Pharmacological management of rare coagulation factor deficiencies besides hemophilia.

INTRODUCTION: Rare coagulation factor deficiencies are less-known disorders with variable effects on the patient's life. Management of such patients is a challenge due to the paucity of evidence-based data, more so when patients with these rare disorders encounter a more rare, related condition, like inhibitor development or thrombosis. AREA COVERED: A comprehensive literature search related to RCFDs and management was performed in PubMed in order to discuss therapeutic options and challenges, prophylaxis, management of minor and major surgeries, obstetric and gynecological complications, inhibitor development, and thrombosis. EXPERT OPINION: Although significant changes have occurred in the management of RCFDs in recent years, more evidence-based studies besides expert opinion are needed for optimal management.

On-label compared to off-label four-factor prothrombin complex concentrate use: a retrospective, observational study.

BACKGROUND: Four-factor prothrombin complex concentrate (4F-PCC) is US Food and Drug Administration approved for the urgent reversal of coagulation factor deficiency induced by a vitamin K antagonist complicated by acute major bleeding or in situations in which invasive procedures are urgently needed. Although recent evidence suggests the superiority of 4F-PCC over plasma for on-label indications, the off-label use of 4F-PCC has not been rigorously studied. STUDY DESIGN AND METHODS: Eighty-nine patients receiving 4F-PCC at a single institution from July 2016 to December 2017 were retrospectively analyzed. Two cohorts, "On-Label" and "Off-Label" uses of 4F-PCC, were evaluated, comparing patient characteristics, blood utilization, and clinical outcomes including in-hospital mortality. RESULTS: Patients receiving 4F-PCC for off-label reasons (n = 46) were younger and sicker compared to those receiving 4F-PCC for on-label reasons (n = 43). Notably, the mortality rate for off-label use was approximately twofold greater than the mortality rate for on-label use (26 of 46 [56.5%] vs. 12 of 43 [27.9%]; p = 0.006). Patients receiving 4F-PCC for off-label reasons received more units per patient of each blood component than their on-label counterparts. The average cost estimate per patient for 4F-PCC was similar (approx. $4300) in each cohort. CONCLUSION: 4F-PCC is an effective but expensive treatment option for those requiring urgent reversal of vitamin K antagonist-induced coagulopathy. However, providers should be conscious of the high costs and questionable efficacy when using 4F-PCC off-label.

Treatment of rare factor deficiencies in 2016.

Rare bleeding disorders (RBDs) are a heterogeneous group of coagulation disorders characterized by fibrinogen, prothrombin, factors V, VII, X, XI, or XIII (FV, FVII, FX, FXI, or FXIII, respectively), and the combined factor V + VIII and vitamin K-dependent proteins deficiencies, representing roughly 5% of all bleeding disorders. They are usually transmitted as autosomal, recessive disorders, and the prevalence of the severe forms could range from 1 case in 500 000 for FVII up to 1 in 2-3 million for FXIII in the general population. Patients affected with RBDs may present a wide range of clinical symptoms, varying from mucocutaneous bleeding, common to all types of RBDs to the most life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Treatment of these disorders is mainly based on the replacement of the deficient factor, using specific plasma-derived or recombinant products. In countries where these facilities are not available, bleedings could be managed using cryoprecipitate, fresh frozen plasma (FFP), or virus-inactivated plasma. Minor bleedings could be managed using antifibrinolytic agents. Recently, 2 novel drugs, recombinant FXIIIA and a plasma-derived FX, have been added to the list of available specific hemostatic factors; only prothrombin and FV deficiencies still remain without a specific product. Novel no-replacement therapies, such as monoclonal antibody anti-tissue factor pathway inhibitor, RNA interference, and a bispecific antibody that is an FVIIIa mimetic, enhancing thrombin generation through different mechanisms, were developed for patients with hemophilia and may in the future be a good therapeutic option also in RBDs.

