Thrombophilia Testing - a Systematic Review.

BACKGROUND: Thrombophilia testing is controversial, not least because of its high cost. Because comprehensive valid testing requires standardized blood collection close by the specialized laboratory, and interpretation of findings together with clinical data, often only part of the necessary laboratory analyses can be performed in remote central laboratories. Restrictive indications for testing, as have been recommended by previous reviews on the topic, have been based on incomplete analytics, studies with small case numbers, or short observation periods, and on an inappropriate, simple risk stratification for venous thromboembolism (VTE), further subdivided into provoked and unprovoked events. METHODS: The authors reviewed four electronic databases for all peer-reviewed and in-press articles about thrombophilia, VTE, obstetric complications, and arterial thrombosis. After confirmation for relevance to the topic, 201 articles were accepted for inclusion in this article. This review summarizes the studies relevant to the evaluation of thrombophilic conditions, and their combination with each other and with clinical risk factors, to stratify individual risk for thromboembolism and obstetric complications. RESULTS: Thrombophilia testing requires highly skilled personnel for laboratory analysis and interpretation. Clinical conditions that influence the results as well as special preanalytical, analytical, and postanalytical aspects must be considered if valid results are to be obtained. Tests involved include the natural anticoagulants antithrombin, protein C, and protein S; the procoagulants fibrinogen (dysfibrinogen), prothrombin (mutation G20210A), factor V (Leiden mutation), factor VIII/von Willebrand factor/blood group ABO, factor IX, and factor XI; the anti-phospholipid antibodies to detect an antiphospholipid syndrome and potentially additional uncertain thrombophilic conditions. The risks of thrombophilic conditions and clinical risk factors for VTE are cumulative or even supra-additive. Scores from thrombophilic conditions and other genetic and nongenetic risk factors permit estimation of risk for first and recurrent VTE. Therapeutic strategies can be derived from this risk stratification. CONCLUSIONS: Thrombophilia testing is indicated when the results have potential to influence the type and duration of treatment. Indications include certain patients after VTE; or patients without previous VTE but with positive family history regarding VTE or thrombophilia before major surgery, pregnancy, combined oral contraceptives, or hormone replacement therapy. Whether or not thrombophilia is present should help determine anticoagulation, hormonal contraception, or hormone replacement.

Judging Urgency in 343 Ectopic Pregnancies Prior to Surgery - The Importance of Transvaginal Sonographic Diagnosis of Intraabdominal Free Blood.

OBJECTIVES: Assessing urgency in ectopic pregnancies (ECP) remains controversial since the disorder covers a large clinical spectrum. Severe conditions such as acute abdomen or hemodynamic instability are mostly related to intra-abdominal blood loss diagnosed as free fluid (FF) on transvaginal sonography (TVS). The aims of the current study were to investigate the value of FF and to assess other potentially predictive parameters for judging urgency. METHODS: Retrospective cohort analysis on prospectively collected cases of proven ECP (n = 343). Demographics, clinical and laboratory parameters, and findings on TVS and laparoscopy (LSC) were extracted from the digital patient file. FF on TVS and free blood (FB) in LSC were evaluated. Low urgency was defined as FB (LSC) < 100 ml and high urgency as FB (LSC) ≥ 300 ml. The best subset of variables for the prediction of FB was selected and predictors of urgency were evaluated using receiver operator characteristic (ROC) curves. RESULTS: Clinical symptoms, age, ß-HCG, hemoglobin (HB) preoperative, and FF were examined in multivariate analysis for the cutoff values of 100 ml and 300 ml. FF was the only independent predictor for low and high urgency; HB preoperative was only significant for high urgency offering marginal improvement. ROC analysis revealed FF as an excellent discriminatory parameter for defining low (AUC 0.837, 95% CI 0.794-0.879) and high urgency (AUC 0.902, 95 % CI 0.860-0.945). CONCLUSION: Single assessment of FF on TVS is most valuable for judging urgency. However, the exact cutoff values for a low- and high-risk situation must still be defined.

