Severe Bleeding Manifestations Research Articles

Hematologic parameters in thrombocytopenic patients with dengue fever

Background: Dengue fever is an endemic disease in Nepal that has shown increasing incidence each passing year. Dengue has a wide range of clinical presentations and laboratory findings. Thrombocytopenia is a common finding in dengue-infected patients along with other findings like leukopenia, lymphocytosis, raised hematocrit, and elevated liver enzymes. Thrombocytopenia is an indicator of disease severity and can lead to severe bleeding manifestations. This study aims to find the association of thrombocytopenia with other hematologic parameters. Materials and methods: This retrospective study enrolled 651 dengue patients tested at Patan Academy of Health Sciences who also underwent complete blood count at presentation. Results: Dengue-infected patients of all age groups with a slight male predominance. Thrombocytopenia was noted in 48.69% of cases. Thrombocytopenia showed a significant association with age (p=0.009), total leukocyte count(p=0.00), and hemoglobin levels (p= 0.015). Conclusions: Thrombocytopenia in dengue patients is frequently encountered. Increasing age, leukopenia, and anemia are factors significantly associated with thrombocytopenia at presentation.

Systemic Antiangiogenic Therapies for Bleeding in Hereditary Hemorrhagic Telangiectasia: A Practical, Evidence-Based Guide for Clinicians.

Management of bleeding in hereditary hemorrhagic telangiectasia (HHT), the second most common hereditary bleeding disorder in the world, is currently undergoing a paradigm shift. Disease-modifying antiangiogenic therapies capable of achieving durable hemostasis via inducing telangiectasia regression have emerged as a highly effective and safe modality to treat epistaxis and gastrointestinal bleeding in HHT. While evidence to date is incomplete and additional studies are ongoing, patients presently in need are being treated with antiangiogenic agents off-label. Intravenous bevacizumab, oral pazopanib, and oral thalidomide are the three targeted primary angiogenesis inhibitors, with multiple studies describing both reassuring safety and impressive effectiveness in the treatment of moderate-to-severe HHT-associated bleeding. However, at present there is a paucity of guidance in the literature, including the published HHT guidelines, addressing the practical aspects of antiangiogenic therapy for HHT in clinical practice. This review article and practical evidence-based guide aims to fill this unaddressed need, synthesizing published data on the use of antiangiogenic agents in HHT, relevant data for their use outside of HHT, and expert guidance where evidence is lacking. After a brief review of principles of bleeding therapy in HHT, guidance on hematologic support with iron and blood products, and alternatives to antiangiogenic therapy, this article examines each of the aforementioned antiangiogenic agents in detail, including patient selection, initiation, monitoring, toxicity management, and discontinuation. With proper, educated use of antiangiogenic therapies in HHT, patients with even the most severe bleeding manifestations can achieve durable hemostasis with minimal side-effects, dramatically improving health-related quality of life and potentially altering the disease course.

Haemoptysis in Pulmonary Arterial Hypertension Associated with Congenital Heart Disease: Insights on Pathophysiology, Diagnosis and Management.

Haemoptysis represents one of the most severe major bleeding manifestations in the clinical course of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). Accumulating evidence indicates that dysfunction of the pulmonary vascular bed in the setting of PAH predisposes patients to increased hemorrhagic diathesis, resulting in mild to massive and life-threatening episodes of haemoptysis. Despite major advances in PAH targeted treatment strategies, haemoptysis is still correlated with substantial morbidity and impaired quality of life, requiring a multidisciplinary approach by adult CHD experts in tertiary centres. Technological innovations in the field of diagnostic and interventional radiology enabled the application of bronchial artery embolization (BAE), a valuable tool to efficiently control haemoptysis in modern clinical practice. However, bleeding recurrences are still prevalent, implying that the optimum management of haemoptysis and its implications remain obscure. Moreover, regarding the use of oral anticoagulation in patients with haemoptysis, current guidelines do not provide a clear therapeutic strategy due to the lack of evidence. This review aims to discuss the main pathophysiological mechanisms of haemoptysis in PAH-CHD, present the clinical spectrum and the available diagnostic tools, summarize current therapeutic challenges, and propose directions for future research in this group of patients.

Identification By Whole Exome Sequencing of the Molecular Defect in a Novel Gene Related to Glycosylation in Two Unrelated Families with Syndromic Macrothrombocytopenia

