凝血酶生成试验在遗传性凝血因子缺陷症患者出血评估中的价值

目的 探讨遗传性凝血因子V(FV)、X(FX)和XI(FXI)缺陷及FV和凝血因子VⅢ(FVⅢ)联合缺陷(F5F8D)患者的血浆凝血因子活性、凝血酶生成曲线各参数和临床出血症状之间的关系.方法 采集遗传性FV(n=24)、FX(n=14)和FXI(n=18)缺陷及F5F8D(n=8)患者及携带者的外周血进行常规出凝血检...     

Prevalence of hemorrhagic ovarian cysts in patients with rare inherited bleeding disorders

BackgroundIn comparison with the general population, women with bleeding disorders are more prone to develop obstetrical and gynecological problems. However, no comprehensive evaluation has investigated the prevalence of hemorrhagic ovarian cysts (HOCs) in rare bleeding disorders (RBDs). In this study, we sought to determine the prevalence of HOCs in a large cohort of Iranian patients with RBDs.MethodsA total of 210 symptomatic patients suspected of HOCs with RBD were included. The median age of the study population was 24 years. Patients were diagnosed with fibrinogen disorders (n = 7, 3%), factor (F) II (n = 4, 2%), FV (n = 28, 13%), FVII (n = 4, 2%), FX (n = 6, 3%), FXIII (n = 122, 58%), combined FV and FVIII (n = 8, 4%), Glanzmann’s thrombasthenia (n = 10, 5%), and von Willebrand disease (VWD) type 3 (n = 21, 10%).ResultsFollowing further clinical and ultrasound examinations of these 210 patients, 68 (32.4%) were confirmed with a diagnosis of HOCs. Of which, FXIII deficiency with 46 cases (67.6%), followed by VWD type 3 (6 cases, 8.8%) showed the highest number. Other coagulation defects associated with HOCs were including fibrinogen deficiency (n = 2, 3%), FII (n = 2, 3%), FV (n = 4, 6%), FVII (n = 2, 3%), FX (n = 1, 1.5%), combined FV and FVIII (n = 2, 3%), and Glanzmann’s thrombasthenia (n = 3, 4.5%).ConclusionThis study found a high prevalence of HOCs in patients with RBDs, indicating the importance of early diagnosis and optimal management of obstetric and gynecological complications in these patients.     

Factor XIII – an under diagnosed deficiency – are we using the right assays?

Summary. Background: The clot solubility test is the most widely used method for detection of factor (F)XIII deficiency. However, it will only detect severe deficiencies; consequently mild deficiencies and heterozygous states are probably under diagnosed. Objective: As an alternative first‐line screening test, we assessed an automated quantitative ammonia release assay (QARA). Patients/methods: Inter‐assay imprecision was evaluated with commercial normal and pathological control plasmas (10 replicates on each of 5 days). Using the QARA and other commercial assays a comparative assessment of congenital (FXIII range < 1–70 u dL^?1, n = 9) and acquired (n = 43) deficiencies was made. We also investigated the prevalence of acquired deficiencies in hospitalized patients using residual samples from adult patients (n = 1004) and from a paediatric intensive care unit (ICU, n = 56). Results: Assay imprecision was acceptably low (normal control: mean 86.6 u dL^?1; cv = 2.0%; pathological control: mean 27.5 u dL^?1; cv = 3.8%). Using an iodoacetamide blanking procedure, the QARA results (FXIII range < 1–70 u dL^?1) exhibited close agreement with those from an immuno‐turbidometric FXIII A‐subunit (FXIII‐A) method. There was also good correlation (R² ≥ 0.89) between the QARA (range 20–180 u dL^?1), a second chromogenic assay, the FXIII‐A and FXIII A+B‐subunit ELISA. We found that 21% of samples from adult patients had FXIII levels < 70 u dL^?1 (mean normal ± 2 SD 73–161 u dL^?1) with 6% < 50 u dL^?1. Within the paediatric ICU samples, 52% were < 70 u dL^?1, with 21% < 50 u dL^?1. Conclusions: Our data demonstrates that the automated assay is sensitive, highly reproducible and the results from clinical samples suggest that acquired FXIII deficiency is a relatively common phenomenon in hospital patients after surgery and in ICU.     

