Factor VIIa

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Factor VIIa Man-Chiu Poon Division of Hematology and Hematologic Malignancies, Department of Medicine, University of Calgary—Foothills Medical Centre, Calgary, AB, Canada

INTRODUCTION 1121 PHARMACOLOGY 1121 rFVIIa IN THE TREATMENT OF THROMBOCYTOPENIA 1123 Preclinical Studies 1123 Positive Clinical Studies and Case Reports 1123 Negative Clinical Studies and Case Reports 1123 Summary 1124 rFVIIa IN THE TREATMENT OF PLATELET FUNCTION DISORDERS 1124 Congenital Platelet Function Disorders 1124 Acquired Platelet Function Disorders 1126 Summary 1126 ADVERSE EVENTS 1126 Thromboembolic Adverse Events of rFVIIa Use in Platelet Disorders 1126 Thromboembolic Adverse Events in Other Approved Indications for rFVIIa Use 1126 Thromboembolic Adverse events in rFVIIa Off-Label and Investigational Use 1127 Summary 1127 MECHANISMS OF ACTION 1127 High-Dose FVIIa-mediated Thrombin Generation: TF-dependent and TF-independent Models, and Effects on Fibrin Clot Structure 1127 High-Dose FVIIa in Thrombocytopenia 1128 High-Dose FVIIa in Platelet Function Defects 1128 FVIIa ANALOGS IN CLINICAL DEVELOPMENT 1129 FVIIa Analogs With Prolonged T1/2 1130 FVIIa Analogs With Enhanced Enzymatic Activity and Prolonged T1/2 1130 Subcutaneous Preparations Development 1130 Challenges in FVIIa Analog Development 1130 CONCLUSIONS 1130 REFERENCES 1130

INTRODUCTION Bleeding in patients with platelet disorders can often be treated by conservative means including: local compression, gelatin sponge, local hemostatic agents (e.g., topical thrombin or fibrin glue), hormonal manipulation (e.g., birth control pills), and antifibrinolytics (e.g., tranexamic or epsilon aminocaproic acid). In some patients, desmopressin acetate may be effective (as described in Chapter 62). When these measures have failed, or in the case of severe bleeding or surgery, transfusion of platelet concentrates is required. Repeated transfusion of platelets may however result in the development of allergic reactions, Platelets. https://doi.org/10.1016/B978-0-12-813456-6.00063-1 Copyright © 2019 Elsevier Inc. All rights reserved.

as well as the development of allo-antibodies that may render future platelet transfusion ineffective (see Chapter 64). Blood products also carry a risk of blood-borne infection transmission.1–3 It is therefore desirable to have available safe and effective alternative agents to platelet transfusions. This is especially important for patients who are already refractory to platelet transfusion and for patients who live in an area where platelets are not readily available. Recombinant factor VIIa (rFVIIa) has been used extensively in patients with inhibitors to factor VIII (FVIII) or factor IX (FIX) (congenital or acquired hemophilia) with good efficacy and safety record.4–9 In the last 2 decades, investigators have been exploring the use of rFVIIa as an alternative to platelet transfusion. This chapter focused on the experience with rFVIIa for the treatment and prevention of bleeding in patients with quantitative and qualitative platelet defects and the possible mechanism of actions of high-dose rFVIIa in these platelet disorders. Looking into the future, the chapter also briefly discusses FVIIa preparations that are long-acting and/or with enhanced biologic activities currently in development or in clinical trials.

PHARMACOLOGY FVII, a vitamin K-dependent coagulation protein, is a single chain glycoprotein (Mr
50,000) that is synthesized in the liver.10 FVII circulates as a zymogen composed of 406 amino acids at a plasma concentration of
10 nM. Activated factor VIIa (FVIIa), a disulfide-linked 2 chain procoagulant enzyme active only when complexed to tissue factor (TF) (Fig. 63.1A), is formed by cleavage of the zymogen at Arg152-Ile153, and circulates in a low concentration (
100 pM).10 TF is normally not exposed to flowing blood, but is found in various cells in the deeper layer of the blood vessel wall. Thus, under normal physiological circumstances, clotting is initiated at the site of tissue injury, and FVIIa in the circulation is otherwise proteolytically inert. In this TF-dependent pathway, TF-FVIIa complex initiates hemostasis by activating factors IX and X. Fig. 63.1B shows FXa generated from FX, the preferred substrate of TF-FVIIa, remaining associated with TF-FVIIa complex.10,11 Normal thrombin generation also requires the presence of factors VIII, V, and prothrombin (FII). Other cells that express TF include some tumor cells, monocytes and neutrophils that have been stimulated by bacterial endotoxin and certain other inflammatory mediators.12–16 rFVIIa is produced by biotechnology.17 Baby hamster kidney (BHK) cells cultured in medium containing fetal calf serum are transfected with human FVII gene. The rFVII produced undergoes auto-activation to rFVIIa during the purification procedures that include detergent treatment, ion-exchange chromatography, and mouse monoclonal antibody immunoaffinity chromatography. Human proteins or their derivatives are absent in the culturing, processing, purification, and formulation procedures, so that there is virtually no risk of transmission of infectious agents of human origin. The pharmacokinetics of rFVIIa has been studied in patients with hemophilia and FVII deficiency. In adult hemophilia patients with or without inhibitors, after a bolus intravenous rFVIIa infusion at doses of 17.5, 35 and 70 μg/kg, median

