Lupus anticoagulant-hypoprothrombinemia syndrome and immunoglobulin-A vasculitis: a report of Japanese sibling cases and review of the literature.

Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare bleeding disorder caused by antiprothrombin antibodies. LAHPS is associated with systemic lupus erythematosus (SLE) or infections. We describe two Japanese brothers with immunoglobulin-A vasculitis (IgAV) who met the diagnostic criteria of LAHPS. They presented with palpable purpura and abdominal pain, and had a prolonged activated partial thromboplastin time (APTT) and prothrombin deficiency with the presence of lupus anticoagulant. Pediatric LAHPS was reviewed in abstracts from the Japan Medical Abstracts Society that were written in Japanese and PubMed or Web of Science-listed articles in English between 1996 and 2019. Including our cases, pediatric LAHPS has been reported in 40 Japanese and 46 non-Japanese patients. We summarized the clinical and laboratory characteristics of all 86 cases, and found only one Japanese LAHPS case with IgAV, except for our cases. Of the 86 cases, most were associated with infections followed by SLE. The presence of SLE, older age, lower prothrombin levels, severe bleeding symptoms, and positivity of immunoglobulin G anticardiolipin antibodies and anticardiolipin/ß2-glycoprotein I antibodies and/or ß2-glycoprotein I-dependent anticardiolipin antibodies had higher odds of requiring treatment. Measuring the APTT and prothrombin time (PT) might be required in patients with IgAV when they do not have a typical clinical course or distinctive symptoms. LAHPS should be considered with prolongation of the APTT and/or PT. Additionally, it is important to maintain a balance between the risk of thrombosis and hemorrhage when normalization of the PT and FII levels occurs in LAHPS cases under treatment.

Lupus anticoagulant-hypoprothrombinemia syndrome and similar diseases: experiences at a single center in Japan.

Patients with lupus anticoagulant (LA), a thrombotic risk factor, along with decreased prothrombin (FII) activity are classified as lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) and occasionally show bleeding symptoms, although this is not essential for diagnosis. We treated 20 cases of LAHPS over a 3-year period. Median FII activity was 20.9% and the anti-prothrombin antibody (anti-II Ab), shown by ELISA findings, was detected in 55%. Bleeding symptoms were observed in 20%, although that finding was not correlated with FII activity or anti-FII Ab quantity. We also observed 21 LA cases with decreased activity of coagulation factors other than FII, which we have designated LAHPS-like syndrome (LLS). Among LLS patients, anti-FII Ab and bleeding symptoms were seen in 47.6% and 14.3%, respectively. Our findings suggest that bleeding in LAHPS and LLS cannot be explained only by FII activity decreased by anti-FII Ab. Low FVIII activity and the anti-FVIII antibody (anti-FVIII Ab) were detected in some LAHPS and LLS patients, making it difficult to distinguish those from acquired hemophilia A cases. Detection of anti-FVIII Ab quantity by ELISA may be useful for accurate determination, as that was not performed in our LAHPS or LLS patients.

Lupus anticoagulant-hypoprothrombinemia syndrome and catastrophic antiphospholipid syndrome in a patient with antidomain I antibodies.

Lupus anticoagulant-hypoprothrombinemia syndrome is a rare condition characterized by the association of acquired factor II deficiency and lupus anticoagulant. Contrary to classical antiphospholipid syndrome, it may cause severe life-threatening bleeding (89% of published cases). We report a patient, positive for antidomain I antibodies, with initially primary lupus anticoagulant-hypoprothrombinemia syndrome without previous clinical manifestation or underlying systemic disease. Five years later, he experienced the first systemic lupus erythematous flare. Within a few days, catastrophic antiphospholipid syndrome was diagnosed with heart, liver and kidney involvement. The patient recovered under pulse steroids, intravenous heparin and intravenous immunoglobulins.

[A Case of Lupus Anticoagulant-Hypoprothrombinemia Syndrome with Phosphatidylserine-Dependent Anti-Prothrombin Antibody].