Recombinant ADAMTS13 for Hereditary Thrombotic Thrombocytopenic Purpura.

A 27-year-old patient with a history of severe obstetrical complications and arterial thrombosis received a diagnosis of hereditary thrombotic thrombocytopenic purpura (TTP) due to severe ADAMTS13 deficiency when she presented with an acute episode in the 30th week of her second pregnancy. When the acute episode of hereditary TTP became plasma-refractory and fetal death was imminent, weekly injections of recombinant ADAMTS13 at a dose of 40 U per kilogram of body weight were initiated. The patient's platelet count normalized, and the growth of the fetus stabilized. At 37 weeks 1 day of gestation, a small-for-gestational-age boy was delivered by cesarean section. At the time of this report, the patient and her son were well, and she continued to receive injections of recombinant ADAMTS13 every 2 weeks. (Funded by the Swiss National Science Foundation.).

Thromboprophylaxis with argatroban in critically ill patients with sepsis: a review.

During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.

Accuracy of a Single, Heparin-Calibrated Anti-Xa Assay for the Measurement of Rivaroxaban, Apixaban, and Edoxaban Drug Concentrations: A Prospective Cross-Sectional Study.

Background: Applying a single anti-Xa assay, calibrated to unfractionated heparin to measure rivaroxaban, apixaban, and edoxaban would simplify laboratory procedures and save healthcare costs. Aim: We hypothesized that a heparin-calibrated anti-Xa assay would accurately measure rivaroxaban, apixaban, and edoxaban drug concentrations and correctly predict clinically relevant drug levels. Methods: This analysis is part of the Simple-Xa study, a prospective multicenter cross-sectional study conducted in clinical practice. Patients treated with rivaroxaban, apixaban, or edoxaban were included. Anti-Xa activity was measured using the Siemens INNOVANCE® Heparin assay. Drug concentrations were determined using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cut-off levels were determined in a derivation dataset (50% of patients) and sensitivities and specificities were calculated in a verification dataset (50% of patients). Results: Overall, 845 patients were available for analysis. Correlation coefficients (r s ) between the heparin-calibrated anti-Xa assay and drug concentrations were 0.97 (95% CI 0.97, 0.98) for rivaroxaban, 0.96 (0.96, 0.97) for apixaban, and 0.96 (0.94, 0.99) for edoxaban. The area under the receiver operating characteristics curve (ROC) was 0.99 for all clinically relevant drug concentrations. In the verification dataset, the sensitivity was 94.2% (95% CI 90.8-96.6) for 30 µg L-1, 95.8% (92.4-98.0) for 50 µg L-1, and 98.7% (95.5-99.9) for 100 µg L-1. Specificities were 86.3% (79.2-91.7), 89.8% (84.5-93.7), and 88.7% (84.2-92.2), respectively. Conclusion: In a large prospective study in clinical practice, a strong correlation of heparin-calibrated anti-Xa measurements with LC-MS/MS results was observed and clinically relevant drug concentrations were predicted correctly.

Factor XIII and surgical bleeding.

Factor XIII (FXIII) is the final factor in the coagulation cascade. It converts soluble fibrin monomers into a stable fibrin clot, prevents premature degradation of fibrin, participates in wound healing, and helps prevent the loss of the endothelial barrier function. FXIII deficiency is believed to be rare, and this may explain why clinicians do not routinely take it into consideration. Congenital FXIII deficiency is a rare disease with a reported prevalence of 1 per million. However, the prevalence of acquired FXIII deficiency is much higher. Acquired forms have been described in patients with decreased hepatic or bone marrow synthesis, overconsumption and increased degradation by autoantibodies. This review offers guidance on how to suspect and diagnose FXIII deficiency in both the preoperative consultation and different surgical settings. We also analyze current scientific evidence in order to clarify when and why this clinical situation should be suspected, and how it may be treated.

The Angiostrongylus vasorum Excretory/Secretory and Surface Proteome Contains Putative Modulators of the Host Coagulation.

