Authors: Ali Shakhshir, Mo’tasem Z. Dweekat, Ameer Awashra, Ahmad Nouri, Hadi Rabee’, Alaa Shamlawi, Khaled Al-ali
Categories: Case Report, Catastrophic antiphospholipid syndrome, SLE
Source: SAGE Open Medical Case Reports
Catastrophic antiphospholipid syndrome (CAPS) is a very severe form of the classic antiphospholipid syndrome (APS). Although CAPS occurs in less than 1% of all patients with APS, it is considered a life-threatening condition. This report highlights an interesting case of a 45-year-old male diagnosed with CAPS. Unfortunately, the diagnosis was followed by devastating complications. Moreover, this report tried to gather the significant medical information available about CAPS in light of the obvious shortage of epidemiology, signs, symptoms, mechanisms of action and options of treatment in relation to the current guidelines.
Keywords: Catastrophic antiphospholipid syndrome, SLE
Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder related to the presence of antiphospholipid antibodies APS.^ 1 ^
APS clinical manifestations include recurrent arterial and/or venous thrombosis as well as pregnancy-related complications, but a wide spectrum of events could also be observed.^ 2 ^ Approximately 1% of APS patients develop a severe clinical picture characterized by multiple thromboses involving mainly small vessels, called catastrophic antiphospholipid syndrome (CAPS).^ 3 ^ These successive thromboembolic events can lead to multi-organ failure,^ 4 ^ with a mortality rate of 50%.^ 5 ^ In fact, only a handful of case reports of CAPS are available, especially with life-threatening complications.
Herein, we present a case of a 45-year-old male who had several thromboembolic events due to APS, which, eventually, was diagnosed with catastrophic anti-phospholipid syndrome. These thromboembolic events were followed by life-threatening complications that were managed successfully.
This is a 45-year-old male patient, married, non-smoker, who was in his usual state of health of unlimited exercise tolerance until one and a half years prior to presentation, when the patient started complaining of right-sided neck swelling and pain associated with resting shortness of breath and recurrent haemoptysis of small amounts of blood. One week later, the patient presented to our hospital’s emergency department. After obtaining a left neck ultrasound and pulmonary computed tomography (CT) angiography, he was diagnosed with pulmonary embolism (PE) of the lower lobe branches of the left and right pulmonary arteries, as well as right internal jugular vein thrombosis, as shown in Figure 1. The patient was then started on apixaban 5 mg twice daily. Investigations for thrombophilia turned back a positive antiphospholipid profile (high antiphospholipid antibody IgG: 237 GPL (normal: <10 GPL), high lupus anticoagulant 164 s (normal: 24–36 s), low factor V Leiden: 49% (normal: 78%–152%). At the time, secondary causes for antiphospholipid were ruled out, including Behcet’s disease and systemic lupus erythematous. Consequently, he was diagnosed with primary APS. Additionally, the patient denied any history of skin rash, oral ulcers, genital ulcers, changes in bowel habits, joint pain, swelling or weight loss.
Figure 1. CT angiography showing a filling defect of the right internal jugular vein which was confirmed on ultrasound Doppler imaging. The blue arrow shows the right internal jugular vein.CT: computed tomography.
He was discharged home and remained on regular follow-up in the internal medicine outpatient clinic. He was in a stable condition with occasional episodes of shortness of breath for 1 year until he started to complain of left upper quadrant abdominal pain, which was dull in nature and moderate in severity with no radiation. For 3 weeks, he sought medical advice in the emergency department for his pain, which was treated for presumed indigestion with no significant improvement. On examination, the abdomen was slightly distended, with left upper quadrant localized tenderness along with voluntary guarding. As his pain persisted, he underwent abdominal ultrasound and then an abdomen CT scan, which showed splenomegaly along with two hypodense lesions consistent with splenic infarctions, as shown in Figure 2. The patient was consequently admitted for evaluation and management. He was treated with bridging intravenous (IV) heparin along with warfarin in addition to prednisolone 40 mg. Rheumatologic workup showed positive extractable nuclear antigen, antiphospholipid, perinuclear anti-neutrophil cytoplasmic antibody and lupus antibodies. However, Antinuclear antibody (ANA) and C-Anca antibodies were negative. International normalized ratio and partial thromboplastin time (PTT) were 2.2 and 70, respectively (normal 1 and 25–35, respectively).
