Catastrophic Antiphospholipid Syndrome as a Complication of COVID-19 Infection

Abstract

COVID-19 infection has been found to precipitate hypercoagulability and transiently increase antiphospholipid antibodies. However, it is yet to be determined how likely these transient changes contribute to thrombotic events and antiphospholipid syndrome. We present a case in which antiphospholipid antibodies were detected in the presence of significant thromboses. The patient was subsequently treated for suspected catastrophic antiphospholipid syndrome following COVID-19 infection.

Introduction

COVID-19 is commonly clinically characterized by cough, shortness of breath, respiratory failure, fever, and loss of taste and/or smell. While these may be primary symptoms, COVID-19 infection has also been associated with hypercoagulability. Ongoing studies and observations are identifying a significant incidence of thrombotic events in patients with COVID-19 such as pulmonary embolism, deep vein thrombosis, and limb ischemia. The pathophysiology of this hypercoagulability is likely multifactorial—severe inflammatory response from massive cytokine release, mononuclear phagocyte involvement, neutrophil extracellular traps, and uncontrolled complement activation are some of the hypothesized and studied mechanisms. Coagulation workup in patients with COVID-19 frequently uncovers an elevated D-dimer, prothrombin time, partial thromboplastin time (PTT), and fibrinogen.^1,2 Notably, the presence of antiphospholipid antibodies have also been found in many patients with COVID-19, especially those who experience thrombosis.^3,4 While antiphospholipid antibodies can be transiently present in severe infections, they play a significant role in the pathogenesis of thromboembolic events associated with antiphospholipid syndrome (APS)—bringing into question the significance of antiphospholipid antibodies in COVID-19 hypercoagulability.

Antiphospholipid syndrome is an autoimmune disorder associated with thrombosis and the serological presence of antiphospholipid antibodies. This is commonly seen in younger patients in conjunction with other autoimmune disorders. One possible complication of APS is catastrophic antiphospholipid (CAPS). The criteria for CAPS are as follows: history of APS or antiphospholipid antibodies, evidence of 3 or more organ systems involved, manifestations of these organs’ involvements within 1 week of one another, and histopathologic confirmation of small vessel thrombosis on biopsy. Given that CAPS is associated with a 50% mortality rate, it is important to identify those who are at risk for CAPS early so they can be treated in a timely manner. This report presents a unique case of suspected CAPS following COVID-19 infection.

Case Presentation

A 47-year-old female with a medical history of type 2 diabetes mellitus (T2DM), hypertension, obesity, and thyroid papillary carcinoma in remission, and COVID-19 infection 1 month prior presented to the emergency department of Loma Linda University Medical Center (LLUMC), with a 3-week history of left upper quadrant abdominal pain. Her COVID-19 infection was mild with her only symptom being rhinorrhea. She had previously been seen at an outside hospital 2 days prior to her presentation to LLUMC and was found to have a splenic infarct and bilateral renal infarcts per computed tomography (CT) abdomen/pelvis (Figure 1).

Figure 1.

Computed tomography showing patient’s splenic infarcts.

Physical examination was notable for left upper quadrant tenderness without guarding. Further imaging to assess for additional thromboembolic disease with CT angiography of chest and transthoracic echocardiogram were unremarkable for thromboses. Labs done for a hypercoagulable workup revealed positive ANA (antinuclear antibody), triple positive antiphospholipid antibodies including positive LAC (lupus anticoagulant), aB2GP (anti-beta-2-glycoprotein) immunoglobulin G (IgG) and immunoglobulin M (IgM), and anticardiolipin antibody IgM and IgG (Figure 2). PTT was also notably elevated on labs drawn before she was given enoxaparin 80 mg. The rest of the hypercoagulable labs including factor V Leiden, antithrombin activity, protein C activity, and protein S activity were within normal limits. Complete autoimmune workup was performed, which was negative for other antibodies.

Figure 2.

Computed tomography showing patient’s bilateral renal infarcts.

Figure 3.

Patient’s rheumatological labs.

