Consumption Of Coagulation Factors Research Articles

Disseminated Intravascular Coagulation

To provide a review of the definition, pathophysiology, differential diagnosis, and treatment of disseminated intravascular coagulation (DIC). A case scenario and a review of the literature related to the pertinent facts concerning DIC are provided. DIC is a systemic pathophysiologic process and not a single disease entity, resulting from an overwhelming activation of coagulation that consumes platelets and coagulation factors and causes microvascular fibrin thrombi, which can result in multiorgan dysfunction syndrome from tissue ischemia. Some conditions associated with acute DIC include septic shock, exsanguinating trauma, burns, or acute promyelocytic leukemia. The massive tissue factor stimulus results in excess intravascular thrombin, which overcomes the anticoagulant systems and leads to thrombosis. Because of consumption of coagulation factors and platelets, DIC also has a hemorrhagic phase. Treatment of the bleeding patient with DIC is supportive with the use of blood components.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is characterized by an acute generalized, widespread activation of coagulation, which results in thrombotic complications, due to the intravascular formation of fibrin, as well as diffuse hemorrhages, due to the consumption of platelets and coagulation factors. In this lecture, we discuss regarding the controversies in diagnosis and management of DIC. Bleeding is a more common manifestation of DIC. We report the present knowledge about the treatment of DIC. Therapy of DIC aims at treating the primary cause. We focus on the current standard treatment of overt DIC in clinical practice. Moreover, particular attention is made to novel therapeutic strategies, who reflect the important progresses in the understanding of the pathogenesis of this syndrome in the last few years.

Optimization of home treatment in haemophilia: effects of transmural support by a haemophilia nurse on adherence and quality of life

Transmural support by a haemophilia nurse may improve treatment and may empower parents and patients. To measure the effect of structured home visits by a haemophilia nurse in (parents of) patient on aspects of prophylactic home treatment. A multicentre intervention study in two paediatric haemophilia treatment centres was performed. Primary outcome measures were: adherence to prescribed treatment, health-related quality of life and behavioural scores. Secondary outcome measures were: total clotting factor consumption, self-efficacy and number of joint bleeds. Over a period of 22 months (median, IQR 21-23), four to seven home visits in 46 patients (mean age 9.4 ± 4.2 years) were made. No difference in adherence to prescribed treatment was seen after the home visits when compared to baseline measurements. Both the Child Health Questionnaire (CHQ) scales on 'Role functioning - Emotional/Behavioural' (P = 0.02, d = 0.53) and 'Parental Time Impact' (P = 0.04, d = 0.33) were reduced after intervention. The disease-specific Haemo-QoL questionnaire showed improvement in domains: 'Family' (P = 0.04, d = -0.14), 'Friends' (P = 0.03, d = -0.29) and 'Perceived support' (P = 0.03, d = -0.37). Significant improvement was observed with regard to domain 'Communication' of the VERITAS-Pro scale (P = 0.03, d = -0.28). After a period of transmural care by a haemophilia nurse, significant but small positive effects were demonstrated with regard to communication and increase of perceived support between parents and haemophilia treatment centre. No improvement was observed in other outcome measures.

