**4. Probable catastrophic antiphospholipid antibody syndrome**


There are several reports during this pandemic where a high incidence of antiphospholipid antibodies has been demonstrated in patients with COVID-19. In addition, multiorgan failure and the presence of microthrombosis in critical patients have been associated with cytokine storm and the elevated ferritin. From the first reports in Wuhan, elevated ferritin was identified as a marker of severity in critically ill patients with COVID-19. Four well-recognized clinical conditions may be associated with high ferritin levels: the macrophage activation syndrome (MAS), adult-onset Still's disease (AOSD), catastrophic antiphospholipid syndrome (CAPS), and septic shock. The presentation of critical patients with COVID-19 does not meet the criteria to make a diagnosis of any of these diseases, however, they do meet the criteria to make the diagnosis of complete or incomplete CAPS [9, 10].

However a study by the American society of Hematology (ASH) in which they performed an antiphospholipid antibody (aPL) screen in 27 patients with COVID-19. Only four of these patients were positive for lupus anticoagulant. None of these patients were positive for anticardiolipin or anti-β-2 glycoprotein I antibodies. Given the fact that antiphosholipid antibodies may transiently be elevated during acute infections, thrombosis or inflammation, the American Society of Hematology has strongly recommended against routinely testing for these antibodies (aPL) in COVID-19 patients unless clinically indicated by the history.

It is however important to note that most studies that have been published in this regard do not report findings specific for critical patients with COVID-19. Inclusion criteria have been more generalized targeting patients with COVID-19. This could lead to recording lower positivity rate for aPL antibodies. Also, most of these studies have only tested specifically for lupus anticoagulant which is the least sensitive among the different types of antiphospholipid antibodies which could be positive among this group [11].

This recently led Amezcua-Guerra et al. to test a panel of aPL antibodies in blood specimens from 21 patients hospitalized in the intensive care unit due to severe or critical COVID-19. Anticardiolipin, anti-β2 glycoprotein I, antiprothrombin, antiphosphatidylserine, antiphosphatidylinositol and antiannexin V antibodies were measured, each in IgM and IgG isotypes. Subsequently, demographic and clinical data were obtained from electronic medical records. Samples (sera) collected before the SARS-CoV-2 pandemic from 12 healthy individuals, matched for age and sex, were tested as controls. A total of 19 patients (90%) had dyspneoa while on admission, 57% eventually required mechanical ventilation (invasive) during their stay in the hospital. All of these patients had elevated levels of D-dimer, ferritin and C reactive protein at time of presentation.

Out of the 21 patients with COVID-19, 12 of them tested positive for at least one aPL antibody with only 1 of the 12 controls yielding a positive result. Age and number of comorbidities tended to be lower in patients with aPL antibodies. In contrast, levels of D-dimer, ferritin and C reactive protein were higher both on admission and throughout the hospital stay in the patients. Patients who were positive for aPL demonstrated elevated levels of interleukin-6 (>40 pg./mL) [12].

Interestingly, significant levels of circulating anticardiolipin and anti-β-2glycoprotien I antibodies have recently been described in three severely ill COVID-19 patients with multiple cerebral infarctions by Zhang et al. This is suggestive that coagulopathy associated with COVID-19 could be within or close to the spectrum of antiphospholipid syndrome. A higher-than-expected number of thrombotic episodes have been reported involving both veins and arteries (pulmonary thromboembolism, deep venous thromboses, myocardial infarction and stroke even with the use of anticoagulant therapy or prophylaxis [13].

It is now established that vascular changes are well associated with COVID-19. Formation of fibrin thrombi has been observed in some patients. Many patients with severe illness have shown elevated levels of D-Dimers with other clinically relevant findings suggesting thrombotic microangiopathy such as cutaneous changes in the limbs. Autopsy finding of four out of seven patients with COVID-19 showed that thrombi were consistently present in all pulmonary vessels with a diameter of 1 mm- 2 mm. Also, microthrombi were 9 times more likely to be found in the alveolar capillaries of patients with COVID-19 than in patients with influenza [14].

#### **5. Clinical manifestations of CAPS**

Renal (70%): usually accompanied by hypertension and acute renal failure. Pulmonary (65%): severe dyspnea, frank adult respiratory distress syndrome (ARDS), pulmonary emboli, sometimes multiple pulmonary infarction, interstitial infiltrates, and intraalveolar hemorrhage.

Central nervous system (55%): major cerebral infarctions, cerebral sinus thrombosis, encephalopathy and seizures.

#### *COVID-19 and Catastrophic Antiphospholipid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.99896*

Cardiac (50%): typical myocardial infarction, diffuse myocardial involvement with congestive heart failure or valve lesions.