Figure 2. Abdominal CT scan with contrast showing two non-enhancing hypodense lesions of the spleen pointed at with blue arrows.CT: computed tomography.
A few days later, the patient developed sudden right-side weakness, with dysarthria in addition to vomiting and sweating. On the exam, the Glasgow Coma Scale^ 6 ^ was 15/15 with intact cranial nerves and sensation. The patient had right-sided upper and lower limb weakness with normal left side. The Babinski reflex^ 7 ^ was upward on the right side and downward on the left side.
All tendon reflexes were normal, with negative cerebellar signs. Brain CT was unremarkable. Following that, as shown in Figure 3, brain magnetic resonance imaging (MRI) showed acute ischaemic infarction in the right brain stem, acute lacunar infarction in the medial left occipital lobe, subacute ischaemic infarction with cortical laminar necrosis and an old superior sagittal sinus thrombus. The patient also underwent a transthoracic echocardiogram, which revealed a left ventricle thrombus and a left ventricular ejection fraction of 55% (reference 50%–70%). To exclude alternative diagnoses, including disseminated intravascular coagulation (DIC) and thrombotic thrombocytopenic purpura (TTP), we performed a peripheral blood smear, which showed slightly reduced red cells with no nucleated or helmet cells along with neutrophilia. Following these findings, he was diagnosed with CAPS.
Figure 3. MRI sequences showing the acute ischaemic infarction pointed at by the blue arrows in each sequence at the level of the medulla oblongata. DWI and ADC show clear diffusion restriction indicating an acute infarction.MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; DWI: diffusion-weighted imaging; ADC: apparent diffusion coefficient.
The patient developed aspiration during eating, followed by shortness of breath, fever and a productive cough. He was consequently admitted to the medical intensive care unit (ICU), where a nasogastric tube was inserted. Laboratory investigations showed high inflammatory markers as well as acute kidney injury with a creatinine level of 3 mg/dL (reference range 0.6–1.2 mg/dL). He was treated as a case of aspiration pneumonia and prerenal azotaemia with oxygen (O2), IV fluids and IV antibiotics, including meropenem, vancomycin and levofloxacin.
Soon after ICU admission, he developed hemodynamic instability, required vasopressors and required oxygen support of 6 L/min through a simple face mask. His respiratory failure was deemed to be due to aspiration pneumonia, with a possibility of PE. As he was already on anticoagulation and with a recent stroke contraindicating thrombolysis, CT pulmonary angiography was not done. Respiratory condition continued to deteriorate despite no change in his chest imaging. Escalating respiratory support resulted in no improvement in his condition, so he eventually underwent endotracheal intubation. He initially required high levels of respiratory support, with difficulty with oxygenation and ventilation. His creatinine level was 3.2, which improved over the following few days. Kidney injury is considered multifactorial due to contrast-induced nephropathy, sepsis and his disease. Investigations for the underlying cause revealed negative ANA and anti-DsDNA >200 international units per mL (IU/mL, reference <10 IU/mL), with positive antiphospholipid antibodies, including lupus anticoagulant. The patient was kept on IV anticoagulation by a heparin infusion. Then, he was given a pulse steroid for 5 days and then switched to oral prednisolone. He also underwent seven sessions of plasmapheresis. He also received two doses of cyclophosphamide, with financial burdens preventing him from receiving the planned six cycles.
As he had weak gag reflexes and cough reflexes likely due to an ischaemic stroke, a tracheostomy was inserted 1 week following admission. His pneumonia and shock resolved just to develop ventilator-associated pneumonia (VAP) due to Acinetobacter baumannii and Methicillin-resistant Staphylococcus epidermidis, for which he received Colistin and Tigecycline. Soon after improvement, he developed another VAP due to sensitive Klebsiella pneumoniae, for which he received ceftazidime. Unfortunately, he then went on to develop yet another VAP due to multiple organisms, including carbapenemase-producing K. pneumoniae and Acinetobacter baumannii. He also developed uncomplicated central line-associated candidemia, which was treated with caspofungin.