IntroductionInherited thrombocytopenias (ITs) are a heterogeneous group of rare platelet disorders. which lead not only to increased bleeding, but also to syndromic forms. ITs are caused by genetic alterations in megakaryopoiesis-related genes. In the last years, whole-exome sequencing (WES) has allowed the identification of novel genes involved in IT.AimTo perform the molecular, clinical and platelet characterization of two unrelated families with syndromic IT, to unveil the underlaying alteration leading to the disease. To explore the functional role of the identified alterations during megakaryocytic (Mk) differentiation.MethodsWES was performed in two unrelated non-consanguineous families with lifelong severe macrothrombocytopenia (MCT), bleeding, and extra-hematological manifestations. Bleeding score (BS) was recorded by ISTH-BAT. Platelet phenotyping included platelet count (P), blood film, aggregometry (LTA) and flow cytometry (FC). UDP-galactose-4-epimerase enzymatic activity was measure by HPLC/MS/MS. In vitro functional studies were performed through overexpression of GALE genetic variants in human K562 cell line to elucidate its role in Mk differentiation, by measuring cell ploidy and expression of CD41, CD61 and CD42b surface markers after 7-days of PMA treatment.ResultsFamily pedigrees are shown in Figure 1. Three patients (A.II.1, A.II.2 and B.II.1) were referred due to lifelong severe MCT and moderate-severe bleeding tendency (Figure 1). Moreover, they presented mental retardation, mitral insufficiency, and increased bilirubin levels. Blood film revealed enlarged, giant, and grey platelets (A.II.1: 36%, 6% and 54%, respectively; A.II.2: 56%, 4%, 34%, respectively; B.II.1: 32%, 46%, 12%).LTA showed moderate/severe impaired aggregation with ADP, TRAP-6, CRP, epinephrine, arachidonic acid, and ristocetin. FC confirmed null secretion of alpha and dense granules in A.II.1, A.II.2 and reduced levels in B.II.1 (7.8%, 8.1%, 28.3% respectively, vs. 51.7% control platelets with ADP 10µM; 10.8%, 7.8%, 36.7% respectively, vs. 95.6% control platelets with TRAP6 25µM).WES revealed that both pedigrees carried compound heterozygous variants in GALE (NM_001127621.2): c.230_231insTGTT; p.Lys78Valfs*32 (exon 3), and c.449C>T; p.Thr150Met (exon 5) in A.II.1 and A.II.2 patients; and, c.668T>C, p.Leu223Pro (exon 7), and c.382G>A, p.Val128Met (exon 5) in B.II.1 (Figure 1). Enzymatic activity of the GALE-encoded protein UDP-galactose-4-epimerase was severely reduced in the affected patients: both A.II.1, A.II.2 patients had 1.3 μmol/h/g hemoglobin (control: 8.8 μmol/h/g hemoglobin), and B.II.1 patient had 0.6 μmol/h/g hemoglobin (control: 8 μmol/h/g hemoglobin).Furthermore, in vitro overexpression assays between wild-type GALE and p.Thr150Met, p.Leu223Pro and p.Val128Met variants, confirmed a delayed maturation of Mks upon PMA treatment (at 3, 5 and 7 days). characterized by a significant reduction in the expression of the megakaryocytic surface markers CD41, CD61 and CD42b.ConclusionWES has allowed us to identify pathogenic variants in GALE, which were associated with syndromic IT characterized by severe macrothrombocytopenia. Patients harboring these pathogenic variants presented moderate to severe bleeding tendency associated with cardiovascular and neurological abnormalities. Regarding the platelet phenotype, the presence of giant and grey platelets and the absence of both platelet granules were the most remarkable features reported. Moreover, these GALE variants led to an alteration in in vitro Mk maturation, supporting the thrombocytopenic phenotype observed in patients.FundingISCIII (PI17/01966, PI 17/01311, PI20/00926), GRS (GRS2061A/19, GRS2135/A/2020), Fundación Séneca (19873/GERM/15), Fundación Mutua Madrileña (AP172142019), Premio López Borrasca (2019), Grupo Trabajo Patología Hemorrágica-SETH (2020). [Display omitted] DisclosuresHernández-Rivas: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Prothrombin “Carmel”: Identification of a Novel Homozygous Mutation in the Prothrombin Gene Causing Coagulation Factor II Deficiency and Inherited Bleeding Disorder in an Israeli Arab Family

Congenital prothrombin deficiency, also known as hypoprothrombinemia is a rare autosomal recessive disorder characterized by severe bleeding manifestations and decreased prothrombin antigen levels below 10% activity of normal. Dysprothrombinemia, which is characterized by normal antigen levels but a dysfunctional prothrombin molecule, shows a more variable level in bleeding tendency, and there is often a good correlation between the levels of prothrombin activity and clinical severity. We have studied a large consanguineous family of thirteen members contains two patients with a prolonged protrombine time (PT) and activated partial thromboplastin time (aPTT) with prothrombin activity of 11%. DNA was isolated from leukocytes and the thrombin exons were amplified by polymerase chain reaction and sequenced. Exon 14 revealed a point mutation in the codon of Tyrosine 560 which is substituted by Histidine (Tyr560His). Mutation at this residue most probably distorts the structure of the peptidase catalytic domain. The variation segregated as expected in the family, it did not appear in dbSNP, EVS or the 1000 genome project. Further investigation is needed to determine the antigen level and to elucidate the potential effect of the mutation on the structure and the activity of the enzyme. This prothrombin is designated as Prothrombin “Carmel”. DisclosuresNo relevant conflicts of interest to declare.