Gastrointestinal (45%): vascular occlusions of mesenteric, portal and inferior vena cava, arterial occlusions accompanied by gangrene of the bowels and splenic infarctions, hepatic involvement and pancreatitis.

Skin (40–45%): livedo reticularis, ulcerations, gangrene, purpura, acrocyanosis or digital ischemia.

Other manifestations: adrenal thrombosis, testicular infarction, necrosis of the prostate gland [7].

The clinical manifestations are described in multiple reports during the coronavirus pandemic including skin involvement, so we believe, according to the evidence, that a high percentage of critically ill patients meet the diagnostic criteria of this entity.

Coagulation disorders were initially thought to be due to diseminated intravascular coagulopathy (DIC), but with the current evidence from all autopsies it has been shown to be due to a procoagulant phenomenon together with a severe inflammatory state. These findings may explain the events of venous thromboembolism observed in some of these patients and support antithrombotic prophylaxis/treatment. The cumulative incidence of thrombotic complications (mostly PE) is high between 25 and 30%.

The incidence of cerebral thrombosis in two weeks is almost 10 times higher in patients with COVID-19 than in the normal population in patients under 50 years of age. In a report of 3 patients with ischemic stroke the association with antiphosphilipid antibodies was 100% [15, 16].

This multisystem inflammatory syndrome is caused by cytokine activation [7]. Cytokines involved include tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-18 and macrophage-migration inhibitory factor. These cytokines are responsible for acute lung inflammation via increasing neutrophil migration and lung vascular permeability, not only for ARDS but also for the cerebral edema, which may be a factor in the initial confusion and deterioration of consciousness in these patients, as well as myocardial dysfunction encountered.

In 6 autopsies performed in a hospital in France it was found that one patient presented a lymphocytic viral pneumonia that could be considered as type L. For five other patients with a phenotype H, the histologic pattern was an acute fibrinous and organizing pneumonia (AFOP), characterized by an extensive intra-alveolar fibrin deposition called fibrin "balls", rather than hyaline membranes. AFOP, a rare form of acute lung injury. This pattern differs from the diffuse alveolar damage (DAD) found in the classic ARDS by the fact that organizing intra alveolar fibrin constitutes the dominant histological finding in AFOP, especially in its subacute presentation by contrast to the fulminant presentation, is a cortico-sensitive pathology.

Kidney histopathology was examined in an autopsy series of 26 patients who died of respiratory failure secondary to COVID-19. All patients had evidence of acute tubular injury (of varying severity); a range of other histopathology findings, such as erythrocyte clusters and pigmented casts, were also present [17].

Myocardial involvement has been described since the first reports adding an increase in the incidence of ACS and arrhythmias in these patients. Reports vary 20–30% of myocardial involvement, even higher percentages of troponin elevation have been found as a marker of myocardial damage [18].

The slightly rarer skin manifestations in this entity, especially when it is secondary to an infectious process, have been reported in two articles, even during the autopsy of these patients with purpuric skin rash. The conclusions of this study were severe COVID-19 may define a type of catastrophic microvascular injury syndrome mediated by activation of complement pathways and an associated procoagulant state.

In the CAPS Registry, CAPS as the initial manifestation of antiphospholipid syndrome occurred in 86.6% of children with infections being the triggering factor in 60.9% of the cases. Cardiac involvement was present in 57.4% of children and included cardiac failure, heart valve lesions, lung 63%, skin 37% and gastrointestinal 17.4% [19, 20].

Infections in children are more frequent than adults, which have been shown to play a role in the theory of "molecular mimic-cry" (molecular imitation) where certain viruses and bacteria that have an amino acid sequence similar to that of B2-GP1 result in an immune response producing antiphospholipid antibodies. B2-GP1 could activate the immune response through interaction with a membrane receptor TLRs (toll-like) and from this a series of signals are generated, which increase the production of proinflammatory cytokines. The medical community recognizes the MIS but most do not agree with the diagnosis of kawassaki disease [16].

Given the data made available from the various studies mentioned earlier, we can say that there is some evidence that critically ill patients with COVID-19 are demonstrating a disease form that meets the criteria for making the diagnosis of complete catastrophic antiphospholipid antibodies syndrome, or at least showing a disease form that is within the spectrum of manifestation of this syndrome. CAPS registry was created in 2000. As of 2012 it had been updated with data from over 400 patients. Not much advancement has been made in the area of this poorly understood syndrome after that. This interesting phenomenon observed during this pandemic which has become the largest public health emergency in recent times calls for more research work in the area of Catastrophic antiphospholipid syndrome. More awareness is required in the medical community in this area [21–23].

*COVID-19 and Catastrophic Antiphospholipid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.99896*