Based on her history, physical examination, and labs, the patient did not meet criteria for diagnosis of systemic lupus erythematous. The patient was also not diagnosed with any other connective tissue diseases. She had no prior history of blood clots or family history of clotting disorders. We evaluated for possible malignancy as well. She was up-to-date on age appropriate cancer screenings. In addition, CEA (carcinoembryonic antigen), myeloma work up, and imaging did not support a diagnosis of occult malignancy. Patient was transferred to LLUMC for further management.

Although the patient did not meet full criteria for definitive CAPS (had thrombosis in 2 organs instead of 3 organs), we diagnosed her with probable CAPS, and she received treatment based on this diagnosis. She was initiated on warfarin for anticoagulation with continuation of therapeutic enoxaparin until she had reached her international normalized ratio goal of 2 to 3. The rheumatology team recommended 5 days of plasma exchange (PLEX). We also administered 1 dose of rituximab 1 gram intravenous infusion after PLEX therapy. The patient’s abdominal pain resolved. The patient did not develop any new thrombosis or symptoms during admission. Patient was discharged on warfarin and will follow up with the rheumatology clinic for continuation of rituximab infusions.

Discussion

Although our patient’s diagnosis of CAPS was probable based on classification criteria, we treated her aggressively to prevent potential mortality. We had an extensive risks/benefits discussion with the patient regarding available treatment, and ultimately, she wished for treatment for CAPS with PLEX and rituximab to prevent further thrombosis. Interestingly, this patient had reported no previous diagnosis of or any previous symptoms concerning for an autoimmune disorder. She has no history of blood clots or family history of clotting disorders. It is important to note that this patient did have T2DM and obesity, both of which are known to cause endothelial damage and, therefore, put patients at a higher susceptibility for vascular complications. In addition, studies have shown that patients who have comorbidities such as T2DM have a higher rate of adverse outcomes associated with COVID-19. ⁵ It is thought that there is a severe inflammatory response that leads to thrombo-inflammation in the presence of COVID-19 infection. It is also suggested that the virus itself can activate the coagulation cascade. The exact mechanism of how the infection leads to thrombosis is yet to be determined. However, a proposed mechanism is that the infection causes a severe inflammatory response triggering release of cytokines, which in turn activate the epithelial cells, monocytes, and macrophages, thus triggering a cascade that leads to expression of tissue factor and platelet activation, leading to increased levels of von Willebrand factor and factor VIII. All of these factors play a large role in thrombin and fibrin clot formation. ¹

Her recent COVID-19 infection was the only identified trigger for the multi-organ thromboses. In a case series of patients with COVID-19, antiphospholipid antibodies were detected, which is thought to be transiently positive. However, a small percentage has been linked to hypercoagulability, resulting in thrombotic events. While these patients with COVID-19 who experience thromboses often show elevated PTT and are positive for antiphospholipid antibodies, antiphospholipid antibodies have been found to be elevated in many COVID-19 patients both with and without thrombosis.^2,4,6 The significance of these serological markers in the role of thrombosis during COVID-19 is unclear. While antiphospholipid antibodies can contribute to the mechanism of hypercoagulability, it may also be an epiphenomenon associated with COVID-19 infection. In addition, whether these markers are transiently or permanently elevated due to COVID-19 has yet to be determined. While there have been no documented cases of CAPS associated with COVID-19 infection, there have been reports of it exacerbating underlying primary APS. A recent case report discussed a patient with known APS who had multiple infarctions with elevated antiphospholipid antibodies in the context of COVID-19 infection. This suggests that COVID-19 may play a role in precipitating APS flares, putting these patients at an even higher risk for thrombotic events. ⁷ It is important to try to identify those who could be at risk of CAPS after COVID-19 infection and treat them early. Current practices for anticoagulation predominately utilize heparin-based therapy for prophylaxis with preliminary data suggesting it lowers mortality.^8,9 However, better understanding the mechanisms of hypercoagulability associated with COVID-19 would prove beneficial for providing and developing more targeted therapies to prevent thrombotic complications.

Our institution does not require ethical approval for reporting individual cases or case series.

Written informed consent was obtained from the patient for their anonymized information to be published in this article.