Fresh frozen plasma prepared with amotosalen HCl (S-59) photochemical pathogen inactivation: transfusion of patients with congenital coagulation factor deficiencies

BACKGROUND: Photochemical treatment (PCT) with amotosalen HCl (S-59) was developed to inactivate pathogens and white blood cells in plasma (PCT-FFP) used for transfusion support. STUDY DESIGN AND METHODS: An open-label, multicenter trial was conducted in patients with congenital coagulation factor deficiencies (factors [F]I, FII, FV, FVII, FX, FXI, and FXIII and protein C) to measure the kinetics of specific coagulation factors, hemostatic efficacy, and safety of PCT-FFP. Posttransfusion prothrombin time (PT), partial thromboplastin time (PTT), and clinical hemostasis were evaluated before and after PCT-FFP transfusions. RESULTS: Thirty-four patients received 107 transfusions of PCT-FFP for kinetic studies or therapeutic indications (mean dose, 12.8 +/- 8.5 mL/kg). Incremental factor recoveries ranged from 0.9 to 2.4 IU per dL per IU per kg (FII, FV, FVII, FX, FXI, and protein C). Mean pretransfusion PT (20.7 +/- 22.2 sec) corrected after PCT-FFP (13.8 +/- 2.4 sec, p < 0.001). Mean pretransfusion PTT (51.2 +/- 29.3 sec) corrected after PCT-FFP (32.0 +/- 5.1 sec, p < 0.001). Thirteen patients required 77 transfusions for therapeutic indications. PCT-FFP provided effective hemostasis and was well tolerated. CONCLUSIONS: Replacement coagulation factors in PCT-FFP exhibited kinetics and therapeutic efficacy consistent with conventional FFP.     

Activity of clotting factors in fresh-frozen plasma during storage at 4°C over 6 days

BACKGROUND: Fresh-frozen plasma (FFP) requires thawing, which delays availability. We investigated clotting factor activity and bacterial contamination of FFP when stored at 4°C ± 2°C for 6 days.
STUDY DESIGN AND METHODS: Plasma of 20 healthy plasma donors was sampled, frozen, and analyzed at baseline and repeatedly over a period of 6 days after thawing. The activity of fibrinogen, Factor (F)II, FV, FVII, FVIII, F IX, FX, XI, FXII, FXIII, antithrombin III (ATIII), von Willebrand factor antigen (VWF-Ag), protein C (PC), and free protein S (FPS) were determined and analyzed over time.
RESULTS: Immediately after thawing there was a significant decrease of fibrinogen (−9%), FII (−7%), FV (−14%), FVII (−12%), FX (−11%), FXIII (−20%), PC (−7%), and ATIII (−4%), whereas FVIII (+8%), F IX (+1%), FXI (+11%), FXII (−1%), FPS (−1%), and VWF-Ag (−6%) remained stable without significant change. Over 6 days after thawing fibrinogen, ATIII (+2%) and VWF-Ag (+2%) remained stable whereas FXII (+2%), FXIII (+6%), and PC (+3%) changed significantly over time and increased at the end. FII (−8%), FV (−16%), FVII (−31%), FVIII (−47%), F IX (−12%), FX (−10%), FXI (−25%), and FPS (±0%) changed also significantly over time and decreased at the end. All clotting factors and inhibitors remained within the reference range requested by quality assurance regulations. No FFP bag showed bacterial contamination.
CONCLUSION: This provides evidence for maintaining quality of thawed FFP and may improve rapid availability in emergency situations and reduce cost for health care givers.     

Whole blood clot formation phenotypes in hemophilia A and rare coagulation disorders. Patterns of response to recombinant factor VIIa

