Impaired endogenous fibrinolysis at high shear using a point-of-care test in STEMI is associated with alterations in clot architecture

© The Author(s) 2019Impaired endogenous fibrinolysis is an adverse prognostic biomarker in acute coronary syndrome (ACS). Abnormally dense in vitro fibrin thrombi have been demonstrated in ACS patients and related to hypofibrinolysis using cumbersome, laboratory-based methods. We aimed to assess endogenous fibrinolysis using a point-of-care technique and relate this to clot architecture. From patients with ST-segment elevation myocardial infarction (STEMI), venous blood was drawn immediately on arrival to assess thrombotic status. Blood was assessed using the point-of-care Global Thrombosis Test which measures occlusive thrombus formation under high shear and subsequently endogenous fibrinolysis (lysis time, LT). Two samples per patient were run in parallel. In one channel, the measurement was allowed to proceed as normal. In the other, after occlusion, thrombus was extracted, washed, fixed in glutaraldehyde, dried, sputter-coated, and assessed using scanning electron microscope. Endogenous fibrinolysis was strongly associated fibrin fibre thickness (p = 0.0001). As LT increased (less efficient fibrinolysis), the fibrin network of the thrombus was significantly more compact and dense, with thinner fibrin fibres and smaller gaps. Fibrin fibre thickness correlated inversely with LT (r = - 0.89, p = 0.001). Adverse clot architecture in vitro is directly related to impaired endogenous fibrinolysis using a relatively new point-of-care technique in patients with STEMI. This may transform the relevance of fibrin clot architecture from an off-line laboratory association to being directly relevant to endogenous fibrinolysis at the patient bedside, which could be used as a near-patient test to guide prognosis and assess the effect of treatment.Peer reviewedFinal Published versio

Monitoring Vascular Permeability and Remodeling After Endothelial Injury in a Murine Model Using a Magnetic Resonance Albumin-Binding Contrast Agent

Background-Despite the beneficial effects of vascular interventions, these procedures may damage the endothelium leading to increased vascular permeability and remodeling. Re-endothelialization of the vessel wall, with functionally and structurally intact cells, is controlled by endothelial nitric oxide synthase (NOS3) and is crucial for attenuating adverse effects after injury. We investigated the applicability of the albumin-binding MR contrast agent, gadofosveset, to noninvasively monitor focal changes in vascular permeability and remodeling, after injury, in NOS3-knockout (NOS3(-/-)) and wild-type (WT) mice in vivo.Methods and Results-WT and NOS3(-/-) mice were imaged at 7, 15, and 30 days after aortic denudation or sham-surgery. T-1 mapping (R-1=1/T-1, s(-1)) and delayed-enhanced MRI were used as measurements of vascular permeability (R-1) and remodeling (vessel wall enhancement, mm(2)) after gadofosveset injection, respectively. Denudation resulted in higher vascular permeability and vessel wall enhancement 7 days after injury in both strains compared with sham-operated animals. However, impaired re-endothelialization and increased neovascularization in NOS3(-/-) mice resulted in significantly higher R-1 at 15 and 30 days post injury compared with WT mice that showed re-endothelialization and lack of neovascularization (R-1 [s(-1)]=15 days: (-/-)(NOS3)4.02 [interquartile range, IQR, 3.77-4.41] versus (WT)2.39 [IQR, 2.35-2.92]; 30 days: (-/-)(NOS3)4.23 [IQR, 3.94-4.68] versus (WT)2.64 [IQR, 2.33-2.80]). Similarly, vessel wall enhancement was higher in NOS3(-/-) but recovered in WT mice (area [mm(2)]=15 days: (-/-)(NOS3)5.20 [IQR, 4.68-6.80] versus (WT)2.13 [IQR, 0.97-3.31]; 30 days: (-/-)(NOS3)7.35 [IQR, 5.66-8.61] versus (WT)1.60 [IQR, 1.40-3.18]). Ex vivo histological studies corroborated the MRI findings.Conclusions-We demonstrate that increased vascular permeability and remodeling, after injury, can be assessed noninvasively using an albumin-binding MR contrast agent and may be used as surrogate markers for evaluating the healing response of the vessel wall after injury.</p

Sequential occurrence of thrombotic thrombocytopenic purpura, essential thrombocythemia, and idiopathic thrombocytopenic purpura in a 42-year-old African-American woman: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Thrombotic thrombocytopenic purpura and idiopathic thrombocytopenic purpura are two well recognized syndromes that are characterized by low platelet counts. In contrast, essential thrombocythemia is a myeloproliferative disease characterized by abnormally high platelet numbers.</p> <p>The coexistence of thrombotic thrombocytopenic purpura and idiopathic thrombocytopenic purpura in a single patient has been reported in the literature on a few occasions. However, having essential thrombocythemia complicating the picture has never been reported before.</p> <p>Case presentation</p> <p>We present a case where thrombotic thrombocytopenic purpura, essential thrombocythemia, and idiopathic thrombocytopenic purpura were diagnosed in a 42-year-old African-American woman in the space of a few years; we are reporting this case with the aim of drawing attention to this undocumented occurrence, which remains under investigation.</p> <p>Conclusions</p> <p>As the three conditions have different natural histories and require different treatment modalities, it is important to recognize that these diseases may be seen sequentially. This case emphasizes the importance of reviewing peripheral blood smears for evaluation of thrombocytopenia and bone marrow aspirations for diagnosis of thrombocythemia in order to reach an accurate diagnosis and tailor therapy accordingly. Moreover, this case demonstrates the variability and complexity of platelet disorders. This occurrence of three different types of platelet disorders in one patient remains a pure observation on our part; regardless, this does raise the possibility of a common underlying, as yet undiscovered, pathophysiology that could explain the phenomenon.</p

