RESUMEN
Disease relapse is recognized as a risk in immune-mediated thrombotic thrombocytopenic purpura (iTTP) after treatment of the acute presenting episode. Identification of patients at risk of relapse and its patterns are yet to be clearly established. We reviewed patients with iTTP having had >3 years of follow-up over 10 years in the United Kingdom to identify patient characteristics for relapse, assess relapse rates and patterns, and response to anti-CD20 therapy in those with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) relapses (ADAMTS13 activity of <20% without thrombocytopenia). We identified 443 patients demonstrating relapse rates of 40% at 5-year follow-up. At 10-year follow-up, no difference in relapse was observed irrespective of whether rituximab was used at acute presentation (P = .39). Black Caribbean ethnicity increased the risk of disease relapse in the British population. There was a distinct population of patients (6%) that relapsed early with subsequent frequent relapses occurring on average within 2 years (average time to relapse in subgroup, 1.7 years). Overall, nearly 60% of relapses described were ADAMTS13 relapses, with subsequent treatment reducing the risk of progression to clinical relapses. We demonstrate that iTTP diagnosed in the latter part of the study period had lower rates of clinical relapses (22.6% vs 11.1%, P = .0004) with the advent of regular monitoring and preemptive rituximab. In ADAMTS13 relapses, 96% responded to anti-CD20 therapy, achieving ADAMTS13 activity of >20%. Anti-CD20 therapy was demonstrated to be an effective long-term treatment regardless of relapse pattern and there was no loss of this treatment response after subsequent treatment episodes.
Asunto(s)
Púrpura Trombocitopénica Trombótica , Humanos , Rituximab/uso terapéutico , Púrpura Trombocitopénica Trombótica/terapia , Proteína ADAMTS13 , Recurrencia , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined. METHODS: Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included. RESULTS: Of 1956 patients attending the Sheffield PE clinic 3â months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.10%, with 1.89% diagnosed within 2â years. Of 809 patients presenting with pulmonary hypertension (PH) and diagnosed with CTEPH, 32 were Sheffield residents and 777 were non-Sheffield residents. Patients diagnosed with CTEPH at the PE follow-up clinic had shorter symptom duration (p<0.01), better exercise capacity (p<0.05) and less severe pulmonary haemodynamics (p<0.01) compared with patients referred with suspected PH. Patients with no major transient risk factors present at the time of acute PE had a significantly higher risk of CTEPH compared with patients with major transient risk factors (OR 3.6, 95% CI 1.11-11.91; p=0.03). The presence of three computed tomography (CT) features of PH in combination with two or more out of four features of chronic thromboembolic pulmonary disease at the index PE was found in 19% of patients who developed CTEPH and in 0% of patients who did not. Diagnostic rates and pulmonary endarterectomy (PEA) rates were higher at 13.2 and 3.6 per million per year, respectively, for Sheffield residents compared with 3.9-5.2 and 1.7-2.3 per million per year, respectively, for non-Sheffield residents. CONCLUSIONS: In the real-world setting a dedicated PE follow-up pathway identifies patients with less severe CTEPH and increases population-based CTEPH diagnostic and PEA rates. At the time of acute PE diagnosis the absence of major transient risk factors, CT features of PH and chronic thromboembolism are risk factors for a subsequent diagnosis of CTEPH.
Asunto(s)
Hipertensión Pulmonar , Embolia Pulmonar , Tromboembolia , Humanos , Hipertensión Pulmonar/complicaciones , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Estudios de Seguimiento , Embolia Pulmonar/complicaciones , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/epidemiología , Factores de Riesgo , Tromboembolia/complicaciones , Tromboembolia/diagnóstico , Sistema de Registros , Enfermedad CrónicaRESUMEN
The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.