Summary. Until now, no routinely used clotting assay has demonstrated the power to reflect significantly a patient's response to recombinant factor (rF)VIIa. Adopting a thrombelastographic principle, profiles of continuous whole blood (WB) coagulation were studied in minimally altered WB activated with a small amount of tissue factor (TF). Investigation of the WB clotting profile was performed before and after ex vivo addition of rFVIIa 20 nm to WB from 26 patients with hemophilia A, two patients with severe hemophilia B, and individuals with deficiencies of FV, FX, FXI, and FXIII. In five patients with hemophilia plus inhibitors, the response to ex vivo added rFVIIa and to activated complex concentrate (APCC) was studied. Patients with severe and moderate hemophilia A demonstrated remarkable variance in the hemostatic characteristics at baseline, even in groups with the same FVIII:C activity levels. The response to rFVIIa at 20 nm also varied extensively, the effect correlating with the continuous WB coagulation phenotype at baseline. This indicates that the efficacy of rFVIIa may be optimized by tailoring the dose according to the hemostatic response to varying doses tested prior to in vivo administration. In patients with inhibitors against FVIII and factor IX, rFVIIa and APCC substitution resulted in quite similar response patterns that appeared to be dose dependent. In severe FV, FX, and FXIII‐deficient WB, rFVIIa addition induced minor changes only. In FXI deficiency, rFVIIa normalized the dynamic properties of clotting, although a reduced clot firmness remained unchanged. In conclusion, the thrombelastographic analysis of WB clotting, as activated with a minute amount of TF, seems an interesting method that detects phenotypic variation amongst hemophilia patients. The method appears useful for assessment of the hemostatic capacity and it seems a promising tool for evaluation of the individual response to rFVIIa or APCC before and during in vivo administration.     

Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study

Summary. Background/Objectives: Age‐related changes in blood coagulation and fibrinolysis are associated with increased risk of thrombotic events. Inherited deficiencies of coagulation proteins, such as factor V (FV) Leiden and prothrombin G20210A, explain a small fraction of venous thromboembolic disease (VTE). Additional genetic factors are likely to underlie the etiology of VTE, some of which may become manifest at older ages. Methods: We tested 290 common SNPs within 51 thrombosis and inflammation genes for association with VTE in the Cardiovascular Health Study, a large, prospective cohort of older adults followed for up to 12 years. Results: There were 184 VTE events that occurred at mean age of 78 years. TagSNPs within four genes encoding FXIII subunit A (F13A), FVII activating protease (HABP2), protease activated receptor‐1 (F2R) and the urokinase receptor (PLAUR) showed the strongest evidence for association with VTE, with each gene having a global P‐value < 0.05 and at least one tagSNP false discovery rate (FDR) q‐value < 0.05. The rs3024409 variant allele of F13A1 was associated with 1.66‐fold increased risk of VTE, while the minor alleles of HABP2 rs6585234 and rs3862019, F2R rs253061 and rs153311, and PLAUR rs344782 were each associated with lower risk of VTE (hazard ratios in the range of 0.49–0.66). Consistent with the observed protective association for VTE risk, the HABP2 rs3862019 variant allele was also associated with lower activity levels of coagulation factors FVIII, FIX, FX and plasminogen. We also confirm previously reported associations between common variants of the coagulation FII, FV, FVIII, FXI, alpha‐fibrinogen and protein C genes and risk of VTE. Conclusions: These findings suggest that several novel common coagulation gene variants may be related to risk of VTE in older adults. Further studies in older adults are needed to validate these findings and assess functional molecular mechanisms.     

Management of rare coagulation disorders in 2018

Rare bleeding disorders (RBDs) comprise inherited deficiencies of factors I (fibrinogen), II (prothrombin), V, VII, X, XI, and XIII as well as combined factor V?+?VIII and vitamin K-dependent factors. They represent 3–5% of all congenital bleeding disorders and are usually transmitted as autosomal recessive traits. These disorders often manifest during childhood and have varied clinical presentations from mucocutaneous bleeding to life-threatening symptoms such as central nervous system and gastrointestinal bleeding. Bleeding manifestations generally vary within the same RBD and may also vary from 1 RBD to the other. Laboratory diagnosis is based on coagulation screening tests and specific factor assays, with molecular techniques providing diagnostic accuracy and enabling prenatal counseling. The approach to treatment of bleeding episodes and invasive procedures needs to be individualized and depends on the severity, frequency and procedure-related risk of bleeding. The first line of treatment of RBDs is replacement of the deficient factor, using specific plasma-derived or recombinant products and using fresh frozen plasma or cryoprecipitate when specific products are not available or in resource-limited countries. Prophylaxis may be considered in individuals with recurrent serious bleeding and especially after life-threatening bleeding episodes. Novel no-replacement strategies promoting hemostasis by through different mechanisms need to be studied in RBDs as alternative therapeutic options.     