Pulmonary embolism in congenital bleeding disorders: intriguing discrepancies among different clotting factors deficiencies.

Pulmonary embolism is a complication of deep vein thrombosis. It occurs in the population with a normal clotting mechanism, but it may also occur in patients with congenital bleeding conditions. Here, we report on all cases of pulmonary embolism in congenital hemorrhagic disorders. All reported cases of pulmonary embolism in congenital coagulation disorders have been gathered by a time-unlimited PubMed search. Cross-checking of the references listed at the end of the single papers was carried out to avoid omissions. Seventy-two patients had an objectively demonstrated pulmonary embolism. The event occurred in patients with fibrinogen, factor V, factor VIII (FVII), FVIII, FIX, and FXI deficiency, and in those with von Willebrand's disease. No embolism was reported in FII, factor X, and FXIII deficiency. Thirty were women and 28 were men, whereas in the remaining 14 cases, sex was not reported. Age varied from 6 to 81 years (mean age 34.3 years). The management varied from only supportive to the administration of unfractionated heparin, low-molecular-weight heparin, and anti-vitamin K medications, accompanied by adequate replacement therapy. Evolution was fair or good in the majority of cases, but there were 10 fatalities. Risk factors were present in 61 patients. The most frequent of these were replacement therapy (35 cases), surgery (34), and old age (13). Some patients had more than one risk factor. Eleven patients had no risk factors. There are discrepancies in the prevalence of pulmonary embolism among different clotting disorders. The conditions most frequently affected are FVII deficiency and fibrinogen defects. The significance of the findings is discussed.

Clinical analysis of six cases of multiple myeloma first presenting with coagulopathy.

This is a retrospective study on six multiple myeloma patients with upfront coagulopathy and bleeding. A detailed description and analysis of clinical characteristics, coagulation factor deficiencies, treatments and outcome of those six multiple myeloma patients are presented. All six patients presented with significant bleeding. One patient was detected with single factor X deficiency and another with single factor VII (FVII) deficiency, whereas four other patients had complex factor deficiencies. The time from symptom presentation to diagnosis ranged from 3 to 10 months. After correct diagnosis and coagulation factor supplementation, those patients were treated with bortezomib/adriamycin/dexamethasone (PAD) or melphalan/dexamethasone/thalidomide (MTD) regimen. It took 29-71 days (median time 46 days) to completely correct coagulation factor deficiencies since the start of therapy for multiple myeloma. Multiple myeloma patients with acquired bleeding disorders may present with large, deep and multiple sites of haematoma or other types of significant bleeding, which may affect bone marrow examination in some of the cases. Patients may be easily misdiagnosed. The routine examinations of erythrocyte sedimentation rate, serum immunoglobulins and blood urine light chain are the key to diagnosis, hence requiring the treating physician to think broadly and look for traits suggesting myeloma as the underlying cause.

Surgical interventions in childhood rare factor deficiencies: a single-center experience from Turkey.

Congenital rare factor deficiencies may present in infancy by life-threatening bleedings or may not show any symptoms until adulthood. It is reported more commonly in countries having consanguineous marriages. Data regarding surgical interventions of rare congenital factor deficiencies are based on case reports and records of guidelines. There are no well documented and separately prepared directories related to pre-surgical and prophylactic approaches of surgical interventions of these deficiencies. Our retrospective study consisted of 171 rare factor deficiencies that were followed up in our clinic, and of whom 61 had 88 surgical interventions between 1990 and 2012. Of these patients, 45 were having factor VII deficiency, and factor V, X, XI, XIII and fibrinogen deficiencies were present in five, four, three, two and two patients, respectively. In 23 patients, factor coagulant activities were under 5% (37.7%), in 15 it was between 5 and 30% (24.6%), and in 23 between 30 and 50% (37.7%). Twenty-eight were symptomatic and 33 were asymptomatic. Information of 51 (83.6%) male and 10 (16.4%) female patients with an age range of 5-25 years (13 ±â€Š5.27), whose age at presentation ranged between 3 weeks and 18 years (7 ±â€Š4.66), were retrieved from patient records and from the records contained in the data-processing environment introduced in 2005. The rate of familial consanguinity was 49.2%. Of the surgical interventions, 24 (27.3%) were major, 24 (27.3%) were minor and 40 (45.4%) were circumcision. We used fresh frozen plasma in 32, recombinant factor (rF)VIIa in 20, prothrombin complex concentrate in five and fibrinogen in three patients during surgical interventions. In 18 patients, antifibrinolytic agents were also used. In 27 patients, surgical interventions were applied without any replacement therapy. No additional doses were required after surgical prophylaxis doses. Thrombotic events were not observed. Antibody occurrence was not detected in these patients. In our study, we evaluated preparation for surgical procedures, factor replacement therapy before surgical intervention and postoperative follow-up in patients with rare coagulation factor deficiency.