An Unusual Cause of Chest Pain: Kasabach-Merritt Syndrome

Kasabach-Merritt syndrome (KMS) is a rare complication of hemangiomas that includes both thrombocytopenia and consumptive coagulopathy. Initial cases reported in the pediatric population in the 1940s predominantly involved tufted hemangiomas and kaposiform hemangioendotheliomas. However, this syndrome also includes visceral hemangiomas in adults and has been associated with a broad range of mortality. Abnormal platelet-endothelial interactions lead to platelet sequestration and coagulation factor consumption as a result of these large vascular lesions. Resultant bleeding and thrombosis presents as a localized mimicker of disseminated intravascular coagulopathy (DIC) and can progress to cause compression of nearby organs. Importantly, adults with visceral involvement are often unaware of the presence of these hemangiomas at time of diagnosis and management must be carefully selected with the patient. A multidisciplinary approach including corticosteroids, chemotherapeutics, interferon alpha, antiplatelet agents, embolization, and surgical excision have each been employed in efforts to treat KMS. We present a case of a 36 year-old male with past medical history of hypertension with new-onset chest pain and left arm numbness. He had no nausea, vomiting, melena, or hematochezia. He had no personal or family history of bleeding or clotting disorders. Vital signs were within normal limits and physical examination was unremarkable. After negative serial cardiac enzymes and stable electrocardiograms, Computed tomography (CT) evaluation of the chest was notable for multiple liver lesions. Further evaluation with magnetic resonance imaging (MRI) of the abdomen revealed multiple hepatic hemangiomas with the largest encompassing 15 cm in diameter. Laboratory studies were pertinent for thrombocytopenia, elevated fibrin split products, and a “clotted” PT, PTT, and fibrinogen study. Transaminases, bilirubin, viral hepatitis panel and urine drug screen were negative. The patient's atypical chest pain resolved and was likely attributed to the large liver hemangiomas. Surgery consultation recommended close outpatient follow up to further discuss elective surgical intervention. This case illustrates the importance of maintaining occult etiologies, such as KMS, in the differential of seemingly-routine chief complaints. Medical awareness of this rare syndrome is essential for follow-up, treatment, and prevention of potential life-threatening complications.Figure 1Figure 2Figure 3

Modelling lifelong effects of different prophylactic treatment strategies for severe haemophilia A.

Lifelong prophylactic replacement therapy with clotting factor concentrates is recommended for severe haemophilia. The prophylactic dose determines both clinical outcome and treatment cost. In the absence of clinical studies, computer simulation was used to explore lifelong effects and clotting factor consumption for various prophylactic dose levels, and optimize strategies for switching between prophylactic and on-demand treatment. Individual patients' lifetime joint bleeds, radiological arthropathy (Pettersson score, 0-78) and consumption were simulated for each treatment strategy. Treatment effectiveness (expressed as % of patients maintaining a lifetime Pettersson score ≤14) and clotting factor consumption were modelled for lifelong prophylaxis at dose levels 1000-4500 IU kg(-1) year(-1) , for on-demand treatment and for switching strategies. Treatment efficiency (consumption per unit of effectiveness) was used to compare strategies. Compared to lifelong on-demand treatment, lifelong prophylaxis at 1000 IU kg(-1) year(-1) increased effectiveness from 21 to 36%, at an additional consumption of 0.9 × 10(6) IU kg(-1) . For lifelong prophylaxis, each additional 1000 IU kg(-1) year(-1) resulted in a proportional increase in consumption by ±5 × 10(6) IU kg(-1) but a less than proportional reduction in arthropathy by ±50%; consequently, increasing consumption progressively diminished treatment efficiency. Switching strategies slightly reduce effectiveness and consumption. Optimum switching criteria were similar across prophylactic dose levels. According to the simulation model, low-dose prophylaxis (1000 IU kg(-1) year(-1) ) improved outcome at a limited increase in consumption compared to on-demand treatment. Increasing prophylactic dose further improved health outcomes, but at decreasing efficiency. Optimal prophylactic dose should therefore be selected balancing acceptable health impact and available budget.

Adherence to prophylaxis and bleeding outcome in haemophilia: a multicentre study.

Prevention of bleeding and joint damage in severe haemophilia is dependent on adherence to prophylactic replacement therapy. The aim of this study was to assess adherence to prophylaxis, including associations with age, bleeding and clotting factor consumption (CFC). In three Dutch haemophilia centres, semi-structured interviews about adherence to prophylaxis in the previous 2weeks were conducted with patients or parents of a child with haemophilia. Patients were classified, according to pre-specified definitions, as adherent, sub-optimally adherent or non-adherent based on missing, timing, and dose of infusions. Association of annual bleeding rates, mean CFC, person performing the infusion (parents verus patients) with adherence categories were analysed. Overall, 241 patients with haemophilia using prophylaxis were studied. Parents were more adherent (66%; n=48/73) than patients (43%; n=72/168). Sub-optimal adherence occurred in 29% of parents and 37% of patients and was characterized by changes in timing of infusion (mostly from morning to evening), while missing <6% of infusions. Non-adherence occurred less often: in 5% of parents and 20% of patients. Reduced adherence was associated with lower CFC, but not with joint bleeding. In conclusion, non-adherence in haemophilia was relatively rare, yet 1/3 of patients struggled to administer prophylaxis at the appropriate time of day.