Lupus anticoagulant-hypothrombinemia syndrome (LAHS) is a rare disease involving hemorrhagic diathe- sis due to hypothrombinemia with lupus anticoagulant. We report a 28-week-pregnant woman at twenty years of age, who had been hospitalized with jaundice. In laboratory data, AST, ALT, and bilirubin were elevated and the prothrombin time (PT) and activated partial thromboplastin time (APTT) were prolonged. Although the liver failure was improved after she delivered a baby by Caesarean section, postoperative intraperitoneal bleeding persisted. The diagnosis by liver biopsy was autoimmune hepatitis. Although the bleeding was stopped on the seventh postoperative day, the prolongation of PT and APTT remained. LA was positive in the diluted Russell's viper venom time. Anti-cardiolipin and anti-beta-2-glycoprotein anti- bodies were also positive. The prothrombin activity was reduced. A high titer of phosphatidylserine- dependent antiprothrombin antibody (aPS/PT), which causes bleeding, was observed. Based on these data, she was diagnosed with LAHS. The liver dysfunction and prolongation of PT and APTT were normalized following the administration of corticosteroids. In this case, aPS/PT may have contributed to the pathological physiology of LAHS. [Case Report].

Severe postoperative hemorrhage caused by antibody-mediated coagulation factor deficiencies: report of two cases.

Antibody-mediated coagulation factor deficiencies constitute a rare disorder that may develop in elderly patients without any history of a bleeding diathesis. Patients may present with severe and sometimes catastrophic bleeding. We report two cases of postoperative hemorrhage caused by a coagulation factor deficiency. In Case 1, massive intraabdominal bleeding occurred on day 3 after pancreaticoduodenectomy for bile duct cancer, and was caused by an acquired inhibitor of coagulation factor VIII. Hemostasis was achieved and the factor VIII inhibitor titer decreased to zero with activated prothrombin complex concentrates, prednisolone, and cyclophosphamide. In Case 2, intraabdominal bleeding occurred on day 7 after hepatectomy for hepatocellular carcinoma, and was caused by an acquired inhibitor against factors II (prothrombin) and V. This patient was treated with hemostatic agents containing bovine thrombin during surgery and also with prednisolone. We report these cases to highlight that antibody-mediated coagulation factor deficiencies should be considered when an elderly patient suffers sudden postoperative hemorrhage and to stress the importance of prompt diagnosis because of the risk of potentially life-threatening hemorrhage.

Lupus anticoagulant-hypoprothrombinemia syndrome: report of 8 cases and review of the literature.

The lupus anticoagulant-hypoprothrombinemia syndrome (LAHS)--the association of acquired factor II deficiency and lupus anticoagulant--is a rare disease drastically different from antiphospholipid syndrome in that it may cause predisposition not only to thrombosis but also to severe bleeding. We performed a retrospective study of 8 patients with LAHS referred to 6 French tertiary care centers between January 2003 and February 2011, and a literature review retrieving all related articles published between 1960 and April 2011. Including our 8 new cases, LAHS has been reported in 74 cases. The disease mostly occurs in young adults, with a female to male sex ratio of 1.4. Associated conditions mostly include autoimmune diseases such as systemic lupus erythematosus and infectious diseases. Bleeding is a frequent feature (89% of cases), while arterial and/or venous thrombosis is less common (13%). Factor II level is severely decreased at diagnosis (median value, 11%; range, 1%-40%). LAHS associated with autoimmune diseases is more persistent than LAHS associated with infection, and hemorrhagic complications are more common. Corticosteroids should be considered the first-line treatment, but the thrombotic risk strongly increases during treatment because of the improvement of factor II level. Despite the fact that 50% of patients develop severe bleeding, the mortality rate is <5%, after a median follow-up of 13 months (range, 0.5-252 mo). LAHS associated with autoimmune diseases should be diagnosed and managed carefully because the disease is persistent and severe hemorrhagic complications are common.

Lupus anticoagulant-hypoprothrombinemia in healthy adult.