[Rare bleeding disorders and invasive procedures]. / Déficits rares de la coagulation et gestes invasifs.

Rare inherited bleeding disorders include fibrinogen disorders, and deficiencies of factors II (prothrombin), V, VII, X, XI, XIII, and combined V+VIII, and combined vitamin K-dependent factors, with general population prevalence rates between 1/500,000 and 1/2,000,000. These inherited disorders, transmitted as autosomal recessive traits, are characterized by a heterogeneous clinical presentation (asymptomatic, mild, moderate or severe bleeding tendency); this variability is more important for deficiencies with factor levels ranging from 5 to 50%. Individual bleeding risk assessment before an invasive procedure or during peri-partum period remains difficult, although an essential step to decide whether a substitution with clotting factor is necessary or not. Because there is a poor correlation between factor activity levels and the severity of bleeding symptoms, factor correction before an invasive procedure should not be based on factor level only, but physicians must also take into account the patient phenotype as well as the haemorrhagic risk of the procedure.

Concentrado de complejo protrombínico para el tratamiento de deficiencias congénitas o adquiridas en factores de coagulación / Concentrate of prothrombin complex for the treatment of congenital or acquired deficiencies in coagulation factors

INTRODUCCIÓN: Los FII, FVII, FIX y FX son denominados como factores de coagulación dependientes de vitamina K. La deficiencia adquirida de estos factores comúnmente ocurre durante el tratamiento de antagonistas de la vitamina K. Estas situaciones pueden ser revertidas por la suspensión del tratamiento con antagonistas de vitamina K, la administración de vitamina K o la administración de plasma fresco congelado (PFC). Sin embargo, en pacientes con hemorragia severa espontánea o inducida por traumatismo, o pacientes con riesgo de hemorragia que requieran una intervención de emergencia, la administración de concentrado de complejo protrombínico parece ser una opción más adecuada. La Hemofilia A (deficiencia de FVIII), B (deficiencia de FIX) y la enfermedad de von Willebrand (deficiencia de factor von Willebrand) representan la mayor parte los desórdenes de la coagulación congénitos. El tratamiento consiste básicamente en la reposición de los FVIII y FIX en dos modalidades: a demanda o preventivo. En Uruguay se encuentra incluido en el FTM únicamente el FVIII, el cual está indicado para el tratamiento y profilaxis de hemorragias en pacientes con hemofilia A (deficiencia congénita del factor VIII) y deficiencia adquirida del FVIII. Adicionalmente se encuentra disponible en el mercado nacional, pero no incluidos en el FTM el FVIIa, FVIII con factor de Willebrand y FIX. Octaplex® es un concentrado de complejo protrombínico (CCP) de administración intravenosa conteniendo como principios activos Factor II, Factor VII, Factor IX, Factor X, proteína C, proteína S y heparina.OBJETIVOS: Evaluar la eficacia y seguridad del concentrado de complejo protrombínico (CCP) para el tratamiento deficiencias congénitas o adquiridas en factores de coagulación. MÉTODOS: Se realizó una revisión sistemática de la evidencia clínica y posterior análisis de las principales variables de eficacia y seguridad. RESULTADOS: Los 2 principales estudios de Octaplex® incluyeron pacientes en tratamiento con anticoagulantes con hemorragia grave o que requerían de una intervención quirúrgica o de un procedimiento diagnóstico invasivo urgente. El estudio LEX-201 incluyó solamente 10 pacientes