Management of cancer-associated disseminated intravascular coagulation

Cancer may be complicated by the occurrence of disseminated intravascular coagulation (DIC). DIC is characterized by a widespread and intravascular activation of coagulation (leading to intravascular fibrin deposition) and simultaneous consumption of coagulation factors and platelets (potentially resulting in bleeding). Clinically, DIC in cancer has in general a less fulminant presentation than the types of DIC complicating sepsis and trauma. A more gradual, but also more chronic, systemic activation of coagulation can proceed subclinically. Eventually this process may lead to exhaustion of platelets and coagulation factors and bleeding (for example at the site of the tumor) may be the first clinical symptom indicating the presence of DIC. In some cases, the clinical presentation of DIC in cancer may be reminiscent of thrombotic microangiopathies, which is understandable in view of the role of endothelium in both conditions. The therapeutic cornerstone of DIC is treatment of the underlying disorder but supportive treatment, specifically aimed at the hemostatic system may be required.

Assessment of Haemostasis in Disseminated Intravascular Coagulation by Use of Point-of-Care Assays and Routine Coagulation Tests, in Critically Ill Patients; A Prospective Observational Study.

BackgroundDisseminated intravascular coagulopathy (DIC) relates to the consumption of coagulation factors and platelets with bleeding and micro thrombosis events.AimThe aim of this study was to compare haemostasis parameters in critically ill patients with DIC versus patients without DIC, and in survivors versus non-survivors over time. Correlations between the DIC-score, the degree of organ failure and the haemostasis were assessed.MethodPatients admitted to the intensive care unit with a condition known to be associated with DIC and with an expected length of stay of >3 days were included. Routine laboratory tests, prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen concentration and D-dimer were measured. Coagulation and platelet function were assessed with two point-of-care devices; Multiplate and ROTEM. DIC scores were calculated according to the International Society on Thrombosis and Haemostasis and Japanese Association for Acute Medicine.ResultsBlood was sampled on days 0–1, 2–3 and 4–10 from 136 patients with mixed diagnoses during 290 sampling events. The point-of-care assays indicated a hypocoagulative response (decreased platelet aggregation and reduced clot strength) in patients with DIC and, over time, in non-survivors compared to survivors. Patients with DIC as well as non-survivors had decreased fibrinolysis as shown by ROTEM. DIC scores were higher in non-survivors than in survivors.ConclusionsPatients with DIC displayed signs of a hypocoagulative response and impaired fibrinolysis, which was also evident over time in non-survivors. Patients with DIC had a higher mortality rate than non-DIC patients, and DIC scores were higher in non-survivors than in survivors.

PLASMA RESUSCITATION PROMOTES COAGULATION HOMEOSTASIS FOLLOWING SHOCK-INDUCED HYPERCOAGULABILITY.

Increased thrombin generation in injured patients possibly contributes to early consumption of coagulation factors, exacerbating hemorrhage. Identifying optimal resuscitation products for restoring plasma homeostasis following injury is important for improving management of these patients. To determine the effects of crystalloid versus plasma resuscitation on thrombin generation in a rat model of trauma and hemorrhagic shock (HS). Rats were subjected to trauma and HS followed by resuscitation with Lactated Ringer's solution (LR) or fresh frozen plasma (FFP). Blood was collected at baseline, decompensation, and 3-h post-resuscitation. Thrombin generation was measured by calibrated automated thrombogram and antithrombin III (AT) by ELISA. In a prospective observational study, admission blood samples were collected on highest-level activation trauma patients and diluted with LR or FFP for thrombin generation analysis. Resuscitation with LR resulted in persistent hypercoagulability; however, FFP resuscitation reversed this hypercoagulability to baseline thrombin generation or below. Plasma AT levels decreased following HS and remained low in rats receiving LR, but were corrected in rats receiving FFP. Similarly, in trauma patient plasma LR increased thrombin generation while FFP reduced it. However, results with AT-deficient plasma dilution were similar to LR. In patients with admission hypocoagulability, FFP slightly increased thrombin generation. HS in rats is associated with increased thrombin generation and resuscitation with FFP, not LR, reverses hypercoagulability. Dilution of trauma patient plasma with LR or FFP yielded similar results; however, the modulatory effects of FFP were attenuated when AT was absent. Importantly, FFP reduced thrombin generation in hypercoagulable patient plasma, but slightly increased thrombin generation in hypocoagulable patient plasma. Thus, FFP restores hemostatic balance following trauma and HS which is, in part, by delivering AT.