Severe Hemophilia A in a Patient with Sexual Differentiation Disorder: A Case Report

Hemophilia A is an inherited X-linked disease where the VIII Factor (FVIII) production is altered, causing hemorrhagic diathesis. It can be classified into mild, moderate or severe, depending on the levels of circulating FVIII. It is suffered by males with an incidence of 1 in 5000 live births. Women are carriers, and they transmit the mutation in 90% of the cases, whereas 10% are de novo mutations. Females are usually asymptomatic, showing normal or intermediate FVIII factor, although it is estimated that 1 in 100.000 carriers will show severe bleeding manifestations due to FVIII severe deficit. For this to occur, some of the following physiopathologic mechanisms should be present: 1) heterozygous compound mutations affecting both alleles of the FVIII; 2) Homozygous mutations; 3) Extreme lionization of all the normal X chromosomes; 4) Numerical or structural alterations of the X chromosomes, as in Turner´s syndrome; 5) Genetical mutation in a patient with XY genotype and female phenotype.The objective of this report is to describe the case of a girl with severe Hempohilia A and XY cariotype.Case report:A 2-year-old female patient presented to consultation, with no remarkable previous perinatal history nor family history of hematologic diseases, referred due to spontaneous hematomas and bleeding events of difficult medical management with a 4 ISTH score. Coagulation studies were performed, showing a FVIII level of less than 1%, with the rest of the blood parameters being normal. Coagulation studies of the mother showed FVIII levels of 30%, Von Willebrand antigen of 59% and ristocetin cofactor of 43%. The genetic analysis of both the child and mother informed a type I inversion of the 22 intron. A karyotype analysis of the patient is done. She is phenotypically a female, but she has a 46XY genotype. At present she is being studied to rule out if the sexual differentiation disorder is due to the lack of SRY gen (Swyer´s syndrome) or to insensitivity to androgens (Morris´syndrome).From the moment of the diagnosis, the patient started prophylaxis with recombinant FVIII factor, not showing complications.DiscussionThe severe manifestations of the X linked diseases are infrequent in females. Approximately 30% of the carriers of hemophilia have an activity of the FVIII of less than 40%, with the consequent risk of bleeding. The most common cause for this is the selective inactivation of the normal X chromosome, that usually occurs in a balanced and randomized fashion. The diagnosis of hemophilia is made based on the FVIII activity dosage, and is confirmed with the molecular study of the mutations of the gene. In asymptomatic carriers, the status of homozygous or heterozygous mutation must be determined.Similarly, it is important to know what is the patient´s karyotype, because although its frequency is low, the disease can be the result of a sexual differentiation disorder, as it is the case presented here, or a chromosomopathy. In both cases is important to follow up the patient interdisciplinary with endocrinology, to treat the hormonal disorders related to each situation.ConclusionIt is of paramount importance to obtain a complete clinical and molecular diagnosis, to perform a correct treatment and follow up, and also offer an adequate genetic counseling. DisclosuresNo relevant conflicts of interest to declare.

Pediatric systemic lupus erythematosus with lupus anticoagulant hypoprothrombinemia syndrome—A case series with review of literature

Lupus anticoagulant hypoprothrombinemia syndrome (LAHPS) is a rare phenomenon that leads to concomitant thrombosis and hemorrhage in children with SLE. LAHPS in pediatric SLE (pSLE) has a protracted course requiring long-term immunosuppressive therapy. Due to the rarity of this syndrome and paucity of reported cases, there is lack of standardized management. We herewith report 5 children with pSLE with LAHPS.Methodology: We retrospectively reviewed clinical features, laboratory features, treatment and outcome for 5 children with lupus anticoagulant hypoprothrombinemia syndrome with SLE and a review of literature of similar cases published. Mean age of presentation was 10.2 ± 2.38 years (mean ± SD) and female to male ratio was 4:1. All children presented with mild to severe bleeding manifestations like gum bleed, epistaxis, hematuria, menorrhagia and subarachnoid bleed. Coagulation profile revealed prolonged PT and aPTT, with low prothrombin levels and positive Lupus anticoagulant in all children. Mixing studies were characteristic in these children. On comparing laboratory parameters majority had low C3, C4 levels, ANA and anti-DsDNA antibody positivity and three children had anticardiolipin positivity. One child had lupus nephritis along with LAHPS at presentation. All responded well to steroids and supportive measures. High index of suspicion is needed when child with lupus presents with bleeding manifestations for early diagnosis and treatment.

Traitements de première ligne au cours du purpura thrombopénique immunologique de l'adulte : état des lieux et perspectives

The first line treatment of immune thrombocytopenic purpura (ITP) is well established and based on short course of corticosteroids associated with intravenous immunoglobulins (IVIg) for the most severe forms. Predniso(lo)ne is the corticosteroid agent usually given but dexamethasone appears as an alternative. Some guidelines recommend to use dexamethasone as first line when a rapid increase of platelet count is required. Dexamethasone could be used rather than IVIg for moderate to severe but non life-threatening bleeding manifestations. Other therapeutic options such as anti FcRn monoclonal antibodies or recombinant FcγR currently in development for ITP could be an option in the future. In newly diagnosed ITP, we unfortunately lack robust predictive risk factors of severity and chronic outcome. Identifying such factors could be helpful for considering the early use of some treatments which are commonly used as second or third line.