con hemofilia B o deficiencia del FVII, por lo que no fue considerado. Fueron identificados otros 10 estudios, los cuales evaluaron otras marcas comerciales con similar composición a Octaplex®. Esto hace que los resultados deban ser considerados con cautela, principalmente los de seguridad. Los ensayos fueron mayormente no controlados y con bajo número de pacientes, por lo que la calidad de la evidencia no es óptima. Los pacientes tratados con CCP (Octaplex®) presentaron una reducción del INR a partir de los 10 a 15 minutos post-infusión, al igual que un aumento en las concentraciones de los factores de coagulación. En cuanto a seguridad, el tratamiento con CCP principalmente puede producir transmisiones virales como hepatitis A u otros (4 de 80 pacientes) y aumento en la incidencia de eventos tromboembólicos. DISCUSIÓN: El producto Octaplex® es utilizado desde hace varios años en distintos países, sin embargo cuenta con una reducida evaluación clínica. En particular, no tiene ningún ensayo clínico finalizado comparando Octaplex® versus PFC. La falta de evidencia no permite conocer la eficacia y seguridad de Octaplex® en el tratamiento de deficiencias congénitas en factores de coagulación dependientes de vitamina K, siendo los ensayos mayormente en población con deficiencias adquiridas. CONCLUSIONES: La inclusión del CCP al FTM puede presentar beneficios clínicos en el tratamiento de pacientes que requieren de profilaxis, reposición perioperatoria y tratamiento de hemorragias graves con deficiencia adquirida de factores de coagulación del complejo protrombínico, cuando sea requerida una corrección rápida de la deficiencia. No hay suficiente evidencia clínica que permita recomendar la utilización de CCP en otras indicaciones. Previo a la toma de decisión, es necesario contar con un impacto presupuestal de la inclusión de este medicamento desde la perspectiva del sistema de salud.(AU)

Therapeutic recombinant murine activated protein C attenuates pulmonary coagulopathy and improves survival in murine pneumococcal pneumonia.

BACKGROUND: Recombinant human activated protein C (APC) improves survival of patients with severe sepsis; this beneficial effect is especially apparent in patients with pneumococcal pneumonia. The aim of this study was to determine the effect of APC treatment initiated after induction of pneumococcal pneumonia on pulmonary coagulation, inflammation, and survival, with or without concurrent antibiotic therapy. METHODS: Mice were infected intranasally with viable Streptococcus pneumoniae and were treated intraperitoneally after 24 h of infection with vehicle, recombinant mouse (rm) APC (125 µg), ceftriaxone (500 µg), or rm-APC plus ceftriaxone. Treatment with rm-APC or vehicle was repeated every 8 h for a maximum of 96 h. Animals were either killed 48 h after infection or were monitored in a survival study (with an extra dose of ceftriaxone given after 72 h). RESULTS: Rm-APC treatment inhibited pulmonary activation of coagulation, as reflected by lower levels of thrombin-antithrombin complexes and D-dimer. Rm-APC did not affect the pulmonary levels of 55 inflammatory mediators in the context of antibiotic therapy. Rm-APC added to ceftriaxone markedly improved survival, compared with ceftriaxone treatment alone. CONCLUSIONS: Rm-APC inhibits pulmonary activation of coagulation and, when added to antibiotic therapy, improves survival in murine pneumococcal pneumonia.

Novel splice site mutations in the gamma glutamyl carboxylase gene in a child with congenital combined deficiency of the vitamin K-dependent coagulation factors (VKCFD).