A simple technique can reduce cardiopulmonary bypass use during lung transplantation

Cardiopulmonary bypass causes an inflammatory response and consumption of coagulation factors, increasing the risk of bleeding and neurological and renal complications. Its use during lung transplantation may be due to pulmonary hypertension or associated cardiac defects or just for better exposure of the pulmonary hilum. We describe a simple technique, or open pericardium retraction, to improve hilar exposure by lifting the heart by upward retraction of the pericardial sac. This technique permits lung transplantation without cardiopulmonary bypass when bypass use is recommended only for better exposure.

Protein Z efficiently depletes thrombin generation in disseminated intravascular coagulation with poor prognosis.

Disseminated intravascular coagulation (DIC) is characterized by consumption of coagulation factors and anticoagulants. Thrombin generation assay (TGA) gives useful information about global hemostatic status. We developed a new TGA system that anticoagulant addition can deplete thrombin generation in plasma, which may reflect defective anticoagulant system in DIC. TGAs were measured on the calibrated automated thrombogram with and without thrombomodulin or protein Z in 152 patients who were suspected of having DIC, yielding four parameters including lag time, endogenous thrombin potential, peak thrombin and time-to-peak in each experiment. Nonsurvivors showed significantly prolonged lag time and time-to-peak in TGA-protein Z system, which was performed with added protein Z. In multivariate Cox regression analysis, lag time and time-to-peak in TGA system were significant independent prognostic factors. In TGA-protein Z system, lag time and time-to-peak were revealed as independent prognostic factors of DIC. Protein Z addition could potentiate its anticoagulant effect in DIC with poor prognosis, suggesting the presence of defective protein Z system. The prolonged lag time and time-to-peak in both TGA and TGA-protein Z systems are expected to be used as independent prognostic factors of DIC.

A reduction of prothrombin conversion by cardiac surgery with cardiopulmonary bypass shifts the haemostatic balance towards bleeding.

Cardiac surgery with cardiopulmonary bypass (CPB) is associated with blood loss and post-surgery thrombotic complications. The process of thrombin generation is disturbed during surgery with CPB because of haemodilution, coagulation factor consumption and heparin administration. We aimed to investigate the changes in thrombin generation during cardiac surgery and its underlying pro- and anticoagulant processes, and to explore the clinical consequences of these changes using in silico experimentation. Plasma was obtained from 29 patients undergoing surgery with CPB before heparinisation, after heparinisation, after haemodilution, and after protamine administration. Thrombin generation was measured and prothrombin conversion and thrombin inactivation were quantified. In silico experimentation was used to investigate the reaction of patients to the administration of procoagulant factors and/or anticoagulant factors. Surgery with CPB causes significant coagulation factor consumption and a reduction of thrombin generation. The total amount of prothrombin converted and the rate of prothrombin conversion decreased during surgery. As the surgery progressed, the relative contribution of α2-macroglobulin-dependent thrombin inhibition increased, at the expense of antithrombin-dependent inhibition. In silico restoration of post-surgical prothrombin conversion to pre-surgical levels increased thrombin generation excessively, whereas co-administration of antithrombin resulted in the normalisation of post-surgical thrombin generation. Thrombin generation is reduced during surgery with cardiopulmonary bypass because of a balance shift between prothrombin conversion and thrombin inactivation. According to in silico predictions of thrombin generation, this new balance increases the risk of thrombotic complications with prothrombin complex concentrate administration, but not if antithrombin is co-administered.

Coagulation Profile in Perinatal Asphyxia

Introduction: Perinatal asphyxia is a common problem with devastating consequences in neonatal practice. Bleeding due to coagulation abnormality is very common and is potentially treatable. Various mechanisms includi ng liver dysfunction, unresponsiveness to Vitamin K and consumption of coagulation factors all have been implic ated in severe bleeding in asphyxiated neonates. The magnitude of this problem and therapeutic window if present has not been well studied. Methods: this was a prospective study undertaken in a terti ary care centre. 20 babies were recruited for the study. Asphyxia was defined on pragmatic basis of Apgar score and need for resuscitation followed by c linical course. The blood sample was collected in citrated tubes an d analysed for coagulation parameters. Results: 55% of our subjects were having deranged coagulation. APTT was the commonest deranged parameters in all our subjects (11/2 0). PT was deranged in only 2 of 20 patients. Patients who had deranged coagulation had poor outcomes. Coagulation abnormalities within first 24 hours had a positive predictive val ue of 18% and negative predictive value of 100% wit h respect to later bleeding. Conclusion: Deranged coagulation is very common in asphyxiated neonates and is associated with poor outcome.