Angiostrongylus vasorum is a cardiopulmonary nematode of canids and is, among others, associated with bleeding disorders in dogs. The pathogenesis of such coagulopathies remains unclear. A deep proteomic characterization of sex specific A. vasorum excretory/secretory proteins (ESP) and of cuticular surface proteins was performed, and the effect of ESP on host coagulation and fibrinolysis was evaluated in vitro. Proteins were quantified by liquid chromatography coupled to mass spectrometry and functionally characterized through gene ontology and pathway enrichment analysis. In total, 1069 ESP (944 from female and 959 from male specimens) and 1195 surface proteins (705 and 1135, respectively) were identified. Among these were putative modulators of host coagulation, e.g., von Willebrand factor type D domain protein orthologues as well as several proteases, including serine type proteases, protease inhibitors and proteasome subunits. The effect of ESP on dog coagulation and fibrinolysis was evaluated on canine endothelial cells and by rotational thromboelastometry (ROTEM). After stimulation with ESP, tissue factor and serpin E1 transcript expression increased. ROTEM revealed minimal interaction of ESP with dog blood and ESP did not influence the onset of fibrinolysis, leading to the conclusion that Angiostrongylus vasorum ESP and surface proteins are not solely responsible for bleeding in dogs and that the interaction with the host's vascular hemostasis is limited. It is likely that coagulopathies in A. vasorum infected dogs are the result of a multifactorial response of the host to this parasitic infection.

Management of bleeding events and invasive procedures in patients with haemophilia A without inhibitors treated with emicizumab.

INTRODUCTION: Emicizumab (Hemlibra®, Hoffmann-La Roche, Switzerland) is now available for haemophilia A patients with or without factor VIII inhibitors. Management of bleeding events and replacement therapy for invasive procedures have to be adapted. OBJECTIVE: To provide a practical guidance for the management of breakthrough bleeding events and elective or urgent surgery in adult and paediatric patients with haemophilia A without inhibitors treated with emicizumab. METHODS: Based on the available literature and the experiences collected from adult and paediatric patients treated in Switzerland, the Working Party on Haemostasis of the Swiss Society of Haematology and the Swiss Haemophilia Network worked together to reach a consensus on the management of bleeding events and invasive procedures. RESULTS AND CONCLUSION: Minor bleeding events and invasive procedures associated with low bleeding risk can be treated without factor replacement therapy in most cases, whereas major bleeding events and high-risk surgery require additional factor VIII replacement at usual doses, at least for the first days. Emicizumab treatment should be continued throughout the procedure and during the postoperative period. Elective major surgery should be planned according to emicizumab dosing for patients with a once-a-month posology. Of note, so far only few data are available on the management of major bleeds and surgery in patients with haemophilia A treated with emicizumab and this practical guidance will have to be regularly updated with growing experience.  .

Recommendations on the use of anticoagulants for the treatment of patients with heparin-induced thrombocytopenia in Switzerland.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect that occurs in 0.1–5% of heparin treated patients. Management of acute HIT currently involves (1) cessation of heparin exposure, and (2) inhibition of coagulation with an anticoagulant other than heparin. Several anticoagulants can be considered for the treatment of HIT. Anticoagulant monitoring, management of drug-induced adverse events including bleeding, and therapeutic dosing schedules in selected clinical settings represent challenges to the clinician treating HIT patients. Moreover, the fact that not all registered anticoagulants are approved for HIT in Switzerland further complicates the management of HIT. The present recommendations on the anticoagulant treatment of HIT in Switzerland have been elaborated by a panel of Swiss experts belonging to the Working Party Hemostasis (WPH) of the Swiss Society of Hematology (SGH-SSH). They are intended to support clinicians in their decision making when treating HIT patients.

Efficacy of a new pathogen-reduced cryoprecipitate stored 5 days after thawing to correct dilutional coagulopathy in vitro.