Clustering of Bleeding Symptoms in Patients Previously Diagnosed As Type 3 Von Willebrand Disease: Results from a Large Cohort of Type 3 Von Willebrand Disease (the 3Winters-Ips Project)

Clustering of Bleeding Symptoms in Patients Previously Diagnosed As Type 3 Von Willebrand Disease: Results from a Large Cohort of Type 3 Von Willebrand Disease (the 3Winters-Ips Project)

Clinical and diagnostic features of dengue haemorrhagic fever in children

Background: Diagnosis of dengue hemorrhagic fever (DHF) in children is based on clinical suspicion and prompting laboratory criteria.Methods: This prospective study in children (6 months-14 years) presenting with features of DHF aimed to identify symptoms and signs, laboratory parameters for in early detection and assessed the association between clinical, laboratory, immunological parameters and outcome.Results: Of 50 children, 26 were females, mean±SD age was 8.3±3.02 years; age group 8-12 years were affected the most (38.0%) and infants the least (4.0%). Fever (100%), followed by skin rash (56.0%), myalgia (52.0%) and head ache (48.0%) were the symptoms. Fever of 4-5 days (52.0%), high grade fever (84.0%) and of sudden onset (76.0%) were common. Ascitis was seen in nine. Peteche and malena (48.0%) were predominant manifestation of bleeding tendency (100%). Positive tourniquet test (48.0%) did not correlate with bleeding tendency. Lower levels of Hemoglobin (<12gms%, 100%), hematocrit (<40%, 98.0%), platelet count (<100000/mm3, 100%), serum albumin (76.0%), and abnormal liver enzymes (64.0%) along with prolonged prothrombin time (44.0%) and aPTT (18.05%) were noted. Ultrasound abdomen confirmed Pleural effusion (52.0%), ascitis (22.0%), Hepatomegaly (68.0%). Mean detection time was 4 days. Positive dengue IgM and IgG (60.0%), IgM (16%), and IgG (24%) were observed with increase of IgM in early phase.Conclusions: lower platelet count, raising haematocrit, increased liver enzymes with low serum albumin levels are early indicators. Prolonged PT and APTT are associated with severe bleeding manifestations. Apart from clinical expertise, chest X-ray, abdominal ultrasonogram are useful diagnostic tools.

A Multicenter Study Evaluating the Safety of Romiplostim at Maximal Dosage for Emergency Bleeding Situations in Immune Thrombocytopenia

Introduction: The serious consequences of severe, life-threatening bleeding in immune thrombocytopenia (ITP) justify the use of several regimens, including platelet transfusions, high-dose parenteral glucocorticoid and intravenous immunoglobulins. The goal of such treatments is to rapidly elevate the platelet count to a level where the risk of severe bleeding is minimized. We lack experience with the use of thrombopoetin receptor agonists (Tpo-RAs) in this situation of emergency. The aim of this study was to evaluate the safety of the use of romiplostim at maximal dosage in patients with severe bleeding manifestations, who have previously failed to respond to corticosteroids (CST) and intravenous immunoglobulin (IVIg).Patients and Methods: We carried out a multicenter retrospective study in France. We included ITP patients with platelet count < 30 x 109/L.and severe bleeding manifestations, who have failed to respond to corticosteroids and IVIg, and have received a rescue therapy with romiplostim at maximal dosage (ie., 10 mg/kg body weight per week). Failure to treatment was defined according to standardized international criteria and severe bleeding manifestations as a score >8 according to the bleeding score previously reported by our group that take into account cutaneous, mucosal and visceral bleeding. Physicians were interviewed and patients’ medical charts collected using the standardized form of the Referral Center for Adult ITP. Complete response (CR) and Response (R) were defined according to standardized international criteria: platelet count > 30x109/L with at least a doubling of the baseline value or >100 x109/L. Non-response (NR) was defined as the absence of platelet count increase >30 x109/L with at least a doubling of the baseline count.Results: Fifteen patients (8 men/7 women) were included in the study. The median age was 68 ± 20.9 years [range 17-92]. Two patients presented secondary ITP according to the international definition criteria. Eleven were newly diagnosed ITP, and 4 chronic ITP. Severe bleeding symptoms were the manifestation of ITP in all cases, with a median bleeding score of 16 [9-28], including 4 intracranial hemorrhage, 2 metrorrhagia, 1 macroscopic hematuria, 3 gastrointestinal bleeding and 1 haemoperitoneum. The median platelet count was 1 [0-4]. All patients had received corticosteroids (1mg/bw/day) including 12 pulses of methylprednisolone and IVIg (median dose 2 g/bw). Twelve have also received 8 mg of vinblastine (1 to 3 injections). Nine received platelet transfusions and 4 received blood tranfusions. One patient had received anti-CD20 therapy (rituximab) the same day as TPO-RA therapy, and another hydroxychloroquine before starting TPO-RA therapy. Romiplostim was started 12 days [range 6-32] in median after the first bleeding episode. At that time bleeding symptoms were severe (>8), and the median platelet count was 4 [1-47]. All received 10 mg/kg body weight of romiplostim (including 3 escalating dose). At day 7 after TPO-RA initiation, 9 patients achieved a CR, 1 patient achieved a R and 5 were still non-responder. At days 14, 10 patients achieved a CR and 5 were still non-responder. During the first month of follow-up, the maximal platelets count among the responders was 590 [range: 312-1169], 9 patients experienced a platelet count > 500 x 109/L. One 51 years old patient, bed bound for a muscular hematoma, experienced a deep vein thrombosis with asymptomatic pulmonary embolism, 13 days after IVIg and 5 days after TPO-RA initiation, with a platelet count of 629.109/L. One patient presented superficial thromboembolism of the arm, 14 days after IVIg and 9 days after TPO-RA initiation with a platelet count of 162.109/L. They were both treated with anticoagulation without complication. After a median follow-up of 10 months, no other TPO-RA-related side effects were observed, TPO-RA was discontinuated in 10 patients.Conclusion: Our study demonstrated the relative safety and the interest of the use of romiplostim at the maximal dose in emergency bleeding situation in patients with failure of conventional therapy. However, risk of venous thromboembolism should be carrefully assess in this situation. DisclosuresTerriou:amgen: Consultancy; Novartis: Consultancy.