Utilization Patterns of Coagulation Factor Consumption for Patients with Hemophilia.

Hemophilia is a serious rare disease that requires continuous management and treatment for which the medicine is costly at the annual average of 100 million KRW for an individual. The aim of this study was to investigate trends in the utilization of coagulation factor (CF) used for hemophilia treatment using the National Health Insurance database from 2010 to 2013 in Korea and compare the utilization of CF with other countries. The consumption of CF per capita (IU) in Korea was not more than other countries with similar income to Korea. However, CF usage per patient IU was higher because the prevalence rate of hemophilia in Korea was lower than in other countries while the number of serious patients was much more. Therefore, it is difficult to say that the consumption of hemophilia medicine in Korea is higher than that in other countries. The consumption and cost of hemophilia medicine in Korea is likely to increase due to the increased utilization of expensive bypassing agents and the widespread use of prophylaxis for severe hemophilia. Even during the research period, it increased slightly and other countries show a similar trend. Thus, hemophilia patient management should accompany active monitoring on the health and cost outcomes of pharmaceutical treatment in the future. This study is expected to contribute to further insight into drug policies for other countries that face similar challenges with high price pharmaceuticals.

Restoration of Procoagulant Factor Levels after Cardiac Surgery Causes Thrombin Generation to Rise to Thrombotic Levels

IntroductionCardiac surgery with cardiopulmonary bypass (CPB) causes hemodilution and coagulation factor consumption. The administration of unfractionated heparin accelerates thrombin inactivation and leads to elevated consumption of antithrombin (AT). The heparin-mediated release of tissue factor pathway inhibitor (TFPI) from the vessel wall reduces prothrombin activation. CPB surgery thus affects both pro- and anticoagulant processes, which are reflected in changes in a patient's thrombin generation potential.In this study we investigated how cardiac surgery changes thrombin generation (TG), prothrombin conversion and thrombin inactivation. In addition, we studied the consequences of these changes in pro- and anticoagulant processes for transfusion management using in silico experimentation.MethodsThirty patients undergoing cardiac surgery with CPB were included and samples were collected before and after surgery and protamine administration. AT and prothrombin levels were determined and TG was measured at 5 pM tissue factor by calibrated automated thrombinography. Prothrombin conversion and thrombin inactivation were quantified from each TG curve.The effect of transfusion of prothrombin complex concentrate (PCC) was simulated by an in silico increase of prothrombin conversion. The effect of PCC administration in combination with AT was modeled as an increase of prothrombin conversion and antithrombin levels. The effect of in silico transfusion of PCC on coagulation was quantified by TG parameters.ResultsCPB surgery causes a reduction of plasma coagulation factor levels: AT (47%, p<0.001), prothrombin (63%, p<0.001), and decreases TG peak height by 71% (p<0.001). After surgery prothrombin conversion is significantly impaired (402 ± 218 vs 701 ± 181 nM; p<0.001), which is partly compensated for by lower thrombin inactivation (63%, p<0.001), resulting in a reduction of TG.We modeled the effect of the transfusion of prothrombin complex concentrate with or without added antithrombin on TG. If the prothrombin conversion capacity was increased to pre-surgery levels in the absence of antithrombin, TG peak height increases to 454 ± 72 nM (figure A). A slight increase of prothrombin conversion (up to 83% of the pre-surgery level) brings TG peak height into the normal range (386±61 nM), but the ETP remains elevated (3278 ± 1141 nM). The optimal way to restore thrombin generation is the simultaneous infusion of PCC and antithrombin. Our in silico experiments indicate that this restores both the peak height (362 ± 69 nM) and the ETP (1601 ± 369 nM∙min) to the pre-surgery level (figure B).ConclusionsCardiac surgery with CPB causes the hemostatic balance to shift toward bleeding due to a reduction of prothrombin conversion. This is only partially compensated by a reduction of thrombin inactivation, resulting in reduced TG after surgery.Post-surgery bleeding can be (and often is) remedied by the transfusion of PCC. However, full restoration of the prothrombin conversion capacity results in a TG profile that predicts a prothrombotic state, as an ETP value in the highest quartile is associated with a 5 times elevated thrombosis risk according to Winckers et al. Equilibrated restoration of the hemostatic capacity asks for the simultaneous supplementation of both pro- and anticoagulant factors, i.e. PCC containing AT or fresh frozen plasma. [Display omitted] DisclosuresKremers:Synapse bv: Employment. Bloemen:Synapse bv: Employment. De Laat:Synapse bv: Employment. Wagenvoord:Synapse bv: Employment. Al Dieri:Synapse bv: Employment. Hemker:Synapse bv: Employment.