Asunto(s)
Fibrinolíticos/uso terapéutico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Anticuerpos de Dominio Único/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Manejo de la Enfermedad , Femenino , Fibrinolíticos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/epidemiología , Anticuerpos de Dominio Único/efectos adversos , Resultado del Tratamiento , Reino Unido/epidemiología , Adulto Joven , Factor de von Willebrand/antagonistas & inhibidoresRESUMEN
Acquired immune thrombotic thrombocytopenic purpura (iTTP) is a rare disease with a poor prognosis if undiagnosed. It is caused by autoantibody production to the von Willebrand factor (VWF) cleaving protease, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Caplacizumab, an immunoglobulin directed to the platelet glycoprotein Ibα receptor of VWF, has been reported to induce quicker resolution of iTTP compared to placebo. The laboratory measurement of VWF activity was significantly reduced in clinical trials of caplacizumab. Several VWF assays are available in the UK and this study investigated whether differences in VWF parameters were present in 11 patients diagnosed with iTTP and treated with daily caplacizumab. Chromogenic factor VIII activity, VWF antigen, collagen binding activity, VWF multimers and six VWF activity assays were measured prior to caplacizumab therapy and on several occasions during treatment. VWF antigen and collagen binding activity levels were normal or borderline normal in all patients. Ultra-large molecular weight multimers were present in all patients following treatment. VWF activity assays were normal or reduced during treatment, but this was reagent and patient dependant. In the unusual scenario of a caplacizumab-treated patient requiring measurement of VWF activity, it is important that laboratories understand how their local reagents perform as results cannot be predicted.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Púrpura Trombocitopénica Trombótica , Anticuerpos de Dominio Único , Proteína ADAMTS13/metabolismo , Humanos , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Trombótica/diagnóstico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Factor de von Willebrand/metabolismoRESUMEN
Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.
Asunto(s)
Proteína ADAMTS13/genética , Púrpura Trombocitopénica Trombótica/congénito , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Proteína ADAMTS13/deficiencia , Adulto , Preescolar , Factor VIII/uso terapéutico , Femenino , Humanos , Masculino , Mutación , Plasma , Embarazo , Premedicación/métodos , Púrpura Trombocitopénica Trombótica/complicaciones , Púrpura Trombocitopénica Trombótica/genética , Accidente Cerebrovascular/prevención & controlRESUMEN
BACKGROUND: People with a low platelet count (thrombocytopenia) often require lumbar punctures or an epidural anaesthetic. Lumbar punctures can be diagnostic (haematological malignancies, subarachnoid haematoma, meningitis) or therapeutic (spinal anaesthetic, administration of chemotherapy). Epidural catheters are placed for administration of epidural anaesthetic. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to lumbar punctures and epidural anaesthesia, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to these procedures varies significantly from country to country. This indicates significant uncertainty among clinicians regarding the correct management of these patients. The risk of bleeding appears to be low, but if bleeding occurs it can be very serious (spinal haematoma). Consequently, people may be exposed to the risks of a platelet transfusion without any obvious clinical benefit.This is an update of a Cochrane Review first published in 2016. OBJECTIVES: To assess the effects of different platelet transfusion thresholds prior to a lumbar puncture or epidural anaesthesia in people with thrombocytopenia (low platelet count). SEARCH METHODS: We searched for randomised controlled trials (RCTs), non-randomised controlled trials (nRCTs), controlled before-after studies (CBAs), interrupted time series studies (ITSs), and cohort studies in CENTRAL (the Cochrane Library 2018, Issue 1), MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 13 February 2018. SELECTION CRITERIA: We included RCTs, nRCTs, CBAs, ITSs, and cohort studies involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people of any age with thrombocytopenia requiring insertion of a lumbar puncture needle or epidural catheter.The original review only included RCTs. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane for including RCTs, nRCTs, CBAs, and ITSs. Two review authors independently assessed studies for eligibility and risk of bias and extracted data. Results were only expressed narratively. MAIN RESULTS: We identified no completed or ongoing RCTs, nRCTs, CBAs, or ITSs. No studies included people undergoing an epidural procedure. No studies compared different platelet count thresholds prior to a procedure.In this update we identified three retrospective cohort studies that contained participants who did and did not receive platelet transfusions prior to lumbar puncture procedures. All three studies were carried out in people with cancer, most of whom had a haematological malignancy. Two studies were in children, and one was in adults.The number of participants receiving platelet transfusions prior to the lumbar puncture procedures was not reported in one study. We therefore only summarised in a narrative form the relevant outcomes from two studies (150 participants; 129 children and 21 adults), in which the number of participants who received the transfusion was given.We judged the overall risk of bias for all reported outcomes for both studies as 'serious' based on the ROBINS-I tool.No procedure-related major bleeding occurred in the two studies that reported this outcome (2 studies, 150 participants, no cases, very low-quality evidence).There was no evidence of a difference in the risk of minor bleeding (traumatic tap) in participants who received platelet transfusions before a lumbar puncture and those who did not receive a platelet transfusion before the procedure (2 studies, 150 participants, very low-quality evidence). One of the 14 adults who received a platelet transfusion experienced minor bleeding (traumatic tap; defined as at least 500 x 106/L red blood cells in the cerebrospinal fluid); none of the seven adults who did not receive a platelet transfusion experienced this event. Ten children experienced minor bleeding (traumatic taps; defined as at least 100 x 106/L red blood cells in the cerebrospinal fluid), six out of the 57 children who received a platelet transfusion and four out of the 72 children who did not receive a platelet transfusion.No serious adverse events occurred in the one study that reported this outcome (1 study, 21 participants, very low-quality evidence).We found no studies that evaluated all-cause mortality within 30 days from the lumbar puncture procedure, length of hospital stay, proportion of participants who received platelet transfusions, or quality of life. AUTHORS' CONCLUSIONS: We found no evidence from RCTs or non-randomised studies on which to base an assessment of the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future study would need to be very large to detect a difference in the risk of bleeding. A study would need to be designed with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000. The use of a central data collection register or routinely collected electronic records (big data) is likely to be the only method to systematically gather data relevant to this population.
