Association between Severe Acute Respiratory Syndrome Coronavirus 2 Infection (Coronavirus Disease 2019) and Lupus Anticoagulant-Hypoprothrombinemia Syndrome: A Case Report and Literature Assessment

Among the tests that study the presence of circulating antiphospholipid antibodies, the so-called lupus anticoagulant (LA) is considered the main risk factor for venous and arterial thromboembolic disease.[1] However, in some cases, this laboratory test is associated with hemorrhagic diathesis. This primarily occurs when antiprothrombin antibodies with LA activity cause a reduction in plasma prothrombin levels such that hemorrhagic events occur. This clinical situation can be called LA/hypoprothrombinemia syndrome (LAHS).[2] LAHS is considered relatively rare, especially as associated with infection, and specifically SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection.

We, therefore, wish to report the case of a 5-year-old girl, evaluated by our hospital's Center for Congenital Bleeding Disorders for spontaneous ecchymoses on her back and thighs. An episode of diarrhea and vomiting 2 weeks earlier, in the absence of previous pathological data, was also reported.

The blood count revealed a leukocyte count of 10.17 × 10⁹/L (reference values [RV]: 6.00–17.00), a hemoglobin of 129 g/L (RV: 110–138), and a platelet count of 403 × 10⁹/L (RV: 140–400). Initial coagulation screening showed an increase of both international normalized ratio (PT/INR) [1.71 (RV: 0.80–1.20)] and activated partial thromboplastin time (aPTT) ratio (2.34 [RV: 0.80–1.20])) with a normal fibrinogen level (3.1 g/L [RV: 1.5–4.0]).

One-stage clotting factor activities of FII, FV, FVII, FVIII, FIX, FX, FXI, and FXII were then assayed with Sysmex CS-5100 (Siemens Healthcare Diagnostic, Erlangen, Germany). All measured factors were normal, except FII, which showed a reduced activity [25% (RV: 70–154%)].

Considering the patient's age and clinical history together with the laboratory tests results, LA was also investigated using a two-test procedure employing aPTT reagent silica clotting test, SCT (PTT-LA, Stago) and the dilute Russell's viper venom test, DRVVT (LA-1, Siemens). In the screening phase, both tests were prolonged: SCT screening ratio 3.89 (RV: <1.35) and DRVVT screening ratio 2.81 (RV: <1.22). The patient plasma and pooled normal plasma mixture (1:1) did not normalize either test, the SCT mixing test having a ratio of 3.89 (RV: <1.18), and DRVVT mixing test having a ratio of 2.65 (RV: <1.14), suggesting the presence of an inhibitor. The addition of the phospholipid-rich reagent partially normalized the two tests: SCT ratio of 2.30 and DRVVT ratio of 1.49. The screen/confirm ratio for both tests was consistent with the LA phenomenon. Anticardiolipin and anti-β2-glicoprotein-I IgG and IgM antibodies were in the normal range.

The parents were evaluated, and no coagulation factor abnormalities were observed. This strengthened the hypothesis of an acquired deficit occurring in the child due to infectious or autoimmune disease. The antiphosphatidyl-serine/prothrombin enzyme-linked immunosorbent assay showed a high titer of IgG 260U (RV: <30U) and IgM 40U (RV: <30U) antibodies. Additional laboratory tests, performed with a chemiluminescent immunoassay, highlighted the presence of anti-SARS-CoV-2 IgG and a weak positivity for anti-SARS-Cov-2 IgM + IgA suggesting a recent viral infectious trigger.

A nonspecific autoimmune workup was also observed: antinuclear antibodies with a 1:320 nucleolar pattern and negative anti-DNA antibodies.

No drug therapy was administered, and after 5 days of hospitalization and observation, the patient was discharged. Upon follow-up, there was a spontaneous resolution of bruising at three months postpresentation ([Fig. 1]). FII activity normalized at day 20 (93%). The LA phenomenon completely resolved after 4 months ([Fig. 2]).

Fig. 1 Ecchymosis in the legs at the time of hospitalization (A) and resolution after 90 days (B).

Fig. 2 Descriptive timeline figure of the case. FII (prothrombin) was low (25%) on day 2. Diagnosis of LAC (lupus anticoagulant) was made on day 3 and was associated with high titer aPS/PT (anti phosphatidyl-serine/prothrombin) antibodies of IgG isotype. The same day, diagnosis of SARS-CoV-2 infection was made. On day 20, FII level was normal, and LA was weak and then disappearing after 120 days. Bruising completely resolved after 3 months.

LAHS is a rare acquired disorder caused by prothrombin antibodies. This condition should be suspected in a bleeding patient, more frequently in children[3] [4] [5] and women,[4] with prolonged PT and aPTT and a reduced factor II activity in combination with LA. The presence of antiphosphatidyl-serine/prothrombin antibodies explains the reduced level of factor II, likely due to a rapid clearance of the prothrombin-antibody complex. Moreover, two distinct patterns of LAHS are reported in children[3]: associated with viral infections, more frequently in children under 10 years of age, or autoimmune conditions. In this case, positivity to anti-SARS-CoV-2 IgM and IgA, clinical gastrointestinal symptoms, self-limiting and shorter duration of the condition suggest a diagnosis of LAHS associated with a viral infection, in this case SARS-CoV-2. The most frequently reported viruses involved in LASH to date have been Adenovirus, Cytomegalovirus, Varicella-Zoster virus, and Epstein-Barr. However, following the COVID-19 (coronavirus disease 2019) pandemic, SARS-CoV-2 must also be considered a possible trigger. To date, only a single case of LAHS in an adult has been reported in the literature, but to our knowledge, apart from our case, none have been reported in childhood.[6] Like most cases of LA and antiphospholipid antibodies reported to be associated with COVID-19,[7] [8] the LA in our case was transient and not the characteristic of an antiphospholipid (antibody) syndrome.

^* These authors contributed equally to this work.

Publication History

Article published online:
20 February 2023

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