Congenital combined deficiency of the vitamin K-dependent coagulation factors is a rare bleeding disorder caused by either a defect in the gamma-glutamyl carboxylase or the vitamin K epoxide reductase enzyme complex. The diagnosis should be considered when vitamin-K dependent factor activities are decreased and liver dysfunction, vitamin K deficiency, and factitious coumarin ingestion have been excluded. We report a case of VKCFD in a child resulting from compound heterozygosity for two novel splice site mutations of the gamma-glutamyl carboxylase gene. Oral vitamin K supplementation resulted in partial resolution of proteins and complete resolution of bleeding.

Pharmacokinetics of protein C and antithrombin in the fetal lamb: a model to predict human neonatal replacement dosing.

BACKGROUND: The preterm infant is at risk for consumptive coagulopathy and thrombosis due to late maturation of coagulation regulatory proteins. Replacement proteins are available, but neonatal pharmacokinetic data are lacking. OBJECTIVE: The objective was to determine the pharmacokinetic properties of antithrombin (AT) and protein C (PC) in order to provide data for estimating doses in human infants. METHODS: A catheterized ovine model was used to determine pharmacokinetic properties of AT and PC, including plasma recovery, volume of distribution (V(d)), clearance (Cl) and half-life (t((1/2))), in the fetal lamb relative to the ewe. RESULTS: AT studies showed statistically significant differences between ewes and fetuses in recovery (p < 0.0001), V(d) (p = 0.0002) and Cl (p < 0.0001). The AT t((1/2)) was significantly shortened among fetuses (5.55 h, 95% CI: 4.01-7.08) compared to ewes (18.7 h, 95% CI: 11.6-25.8). PC recovery (p < 0.0001), V(d) (p < 0.0001) and Cl (p = 0.004) differed significantly between ewes and singleton fetuses as did the t((1/2)): 3.86 h (95% CI: 3.35-4.36) and 11.9 h (95% CI: 10.9-12.9) in the singletons and ewes, respectively. All PC parameters were significantly different for twins compared to ewes. CONCLUSIONS: AT and PC show decreased recovery and t((1/2)) in the fetal lamb. These data can be used to estimate dosing for human neonates in comparison with human adult dosing recommendations.

Further understanding of recombinant activated factor VII mode of action.

Recombinant activated factor VII (rFVIIa) is being increasingly used to treat bleeding associated with a variety of non-hemophilic coagulopathic indications, and its mechanism of action in these areas is under active investigation. Numerous studies have shown that FVIIa binds with low affinity to activated platelets; rFVIIa can subsequently enhance platelet-surface thrombin generation by activating factor (F) X and by contributing additional FIXa to the hemostatic process. This FIXa can rapidly activate additional FX, which may explain why non-hemophilic coagulopathic bleeds respond to lower doses of rFVIIa than do hemophilic bleeds. However, the platelet surface may be able to process only a limited amount of FXa, accounting for the observation that some models of non-hemophilic coagulopathy show a plateau in the effect of rFVIIa.

Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders.

Desmopressin (DDAVP) affects haemostasis by the release of von Willebrand factor and coagulation factor VIII from endothelium. The aim of the study was to evaluate the results of DDAVP testing in paediatric patients with congenital bleeding disorders. Forty-one patients consisting of children with von Willebrand's disease (VWD, n = 26) and platelet function defects (PFD, n = 15) received DDAVP intravenously at a dosage of 0.3 mug/kg over 30 min. FVIII activity (FVIII), von Willebrand factor antigen (VWF:Ag), collagen-binding activity (VWF:CB) and PFA 100((R)) closure times (CT) were measured before, 60, 120 and 240 min after DDAVP. In VWD, the VWF:Ag increased threefold until 60 min and then it decreased continuously. Compared with baseline, VWF:Ag was significantly higher at 60 and 120 min but not at 240 min. In contrast, in PFD, the peak of VWF:Ag was reached after 120 min. Two hundred and forty minutes after DDAVP, the mean was still significantly elevated compared with baseline values. The course of VWF:CB corresponded to that of VWF:Ag. In patients with VWD and PFD, FVIII rose two- to threefold within 2 h after DDAVP. CT in patients with VWD shortened markedly within 120 min and then rose again. In all children with PFD, except one non-responder, the CT shortened within 240 min after DDAVP. Two non-responders with VWD were identified by the failed increase of VWF:Ag, VWF:CB and by prolonged CT. Haemostatic effects of DDAVP differ interindividually and dependent on the coagulation disorder. DDAVP was effective in most, but not in all patients. DDAVP testing is recommended to determine the individual haemostatic response.