Patient-reported treatment burden of chronic immune thrombocytopenia therapies

<p>Abstract</p> <p>Background</p> <p>Chronic immune thrombocytopenia (ITP) is a debilitating autoimmune disorder that causes a reduction in blood platelets and increased risk of bleeding. ITP is currently managed with various pharmacologic therapies and splenectomy.</p> <p>This study was conducted to assess patient perceived and reported treatment side effects, as well as the perceived burden or bother, and need to reduce or stop treatment, associated with these side effects among adult patients with chronic ITP.</p> <p>Methods</p> <p>A Web-enabled survey was administered to members of a US-based ITP patient support group. Patients reported demographic and clinical characteristics, ITP treatments' side effects for treatments received since diagnosed, level of bother (or distress), and need to reduce or stop treatment, associated with side effects. Current and past exposure was assessed for five specific treatment types: corticosteroids (CS), intravenous immunoglobulin (IVIg), anti-D immunoglobulin (anti-D), rituximab (RT), and splenectomy (SPL), as well as for other patient-referenced therapies (captured as "other").</p> <p>Results</p> <p>The survey was completed by 589 patients; 78% female, 89% white, mean age 48 years (SD = 14.71), and 68% reported a typical low platelet count of < 50,000/μL. Current or past treatment with CS was reported by 92% (n = 542) of patients, 56% (n = 322) for IVIg, 36% (n = 209) for anti-D, 36% (n = 213) for RT, and 39% (n = 227) for SPL. A substantial proportion of CS-treated patients reported side effects (98%, <it>P </it>< 0.05), were highly bothered by their side effects (53.1%, <it>P </it>< 0.05), and reported the need to stop or reduce treatment due to side effects (37.8%, <it>P </it>< 0.05). Among patients reporting side effects of treatment, significant associations were noted for the number of side effects, aggregate bother of reported side effects, and the need to stop or reduce treatment (all <it>P </it>< 0.05).</p> <p>Conclusions</p> <p>Current ITP treatments, particularly corticosteroids, are associated with multiple bothersome side effects that may lead to patients stopping or reducing therapy. Open, informed and complete communication between clinician and patient regarding both the benefits and the side effects of ITP treatment may better prepare patients for their prescribed regimens.</p

Effect of splenectomy on type-1/type-2 cytokine gene expression in a patient with adult idiopathic thrombocytopenic purpura (ITP)

BACKGROUND: In view of clinical observations and laboratory results that support a central role of the spleen in idiopathic thrombocytopenic purpura (ITP) pathophysiology, we studied the effect of splenectomy on type-1 and type-2 cytokine gene expression in an adult ITP case, refractory to conservative treatment. CASE PRESENTATION: The patient was subjected to splenectomy 9 months after the diagnosis with complete response, attaining platelet counts over 150 × 10(6)/L within 10 days after the operation. Two consecutive blood samples were obtained from the patient, 3 and 7 months after the splenectomy for the purposes of this study. A control group consisted of 11 healthy adults. Peripheral blood mononuclear cells were prepared from each blood sample and cultured in vitro for 8 h with the addition of the mitogens phorbol myristate acetate and ionomycin. Total cellular RNA extracted from 10(6 )cells was submitted to semiquantitave reverse transcriptase-polymerase chain reaction (RT-PCR) for the amplification of IL-2, IFN-γ, IL-4, IL-5, and IL-10 metagraphs. The PCR products were run on ethidium-stained agarose gels, photographed and quantified by densitometry. A steep decrease of type-1 cytokine expression (IL-2, IFN-γ) and their calculated sum expressing Th1 activity was observed at 7 months post-splenectomy compared to 3 months post-splenectomy, in parallel with a rise of platelet count from 190 × 10(6)/L to 265 × 10(6)/L. The change of type-2 cytokine expression (IL-4, IL-5, IL-10) was slight and the Th2 activity (IL-4+IL-5) remained largely unchanged. The Th1/Th2 ratio, that reflects the pathogenic disease-specific T-cell immune deviation, was accordingly reduced 7 months post-splenectomy (Th1/Th2 = 1.3) compared to 3 months (Th1/Th2 = 3.5). CONCLUSIONS: The reduction of the Th1/Th2 cytokine ratio that was observed over time after splenectomy was accompanied by full clinical remission. Nevertheless, the persistence of a type-1 polarization, even after several months following spleen removal, is suggestive of a more basic abnormality of the immune function in these patients

Complications of Evans' syndrome in an infant with hereditary spherocytosis: a case report

Hereditary spherocytosis (HS) is a genetic disorder of the red blood cell membrane clinically characterized by anemia, jaundice and splenomegaly. Evans' syndrome is a clinical syndrome characterized by autoimmune hemolytic anemia (AIHA) accompanied by immune thrombocytopenic purpura (ITP). It results from a malfunction of the immune system that produces multiple autoantibodies targeting at least red blood cells and platelets. HS and Evans' syndrome have different mechanisms of pathophysiology one another. We reported the quite rare case of an infant who had these diseases concurrently. Possible explanations of the unexpected complication are discussed