During his admission, the patient developed bilateral vitreous haemorrhage, which was treated conservatively. Moreover, he developed rectal bleeding, for which anticoagulation was stopped, and he underwent upper and lower endoscopies multiple times, which did not reveal the source but confirmed blood in the terminal ileum with a likely small bowel source. A percutaneous endoscopic gastrostomy was inserted. Consequently, he underwent CT angiography in preparation for surgical evaluation and possible intervention if bleeding recurs. He was restarted on anticoagulation, Dabigatran, with no recurrence of bleeding.
Eventually, the patient was discharged from the hospital to a rehabilitation centre in Dabigatran. He was on 2 L of oxygen support per minute through a T piece connected to the tracheostomy. He had a weak cough and absent gag reflexes with a power of 1–3 throughout his limbs. His haemoglobin level was stable, with no recurrence of his rectal bleeding.
This report presents a patient who developed devastating, multiple closely timed thromboembolic episodes due to CAPS.^ 8 ^ APS is considered primary when it is not associated with other autoimmune diseases and secondary when it is associated with an autoimmune disease like systemic lupus erythematosus (SLE).^ 9 ^ The diagnostic criteria for CAPS include^ 10 ^ involvement of multiple-organ systems (usually three or more), development over a short period of time (usually 1 week), histopathological evidence of multiple small vessel occlusions and laboratory confirmation of the APS. The patient developed a splenic infarction along with an ischaemic stroke and a left ventricular cardiac thrombus, all within 7 days. Additionally, his laboratory investigations (Table 1) revealed positive antiphospholipid antibodies. In many cases, histopathological confirmation of small vessel occlusions is not possible due to the condition of the patient or due to resources; we experienced both. In such cases, CAPS is considered probable rather than definite. Alternatively, the exclusion of other diagnoses was proposed as an alternative to histopathology in order to consider the diagnosis definite.^ 3 ^
The major differential diagnoses of CAPS are TTP and other thrombotic microangiopathies (TMAs), DIC, heparin-induced thrombocytopenia (HIT) and certain vasculitides. A normal and stable platelet count essentially excludes each of TTP, DIC and HIT. His blood film did not show any features of hemolysis or TMA. Our patient did not have any of the features common for a presentation of vasculitis, including fever, skin lesions, weight loss or joint pains. He additionally had a negative screen for vasculitis except for p-ANCA, which had a low titre.
Left ventricular thrombi usually form in patients with transmural myocardial infarction of the left ventricle. Usually, cardiomyopathy with reduced ejection fraction especially ischaemic cardiomyopathy is the usual condition in which these thrombi form. Our patient had no evidence of myocardial ischaemia, coronary artery disease or cardiomyopathy. Though he did not undergo coronary angiography or advanced cardiac imaging, it is extremely unlikely that he developed this thrombus due to cardiomyopathy or cardiac ischaemia.^ 11 ^
The pathophysiology of CAPS, according to several studies, is not well understood. The explanation for the lack of studies on the pathophysiological mechanisms of CAPS is the difficulty in collecting serum samples during an acute episode due to the low incidence of the condition, the difficulty of differential diagnosis with other microangiopathic conditions and the high mortality.^ 3 ^ However, some studies have reported a proposed mechanism. Golden and colleagues have emphasized the importance of endothelial cell activation as a major component of thrombosis involving the microcirculation.^ 12 ^ CAPS is associated with endothelial cell activation as a result of antigen–antibody interaction on the surface of endothelial cells, or monocytes. The ‘activated endothelial cells’ provide an environment conducive to thrombotic occlusion of the microvascular circulation. Antiphospholipid antibodies (APA) recognize plasma proteins that bind to activated cellular membranes (e.g., platelets, monocytes, tumour cells) or phospholipid microparticles present in the circulating plasma. These proteins include β2-glycoprotein I (β2-GPI), prothrombin, annexin V and high and low molecular weight kininogens. Proteins bound to phospholipid surfaces facilitate bivalent bonding of APA and transmembrane signalling, resulting in ‘activation’ of the involved cells (e.g., endothelial cells, platelets and monocytes). In endothelial cells, intercellular adhesion molecule 1 (ICAM-1) and E-selectin are upregulated. The increased expression of adhesion molecules favours leukocyte–endothelial adhesion, further promoting a procoagulant state. APAs with β2-GPI specificity also increase production of 6-keto-PGF1- α- [a metabolite of arachidonic acid].^ 13 ^ These mechanisms may help explain the pathophysiology of the microvascular thrombosis seen in CAPS.