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Fig. 63.1 Molecular models of activated factor VII (FVIIa) complexed with tissue factor (TF), with and without FXa. (A) Molecular model of FVIIa/TF complex. Shown are the light chain (dark blue) and heavy chain (light blue) of FVIIa complexed with tissue factor (surface representation in gray). The catalytic site of FVIIa is occupied by an active site inhibitor (yellow). The two N-glycans (ball-and-stick representations in gray) on FVIIa and the membrane layer (gray) were modelled using the available structure of the FVIIa-soluble TF complex (PDB code 1DAN). (B) Molecular model of FVIIa-TF in complex with the activated form of its physiological substrate factor X (FXa) (shown as a surface representation in light blue). FXa was docked onto the FVIIa-TF-membrane complex according to the available model of the ternary FVIIa-TF-FXa complex (1NL8.pdb) by Norledge et al.11 (Figures were generated by Drs. Jens Breinholt and Henrik Østergaard, Global Research, Novo Nordisk A/S, Malov, Denmark.)

in vivo plasma recovery in the bleeding and nonbleeding state was respectively
46% and
44% and the median half disappearance time (T1/2) was respectively
2.3 and
2.9 h.18 A subsequent study on severe hemophilia patients in the nonbleeding state given rFVIIa at 90 μg/kg, the estimated mean initial and terminal T1/2 were 0.6 and 2.6 h, respectively with a clearance of 38 mL/h/kg.19 Similar mean T1/2 was also found in children (2.6 h vs. 3.1 h in adults, rFVIIa dose 90–180 μg/kg)20 and in patients with FVII deficiency (
3 h, nonbleeding state).21 Complex formation between rFVIIa and antithrombin is an important clearance pathway for rFVIIa in the circulation, accounting for 65% of an intravenous dose of 90 μg (1.8 nmol)/kg rFVIIa in hemophilia patients.19 In a mouse model, hepatocytes and Kupffer cells are involved in the hepatic clearance and metabolism of both full-length rFVIIa and rFVIIa complexed with antithrombin and α-2 macroglobulin.22,23 The kidney and renal tubular cells also play a role in rFVIIa clearance.24,25 Nephrectomized rats (compared to sham operated rats) had a decreased rFVIIa clearance (34 mL/h/kg vs. 68 mL/h/kg) and increased terminal half-life (2.8h vs. 1.9 h). It was estimated that about 50% of the total clearance of rFVIIa from circulation in rats under isoflurane anesthesia is due to renal clearance.25 rFVIIa has been used effectively for prophylaxis in patients with hemophilia and inhibitors (as daily single dose infusions)26 and with FVII deficiency (as 2–3 times weekly infusions) despite its very short T1/2.27 In a hemophilia inhibitor patient trial, the benefit after 3 months prophylaxis was apparently extended for the next 3 months when rFVIIa was not given.26 It was recently demonstrated that rFVIIa apparently has a high distribution volume following infusion in severely FVII deficient patients.28 In pigs, following a single intravenous rFVIIa administration, elevated and hemostatically active plasma and platelet FVIIa levels were detectable up to 24– 48 h.29 In mice, after a single intravenous infusion, rFVIIa apparently rapidly associated with the vascular endothelium

