness of breath on exertion over several months which his general practitioner had described as likely anxiety related. The patient denied illicit drug use and his family history was initially reported to be only of several postpartum DVTs in his maternal aunt and maternal grandmother.

Investigations

Initial laboratory tests (full blood count, coagulation screen, renal function, liver function, blood glucose, C reactive protein, calcium level, cholesterol, thyroid-stimulating hormone) were unremarkable and within normal limits and an ECG was also normal. On admission the coagulation screen was—Prothrombin time (PT) 13.5 s, Prothrombin time ratio (PTr) 1.2, Activated Partial Thromboplastin Time (APTT) 30.0 s and Activated Partial Thromboplastin Time ratio (APTTr) 1.0.

The patient underwent transthroacic echocardiogram (figure 3) which showed a patent ostium secundum causing an atrial septal defect with right heart strain giving an intermediate risk of pulmonary hypertension. The patient then underwent a CT pulmonary angiogram to further characterise the pulmonary and cardiac anatomy (figure 4). This revealed large bilateral pulmonary emboli, besides also demonstrating atrial septal defect. Given the volume and size, these emboli were believed to have been present before the alteplase dose was administered. Daily treatment dose dalteparin prescription (15 000 units) was initiated to treat the pulmonary emboli but was given as two times a day split dose (rather than single dose or constant infusion) to reduce the risk of haemorrhagic transformation of the infarction, after advise from the haematologist. It was suggested that these large bilateral pulmonary emboli were likely the cause of the patient’s previous breathlessness on exhaustion. A subsequent trans-oesophageal echocardiogram further confirmed the patent ostium secundum and described slightly reduced right heart strain since the introduction of anticoagulation. A doppler ultrasound of both lower limbs also revealed a DVT in the right lower limb which accounts for the calf pain that the patient described. A CT scan of the patient’s abdomen and pelvis was completed to rule out any undiagnosed malignancy as being responsible for his prothrombotic state, this returned as normal.

Figure 3.

Transthoracic echocardiogram (A) and trans-oesophageal echocardiogram (B) showing the atrial septal defect (arrows).

Figure 4.

CT pulmonary angiogram. White arrows in (A–C) shows filling defects in bilateral pulmonary arteries consistent with pulmonary embolism. Black arrow in (D) demonstrates the atrial septal defect.

At this time, the patient’s thrombophilia screen, total homocysteine and connective tissue disease screen had returned as broadly normal and a genetic analysis showed no mutation in either the factor V Leiden gene or the prothrombin gene. The patient’s lupus anticoagulant, however returned as positive with a Dilute Viper Venom Time (DVVT) ratio:DVVC ratio of 1.25.

Differential diagnosis

The patient was provisionally diagnosed as primary APS. On this tentative diagnosis, a more in-depth family history was sought where his mother described several spontaneous abortions without personal history of APS and his sister was reported to have been diagnosed with a pulmonary embolism in the context of pregnancy. Later samples sent for β₂-glycoprotein-I antibodies returned as negative. As noted, a positive second sample at 12 weeks, is required for conclusive diagnosis of APS however unfortunately, given that the patient’s bilateral pulmonary emboli were treated with apixaban, this rendered the test result at 12 weeks void.

Since the presence of DVT, pulmonary embolism and ASD was confirmed, the cerebral infarct was strongly considered as a result of paradoxical embolism. Other potential causes of stroke were excluded. APS itself could have been a potential cause of stroke but the likelihood was very low, considering other factors involved.

Treatment

As mentioned above, the patient was initially thrombolysed and subsequently with dalteparin for pulmonary embolism. Patient’s ASD has since been closed.

Outcome and follow-up

The patient continues to be on follow-up by stroke and cardiovascular team. There has been no new stroke or other clinical events.

Discussion

As described, in order to diagnose APS, thrombus or recurrent miscarriage must have occurred in combination with the presence of antibodies such as the lupus anticoagulant, β₂-glycoprotein-I antibodies or anticardiolipin antibodies on two separate samples 12 weeks apart.². Given that the patient had one sample positive for lupus anticoagulant, this supports the preliminary diagnosis of primary APS. Due to the treatment of the patient’s pulmonary emboli with apixiban (the duration of which is currently anticipated to be lifelong) it was not possible to definitively diagnose APS at this time.