The presence of lupus anticoagulant is associated with an elevated risk of venous and arterial thrombosis, and recurrent miscarriages as well. For some cases, this disease can present with bleeding as a consequence of lupus anticoagulant hypoprothrombinemia (LAHPS). LAHPS is a rare disease and it is reported to be most frequent in young females with/without systemic lupus erythematosus or in healthy children who are suffering with a viral infection. In such cases, steroid therapy is usually effective in normalizing the biological abnormalities and controlling the bleeding problems. A 34-year-old previously healthy man was admitted to our department because of his prolonged coagulation times; these abnormalities were discovered before performing orthopedic surgery. The prothrombin time (PT) was 15.2 sec, and the activated partial thromboplastin time (APTT) was 37.7 sec. A 1:1 dilution of patient plasma with normal plasma nearly corrected the PT, but this failed to correct the APTT. Evaluation of the clotting factors revealed decreased levels of factors II, V, VIII, IX and XI. The presence of LA was demonstrated by the dRVVT test, and the patient was diagnosed with LAHPS. He was successfully treated with corticosteroid before performing the orthopedic surgery.

[Serious bleeding in systemic lupus erythematosus complicated by lupus anticoagulant-hypoprothrombinaemia syndrome]. / Alvorlig blødning ved systemisk lupus erythematosus kompliceret med lupusantikoagulans-hypoprotrombinaemisyndromet.

Severe hemorrhagic diathesis due to lupus anticoagulant complicated by hypoprothrombinaemia resulting from prothrombin autoantibodies is a rare disorder and is often associated with systemic lupus erythematosus (SLE). We report a case in which a 15-year-old girl with SLE developed marked haemorrhagic manifestations due to menorrhagia and nosebleeds. The acute bleeding episode was treated with SAGM, tranexamic acid and recombinant factor VIIa. Lupus anticoagulant, cardiolipin antibodies and antiprothrombin antibodies were successfully depressed within weeks after corticosteroid therapy was begun.

[Pulmonary hemorrhage and anti-phospholipid syndrome]. / Hemorragia pulmonar y síndrome antifosfolipídico.

The presence of anti-phospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) associated to venous and/or arterial thrombotic phenomena and fetal losses define the anti-phospholipid syndrome. On rare occasions severe hypoprothrombinemia associated with this disease as a cause of hemorrhagic manifestations has been described. In addition very few cases of alveolar hemorrhage in anti-phospolipid syndrome (APS) have been described, being this complication usually related to microthrombosis and/or capillaritis of pulmonary vessels. We describe two patients without previous clinical manifestations of anti-phospholipid syndrome that showed pulmonary hemorrhage with anticardiolipin antibodies positivity. The first of them, a 33-year-old male, began his disease with low prothrombin time and the presence of antiprothrombin antibodies. In the biopsy by thoracoscopy the presence of pulmonary hemorrhage without capillaritis nor thrombotic phenomena was demonstrated, becoming evident certain clinical improvement and normalization of the prothrombin time after receiving immunosuppressive treatment but with persistence of the pulmonary hemorrhage 5 years later. The second case, a 89-year-old male, began his condition with bilateral lung infiltrates and hemoptysis, anticardiolipin antibodies positivity, and thrombopenia, with recurrence of the condition 1 year later. After other etiological possibilities were ruled out, and despite hemorrhagic trait in both patients, we consider that they should be in the clinical context of the anti-phospholipid syndrome, although at this time they did not meet the criteria recognized in order to diagnose this disease. Within the ampliable clinical spectrum of the anti-phospholipid syndrome we should take into account the pulmonary hemorrhage.

Acquired bleeding disorder in a patient with malignant lymphoma: antibody-mediated prothrombin deficiency.

BACKGROUND: Bleeding manifestations secondary to acquired hemostatic abnormalities in cancer patients have been well described. Bleeding due to the development of hemostatic inhibitors is observed less frequently. In this report, the authors describe a patient with a low grade lymphoma who presented with an acquired bleeding disorder and abnormal hemostatic screening tests. METHODS: Patient plasma samples were collected initially and during the course of treatment. Mixing studies and specific coagulation factor assays were performed to detect and confirm any deficiencies. Patient immunoglobulin G was isolated from plasma, and binding to prothrombin was demonstrated by immunoblot method and enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: Initial prolongations in the prothombin time and the activated partial thromboplastin time suggested a factor deficiency in the common pathway of coagulation. Factor assays confirmed that the coagulation abnormality in this patient was the result of an acquired prothrombin (factor II) deficiency. This was confirmed by an immunoassay for prothrombin antigen. Further studies demonstrated the presence of a noninhibitory antibody to prothrombin that interacted with a calcium dependent epitope. CONCLUSIONS: Successful treatment of the lymphoma resulted in clearance of the antibody and complete correction of all hemostatic abnormalities and manifestations. An acquired prothrombin deficiency has not been reported previously in association with a malignancy, and this patient represents the first such documented case.