United Kingdom Experience of Intracranial Bleeds in Childhood Immune Thrombocytopenia

Childhood immune thrombocytopenia (ITP) is an uncommon disease that is usually self-limiting and resolves spontaneously without treatment. Less than 1% of children with ITP will develop an intracranial haemorrhage (ICH). The aim of this project was to review data from all available cases of ICH and identify features associated with an increased risk of intracranial bleeding. The data were obtained from three main resources: patient notes, the UK ITP Registry and surveys sent out to centres across the UK. 19 cases were reviewed, occurring over a period of 12 years from 2004 to 2016.Platelet counts below 20x109/L were associated with severe bleeding, as were moderate or severe bleeding manifestations beyond cutaneous bleeding in the 28 days leading up to an ICH. Patient comorbidity was also reviewed and a significant number of patients had co-existing issues, including positive autoantibody tests. Presentations of ICH varied. In 10 patients, headache was a presenting feature. 3 patients presented with seizures, and 5 with vomiting. The majority of patients also had at least one active bleeding site in the 28 days before the episode of ICH. The mouth and nose were the most common bleeding sites. The mortality rate was 4/19, 21%. Neurological disability on discharge was present in 4/15, 27% of the patients who survived. Most identified risk factors for ICH were consistent with previous research, however none had an arteriovenous malformation and only three of 19 cases were documented to have experienced head trauma prior to ICH. Based on UK ITP registry data the incidence of ICH is estimated to bet 0.14-0.57% of paediatric ITP patients. DisclosuresGrainger:Amgen: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bolton-Maggs:Novartis: Honoraria; Grifols: Honoraria.

Combined variants in factor VIII and prostaglandin synthase‐1 amplify hemorrhage severity across three generations of descendants

Background Inherited human variants that concurrently cause disorders of primary hemostasis and coagulation are uncommon. Nevertheless, rare cases of co-existent damaging variants are likely to cause more severe bleeding and may go undiagnosed. Objective We prospectively sought to determine pathogenic variants in a three-generational pedigree with excessive bleeding. Patients/methods Platelet number, size and light transmission aggregometry to multiple agonists were evaluated in pedigree members. Transmission electron microscopy determined platelet morphology and granule content. Thromboxane release studies and light transmission aggregometry in the presence or absence of prostaglandin G2 assessed specific functional defects in the arachidonic acid pathway. Whole exome sequencing (WES) and targeted nucleotide sequence analysis identified potentially deleterious variants. Results Pedigree members with excessive bleeding had impaired platelet aggregation with arachidonic acid, epinephrine and low-dose ADP, as well as reduced platelet thromboxane B2 release. Impaired platelet aggregation in response to 2MesADP was rescued with prostaglandin G2 , a prostaglandin intermediate downstream of prostaglandin synthase-1 (PTGS-1) that aids in the production of thromboxane. WES identified a non-synonymous variant in the signal peptide of PTGS-1 (rs3842787; c.50C>T; p.Pro17Leu) that completely co-segregated with disease phenotype. A variant in the F8 gene causing hemophilia A (rs28935203; c.5096A>T; p.Y1699F) was also identified. Individuals with both variants had more severe bleeding manifestations than characteristic of mild hemophilia A alone. Conclusion We provide the first report of co-existing variants in both F8 and PTGS-1 genes in a three-generation pedigree. The PTGS-1 variant was associated with specific functional defects in the arachidonic acid pathway and more severe hemorrhage.