BACKGROUND: Fibrinogen supplementation during bleeding restores clot strength and hemostasis. Cryoprecipitate, a concentrated source of fibrinogen, has prolonged preparation time for thawing, a short shelf life resulting in frequent wastage, and infectious disease risk. This in vitro study investigated the efficacy of a new pathogen-reduced cryoprecipitate thawed and stored at room temperature for 5 days (PR Cryo) to treat dilutional hypofibrinogenemia, compared to immediately thawed standard cryoprecipitate (Cryo) or fibrinogen concentrate (FC). STUDY DESIGN AND METHODS: Ten phlebotomy specimens from healthy volunteers were diluted 1:1 with crystalloid and supplemented with PR Cryo and Cryo (at a dose replicating transfusion of two pooled doses [10 units]) and FC at a dose replicating 50 mg/kg. Changes in clot firmness (thromboelastometry) and in coagulation factor activity were assessed at baseline, after dilution, and after supplementation. RESULTS: Clinical dosing was used, as described above, and consequently the FC dose contained 24% and 36% more fibrinogen versus PR Cryo and Cryo, respectively. At baseline, subjects had a median FIBTEM maximum clot firmness of 13.5 mm, versus 6.5 mm after 50% dilution (p = 0.005). After supplementation with PR Cryo, a median FIBTEM maximum clot firmness of 13 mm was observed versus 9.0 mm for Cryo (p = 0.005) or 16.5 mm for FC (p = 0.005). Median factor XIII was higher after PR Cryo (64.8%) versus Cryo (48.3%) (p = 0.005). Fibrinogen activity was higher after FC (269.0 mg/dL) versus PR Cryo (187.0 mg/dL; p = 0.005) or Cryo (193.5 mg/dL; p = 0.005); the difference between PR Cryo and Cryo supplementation (p = 0.445) was not significant. CONCLUSION: PR Cryo used 5 days after thawing effectively restores clot strength after in vitro dilution.

Comparison of platelet function tests for the in vitro quality assessment of platelet concentrates produced under real-life conditions.

Platelet quality in different platelet concentrates (PCs) has been the subject of several studies. Nonetheless, there is a lack of robust data on the correlation and agreement among platelet function tests as a prerequisite for the association of PC functionality in vitro with platelet function in vivo post PC transfusion. The purpose of our study was to correlate a larger panel of platelet function assays in PCs and to assess whether the methods agree sufficiently and can be used interchangeably. Twelve apheresis platelet concentrates in plasma (APC), 16 pooled platelet concentrates in plasma (PPC), and 12 PPC in T-sol (PPCA) were examined on days 1 and 4 after production. PCs were tested for platelet count, light transmission aggregation (LTA) induced by ADP, collagen, or TRAP; platelet ATP release induced by collagen; and spontaneous and ADP and TRAP-induced increase in CD62P and PAC1 expression measured by flow cytometry. All tests were performed in undiluted platelet-rich plasma, recalcified and mixed with an inhibitor of factor Xa and thrombin. Most platelet function parameters correlated significantly with each other, but agreement among methods was insufficient. A proper inverse correlation was observed between ADP-induced LTA and spontaneous platelet activation assessed by CD62P expression (r = -0.61, p < 0.0001). Spontaneous CD62P correlated also significantly with spontaneous PAC1 (r = 0.69, p < 0.0001) and inversely with TRAP-induced CD62P expression (r = -0.86, p < 0.0001). We found significant correlations among all flow cytometric assays measuring platelet CD62P and PAC1 expression induced by ADP or TRAP. Subsequent Bland Altman analysis revealed insufficient agreement between methods. With one exception (collagen-induced LTA compared with TRAP-induced LTA, percentage error = 16%) the limits of agreement expressed as percentage error exceeded the chosen acceptable difference of 30%. In APC, platelet count was 41% and 44% higher, respectively, than in PPC and PPCA (p < 0.0001). Spontaneous CD62P and PAC1 expression were significantly greater, and ADP-induced aggregation and agonist-induced increase in CD62P and PAC1 were significantly lower in PPCA compared to APC and PPC on day 4 of storage. ADP and TRAP-induced CD62P and PAC1 activatability fell significantly during storage between day 1 and day 4 in APC and PPCA, but not in PPC. In conclusion, different platelet function tests capture different aspects of platelet function and do not correlate and agree sufficiently to be used interchangeably.