expressing endothelial cell protein C receptor23 that is responsible for FVIIa binding,30 and subsequently entered into the extravascular spaces, localizing mostly to regions that contain TF expressing cells where it is sequestered and retained for a prolonged period of time—up to one week in calcified cartilage and skin.23 Importantly, infused rFVIIa failed to enter the TFcontaining lung and brain tissue where thrombin generation is not desirable. It has also been shown that that rFVIIa exposed to platelet-rich plasma (from normal, FVII-deficient patient, and Bernard-Soulier syndrome patient) were internalized to the platelet cytoplasm with redistribution into the open canalicular system and α-granules.31 The internalized rFVIIa apparently improved platelet aggregate formation and fibrin generation in perfusion studies. The prolonged association of infused rFVIIa with TF-expressing cells extravascularly23 and the redistribution of rFVIIa into platelets31 may potentially explain the effectiveness of prophylaxis with relatively infrequent rFVIIa infusions in both FVII deficiency and hemophilia inhibitor patients, as well as the extended effectiveness of rFVIIa beyond the prophylaxis period in hemophilia inhibitor patients despite the short circulating T1/2 of rFVIIa. The potential for thrombogenicity of rFVIIa has been examined in animal studies. In a rabbit stasis model,32 infusion of 100–1000 μg/kg did not result in significant clot formation over 10 min of stasis, although significant clotting occurred over 30 min stasis. In another animal study, Turacek et al.33 found rFVIIa to have low thrombogenic potential, but the thrombotic potential was enhanced by the addition of soluble TF. Infusion of rFVIIa to hemophilia patients with inhibitor resulted in a shortening of prothrombin times (PT) and activated partial thromboplastin times (aPTT). 4–6,8 Generally there were no significant changes in the mean level of antithrombin, fibrinogen, and platelet counts over 48 h after surgery covered with rFVIIa,8 although coagulation activation marker prothrombin F1+2 fragment may increase without clinical sequelae.21,34

Factor VIIa

rFVIIa IN THE TREATMENT OF THROMBOCYTOPENIA Preclinical Studies Animal studies suggest that high-dose rFVIIa could shorten the “total hemostasis time”35 and “nail cuticle bleeding time”36 in rabbits with thrombocytopenia induced respectively by platelet antiserum alone35 or in combination with gamma radiation.36

Positive Clinical Studies and Case Reports Kristensen and his colleagues37 subsequently showed that in some patients with thrombocytopenia, bleeding time could be modestly shortened (by at least 2 min) after administration of rFVIIa at a dose of either 50 or 100 μg/kg. In general, the response rate increased with higher platelet count, but was similar with both rFVIIa doses. The difficulty in interpreting the bleeding time results in this study is that the bleeding time method was not the same in all patients; venostasis was performed in one group of patients but not in another. Furthermore, the significance of bleeding time shortening by 2 min depends on how prolonged the baseline bleeding was in the individual patients. These investigators37 also treated nine bleeding episodes (three epistaxes, four neck incisions, one epistaxis plus neck incision, and one uterine bleeding) in eight patients with platelet counts between 5 and 33  109/L. Bleeding stopped promptly after rFVIIa in six episodes (platelet counts 5–33  109/L) and slowed in two (platelet counts 13 and 19  109/L). Cessation of bleeding was not necessarily accompanied by a shortening or normalization of the bleeding time. No conclusion could be drawn as to which rFVIIa dose (50 or 100 μg/kg) was more effective. Brenner et al.38 analyzed 24 patients (mean age 25.8, range 2–58 years) with thrombocytopenia associated with a variety of hematologic malignancies (some following chemotherapy or after bone marrow transplantation) treated with rFVIIa and entered into the international internet-based registry up to September 2003. The platelet counts at the time of treatment were not stated. Bleeding stopped in 11 of 24 (46%) patients, but one had a rebleed and died from pulmonary hemorrhage and endotoxic shock, so that the overall success rate was 42% (10/24). The 10 successful treatment were for bleeding from the GI tract (n ¼ 6), nose (n ¼ 2), lung (n ¼ 1), and postlymph node biopsy (n ¼ 1). They received rFVIIa at a median dose of 67 μg/kg body-weight (range 18–100) and bleeding stopped after one dose in six and two doses in four. One patient with GI bleed did not respond, and two of the patients whose bleeding decreased (after 1 40 μg/kg and 2 q2h 46 μg/kg) subsequently died from continued bleeding respectively from multiple sites and GI tract. As with any registry data, treatment protocols were heterogeneous. Treatment may not be sufficient for many of the unsuccessful ones, given that 10 of the 14 recurrence and failures received rFVIIa for only one (n ¼ 6) to two doses (n ¼ 4). Eleven patients also received antifibrinolytics but whether some of these patients also received concurrent platelet transfusion was not clear. One patient apparently developed ischemic stroke that was possibly related to rFVIIa administration. Tang et al.39 treated severe GI bleeds with rFVIIa (single dose at 60 mcg/kg) in 16 patients following hematopoietic stem cell transplantation with severe thrombocytopenia (median count 16  106/L) and failing traditional hemostatic treatments including platelet transfusion, antifibrinolytic agents, fresh frozen plasma. Twelve had a response (five complete, seven partial, overall 75%) and four did not. Nine patients (56.3%) died in a follow-up of 90 days, seven from transplant related complications and two of uncontrolled bleeding. This group40 subsequently reported their study on 64 patients with