Characteristics of Patients with Crimean-Congo Haemorrhagic Fever in an Outbreak in Saurashtra region of Gujarat, India in 2013

Background:CCHF (Crimean Congo Hemorrhagic Fever) is a severe fatal viral hemorrhagic fever similar to dengue fever but having potential to cause Nosocomial spread. CCHF virus belongs to RNA virus of Bunyaviridae family and its get transmitted by Hyalomma tick. Viral Illness presents as fever, severe body ache and bleeding manifestations along with thrombocytopenia, altered coagulation profiles and Liver Function Test. Ribavirin, antiviraldrug, if given in early stage may increases survival significantly. Aims: 1) To Study Clinical, Pathological & Biochemical parameters in patients of CCHF 2) To Study the efficacy of Oral Ribavirin in CCHF. Materials and Methods:This retrospective study included 10(ten) patients of RT-PCR confirmed CCHF admitted in Tertiary care teaching hospital of Gujarat, India. Their Clinical Parameters and laboratory finding studied on day to day basis. Oral Ribavirin given to 8 patients as 2 patients died before diagnosis of CCHF established. Results: Almost all patients have had fever of short duration with most having bleeding manifestation with marked thrombocytopenia, altered PT &aPTT, decreased plasma fibrinogen and elevated FDP with mild to modest elevation in liver enzymes .Out of 8 patients who received ribavirin, only one died. Conclusion: Oral ribavirin is to be started empirically in any patients involved in animal husbandry activity and develops acute hemorrhagic febrile illness in which tests for malaria and dengue are negative.

Antiphospholipid syndrome in a pregnant female presenting with severe thrombocytopenia and bleeding.

The antiphospholipid antibody syndrome (APS) is defined by the persistent presence of antiphospholipid antibodies in patients with recurrent venous or arterial thromboembolism or pregnancy morbidity. Antithrombotic therapy is the mainstay of treatment given the high risk of recurrent thromboembolism that characterizes this condition. Despite the prothrombotic nature of APS, thrombocytopenia is present in a proportion of patients, which can complicate management and limit the use of antithrombotic therapy. The mechanism of APS-associated thrombocytopenia is multifactorial and its relation to thrombotic risk is poorly characterized. The presence of thrombocytopenia does not appear to reduce thrombotic risk in patients with APS, who can develop thromboembolic complications necessitating antithrombotic treatment. In these cases, treatment of the thrombocytopenia may be necessary to facilitate administration of antithrombotic agents. We present such a pregnant lady with history of recurrent pregnancy losses who presented with severe thrombocytopenia and bleeding manifestations, who was subsequently diagnosed to have antiphospholipid antibody syndrome. She was initially managed with steroids and when her platelet counts improved, antithrombotic therapy was started. She delivered an uneventful and successful pregnancy outcome without any complications during follow-up.

Defects in Glanzmann thrombasthenia and LAD-III (LAD-1/v) syndrome: the role of integrin β1 and β3 in platelet adhesion to collagen

AbstractPatients with Glanzmann thrombasthenia or Leukocyte Adhesion Deficiency-III syndrome (LAD-III or LAD-1/variant) present with increased bleeding tendency because of the lack or dysfunction of the fibrinogen receptor GPIIb/IIIa (integrin αIIbβ3), respectively. Although the bleeding disorder is more severe in LAD-III patients, classic aggregometry or perfusion of Glanzmann or LAD-III platelets over collagen-coated slides under physiologic shear rate does not discriminate between these 2 conditions. However, in a novel flow cytometry-based aggregation assay, Glanzmann platelets were still capable of forming small aggregates upon collagen stimulation, whereas LAD-III platelets were not. These aggregates required functional GPIa/IIa (integrin α2β1) instead of integrin αIIbβ3, thus explaining the clinically more severe bleeding manifestations in LAD-III patients, in which all platelet integrins are functionally defective. These findings provide genetic evidence for the differential requirements of platelet integrins in thrombus formation and demonstrate that correct integrin function assessment can be achieved with a combination of diagnostic methods.

Homozygous F5 deep‐intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet‐rich plasma

Coagulation factor (F) V deficiency is associated with a bleeding tendency of variable severity, but phenotype determinants are largely unknown. Recently, we have shown that three patients with undetectable plasma FV and mild bleeding symptoms had sufficient residual platelet FV to support thrombin generation in platelet-rich plasma (PRP). Therefore, we hypothesized that FV-deficient patients with severe bleeding manifestations may lack platelet FV. To characterize a FV-deficient patient with a severe bleeding diathesis. We performed FV mutation screening and functional studies in a 31-year-old male (FV:C < 1%) with umbilical bleeding at birth, recurrent hemarthrosis and muscle hematomas, and a recent intracranial hemorrhage. The proband was homozygous for a deep-intronic mutation (F5 IVS8 +268A→G) causing the inclusion of a pseudo-exon with an in-frame stop codon in the mature F5 mRNA. Although platelet FV antigen was detectable by immunoprecipitation followed by Western blotting, no FV activity could be demonstrated in the proband's plasma or platelets with a prothrombinase-based assay. Moreover, no thrombin generation was observed in PRP triggered with 1-50 pm tissue factor (even in the presence of platelet agonists), whereas an acquired FV inhibitor was excluded. Clot formation in the proband's whole blood, as assessed by thromboelastometry, was markedly delayed but not abolished. This is the first report of a pathogenic deep-intronic mutation in the F5 gene. Our findings indicate that the minimal FV requirement for viability is extremely low and suggest that thrombin generation in PRP may predict bleeding tendency in patients with undetectable plasma FV.