Preoperative management of factor XI deficiency with therapeutic plasma exchange: A case report and literature review

Patients with factor XI deficiency may have bleeding complications during surgery. Because bleeding severity and factor levels correlate poorly, factor replacement needs to be personalized based on bleeding history and type of procedure. We report a 65‐year‐old male with factor XI deficiency (7 IU dL^?1) who presented before scheduled hip arthroplasty. He had a history of total hip arthroplasty complicated by bleeding, delayed healing and prosthesis removal, despite receiving prophylactic treatment with plasma infusion. For the current surgery a factor XI ≥50 IU dL^?1 level was targeted. The calculated plasma infusion needed to achieve this goal was 3100 mL (14 U). Because of concerns about circulatory overload and inability to achieve target by simple infusion, prophylactic treatment with therapeutic plasma exchange (TPE) was requested. TPE was performed the morning before the surgery, using 100% plasma as replacement fluid (3912 mL of plasma), and a positive fluid balance of 631 mL. Factor XI activity level was 51 IU dL^?1 immediately post TPE. The patient received daily infusions of 3 U (～ 660 mL) of plasma to maintain a factor XI level of 30 IU dL^?1 until post‐operative day 7. Aminocaproic acid was given during the surgery and until post‐operative day 10. There were no bleeding or thrombotic complications. Conclusion: TPE was effective in increasing factor XI levels; it was well tolerated and did not result in circulatory overload. TPE can be considered when therapeutic factor levels cannot be achieved by simple plasma infusion, or when circulatory overload is a concern. J. Clin. Apheresis 31:579–583, 2016. © 2015 Wiley Periodicals, Inc.     

巴曲亭及其有效成分对出血性疾病患者凝血功能的影响

本研究旨在观察巴曲亭及其有效成分的止血机理及对出血性疾病凝血功能的影响。采用全自动血凝仪检测巴曲亭及其有效成分巴曲酶与凝血因子Ⅹ激活物(FⅩA)对正常人及出血性疾病患者血浆的活化部分凝血活酶时间(APTT)与凝血酶原时间(PT)的影响,用发色底物法检测FⅩA、巴曲酶及巴曲亭对凝血因子Ⅹ(FⅩ)活化及凝血酶生成的影响。结果表明:巴曲亭及其有效成分可以缩短正常人血浆的APTT,其中FⅩA缩短APTT的作用在一定浓度范围内存在量效关系(r=0.889,P<0.05)。FⅩA、巴曲酶及巴曲亭可纠正出血性疾病患者APTT的延长,三者对PT无明显影响。FⅩA能促进FⅩ的活化及凝血酶的生成,巴曲酶及巴曲亭对二者无明显作用。结论:巴曲亭有明显的促进凝血效果,并可纠正出血性疾病的止血异常,其有效成分巴曲酶直接作用于纤维蛋白原,而FⅩA通过活化FⅩ促使凝血酶的生成。     

Advances in the treatment of bleeding disorders

Historically, the bleeding episodes in subjects with coagulation disorders were treated with substitution therapy, initially with whole blood and fresh frozen plasma, and more recently with specific factor concentrate. Currently, patients with hemophilia have the possibility of choosing different effective and safe treatments, including novel extended half‐life and alternative hemostatic drugs. The availability of novel extended half‐life products could probably overcome current prophylaxis limitations, particularly in hemophilia B patients, by reducing the frequency of injections, achieving a higher trough level, and improving the quality of life of the patients. In addition, subcutaneous administration of alternative therapeutics would simplify prophylaxis in patients with hemophilia A and B with and without inhibitors. Regarding von Willebrand disease, a recombinant von Willebrand factor was recently developed to control bleeding episodes in patients with this disease, in addition to available von Willebrand factor/factor VIII concentrates. The management of patients affected by rare bleeding disorders (RBDs) is still a challenge, owing to the limited number of specific products, which are mainly available only in countries with high resources. Some improvements have recently been achieved by the production of new recombinant factor (F) XIII A subunit‐derived and FX plasma‐derived products for the treatment of patients affected by FXIII and FX deficiency. In addition, the development of novel alternative therapeutics, such as anti‐tissue factor pathway inhibitor, ALN‐AT3, and ACE910, for patients with hemophilia might also have a role in the treatment of patients affected by RBDs.     