Lupus anticoagulant-hypoprothrombinemia syndrome associated with systemic lupus erythematosus: report of 2 cases and review of literature.

We describe two patients whose initial presentation of systemic lupus erythematosus (SLE) was accompanied by haemorrhagic episodes and significant coagulopathy. Further investigation demonstrated positive lupus anticoagulant and decreased Factor II (prothrombin) activity. Both patients were diagnosed with lupus anticoagulant-hypoprothrombinemia syndrome (LAC-HPS) as a result of non-neutralizing antibodies directed against Factor II. LAC-HPS is a rare clinical entity that can occur in association with SLE, transient viral infections, drug reactions or even in healthy individuals. Mixing studies, which can be affected by other coagulation factor inhibitors, play an important role in the diagnosis of LAC-HPS. Factor VII level was decreased in the second patient, a finding that has not previously been reported in association with SLE. In both patients, bleeding stopped promptly and coagulation studies improved significantly with high dose corticosteroids. We discuss the pathogenesis, diagnosis and management of LAC-HPS in patients with SLE.

Many faces of lupus anticoagulants.

Lupus anticoagulants (LA) are immunoglobulins which inhibit one or more of the in-vitro phospholipid (PL) dependent tests of coagulation. Virtually any physician may encounter LA-positive patients. Such patients present with a variety of diagnostic challenges including arterial and venous thromboembolic events, recurrent fetal loss, TIAs, livedo reticularis, etc. LA and anticardiolipin antibodies (ACA) are the most common cause of acquired thrombophilia. Consequently, it is imperative for clinicians and laboratorians to work together in establishing the diagnosis of LA/ACA. The laboratory diagnosis of LA requires careful adherence to the SSC Subcommittee on Lupus Anticoagulants/Phospholipid-dependent Antibodies guidelines. Four sequential steps are required, including: screening tests, mixing studies (to establish the presence of an inhibitor), confirmatory tests based on increased or altered PL concentrations, and ruling out other coagulopathies (for example, factor VIII inhibitor).

Anti-prothrombin antibodies and their relation with thrombosis and lupus anticoagulant.

Antiphospholipid antibodies are a heterogeneous group of antibodies, comprising antibodies with different antigen specificity. Prothrombin is one of the antigens which can be detected by antiphospholipid antibodies and therefore anti-prothrombin antibodies belong to the antiphospholipid antibody family. The presence of antiphospholipid antibodies correlates strongly with thromboembolic complications; however a mechanism by which these autoantibodies induce a thrombotic complication in vivo is not understood. The classic assays for the detection of antiphospholipid antibodies (LAC and anticardiolipin ELISAs) aim to measure all the antiphospholipid antibodies present in the samples without making a distinction between the different subspecificities of the antibodies present in one single sample. Moreover, most of the in-vitro studies performed were carried out with total IgGs, which contain a mixture of antibodies. The absence of an accurate characterization of the plasma samples and the lack of specificity of the IgGs used in in-vitro tests makes it difficult to determine the contribution of antiprothrombin antibodies to the thrombotic complications. Here we review and critically analyse the literature regarding the clinical relevance of the presence of antiprothrombin antibodies and the possible participation of these antibodies in the pathogenesis of the thrombotic complications.

Catastrophic haemorrhage in a case of paediatric primary antiphospholipid syndrome and factor II deficiency.

The first case of primary antiphospholipid syndrome associated with recurrent life-threatening haemorrhages, due to the coexistence of acquired prothrombin deficiency, is described. Attention is drawn to the difficulty in diagnosing this situation, and therapeutic options are reviewed. Evidence is presented that implicates prothrombin as the protein cofactor for this lupus anticoagulant.