Biomarkers of Hemostatic Dysregulation, Inflammation, and Infection in Patients Diagnosed with Sepsis Associated Coagulopathy

Introduction: Sepsis associated coagulopathy (SAC) is one of the major pathophysiological mechanisms of sepsis and has been shown to greatly increase mortality in septic patients. SAC is characterized by the inappropriate activation of the coagulation cascade, leading to the formation of microthrombi and the potential for multiple organ failure. Additionally, the excessive consumption of platelets and coagulation factors can create a risk of excessive bleeding. SAC is a complex syndrome, involving coagulation factors, inflammatory cytokines, and several other notable factors of varied origin. In this study, our aim was to evaluate the levels of endocan, pentraxin, and procalcitonin in individuals with SAC diagnosed according to the ISTH criteria in comparison to healthy individuals. Endocan is a soluble, circulating proteoglycan that normally binds to LFA-1 and inhibits leukocyte diapedesis. It is produced by vascular endothelial cells as well as the lung and kidney and has been proposed as a marker of endothelial dysfunction and disease severity in patients with sepsis. Endocan may be useful in the evaluation and tracking of SAC as a marker of endothelial damage caused by excessive inflammation and coagulation. Pentraxin (PTX3) is a protein structurally similar to CRP that is produced by several cell types in response to inflammatory signals and is known to be a marker of inflammation in a number of disease processes. In addition to being the precursor of the hormone calcitonin, procalcitonin is produced by a variety of tissues and may correlate with degree of infection and response to treatment in individuals with sepsis. Taken together, endocan, pentraxin, and procalcitonin may be useful in the evaluation and monitoring of SAC as they are representative of endothelial damage, inflammation, and systemic infection, respectively.Materials and Methods: Blood from 50 patients with SAC and 33 normal individuals obtained from a commercial source (George King Biomedical, Overland Park, KS) were evaluated. Levels of pentraxin, procalcitonin, endocan, and coagulation factors VII, IX, and X were measured using commercially available ELISA kits from Stago (Parsippany, NJ), Lunginnov (Lillie, France) and R&D Systems (Minneapolis, MN). All results are compiled as group mean and expressed as average mean + SD. These values are compared with normal and results were computed as percent increase or decrease.Results: The levels of coagulation factors VII and X were found to be reduced in patients with SAC compared to normal individuals (p < 0.05); the level of factor IX was statistically unchanged. The reduction in factor X was relatively modest, less than a 20% reduction compared to normal, while the reduction in factor VII was more marked, with a greater than 40% reduction compared to normal. The levels of pentraxin, proxalcitonin, and endocan were all found to be significantly elevated in blood from SAC patients compared to blood from normal healthy individuals (p < 0.05). All three markers exhibited a greater than 100% average increase when compared to normal.Discussion: These results indicate that endocan, pentraxin, procalcitonin, and factor VII are all candidates for further investigation in the identification of a more comprehensive molecular profile of SAC and in the development of diagnostic or prognostic tests. The significant degree of change observed in each marker from normal provides a baseline for future studies of these markers in SAC patients. Although these factors individually are not specific markers of SAC, each is a marker for a specific system that is dysregulated in SAC; endocan for endothelial damage, pentraxin for inflammation, procalcitonin for infection, and factor VII for coagulation. Taken together, these biomarkers may be useful in the diagnosis and monitoring of SAC. DisclosuresNo relevant conflicts of interest to declare.