The influence of riboflavin photochemistry on plasma coagulation factors

Studies with riboflavin in the 1960s showed that it could be effective at inactivating pathogens when exposed to light. The principal mode of action is through electron transfer reactions, most importantly in nucleic acids. This suggested that it could act as a photosensitizer useful in the inactivation of pathogens found in blood products.

Objective

To study the influence of photo-inactivation with riboflavin on the coagulation factors of plasma.

Methods

The photo-inactivation procedure of riboflavin plus light was applied. Fifty isogroup pools of two plasmas were made from 100 U of plasma that were derived from whole blood products that had previously been held overnight. Pools were split into two bags. One of them was photo-inactivated, and post inactivation samples were obtained. The second bag was not photo-inactivated and samples were taken. Total protein, fibrinogen, FII, FV, FVII, FVIII, FIX, FX, FXI, FXIII, antithrombin III, PC, PS, α-2 antiplasmin and vWF:Ag, the multimeric structure of vWF and ADAMTS-13 were analyzed.

Results

In plasma, the proteins most sensitive to photo-inactivation were fibrinogen, FXI, FVIII, FV, and FIX (33%, 32%, 30%, 18% and 18% loss, respectively). Coagulation inhibitors, PS, antithrombin III and PC showed little decrease (all 2%). Retention of vWF and ADAMTS-13 were 99% and 88%, respectively.

Conclusions

As with other pathogen reduction procedures for plasma products, treatment with riboflavin and UV light resulted in reduction in the activity levels of several pro-coagulant factors. Coagulation inhibitors are well preserved.     

Interaction between oral contraceptive use and coagulation factor levels in deep venous thrombosis

Summary.  Deep venous thrombosis is a multicausal disease, i.e. more than one risk factor needs to be present to cause the disease. Oral contraceptive use increases the risk of venous thrombosis but since not all women using oral contraceptives develop thrombosis, the presence of additional risk factors in patients is likely. The aim of this study was to assess the joint effect of oral contraceptive use and the levels of procoagulant factors (F)(FII, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII and fibrinogen). Data of premenopausal women were re-analyzed in the Leiden Thrombophilia Study. The highest relative risks were observed for the combination of oral contraceptive use and high levels (>90th percentile) of FII (Odds Ratio [OR]_OC+FII 10.1; 95% confidence interval [CI] 3.5–29.0), FV (OR_OC+FV 12.6; 95% CI 3.8–41.5), and FXI (OR_OC+FXI 11.9; 95% CI 3.6–39.2) and low levels (< 10th percentile) of FXII (OR_OC+FXII 12.3; 95% CI 2.4–63.0). No interaction was observed between oral contraceptive use and high levels of the other coagulation factors, i.e. the joint effect of these risk factors did not exceed the sum of the separate effects. The results of this study indicate that the risk for the joint effects of oral contraceptive use and coagulation factor levels are minor compared with the joint effect of oral contraceptive use and the FV Leiden mutation (RR > 30).     

Effect of gamma irradiation with 30 Gy on the coagulation system in leukoreduced fresh-frozen plasma