Asunto(s)
Anestesia Epidural/efectos adversos , Transfusión de Plaquetas , Punción Espinal/efectos adversos , Trombocitopenia/terapia , Adulto , Niño , Humanos , Estudios Retrospectivos , Trombocitopenia/complicacionesRESUMEN
BACKGROUND: Physicians treating acute pulmonary embolism (PE) are faced with difficult management decisions while specific guidance from recent guidelines may be absent. METHODS: Fourteen clinical dilemmas were identified by physicians and haematologists with specific interests in acute and chronic PE. Current evidence was reviewed and a practical approach suggested. RESULTS: Management dilemmas discussed include: sub-massive PE, PE following recent stroke or surgery, thrombolysis dosing and use in cardiac arrest, surgical or catheter-based therapy, failure to respond to initial thrombolysis, PE in pregnancy, right atrial thrombus, role of caval filter insertion, incidental and sub-segmental PE, differentiating acute from chronic PE, early discharge and novel oral anticoagulants. CONCLUSION: The suggested approaches are based on a review of the available evidence and guidelines and on our clinical experience. Management in an individual patient requires clinical assessment of risks and benefits and also depends on local availability of therapeutic interventions.
Asunto(s)
Embolia Pulmonar/terapia , Enfermedad Aguda , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Medicina Basada en la Evidencia/métodos , Fibrinolíticos/administración & dosificación , Humanos , Selección de Paciente , Embolia Pulmonar/diagnóstico , Índice de Severidad de la Enfermedad , Terapia Trombolítica/efectos adversos , Terapia Trombolítica/métodosAsunto(s)
Coagulación Sanguínea/efectos de los fármacos , Monitoreo de Drogas , Tiempo de Tromboplastina Parcial , Ácidos Pipecólicos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Arginina/análogos & derivados , Monitoreo de Drogas/métodos , Humanos , Tiempo de Tromboplastina Parcial/métodos , Ácidos Pipecólicos/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , SulfonamidasRESUMEN
The activity of the factor VIII coagulation protein can be measured by three methods: a one or two-stage clotting assay and a chromogenic assay. The factor VIII activity of most individuals with mild hemophilia A is the same regardless of which method is employed. However, approximately 30% of patients show marked discrepancies in factor VIII activity measured with the different methods. The objective of this study was to investigate the incidence of assay discrepancy in our center, assess the impact of alternative reagents on factor VIII activity assays and determine the usefulness of global assays of hemostasis in mild hemophilia A. Factor VIII activity was measured in 84 individuals with mild hemophilia A using different reagents. Assay discrepancy was defined as a two-fold or greater difference between the results of the one-stage and two-stage clotting assays. Rotational thromboelastometry and calibrated automated thrombography were performed. Assay discrepancy was observed in 31% of individuals; 12% with lower activity in the two-stage assay and 19% with lower activity in the one-stage assay. The phenotype could not always be predicted from the individual's genotype. Chromogenic assays were shown to be a suitable alternative to the two-stage clotting assay. Thromboelastometry was found to have poor sensitivity in hemophilia. Calibrated automated thrombography supported the results obtained by the two-stage and chromogenic assays. The current international guidelines do not define the type of assay to be used in the diagnosis of mild hemophilia A and some patients could be misclassified as normal. In our study, 4% of patients would not have been diagnosed on the basis of the one-stage factor VIII assay. Laboratories should use both one stage and chromogenic (or two-stage) assays in the diagnosis of patients with possible hemophilia A.