Immune Tolerance Induction Treatment Is Cost-Effective in Adult Patients with Long-Standing High-Responding Inhibitors

Introduction: Despite treatment of hemophilia having achieved considerable improvement over the last decades, inhibitor development remains a major complication for these patients. Inhibitors are alloantibodies that neutralize factor (F) VIII coagulation activity, and occur in approximately 25% of hemophilia A patients. Immune tolerance induction (ITI) is the choice therapy to eradicate these antibodies. There are several ITI protocols with similar success rates, approximately 70%. The presence of long-standing inhibitors in the adult population has usually been associated with poor ITI outcome. In Brazil, as in other countries with constrained resources, limited access to factor concentrates prevented the use of ITI. Thus, almost all patients with inhibitors remained a long time with this complication. Only after 2013 with increased availability of factor concentrates in the country, has assured long-term prophylaxis and ITI treatment been possible.Objective: This study aimed to describe the Brazilian experience in managing ITI in adult patients from seven Hemophilia Treatment Centers with long-standing inhibitor using bypassing agents to control bleeding episodes, considering bleeding frequency, treatment barriers and economic impact of therapy.Patients and Methods: We retrospectively analyzed clinical and laboratory data of hemophilia A patients with high-responding inhibitors (peak titer > 5 Bethesda Unit (BU), anamnestic response to FVIII) over 18 yo who underwent ITI treatment and were using bypass agents before ITI. The initial ITI protocol used was low-dose FVIII concentrate (25-50 IU/kg 3x/week)Results: In Brazil, since the availability of ITI, 39 adult hemophilia A patients with inhibitors, have been submitted to ITI for the first time. In this study, we accessed data from 26 patients, of these 13 (50%) already achieved complete ITI success criteria (inhibitor titer < 0.6 BU; FVIII recovery ≥ 66%, and half-live ≥ 6 h). Another 4 patients with ongoing ITI achieved inhibitor titer < 5 BU and are no longer using bypassing agents. Thus, 17/26 (65%) patients discontinued the bypassing agents in a median period of 2 mo (range 0 to 18 mo) after starting ITI. After 24 months of irregular treatment 2 patients abandoned ITI protocol. Analyses of the 13 patients with complete success revealed mean age at first reported inhibitor of 16.21y (SD ± 11.6; median 21y, range 0.7 to 37y), and mean age at ITI onset of 31.2y (SD ± 10.6; median 27y, range 19 to 47y). The mean period from the first inhibitor detected until starting ITI was 15y (SD ± 5.1), with a 16y median (range 7 to 22y). The historical peak inhibitor mean was 53.1 BU (SD ± 49.5; median 39.4 BU, range 5.5 to 163 BU). The mean pre ITI inhibitor titer was 6.6 BU (SD ± 5.5; median 5.5 BU, range 0.6 to 20.8 BU). Low-dose ITI protocol was initially used for all patients, however 3 patients had the dose increased during treatment (100 IU/kg from 3 to 7 x/week). During ITI, 10/13 patients received prophylaxis with bypassing agents, and 9 began prophylaxis before ITI started. The mean time to achieve inhibitor titer < 0.6 BU was 11.6 mo (SD ± 12.5; median 7 mo, range 0.5 to 44 mo). All 13 patients achieved other ITI success criteria. However, a delay was observed in the majority of patients in FVIII recovery and half-life. Regarding clinical outcome, we observed a significant reduction in both, annualized bleeding rate (ABR), and annualized joint bleeding rate (AJBR), comparing 12 months before ITI, during ITI, and after achieving complete success (figure 1). Regarding economic evaluation, we observed a significant reduction in the median cost of clotting factor consumption, comparing 12 months before starting ITI, and the following years after achieving ITI success. No significant difference was observed between the median cost of 12 months before, and ITI period (figure 2).Conclusion: This study indicated that this treatment is worthwhile even for inhibitor patients with poor prognostic factors for ITI considering both effectiveness to control and prevent bleeding episodes, and economic impact. In this group, 65% of adult hemophilia A high-responding inhibitors patients stopped using bypassing agents after a median period of 2 months after starting ITI. Despite being a high cost treatment, ITI can be cost-effective, especially for patients using bypassing agents. These results reinforce the positive impact of the ITI even in long time inhibitor adult patients. [Display omitted] [Display omitted] DisclosuresOzelo:Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding.