Thrombocytopenic Purpura after Measles-Mumps-Rubella Vaccination: A Systematic Review of the Literature and Guidance for Management

To determine the incidence of immune thrombocytopenic purpura (ITP) after measles-mumps-rubella (MMR) immunization compared with natural measles and rubella, its clinical course and outcome, and the risk of recurrence after repeat MMR vaccination. We performed a systematic review of the Ovid MEDLINE (1950 to present) bibliographic database. We selected studies that reported cases of thrombocytopenia in a known number of children who were immunized with MMR vaccine before development of ITP. We also extracted data from the same and other studies regarding bleeding manifestations and the resolution of MMR-associated thrombocytopenia or thrombocytopenic purpura within 6 months. Finally, we studied the risk of ITP recurrence after MMR immunization or reimmunization. On the basis of 12 studies, the incidence of MMR-associated ITP ranged from 0.087 to 4 (median 2.6) cases per 100,000 vaccine doses. Severe bleeding manifestations were rare, and MMR-associated thrombocytopenia resolved within 6 months from diagnosis in 93% of the children. MMR vaccination of unimmunized patients with ITP and revaccination of patients with prior ITP did not lead to recurrence of thrombocytopenia. MMR-associated ITP is rare, self-limited, and non-life threatening, and susceptible children with ITP should be immunized with MMR at the recommended ages.

Bleeding Manifestations and Management of Children with Persistent and Chronic Immune Thrombocytopenia (ITP): Data From the Intercontinental Cooperative ITP Study Group.

Abstract 1315Poster Board I-339ITP during childhood is generally characterized by acute onset of thrombocytopenia and bleeding in an otherwise well child. While the platelet count has traditionally been viewed as a marker of disease severity, additional patient characteristics such as bleeding severity have not been well defined. The Intercontinental Cooperative ITP Study Group (ICIS) Registry II was designed to characterize the location, frequency, timing, and severity of bleeding in children with ITP (Blood, 2008;112: 4003-8). We report here data from Registry II with a focus on bleeding symptoms reported at 6 and 12 months. Patients enrolled on Registry II had research visits at diagnosis, and 28 days, 6 months, 12 months, and 24 months following diagnosis. Bleeding manifestations were retrospectively recorded at 6 and 12 months capturing all sites of bleeding (e.g skin, epistaxis, and gastrointestinal) since the last research visit. Of the 1318 children enrolled at diagnosis, 891 were evaluated at 6 months and 718 at 12 months. Mean platelet counts were 198 × 109/l (s.d. 130) and 195 × 109/l (s.d.122) at 6 and 12 months respectively. At 6 months 29% (261/891) of patients still had a platelet count <100 × 109/l; of these 45% (118/261) were <30 × 109/l. At 12 months these values were 28% (203/718) and 40% (82/203) respectively. Number of bleeding sites reported since the last research visit at 6 months and 12 months are outlined in Table 1. There were no reports of intracranial hemorrhage (ICH) or fatal hemorrhage. The most common bleeding site reported at both 6 and 12 months was skin, followed by epistaxis. 4 children with a platelet count <30 × 109/l at both 6 and 12 months were reported as having undergone splenectomy. Red cell transfusions were infrequent (3 reported) and administered only in children with bleeding from ≥ 3 sites. The percentage of patients with a platelet count <30 × 109/l who received platelet count enhancing therapy (including platelet transfusions) is outlined in Table 2.Table 1Number of bleeding sites reported since last research visit at 6 and 12 months6 month visit12 month visitNumber of sitesPlatelet count <100 × 109/l (n= 261)Platelet count <30 × 109/l (n= 118)Platelet count <100 × 109/l (n= 203)Platelet count <30 × 109/l (n= 82)None60 (23%)10 (9%)74 (36%)16 (19%)1110 (42%)44 (37%)82 (40%)33 (40%)261 (23%)39 (33%)32 (16%)21 (26%)3330 (12%)25 (21%)15 (7%)12 (15%)Table 2Patients with platelet count <30 × 109/l reported as having received platelet count enhancing therapyNumber of bleeding sites reported between research visitsTreatment reported between 28 days and 6 months (n = 118)Treatment reported between 6 and 12 months (n = 82)None1/10 (10%)4/16 (8%)129/44 (66%)19/33 (58%)3258/64 (91%)26/33 (78%)In summary, approximately 30% of children with ITP enrolled on ICIS Registry II remain thrombocytopenic 6 and 12 months later, many still having a platelet count <30 × 109/l, a threshold value sometimes used to determine drug treatment and enrollment in prospective intervention studies. This cut-off may be appropriate since bleeding was more common when the platelet count was <30 × 109/l. However, even below this threshold life-threatening hemorrhage was uncommon, few patients required packed red blood cell transfusions, and approximately half the patients reported no more than one site of bleeding. Treatment was infrequently used in patients in this group if they had no bleeding, and platelet enhancing therapy was often employed if more bleeding sites were involved. These data suggest a trend towards reserving treatment for patients with more severe bleeding manifestations rather than because of a specific platelet count. DisclosuresBuchanan:AMG 531: Research Funding. Bolton-Maggs:Baxter: Travel support to meetings; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; United Kingdom Immune Thrombocytopenic Pupura Support Association: Research Funding; Glaxo Smith Kline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blanchette:AMG 531: Membership on an entity's Board of Directors or advisory committees. Kuehne:F. Hoffman-La Roche Ltd: Research Funding; Amgen: Research Funding.