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hematologic malignancies and platelet refractory thrombocytopenia and severe bleeding with high bleeding score according to Nevo et al.41 All received conventional hemostatic therapy including platelet transfusion. Thirty patients (mean age 35 years, bleeding score 3.62  0.98 out of 4) treated with additional rFVIIa 60 μg/kg at 8 h intervals for a median of three doses (range 1–15) were compared to another 32 of similar mean age and bleeding score who did not receiving rFVIIa. How patients were designated as experimental vs. control group was not clarified. Bleeding sites include GI (n ¼ 27), lung (n ¼ 13), urinary tract (n ¼ 13), CNS (n ¼ 9) and others (n ¼ 13). Compared to the control group, those receiving rFVIIa had higher overall response rates at 24 h (84.3% vs. 56.2%, P ¼ .014) and 48 h (95.7% vs. 71.8%, P ¼ .02) but not at 72 h. The number of patients who achieved a complete response was significantly higher in the rFVIIa group at all three timepoints and their bleeding score and time to control bleeding also showed significant improvements with an insignificant trend toward less drop in Hb level and lower number of RBC units transfused. There was no obvious overall survival benefit of the rFVIIa group (5.5 m vs. 1.35 m, P ¼ .240), although the survival time of the rFVIIa group with CR was longer than those with PR and no response (282.5 d vs. 8 d, P ¼ .02). In this study, the rFVIIa dosage (60 μg/kg) is lower than average while dosing interval (8 h) was also long. Whether the outcomes will further be improved with higher dose and shorter dosing interval and/ or more dose remains to be studied. A number of case reports on the successful use of high-dose rFVIIa in bleeding thrombocytopenic patients have also been published.42–44 These are in patients with: • ITP45–56; • thrombocytopenia induced by chemotherapy, stem cell transplantation, leukemia, marrow aplasia or other hematologic malignancies39,40,46,57–70; • thrombocytopenia related to hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome71–74; • Wiskott-Aldrich syndrome75; • postsurgical mild thrombocytopenia with drug-induced platelet dysfunction76; and • orthopedic surgery for thrombocytopenia and platelet dysfunction with absent radii syndrome.77 Most of the patients had platelet count <20  109/L. Treatment dosages varied, but most were in the 90 μg/kg range. rFVIIa was used generally because of refractoriness to platelet transfusion, although systemic hemostatics including platelet transfusion, desmopressin and tranexamic acid were also given concurrently with rFVIIa to treat some of the episodes.

Negative Clinical Studies and Case Reports A prospective multicenter, randomized, double-blind, parallel group, placebo-controlled phase II clinical trial78 showed no significant effect of increasing rFVIIa dose (40, 80, 160 μg/kg) in the treatment of bleeding complications in 100 post hematopoietic stem cell transplantation patients (12 years age) with platelet count <50  109/L and moderate or severe bleeding (52 GI; 26 hemorrhagic cystitis, seven pulmonary, one cerebral and 14 others) from days +2 to +180 post-transplant (97 allogeneic, three autologous). The patients received seven doses of rFVIIa or placebo every 6 h in addition to standard management including platelet transfusion (to keep platelet counts above 75  109/L for hemorrhagic cystitis and diffuse alveolar hemorrhage and above 20  109/L for other bleeding). Patients were followed for 96 h and the primary endpoint was the change in a predefined bleeding score41 38 h after initiation of rFVIIa/placebo infusion. Antifibrinolytic drugs were not used. A post-hoc analysis comparing each rFVIIa dose with