Comparison of the efficacy of two human fibrinogen concentrates to treat dilutional coagulopathy in vitro.

Both congenital and acquired fibrinogen deficiency can be safely treated with administration of fibrinogen concentrate. The aim of this study was to test the efficacy of a new fibrinogen product (Fibryga) compared to a licensed product (Haemocomplettan) in an in vitro model of dilutional coagulopathy. Ten blood specimens from healthy volunteers were diluted 1:1 with balanced crystalloid solution and subsequently supplemented with each fibrinogen concentrate at a dose replicating in vivo supplementation (50 mg kg-1). Changes in clot firmness (FIBTEM and EXTEM assay), as well as changes in the fibrinogen antigen level, fibrinogen activity, factor XIII level and fibronectin levels were assessed at baseline, after dilution and after adding fibrinogen concentrate. There was no significant difference between the drugs in their in vitro ability to improve clot firmness in the FIBTEM assay (Fibryga: mean MCF 14.4 mm (SD 3.4 mm) vs. Haemocomplettan: MCF 14.1 mm (2.4); p = .584). Fibryga led to significantly higher clot firmness in EXTEM MCF: 56.7 mm (3.8) vs. 53.7 mm (3.7); p < .001). Distinct differences between FXIII levels (significantly higher in Fibryga; mean 40.9% (6.2%) vs. 31.0% (6.2%); p < .001) and fibronectin levels (significantly higher in Haemocomplettan; mean 0.008 g L-1 (SD 0.002 g L-1) vs. 0.002 g L-1 (SD 0.002 g L-1; p < .001) were observed between products. This is the first study to demonstrate that Fibryga and Haemocomplettan have similar efficacy in improving clot firmness in a dilutional hypofibrinogenemia model in vitro.

Influence of cryoprecipitate, Factor XIII, and fibrinogen concentrate on hyperfibrinolysis.

BACKGROUND: Hyperfibrinolysis is a potentially life-threatening condition associated with poor clot integrity and excessive bleeding. Although antifibrinolytics are an effective treatment, more liberal use of these drugs may lead to a prothrombotic risk, and an earlier and potentially safer treatment option would be desirable. Hyperfibrinolysis has been shown to be attenuated by in vitro supplementation of purified human Factor (F)XIII concentrate. Cryoprecipitate represents an alternative source of FXIII and the only approved source of concentrated FXIII in some countries. The aim of this study was to investigate whether cryoprecipitate, FXIII, and fibrinogen concentrate mitigate hyperfibrinolysis. STUDY DESIGN AND METHODS: Ten citrate blood specimens from healthy subjects were spiked with tissue plasminogen activator (t-PA) and subsequently supplemented with cryoprecipitate, FXIII, fibrinogen concentrate, and ɛ-aminocaproic acid (EACA). Thromboelastometry tests were performed at baseline, after t-PA, and after supplementation. Hyperfibrinolysis was assessed using the clot lysis index at 60 minutes (LI60; reciprocal of maximum lysis). RESULTS: The LI60 was significantly improved (fibrinolysis attenuated) after cryoprecipitate supplementation compared to t-PA alone and compared to FXIII and fibrinogen concentrate. Hyperfibrinolysis was only fully reversed using EACA. In addition, cryoprecipitate demonstrated the least variability in the attenuation of hyperfibrinolysis among 10 healthy subjects, compared to FXIII and fibrinogen concentrate. CONCLUSION: This is the first study to show that cryoprecipitate is able to significantly mitigate hyperfibrinolysis in an in vitro model. Further investigations are warranted to determine whether cryoprecipitate may have a previously unrecognized benefit and should be administered earlier in resuscitation protocols.

Impact of rivaroxaban on point-of-care assays.