BACKGROUND: The aim of this study was to investigate the effect of gamma irradiation with 30 Gy on the coagulation system in leukoreduced fresh-frozen plasma (FFP). STUDY DESIGN AND METHODS: In 74 FFP units that had been stored for 352 +/- 103 days below -30 degrees C, the following variables were determined in parallel in an irradiated and not irradiated half: prothrombin time (PT); activated partial thromboplastin time (APTT); thrombin time; antithrombin III; protein C; protein S; von Willebrand factor antigen; ristocetin cofactor; plasminogen-alpha(2)-antiplasmin; the coagulation factors fibrinogen, factor (F)II, FV, FVII, VIII, F IX, FX, FXI, FXII, FXIII, and activated factor XII (FXIIa); D-dimer; fibrin monomer; thrombin-antithrombin complex; prothrombin fragment 1 + 2 (F1+2); plasmin-alpha(2)-antiplasmin complexes (PAPs); and platelet factor 4. The FVII activity ratio was assayed to quantify activation of FVII. RESULTS: Irradiation with 30 Gy resulted in a reduction of APTT (35.0 +/- 4.1 sec vs. 34.4 +/- 4.1 sec; p = 0.00000006) and PT (89.8 +/- 8.2% vs. 90.7 +/- 8.0%; p = 0.002) and a significant increase of the activities of the coagulation factors FII, FV, FVII, F IX, FX, and FXII. FVIII activity decreased from 118 +/- 31 to 116 +/- 32 percent (p = 0.02). Activation of the coagulation system was shown by an increase in the FVII activity ratio (1.19 +/- 0.29 vs. 1.31 +/- 0.34; p = 0.0000001), FXIIa (0.81 +/- 0.50 ng/mL vs. 0.90 +/- 0.51 ng/mL; p = 0.006), and F1+2 (1.19 +/- 0.20 nmol/L vs. 1.24 +/- 0.20 nmol/L; p = 0.000005) after irradiation with 30 Gy, whereas an increase of PAP (16.2 +/- 11.5 ng/mL vs. 20.2 +/- 12.0 ng/mL; p = 0.0004) demonstrated activation of the fibrinolytic system. No negative influence of irradiation with 30 Gy on inhibitors of coagulation was observed. CONCLUSION: Gamma irradiation of leukoreduced FFPs with 30 Gy results in a significant but very weak activation of the coagulation and fibrinolytic system in FFPs.     

Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias

Summary.  A North American registry for rare bleeding disorders [factor (F)II, factor (F)VII, factor (F)X, factor (F)V, factor (F)XIII, fibrinogen deficiencies and dysfibrinogenemias] was established to gather information about disease prevalence, genotyping frequency, diagnostic events, clinical manifestations, treatment and prophylaxis strategies, as well as disease- and treatment-related complications. Questionnaires were sent to 225 hemophilia treatment centers in the USA and Canada. Among 26% of responding centers, 294 individuals [4.4% of the registered children (200/4583) and 2.4% of adults (94/3809)] were diagnosed with one or more of the rare bleeding disorders (RBDs) included in this survey. The ethnic distribution for each disorder paralleled that of the general US population with the exception of the disproportionately large number of Latinos with FII deficiency. Only 5.4% of affected individuals were genotyped. An abnormal preoperative bleeding screen most often led to diagnosis. The most common coagulopathy was FVII deficiency; however, 40% of homozygous patients were asymptomatic. FX and FXIII deficiencies caused the most severe bleeding manifestations. Among all RBDs, the most common sites of bleeding were skin and mucus membranes. Multiple products were used to treat hemorrhage; however, half of the bleeding episodes required no therapy. The majority of patients suffered no long-term complications from hemorrhage. Treatment-related complications included viral seroconversion, anemia, allergic reactions and venous access device-related events. This registry provides the most comprehensive information to date about North American individuals with RBDs and could serve as an important resource for both basic scientist and clinician.     

Thrombin generation assay using factor IXa as a trigger to quantify accurately factor VIII levels in haemophilia A

Summary. Background: The available methods for measuring factor VIII (FVIII) activity suffer reportedly from lack of sensitivity and precision in the < 1 IU dL^?1 range. This precludes correlation of clinical phenotype with FVIII levels. Objectives: To study a possible association between clinical phenotype in patients with FVIII levels < 1 IU dL^?1. Methods/Results: The FIXa‐driven FVIII assay (FVIII‐CAT) has a detection limit of 0.05 IU dL^?1. For the range of 0–2 IU dL^?1 FVIII, the intra‐assay coefficient of variation (CV) is around 2% and the inter‐assay CV is about 8%. We tested 30 hemophiliacs with FVIII:C between < 1 and 6 IU dL^?1 as measured in the one‐stage clotting assay using the FVIII‐CAT assay. For genetic defects related to moderate hemophilia, the FVIII‐CAT test finds FVIII levels that are in good agreement with those determined with the one‐stage assay. Of the 21 hemophilic patients with FVIII < 1 IU dL^?1, four patients exhibited a mild bleeding phenotype. When we applied TF‐initiated thrombin generation, patients with a mild clinical phenotype showed significantly higher endogenous thrombin potentials. Conclusion: The novel developed FVIII assay measures accurately FVIII levels below 1 IU dL^?1. Its application demonstrated that the clinical heterogeneity in individuals with < 1 IU dL^?1 FVIII is not associated with their FVIII level.     