Asunto(s)
Pruebas de Coagulación Sanguínea/normas , Hemofilia A/sangre , Hemofilia A/diagnóstico , Coagulación Sanguínea/fisiología , Pruebas de Coagulación Sanguínea/métodos , Femenino , Humanos , Masculino , Tromboelastografía/métodos , Tromboelastografía/normasRESUMEN
INTRODUCTION: The Summary of Product Characteristics for the direct thrombin inhibitor argatroban states monitoring should be by activated partial thromboplastin time (APTT), with a target range of 1.5-3.0 times the patients' baseline APTT. APTT may be influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. Previous studies have shown sensitivity differences of APTT reagents to argatroban. Some recent publications have favoured the use of anti-IIa methods to determine the plasma drug concentration of argatroban. This study aims to compare the anti-IIa assays: Hemoclot thrombin inhibitor assay (HTI) and Ecarin chromogenic assay (ECA) alongside the APTT. METHODS: Residual plasma of 25 samples from 8 patients (3 with COVID-19 and HIT: n = 18, 5 with HIT: n = 7) was tested at two sites: site A: Sysmex CS5100 by HTI and APTT (Actin FS and SynthASil), and also on Stago STA Compact Max: ECA and APTT (CK Prest); and site B: Stago STA R Max 2 by ECA and APTT (Cephascreen). RESULTS: Mean APTT ratio was 1.96 (Actin FS), 1.84 (SynthASil), 1.59 (CK Prest) and 2.48 (Cephascreen). Mean argatroban concentration by HTI was 0.60 µg/mL and by ECA was 0.65 µg/mL (site A) and 0.70 µg/mL (site B). There was a poor correlation to HTI in APTT ratios (range r2 = .0235-0.4181) with stronger correlations between ECA methods to HTI (r2 = .8998 site A, r2 = .8734 site B). CONCLUSION: This study confirms previous publications on the unsuitability of APTT and expands this by being multisited and included APTT reagents that use mechanical clot detection. Both anti-IIa methods are more suitable.
Asunto(s)
COVID-19 , Trombocitopenia , Anticoagulantes/efectos adversos , Arginina/análogos & derivados , Monitoreo de Drogas/métodos , Heparina/efectos adversos , Humanos , Tiempo de Tromboplastina Parcial , Ácidos Pipecólicos/farmacología , Sulfonamidas , Trombocitopenia/inducido químicamenteRESUMEN
Neuraxial anaesthesia is increasingly performed in thrombocytopenic patients at the time of delivery of pregnancy. There is a lack of data regarding the optimum platelet count at which spinal procedures can be safely performed. Reports are often confounded by the presence of other risk factors for spinal haematomata, such as anticoagulants, antiplatelet agents and other acquired or congenital coagulopathies/platelet function defects or rapidly falling platelet counts. In the absence of these additional risk factors, a platelet count of 80 x 10(9)/l is a 'safe' count for placing an epidural or spinal anaesthetic and 40 x 10(9)/l is a 'safe' count for lumbar puncture. It is likely that lower platelet counts may also be safe but there is insufficient published evidence to make recommendations for lower levels at this stage. For patients with platelet counts of 50-80 x 10(9)/l requiring epidural or spinal anaesthesia and patients with a platelet count 20-40 x 10(9)/l requiring a lumbar puncture, an individual decision based on assessment of risks and benefits should be made.
Asunto(s)
Anestesia Epidural/efectos adversos , Anestesia Raquidea/efectos adversos , Hematoma Espinal Epidural/etiología , Punción Espinal/efectos adversos , Trombocitopenia/complicaciones , Adulto , Anestesia Obstétrica/efectos adversos , Niño , Femenino , Humanos , Recuento de Plaquetas , Embarazo , Práctica Profesional/normas , Literatura de Revisión como AsuntoRESUMEN
The management of patients with supra-therapeutic INR in a common clinical problem. The risk of bleeding is influenced by the intensity, variability and duration of anticoagulation, patient age, presence of co-morbidities and concomitant drug therapy. For the asymptomatic patient, warfarin discontinuation is all that is usually required but for individuals at high risk of bleeding and those with INR > 10, oral vitamin K administration is recommended. In the presence of major bleeding, treatment with intravenous vitamin K and prothrombin complex concentrate is the most effective therapy.