Prerequisites for recombinant factor VIIa-induced thrombin generation in plasmas deficient in factors VIII, IX or XI.

BACKGROUND: Recombinant factor VIIa (rFVIIa) used for the treatment of hemophilia A or B patients with an inhibitor is hemostatically effective because it induces thrombin generation (TG), despite grossly impaired FVIII- and FIX-dependent amplification of FX activation. Tissue factor (TF) and or activated platelets were shown to be essential for the rFVIIa activity. OBJECTIVE: To evaluate the relative effects of TF and phospholipids on rFVIIa-induced TG in FVIII-, FIX- and FXI-deficient plasmas. METHODS: Phospholipids had an independent effect that was augmented by TF. The contribution of blood-borne TF in FVIII-, FIX- and FXI-deficient plasma to rFVIIa-induced TG was demonstrated by removing microparticles and use of anti-TF antibodies. RESULTS: At increasing concentrations of rFVIIa, the dependence of rFVIIa-induced TG on TF declined, but the presence of phospholipids was essential. rFVIIa was also shown to activate purified FIX and FX in the presence of phospholipids and absence of TF. rFVIIa-induced TG was dramatically augmented in FVIII- or FIX-deficient plasma in which the level of FVIII or FIX was increased to 1 or 2 U dL(-1). CONCLUSIONS: The data indicate that rFVIIa-induced TG is affected by TF, phospholipids, rFVIIa concentration, and the presence of FVIII and FIX.

Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors.

The Italian Association of Haemophilia Centres reviewed and finally approved in November 2004 the new Italian Guidelines for the diagnosis and treatment of patients with clotting factor inhibitors. The recommendations have been based on the identification of levels of clinical evidence derived from the systematic review carried out in 2003 by the School of Health and Related Research, the University of Sheffield, UK, and further integrated by clinical studies published from 2003 to 2004. The Italian guidelines consist of six major domains concerning inhibitor definition, epidemiology, risk factors, diagnosis, inhibitor eradication, management of bleeding episodes, in patients with congenital and acquired coagulation disorders, with 121 statements, 59 synthesis and 54 recommendations. We report here recommendations and open issues concerning the diagnosis and monitoring of inhibitors, inhibitor eradication and the management of bleeding in patients with haemophilia A and B.

Antidotes to haemorrhage: recombinant factor VIIa.

Recombinant Factor VIIa (rFVIIa) concentrates were originally developed to treat the refractory bleeding complications associated with allo-antibody inhibitors in hemophilias A and B. As experience was gained in the hemophilias, the physiology of rFVIIa and its successes in controlling bleeds stimulated rFVIIa use in other challenging medical conditions complicated by bleeding. Thus, rFVIIa has assumed the role of a 'universal pancoagulant' without sufficient evidence-based data from well-designed, adequately powered clinical trials. This chapter discusses the anecdotal experience with rFVIIa based upon the few controlled trials that do exist, and emphasizes that these empirical dosing strategies have not yielded the best approach to achieve effective control of bleeding. Evidence-based data are necessary to establish the cost-benefit and risk-benefit profiles of rFVIIa, and to establish it as a standard treatment for bleeding.