Yu Min Shen

Thrombosis and a hypercoagulable state in HIV-infected patients.

Human immunodeficiency virus infection is an illness with protean manifestations including hematological abnormalities. Thromboembolic complications in HIV-infected patients have been described. Recent literature describes an incidence ranging from 0.26% to 7.6%; higher incidence is seen in patients with active opportunistic infections or malignancy, and in patients with the acquired immunodeficiency syndrome. A variety of potential mechanisms have been proposed to account for the observed hypercoagulability in HIV-infected patients. These include the presence of antiphospholipid-anticardiolipin antibodies, decreased activities of natural anticoagulants (especially protein S), and increased platelet activation. Recent epidemiological studies emphasize the increased incidence of thromboembolic events including myocardial infarction in the HIV-infected population after the introduction of highly active antiretroviral therapy. The use of protease inhibitors in particular is implicated. A hypercoagulable state and especially thromboses are emerging as clinical issues in HIV-infected patients. Further studies are in order to more clearly delineate the pathophysiologic mechanism(s) of thromboses in HIV-infected patients.

A phase I study of a combination of anti-CD19 and anti-CD22 immunotoxins (Combotox) in adult patients with refractory B-lineage acute lymphoblastic leukaemia.

Novel agents are needed for patients with refractory and relapsed acute lymphoblastic leukaemia (ALL). Combotox is a 1:1 mixture of two immunotoxins (ITs), prepared by coupling deglycosylated ricin A chain (dgRTA) to monoclonal antibodies directed against CD22 (RFB4‐dgRTA) and CD19 (HD37‐dgRTA). Pre‐clinical data demonstrated that Combotox was effective in killing both pre‐B‐ALL cell lines and cells from patients with pre‐B ALL. A clinical study of paediatric patients in which 3 of 17 patients with ALL experienced complete remission, supported the preclinical work and motivated this study. This study was a Phase I, dose‐escalation trial using Combotox in adults with refractory or relapsed B‐lineage‐ALL. A cycle consisted of three doses, with one dose given every other day. Dose levels were 3, 5, 6, 7 and 8 mg/m2 per dose. Seventeen patients, aged 19–72 years, were enrolled in this multi‐institution study. The maximum tolerated dose was 7 mg/m2/dose (21 mg/m2/cycle) and vascular leak syndrome was the dose‐limiting toxicity. Two patients developed reversible grade 3 elevations in liver function tests. One patient achieved partial remission and proceeded to allogeneic stem cell transplantation. All patients with peripheral blasts experienced decreased blast counts following the administration of Combotox. Thus, Combotox can be safely administered to adults with refractory leukaemia.

Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP)

The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single‐centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as ‘other microangiopathies’ (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non‐deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.

Higher optical density of an antigen assay predicts thrombosis in patients with heparin-induced thrombocytopenia.

Objectives:  To correlate optical density and percent inhibition of a two‐step heparin‐induced thrombocytopenia (HIT) antigen assay with thrombosis; the assay utilizes reaction inhibition characteristics of a high heparin concentration.

Poor correlation of supratherapeutic international normalised ratio and vitamin K-dependent procoagulant factor levels during warfarin therapy.

Patients with a supratherapeutic international normalised ratio (ST‐INR) are at risk for bleeding. ST‐INR is corrected by withholding warfarin therapy and often by supplementing vitamin K or providing vitamin K‐dependent factors; the exact therapeutic decision is based on the extent of the prolonged INR. Currently, ST‐INRs are frequently observed in clinical practice due to the use of sensitive recombinant tissue thromboplastin reagents and automation. However, there are scant data correlating an ST‐INR with various vitamin K‐dependent factors. This prospective cohort study, set in a large tertiary care teaching hospital for the University of Texas Southwestern Medical Center at Dallas, defined the relationship between ST‐INR (>5·0) and measured vitamin K‐dependent procoagulant factors. Prothrombin time, INR and vitamin K‐dependent factors II, VII, IX and X were measured in 78 patients with an INR > 5·0 (ST‐INR) who were on warfarin therapy for more than 2 months. There was no significant relationship between the ST‐INR and levels of important vitamin K‐dependent factors II and X. These data support the recent guidelines that the management of an INR > 5·0 should be driven by the clinical determinants rather than specific INR values per se.