Characteristics of Sarcoidosis-Associated Immune Thrombocytopenia: a Consecutive Study of 20 Cases.

Abstract 2407Poster Board II-384 Introduction:Although sarcoidosis is far from being a classical cause of secondary-immune thrombocytopenic purpura (ITP), isolated thrombocytopenia may occur during the course of the disease. To better assess the main characteristics and outcome of patients with a sarcoidosis-associated ITP, a survey was initiated throughout the French study group on sarcoidosis and the national referral center for adult's immune cytopenias. The data of the 20 first cases are reported. Patients and Methods:To be included, all patients had to fulfil the following criteria: 1) Definite diagnosis of sarcoidosis according to the standard international criteria (Am J Respir Crit Care Med 1999; 736-55) and 2) Presence of an immune thrombocytopenia according to the ASH criteria twith platelet count below 100 × 109/L on at least two separate occasions 2 weeks. Drug-induced thrombocytopenia were excluded as well as patients with a hypogammaglobulinemia suggesting a underlying common variable immunodeficiency (CVI) and thrombocytopenia related to hypersplenism. All clinical and biological data were reviewed and analyzed by the same investigator by using a standard form. A complete response (CR) was defined as sustained (> 3months) platelet count > 100 × 109/L with at least a twofold increase for baseline. A partial response (PR) was defined as a platelet count 30×109/L or more and at least twice the initial value. Results:Twenty patients (50% men) were included. Median age at ITP diagnosis was 37.5 years (21 to 83) and median age at sarcoidosis diagnosis was 36 yrs (10 to 83). In 4 patients, ITP preceded the diagnosis of sarcoidosis (median: 67.5 months; 15 to 153). In 11 patients (55%), ITP occurred in the course of prior diagnosed sarcoidosis with a median of 48 mths (6 to 216), and concomitantly with the diagnosis of sarcoidosis in 5 patients (25%). In 13 patients (65%), an active localization of sarcoidosis was present at the diagnosis of ITP. Median platelet count at onset was 11×109/L (3 to 90) and nadir platelet count was 10×109/L (1 to 60). Seven patients (35%) had severe (mucosal) bleeding manifestations and a bleeding score ≥ 8 (described by Khellaf et al). Regarding sarcoidosis, during the follow up, 17 patients (85%) had thoracic involvement, and an extra-thoracic involvement was found in 14 patients (70%) including: eye (n=7), liver (n=5), sinus (n=4), peripheral lymph nodes (n=4), skin (n=3), salivary gland (n=2), spleen (n=1) and kidney (n=1).Nineteen out of the 20 patients were treated specifically for their secondary ITP. After the first line therapy (prednisone at 1mg/kg/day for at least 3 consecutive weeks in all patients associated with IVIg in 10 patients), 12/19 (63%) patients achieved a complete response (CR), 6 a partial response (PR) (32%) and only 1 patient failed to respond. The course of ITP was chronic in 4 patients, among them 2 underwent splenectomy and achieved a CR and 2 were treated with Rituximab (375mg/m2, 4 infusions) and achieved a PR at one year. After a median follow up of 70 months (12 to142), 18 patients (90%) were in CR and 2 in PR with chronic ITP. Eight patients were in remission off therapy whereas 12 patients (60%) were still on corticosteroids at time of analysis with a median dose of 10mg/day (5 to 30). During the follow-up period, 11 patients (55%) had a relapse or flare of sarcoidosis (intra thoracic in 5 patients, extra-thoracic in 6 patients). In 2 patients, a simultaneous relapse of both sarcoidoisis and associated-ITP was observed. Comments:Our preliminary data suggest that the association of sarcoidosis and ITP is not fortuitous and that sarcoidosis should be considered as a potential cause of secondary ITP. ITP in this setting is frequently initially severe and symptomatic and therefore requiring treatment. The overall response rate to treatments commonly used in primary ITP is however good and the long term outcome is favorable suggesting that patients with sarcoidosis-associated ITP should be managed as patients with primary ITP. In contrast, relapse of sarcoidosis is frequent and frequently affect extra-thoracic sites. That a majority of the patients had an active and/or relapsing sarcoidosis during the course of ITP suggests that granuloma may be a predisposing condition for triggering autoimmunity and especially ITP as observed in some cases of CVI-associated immune thrombocytopenia. Disclosures:No relevant conflicts of interest to declare.