Simultaneous bilateral total knee arthroplasty in patients with haemophilia: a safe and cost-effective procedure?

Haemophilic arthropathy of the knee is usually a bilateral affliction. The patients usually refer for treatment in young ages and do not have major comorbidities, being fit for bilateral simultaneous total knee arthroplasty. In this study, we assessed the safety and cost-effectiveness of simultaneous bilateral surgery in patients with haemophilia. Between April 2010 and April 2012, eight patients (16 knees) underwent bilateral simultaneous and 19 patients (19 knees) underwent unilateral total knee arthroplasty (TKA) at our institution. We compared the range of motion and flexion contracture, KSS, WOMAC knee score and SF36 quality of life score between two groups. The duration of hospital stay, coagulation factor consumption and all inpatient costs were recorded. The average follow-up was 26 and 29months in unilateral and bilateral groups respectively. At the conclusion of the study, the KSS and WOMAC and SF36 scores were not significantly different between the two groups. Mean ROM and flexion contracture did not differ significantly. The mean length of hospital stay was 15days for bilateral patients and 12days for unilateral patients, the difference being non-significant. None of our patients needed transfusion in any group. The cost of simultaneous bilateral TKA was about half of the expenses of staged bilateral TKA. Simultaneous bilateral TKA seems to be a safe and cost-effective approach without increasing the rate of complications in patients' bilateral haemophilic knee arthropathy. The procedure is, at least, as effective as staged unilateral knee arthroplasty in improving the patients' quality of life.

Point of Care: Assessment of Coagulopathy in Hemorrhagic Shock

Correspondence to: Jung-Min Bae, M.D. Department of Surgery, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: +82-53-620-3580 Fax: +82-53-624-1213 E-mail: netetern@naver.com Traumatic bleeding is a prime cause of mortality after trauma, responsible for 40% of traumarelated early death. Traumatic bleeding often occurs as direct bleeding from injured site and is frequently complicated by trauma-induced coagulopathy (TIC). Traditionally, TIC was related to hemodilution, coagulation factor consumption, acidosis and hypothermia. However, TIC is now considered shock-associated hypoperfusion, a combination that activates the protein C pathway. While this adds to the understanding of this condition, the pathophysiology of TIC is not fully understood. Because TIC is composed of multiple factors, point-of-care testing (POCT) of coagulopathy that can rapidly provide information on an individual patient’s coagulation status is important. Among POCT tests are viscoelastic tests (VET), of which the most commonly used are thromboelastography and thromboelastometry. These provide rapid and dynamic bedside assessment of TIC. Treatment algorithms using VET results reduce mortality, morbidity and amount of transfusion. Although VET offers several advantages, there are limitations. VET cannot reduce mortality and morbidity, cannot fully assess the entire coagulation process, need ongoing quality control protocols, and require trained personnel. In conclusion, despite its limitations, VET has many advantages in assessment of TIC, POCT and treatment of TIC. Efforts to overcome the limitations are needed. (J Acute Care Surg 2015;5:42-46)

Trombelastometria rotaţională (ROTEM) – o nouă metodă de diagnostic al tulburărilor complexe de hemostază la pacientul politraumatizat

The coagulopathy is one of the most frequent causes of early posttraumatic mortality. The changes induced by multiple trauma in the coagulation cascade lead to different shapes: from massive bleeding to thrombosis, with different time evolution. Acute intrinsic coagulopathy arising in severely injured trauma patients is now termed trauma-induced coagulopathy (TIC) and is an emergent property of tissue injury combined with hypoperfusion. Mechanisms contributing to TIC include: coagulation factor and platelet consumption, platelet dysfunction, hyperfibrinolysis. But it also could be induced by iatrogenic factors such as: massive transfusion, hypothermia, quantity and type of replacement solutions. Rotational thrombelastometry (ROTEM) is a rapid method to diagnose the type of coagulopathy, showing graphical and numerical data and provides information on the rapidity of coagulation initiation, kinetics of clot growth, clot strength and breakdown by measuring the viscoelastic changes of clot formation in whole blood under low shear conditions. This method can give a „big picture“ of the coagulation cascade, and it can represent a start for the coagulopathy treatment guideline in multiple trauma.