IgA antiphospholipid antibodies are an independent risk factor for thromboses

Antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin and anti-β2-glycoprotein I antibodies, mostly IgG isotype) are strong risk factors for thrombosis. Because a paucity of information on IgA isotype exists in the literature, we retrospectively evaluated the thrombotic significance of IgA antiphospholipid antibodies. We included 472 patients with clinical information on thrombotic events and complete laboratory work-up for antiphospholipid antibodies syndrome. Odds ratios (OR) of various antiphospholipid antibodies for thrombosis were calculated by univariate and multivariate analyses. Lupus anticoagulant alone was detected in 57 (12%) patients, ELISA-based antibodies (IgG, IgM, IgA) against cardiolipin, phosphatidylserine or β2-glycoprotein-I alone were detected in 131 (28%) patients, whereas 80 (17%) patients had both. Antibody isotype distribution was IgG 32%, IgM 60% and IgA 56%. Univariate analysis showed a statistically significant risk of thrombosis in patients with elevated titres of IgA of any ELISA-based antiphospholipid antibodies (OR 1.77). Stepwise logistic regression (multivariate) analysis identified elevated titres of any ELISA-based IgA antiphospholipid antibodies as an independent risk factor for thrombosis (OR 1.6) in the entire cohort, and in the subgroup of patients without concurrent presence of lupus anticoagulant (OR 1.8). IgA antiphospholipid antibodies appear to be a significant independent risk factor for thrombosis, thereby meriting evaluation in patients with unexpected thrombosis.

Advances in understanding the pathogenesis of primary familial and congenital polycythaemia.

Primary familial and congenital polycythemia (PFCP) is an autosomal‐dominant proliferative disorder characterized by erythrocytosis and hypersensitivity of erythroid progenitors to erythropoietin (Epo). Several lines of evidence suggest a causal role of truncated erythropoietin receptor (EpoR) in this disease. In this review, we discuss PFCP in the context of erythrocytosis and EpoR signalling. We focus on recent studies describing mechanisms underlying Epo‐dependent EpoR down‐regulation. One mechanism depends on internalization mediated through the p85 regulatory subunit of the Phosphoinositide 3‐Kinase, and the other utilizes ubiquitin‐based proteasomal degradation. Truncated PFCP EpoRs are not properly down‐regulated upon stimulation, underscoring the importance of these mechanisms in the pathogenesis of PFCP.

Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: A case report

Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by a severe deficiency of ADAMTS13 activity. Although therapeutic plasma exchange (PLEX) is the standard of care, 30% to 50% patients develop exacerbation or relapse, requiring immunomodulatory agents. Of these agents, glucocorticoids, rituximab, and cyclosporine A are the most frequently used.

Antiphospholipid antibodies and malignancy.

Antiphospholipid antibody syndrome is characterized clinically by venous or arterial thrombosis, recurrent fetal loss, or placental insufficiency in women. This article describes the prevalence of malignancy, the manifestations, and the prognosis for this condition.

Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications and Thrombosis

In the antiphospholipid syndrome (APS), patients produce antiphospholipid antibodies (aPL) that promote thrombosis and adverse pregnancy outcomes. Current therapy with anticoagulation is only partially effective and associated with multiple complications. We previously discovered that aPL recognition of cell surface β2-glycoprotein I (β2-GPI) initiates apolipoprotein E receptor 2 (apoER2)-dependent signaling in endothelial cells and in placental trophoblasts that ultimately promotes thrombosis and fetal loss, respectively. Here we sought to identify a monoclonal antibody (mAb) to β2-GPI that negates aPL-induced processes in cell culture and APS disease endpoints in mice. In a screen measuring endothelial NO synthase (eNOS) activity in cultured endothelial cells, we found that whereas aPL inhibit eNOS, the mAb 1N11 does not, and instead 1N11 prevents aPL action. Coimmunoprecipitation studies revealed that 1N11 decreases pathogenic antibody binding to β2-GPI, and it blocks aPL-induced complex formation between β2-GPI and apoER2. 1N11 also prevents aPL antagonism of endothelial cell migration, and in mice it reverses the impairment in reendothelialization caused by aPL, which underlies the non-thrombotic vascular occlusion provoked by disease-causing antibodies. In addition, aPL inhibition of trophoblast proliferation and migration is negated by 1N11, and the more than 6-fold increase in fetal resorption caused by aPL in pregnant mice is prevented by 1N11. Furthermore, the promotion of thrombosis by aPL is negated by 1N11. Thus, 1N11 has been identified as an mAb that attenuates APS-related pregnancy complications and thrombosis in mice. 1N11 may provide an efficacious, mechanism-based therapy to combat the often devastating conditions suffered by APS patients.