Asunto(s)
Anticoagulantes/efectos adversos , Coagulación Sanguínea/efectos de los fármacos , Coagulantes/administración & dosificación , Hemorragia/tratamiento farmacológico , Warfarina/efectos adversos , Administración Oral , Anticoagulantes/administración & dosificación , Factores de Coagulación Sanguínea/administración & dosificación , Coagulantes/efectos adversos , Esquema de Medicación , Medicina Basada en la Evidencia , Factor VIIa/administración & dosificación , Hemorragia/sangre , Hemorragia/inducido químicamente , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Relación Normalizada Internacional , Guías de Práctica Clínica como Asunto , Proteínas Recombinantes/administración & dosificación , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento , Vitamina K/administración & dosificación , Warfarina/administración & dosificaciónRESUMEN
Contact factor pathway deficiencies do not cause surgical bleeding but make heparin monitoring by the activated partial thromboplastin time (APTT) and activated clotting time (ACT) unreliable. Heparin monitoring during cardiopulmonary bypass (CPB) surgery in these patients is particularly challenging. Here we describe heparin monitoring during CPB using the chromogenic anti Xa assay in two patients with severe factor XII deficiency (FXII < 0.01 U/mL) and one patient with severe prekallikrein (PK) deficiency (PK < 0.01 U/mL). Anti Xa levels of the three patients during CPB varied between 3.8 and 4.8 U/mL in keeping with a control group (mean anti Xa 4.5 U/mL and ACT > 480 s). There were no bleeding or thrombotic complications. We also found that detection of severe PK deficiency by the APTT in the PK deficient patient was dependent on the reagent used and discuss the sensitivity of different APTT reagents for contact factor deficiencies. We conclude that the sensitivity of APTT methods for contact pathway deficiencies is highly variable and although insensitivity is not a clinical problem in terms of bleeding, it can be a cause of discrepancy between different APTT reagents and the ACT. This can lead to confusion about a possible haemorrhagic tendency and delays in surgery. If these patients need to undergo cardiac surgery requiring high dose heparin treatment, monitoring by chromogenic anti Xa assay is a good alternative.
Asunto(s)
Trastornos de la Coagulación Sanguínea/sangre , Trastornos de la Coagulación Sanguínea/diagnóstico , Factores de Coagulación Sanguínea/metabolismo , Puente Cardiopulmonar , Heparina/sangre , Monitoreo Intraoperatorio/métodos , Trastornos de la Coagulación Sanguínea/cirugía , Factor XII/metabolismo , Deficiencia del Factor XII/sangre , Deficiencia del Factor XII/diagnóstico , Humanos , Quininógeno de Alto Peso Molecular/deficiencia , Quininógeno de Alto Peso Molecular/metabolismo , Precalicreína/deficiencia , Precalicreína/metabolismo , Reproducibilidad de los ResultadosRESUMEN
INTRODUCTION: Global coagulation tests may have a better relation with phenotype in haemophilia than traditional coagulation tests. These include the Calibrated Automated Thrombin generation assay (CAT) and modified thromboelastometry using low tissue factor triggering. Both have shown marked variability in thrombin generation and clot formation profiles respectively despite similar FVIII:C levels and have been suggested as means to monitor treatment. Data with modified thromboelastometry are largely limited to severe and moderate haemophiliacs. CAT measurements in haemophilia are generally performed at low TF concentrations (1 pM) because of a higher sensitivity for the intrinsic pathway at this concentration but is also sensitive for FVIII at higher concentrations (5 pM) and this has the advantage that inhibition of contact factor activation can be avoided. No formal comparison of both TF concentrations has been reported and the data on modified thromboelastometry in mild haemophilia are limited. METHODS: In this study we compared thrombin generation at 1 and 5 pM in 57 haemophilia patients without exposure to treatment and 41 patients after treatment. We also assessed the sensitivity of thromboelastometry for haemophilia A in 29 patients. RESULTS AND CONCLUSION: We found that CAT discriminates well between normal individuals and haemophilia patients; also FVIII:C correlates well with the ETP/peak. We found no clear advantages of measurements at 1 compared to 5 pM but found increased variation over time at 1 pM. The sensitivity of modified thromboelastometry for haemophilia A was less than CAT with abnormal measurements largely limited to severe and moderate patients. Larger studies correlating both methods with clinical outcome are required.