CAPS is the initial presentation of APS in nearly half of patients, while the remaining half have a known history of APS. One of the most characteristic findings in CAPS is the presence of precipitating factors. They have been identified in more than 50% of patients. Infections were the most prevalent precipitating factor, with 49%. However, SLE was the least commonly reported, with 3%.^ 14 ^ The detailed analysis of the largest number of 500 patients, called the CAPS Registry, showed that 69% were female, with a mean age of 38 years. 60% suffered from primary APS, while 30% were secondary to SLE. Intra-abdominal thrombotic complications affecting the kidneys, adrenal glands, splenic, intestinal and mesenteric or pancreatic vasculature were the most commonly reported. The patients frequently presented with abdominal pain or discomfort.^ 14 ^
The clinical manifestations of CAPS are usually a consequence of TMA. Therefore, the differential diagnosis is broad and includes haemolytic uremic syndrome (HUS), TTP, DIC and HIT. HUS and TTP are characterized by microangiopathic haemolytic anaemia, thrombocytopenia and ischaemic injury to the visceral organs.^ 15 ^ While fever and neurologic manifestations frequently dominate the clinical picture in TTP, most patients with HUS suffer from significant renal impairment. The differentiation between HUS/TTP and CAPS is sometimes difficult. As a general rule, thrombocytopenia and schistocytosis are marked in HUS/TTP and mild, or even absent, in CAPS. Activated PTT is usually normal in HUS/TTS, but it may be elevated in CAPS in the presence of lupus anticoagulant, which was presented in this patient as he had elevated activated partial thromboplastin time (aPTT). A low prevalence of schistocytes (16% of cases) was also reported in a later study.^ 16 ^ An explanation for the paucity of schistocytes in CAPS is not readily available. It is postulated that the rapidity of onset and completeness of microvascular occlusion prevented enough blood from flowing through thrombotic vessels to cause fragmentation of erythrocytes.^ 9 ^ Some distinguishing results between the previously described common differentials are displayed in Table 2.
CAPS requires an aggressive, multidisciplinary, collaborative treatment strategy. The following treatments, often in combination, have been used for CAPS: anticoagulation (87%), glucocorticoids (86%), plasma exchange (39%), cyclophosphamide (36%), intravenous immunoglobulins (22%) and anti-platelet agents (10%).^ 12 ^ This patient was given anticoagulants along with plasma exchange, steroids and two doses of cyclophosphamide.
The diagnosis of CAPS may be challenging. First of all, a high degree of suspicion is the first step in recognizing this rare and devastating disease. Presentations involving multiple-organ systems especially with a microangiopathic picture should have CAPS in their differential diagnosis. A diagnosis of CAPS becomes much easier when a previous diagnosis of APS or known positivity for aPL-antibodies is known. A detailed patient history is certainly essential in the diagnosis of any disease presentation, and it is equally central for the diagnosis of CAPS. A history of prior thrombosis, pregnancy morbidity or a history of autoimmune disease like SLE would be of much help in the diagnosis of this catastrophic illness.
This report describes a case of catastrophic anti phospholipid syndrome accompanied by terrible complications. The real challenge was to act immediately and accordingly to diagnose, in light of vague symptoms with wide differential diagnosis, and an enriching medical history. The aim was to manage such high mortality disease in light of the significant lack of international guidelines because of the decreased incidence of such diseases. This report supports further studies of different types to be conducted in order to understand the pathophysiology of such diseases and to establish more focused approaches that help to achieve a high survival rate.
We express our deep gratitude to the medical ward staff for their invaluable support in completing this report.