On the use of direct oral anticoagulants (DOACs), The European League Against Rheumatism (EULAR) expert guidelines (2019) on the management of APS in adults have suggested that the rivaroxaban should not be used in patients with a triple positve antibody profiles.⁴ The use of other DOACs (including apixaban as in this case, and edoxaban and dabigatran) have not been specifically contraindicated because there have been no completed trials of these agents in patients with antiphospholipid disease.⁵ Clinical trials on the use of apixiban in patients with APS is currently underway.^{4 5} Indeed, the EULAR group advise that DOACs can be considered in the context of compliant patients struggling to achieve a target international normalised ratio on warfarin or patients with contraindications to warfarin. In this case, the use of apixiban was due to the patient preference of not needing monitoring with apixiban and the recommendation of colleagues in haematology. Initially, it was suggested that by using apixiban instead of warfarin, the patient would be able to undergo repeat APS screening at 12 weeks to confirm diagnosis. It was discovered in retrospect that this would not be possible.

Given the exclusion of malignancy leading to a prothrombotic state or illict drug use, this diagnosis is made more likely. This case was further complicated by the patient’s ASD. ASDs occur in 1 of 1500 live births and secundum-type ASDs constitute 75% of all ASDs (others include ostium primum (15%), sinus venosus (5%) and unroofed coronary sinus defects (1%)).⁶

Paradoxical embolism refers to the clinical phenomenon of thromboembolism originating in the venous vasculature and crossing into the systemic circulation via an intracardiac or pulmonary shunt into the systemic circulation.⁷ Windecker et al comment on the difficulty of establishing the diagnosis of proven or impending paradoxical embolism clinically going as far to call the pulmonary venous system a ‘black box’ of potential source of systemic emboli. An early study reports of a series of 128 reported cases of paradoxical embolism, only 12 have been diagnosed during life.⁸ This makes understanding the true prevalence of paradoxical embolism causing embolic stroke difficult and under-reported in the literature. Studies have shown that strokes, most commonly ischaemic such as that in this case, are the most common clinical manifestations of paradoxical embolism.⁹ As we can say with certainty that this patient has had the combination of an ASD, pulmonary embolism (from DVT) and ischaemic stroke, the diagnosis here is not one of exclusion. A review of the literature has shown some debate in this area. Singular case studies from Japan and England report patients with APS who had ischaemic strokes from confirmed paradoxical embolism of a 42-year-old woman and a 43-year-old man, respectively.^{8 10} The former reports the conclusion of paradoxical embolism is based on the earlier case series which states the salient features in each of their cases were the presence of DVT±pulmonary embolism (PE) with right-to-left intracardiac shunt and no cause for emboli discovered in the left heart.¹¹ Another case study from Poland reports stroke in a young patient (33 years old) who had recurrent ischaemic episodes and was found to have APS and a patent foramen ovale, however, unlike in the case presented, their patient had several additional risk factors for cardiovascular disease including obesity, raised blood pressure, hypercholesterolaemia and hyperuricaemia.¹² More recent evidence disputes that there is any relationship between intracardiac shunt and stroke in patients with APS. A large 2008 study of patients with APS showed no significant increase in the risk of ischaemic stroke/transient ischaemic attack (TIA)/death in patients who had an ischaemic stroke with presence of patent foramen ovale (PFO) and APS.¹³ Similarly, 2012 study of patients with APS showed that there was broadly equivalent rates of right-to-left shunt in the stroke and non-stroke control group of patients, concluding that the theory that paradoxical embolism is an important consideration in stroke in patients with APS cannot be supported.¹⁴ Although it can be argued that the stroke could have resulted from de novo thrombus secondary to APS, after considering all investigations, it is overwhelmingly likely that in our case, it did indeed happen due to paradoxical embolism; this can be an important aspect in determining risk assessment and considering appropriate management of ASD in these patients. Accordingly, since discharge, the patient was reviewed by a cardiovascular surgical team with a view to closing his ASD, which has since been performed by catheterisation in a tertiary care centre. This is the preferred method in the vast majority of cases of ASD, while some of these may need surgery. We also suggest that further studies are performed to ascertain the true importance of ASD in these patients. This case is also unique in being the youngest confirmed case with a primary thrombotic event as a result of likely primary APS, leading to cerebral infarction due to paradoxical embolism from patent foramen secundum.

In conclusion, we have presented a rare case of a young patient of APS with confirmed DVT, pulmonary embolism and ASD, with cerebral infarct, likely due to paradoxical embolus from a confirmed underlying ASD. In view of ongoing debate about clinical importance of ASD in patients with APS with regards to paradoxical embolism leading to stroke, we have highlighted that it does indeed happen. Therefore this factor should be taken into account in risk assessment and management of patients of APS having an ASD.

Learning points.

• Antiphospholipid syndrome (APS) is an important cause of stroke in young.

• APS can cause thrombotic complications, including deep vein thrombosis and pulmonary embolism.

• In patients with atrial septal defect (ASD), there is a debate about increased incidence of stroke due to paradoxical embolism.

• Although exact incidence is uncertain, there are indeed some cases of APS with stroke due to paradoxical embolism.

• Decisions about ASD closure in patients with APS, should take into account, the increased risk of paradoxical embolism.