Asunto(s)
Pruebas de Coagulación Sanguínea/métodos , Hemofilia A/sangre , Tromboelastografía/métodos , Trombina/biosíntesis , Pruebas de Coagulación Sanguínea/estadística & datos numéricos , Estudios de Casos y Controles , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Humanos , Masculino , Valores de Referencia , Tromboelastografía/estadística & datos numéricosRESUMEN
Even though new anticoagulants are being devised with the notion that they do not require regular monitoring, when bleeding occurs, it is important to have an antidote and a reliable test to confirm whether the anticoagulant effects are persisting. We examined the effects of five heparinoids, unfractionated heparin (UFH), tinzaparin, enoxaparin, danaparoid and fondaparinux on the traditional APTT and anti-Xa assays as well as on the calibrated automated thrombogram (CAT). We also studied the ability of protamine sulphate (PS), NovoSeven, FEIBA and FFP to reverse maximum anticoagulation induced by the different heparinoids. The CAT was the only test to detect the coagulopathy of all the anticoagulants. PS produced complete reversal of UFH, and this could be monitored with all three tests. Tinzaparin can also be completely neutralised in vitro with high doses of PS, but the maximum enoxaparin reversal achieved with PS is only approximately 60%. Fondaparinux does not significantly affect the APTT and PS has no significant effect on its reversal. Only NovoSeven was able to correct the fondaparinux induced CAT abnormalities whilst having no effect on the anti-Xa level. None of the reversal agents was very effective in danaparoid spiked plasma but NovoSeven, at high dose, increased the ETP by 40% and reduced the anti-Xa level from 0.93 to 0.78 IU/ml. We conclude that the CAT is superior to the traditional coagulation tests in that it not only detects the coagulopathy of all the heparinoids but can be also be used to monitor their reversal.
Asunto(s)
Anticoagulantes/farmacología , Pruebas de Coagulación Sanguínea/métodos , Monitoreo de Drogas/métodos , Antagonistas de Heparina/farmacología , Protaminas/farmacología , Trombina/metabolismo , Factores de Coagulación Sanguínea/farmacología , Sulfatos de Condroitina/farmacología , Dermatán Sulfato/farmacología , Interacciones Farmacológicas , Enoxaparina/farmacología , Factor VIIa/farmacología , Factor Xa/metabolismo , Fondaparinux , Heparina/farmacología , Heparina de Bajo-Peso-Molecular/farmacología , Heparitina Sulfato/farmacología , Humanos , Técnicas In Vitro , Tiempo de Tromboplastina Parcial , Polisacáridos/farmacología , Proteínas Recombinantes/farmacología , Trombina/biosíntesis , TinzaparinaRESUMEN
The fluorogenic calibrated automated thrombin-generation assay is influenced by contact pathway activation in platelet-rich and platelet-poor plasma. This influence lessens with increasing tissue factor (TF) concentrations and is inhibited by corn trypsin inhibitor (CTI). CTI is expensive and at what TF concentration its influence becomes irrelevant is unclear. Spiking of factor VIII (FVIII)-depleted plasma with FVIII, in samples without CTI, shows a plateau of thrombin generation at low normal FVIII levels. Given the association with thrombosis at high levels, a continuing increase in thrombin generation would be expected. We studied the effect of CTI on this relation by spiking experiments up to 4.8 IU/ml at 1 pmol/l TF and compared the influence of CTI at 1 and 5 pmol/l in platelet-poor plasma. CTI significantly influences thrombin generation in platelet-poor plasma at 1 pmol/l TF (difference of means for endogenous thrombin potential of 232.5 nmol/l per min, P<0.0001) and peak of 48 nmol/l (P<0.0001)) but not at 5 pmol/l. Spiking experiments without CTI confirm the hyperbolic relation between FVIII coagulant activity (FVIII:C) and endogenous thrombin potential with a plateau at 0.70-1.40 IU/ml. With CTI, a near-linear response up to 1.0 IU/ml was found with a plateau at 2.4-4.8 IU/ml. For peak thrombin, no plateau was reached with CTI. The present study confirms and extends previous data on CTI and the relationship between FVIII:C and thrombin generation. CTI is not necessary at 5 pmol/l TF, and thrombin generation remains dependent on FVIII:C up to 4.8 IU/ml at 1 pmol/l with CTI. Higher levels than previously thought may be needed to normalize thrombin generation.