BACKGROUND: Point-of-care testing (POCT) is regularly used to assess haemostasis in various clinical settings. The impact of rivaroxaban on those POCT is still elusive. We aimed to study the effects of rivaroxaban on most commonly used POCT assays. METHODS: Blood samples were taken before, 3h, and 24h after administration of 20mg rivaroxaban to 20 healthy volunteers as part of a prospective, multicenter validation study (clinicaltrials.govNCT01710267). Blood samples were analysed with thromboelastometry (ROTEM®), two platelet function assays (INNOVANCE® PFA-200 and Multiplate®), and the CoaguChek® XS. Rivaroxaban plasma levels were determined using liquid chromatography-mass spectrometry. RESULTS: Rivaroxaban significantly modified some thromboelastometry parameters (CT INTEM: mean difference 56.1s, 95% CI: 41.8, 70.3; CT EXTEM: 47.5s, 95% CI: 37.8, 57.1; CT HEPTEM: 50.1s, 95% CI: 34.7, 65.6), and CoaguChek® XS parameters (prothrombin time: mean difference 3.8s, 95% CI: 3.3, 4.2; INR: 0.32, 95% CI: 0.27, 0.38; prothrombin ratio: -36.1%, 95% CI: -32.3, -39.9). CT EXTEM and INR showed a moderate correlation with rivaroxaban plasma levels (r=0.83; 95% CI 0.69, 0.9 and r=0.83; 95% CI 0.70, 0.91, respectively) and a high sensitivity to detect rivaroxaban treatment at peak levels (0.95; 95% CI: 0.76, 1.0 and 0.90, 95% CI 0.70, 0.99, respectively). CONCLUSIONS: Rivaroxaban 20mg treatment significantly alters ROTEM® and CoaguChek® XS parameters. Even though POCT do not allow precise quantification of rivaroxaban plasma concentration, CT EXTEM and CoaguChek XS detect the presence of rivaroxaban at peak level with a high sensitivity.

Is viscoelastic coagulation monitoring with ROTEM or TEG validated?

Recent years have seen increasing worldwide interest in the use of viscoelastic coagulation monitoring tests, performed using devices such as ROTEM and TEG. The use of such tests to guide haemostatic therapy may help reduce transfusion of allogeneic blood products in bleeding patients and is supported in European guidelines for managing trauma and severe perioperative bleeding. In addition, viscoelastic tests form the basis of numerous published treatment algorithms. However, some publications have stated that viscoelastic tests are not validated. A specific definition of the term validation is lacking and regulatory requirements of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have been fulfilled by ROTEM and TEG assays. Viscoelastic tests have been used in pivotal clinical trials, and they are approved for use in most of the world's countries. Provided that locally approved indications are adhered to, the regulatory framework for clinicians to use viscoelastic tests in routine clinical practice is in place.

Efficacy of solvent/detergent plasma after storage at 2-8 °C for 5 days in comparison to other plasma products to improve factor V levels in factor V deficient plasma.

OBJECTIVES: Factor V (FV) plays an important role in coagulation. As no purified concentrate is available to restore critical FV levels, the main blood product used to replace FV is plasma. The aim of the present in vitro study was to compare the efficacy of the different available plasma products on the reversal of moderate and severe FV deficiency as assessed by ROTEM® and FV levels. METHODS: Five different plasma products (6 batches of each) were compared to determine their effectiveness in replacing FV in plasma moderately or severely deficient in FV. Effectiveness was measured using the ROTEM® EXTEM clotting time (CT) and a factor V assay. RESULTS: FFP, plasma frozen within 24 hours (FP24), Octaplas (solvent/detergent treated pooled plasma), as well as Octaplas and FP24 thawed and stored for 5 days (Octaplas TP and TP), were all used for in vitro replacement of FV. TP was significantly less effective at reversing a prolonged EXTEM CT and FV levels in FV deficient plasma than other tested products. There were no significant differences in EXTEM CT between Octaplas and Octaplas TP, while factor V activity was significantly lower in the Octaplas TP. There was no significant difference between Octaplas and FFP for EXTEM CT or FV activity. CONCLUSIONS: Octaplas and Octaplas TP appear to have an equivalent ability to improve the EXTEM CT and could be considered as a treatment alternative to FFP in patients with FV deficiency.