Population pharmacokinetic modeling for dose setting of nonacog beta pegol (N9‐GP), a glycoPEGylated recombinant factor IX

Summary. Background: nonacog beta pegol (N9‐GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half‐life. Objectives: To provide information on potential dose regimens for N9‐GP for phase 3 pivotal and surgery trials. Methods: A population pharmacokinetic model was developed from single‐dose data derived from the first human‐dose trial with N9‐GP in hemophilia B patients, and was used to extrapolate to steady‐state conditions for different N9‐GP dose regimens for prophylaxis. The model was also used to compare prophylaxis using N9‐GP with standard prophylactic regimens using rFIX or plasma‐derived (pd) FIX (40 IU kg^?1 every third day). Plasma activity following dosing with N9‐GP, rFIX and pdFIX for surgery and on‐demand treatment of bleeds was also simulated. Results: A linear two‐compartmental model best described the pharmacokinetic profiles of N9‐GP, rFIX and pdFIX. A prophylactic regimen of 10 U kg^?1 N9‐GP once weekly predicted mean peak and trough levels of 18 and 4.2 U dL^?1, while 40 U kg^?1 once weekly predicted values of 72 and 17 U dL^?1, respectively. Standard prophylactic regimens with rFIX and pdFIX predicted mean peak and trough levels of 34 and 3.9 IU dL^?1 for rFIX, and mean values of 43 and 2.1 IU dL^?1 for pdFIX. Additional simulations predicted significantly reduced dosing frequency and factor concentrate consumption for N9‐GP vs. rFIX and pdFIX for surgery and the treatment of bleeds. Conclusions: N9‐GP may allow prophylaxis, surgical dosing regimens and on‐demand treatment of bleeding episodes with less frequent injections and lower factor concentrate consumption; this possibility is being investigated in prospective clinical trials.     

Post‐dental extraction bleeding: Emphasis on the diagnosis of rare coagulation disorders

Disorders of the fibrin stabilizing and fibrinolytic pathway should be considered in patients with excessive postsurgical bleeding with normal screening tests of hemostasis. History, clinical assessment of the timing and severity of bleeding along with utilization of advanced tests such as global hemostasis assays and appropriate coagulation factor assays (especially FXIII) will aid in the diagnosis.     

Factor XI promotes hemostasis in factor IX‐deficient mice

Essentials

• Mice lacking factor IX (FIX) or factor XI (FXI) were tested in a saphenous vein bleeding model.
• FIX‐deficient mice displayed a hemostatic defect and FXI‐deficient mice were similar to wild type mice.
• Infusion of FXI or over‐expression of FXI in FIX‐deficient mice improved hemostasis.
• FXI may affect the phenotype of FIX‐deficiency (hemophilia B).

Summary

Background

In humans, deficiency of coagulation factor XI may be associated with a bleeding disorder, but, until recently, FXI‐deficient mice did not appear to have a hemostatic abnormality. A recent study, however, indicated that FXI‐deficient mice show a moderate hemostatic defect in a saphenous vein bleeding (SVB) model.

Objectives

To study the effect of FXI on bleeding in mice with normal levels of the FXI substrate FIX and in mice lacking FIX (a murine model of hemophilia B).

Methods

Wild‐type mice and mice lacking either FIX (F9^?) or FXI (F11^?/?) were tested in the SVB model. The plasma levels of FXI in F11^?/? mice were manipulated by infusion of FXI or its active form FXIa, or by overexpressing FXI by the use of hydrodynamic tail vein injection.

Results

F9^? mice showed a significant defect in the SVB model, whereas F11^?/? mice and wild‐type mice were indistinguishable. Intravenous infusion of FXI or FXIa into, or overexpression of FXI in, F9^? mice improved hemostasis in the SVB model. Overexpression of a FXI variant lacking a FIX‐binding site also improved hemostasis in F9^? mice.

Conclusions

Although we were unable to demonstrate a hemostatic defect in F11^?/? mice in the SVB model, our results support the premise that supraphysiological levels of FXI improve hemostasis in F9^? mice through FIX‐independent pathways.