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placebo did show that 80 μg/kg rFVIIa (but not 40 or 160 μg/kg) resulted in improvement of the bleeding score at the 38 h time point (81% vs. 57%, P ¼ .021). However, only 2 out of 26 patients with the more difficult to treat hemorrhagic cystitis were in this 80 μg/kg rFVIIa treatment group. There were no differences in red cell or platelet transfusion requirements across dose groups. The failure to show increasing effect with increased dose was attributed to the heterogeneity of the patient population (underlying diagnosis, bleeding lesions, comorbidities, mechanisms of bleeding), and long intervals between rFVIIa treatment. Additionally, 34 patients also received medication that can interfere with hemostasis, including heparin prophylaxis (n ¼ 22), defibrotide (n ¼ 15), and NSAIDs (n ¼ 5). There were six episodes of thromboembolic complications in the rFVIIa treatment group (three during and three after the 90-day observation period) but these were considered not statistically significant compared to zero incidence in the placebo group (P ¼ .41). In this study, enrollment exclusion criteria included patients with history of active atherosclerotic disease, stroke or deep vein thrombosis during the previous 3 months, disseminated intravascular coagulation (DIC), moderate or severe thrombotic microangiopathy, severe hepatic veno-occlusive disease, active acute myeloid leukemia, FAB types M3, M4 and M5, or patients who had received granulocyte transfusion within the previous 24 h. Among case reports/series, failure has also been reported for: • three episodes of hemorrhagic cystitis (with or without GI or pulmonary bleeding) associated with thrombocytopenia following bone marrow transplantation using high-dose rFVIIa (90–270 μg/kg) together with platelet transfusion to maintain a platelet count >50  109/L79; • uterine bleeding in a patient with thrombocytopenia (platelet count 4–13  109/L) during induction chemotherapy for acute leukemia80; • GI bleed from cytomegalovirus enterocolitis and acute graft vs. host reaction in a thrombocytopenic patient 18 days after stem cell transplantation for chronic myelogenous leukemia using 10 doses of rFVIIa (90–100 μg/kg every 4–8 h);81 and • postoperative (coronary artery bypass grafting) bleeding in a 70-year-old female with ITP) with thrombocytopenia, coagulation factor “depletion” and acidemia using nine daily doses of rFVIIa (101 μg/kg).52 The dosage interval (daily) in this particular case was, however, excessively long.

Summary rFVIIa appears to have a role in the management of severe bleeding and for surgical prophylaxis in thrombocytopenic patients refractory to platelet transfusion. However, clinical data available in these patients are scant and are mostly confined to individual case reports or small case series, with the inherent shortcoming of reporting bias in which negative outcomes tend not to be published. There is one clinical trial with negative clinical efficacy78 carried out in bleeding patients with thrombocytopenia following transplantation. The failure of this trial was attributed to clinical heterogeneity, varied mechanism of bleeding and long dosing intervals. There is an urgent need for well-designed clinical trials to better assess the clinical efficacy, safety, and optimal treatment regimen of rFVIIa in thrombocytopenic patients. The lack of randomized clinical trials to provide evidence for rFVIIa as alternative agent to prophylactic platelet transfusion for preventing bleeding in patients with thrombocytopenia due to chronic bone marrow failure was highlighted in a meta-analysis and systematic review.82 The relative role of concurrently transfused platelets received by some of the

rFVIIa-treated thrombocytopenic patients needs further clarification. A theoretical advantage is that the transfused platelets may provide increased platelet procoagulant surface to enhance rFVIIa binding for improved thrombin generation (see section on “Mechanisms of Action”). Whether this will translate into clinical efficacy also remains to be proven by clinical trials.

rFVIIa IN THE TREATMENT OF PLATELET FUNCTION DISORDERS Tengborn and Petruson83 were the first to report the effectiveness of rFVIIa in the treatment of a platelet function disorder, in a 2-year-old boy with Glanzmann thrombasthenia (GT) and severe epistaxis. Since then, other patients with congenital or acquired platelet function disorders have been treated with rFVIIa for acute bleeds and for surgical prophylaxis. These include patients with: • GT75,84–114; • GT-like defect related to mutation of the platelet αIIbβ3 activation signaling molecule CalDAG-GEFI (calcium and diacylglycerol-regulated guanine nucleotide exchange factor I)115; • Bernard-Soulier syndrome89,94,112,116–118; • platelet storage pool defect89,112,119–121; • platelet-type (pseudo) von Willebrand disease122,123; and • acquired platelet disorders.34,124,125

Congenital Platelet Function Disorders The majority of reports on the use of rFVIIa in patients with platelet function disorders have been in GT, a disorder which is characterized by a quantitative or qualitative defects of the platelet membrane integrin αIIbβ3 (glycoprotein [GP] IIb-IIIa) (see Chapter 48). The rarity of this disorder and the low number of bleeding episodes requiring systemic hemostatic therapy make a randomized clinical trial comparing the efficacy and safety of rFVIIa to platelet transfusion difficult. In the last 20 years, there have been several surveys or registries on the use of rFVIIa in GT.93,112–114 The international survey. This survey initiated by Poon, d’Oiron and their colleagues93 in 1997 and concluded in 2004 included retrospective data on 59 GT patients from 49 centers in 15 countries treated for 108 bleeding episodes and 34 surgical/invasive procedures. rFVIIa was particularly effective as prophylaxis for a wide variety of surgical and other procedures (94%, of evaluable episodes not receiving platelet transfusions concurrently). The overall success rate for bleeding episodes was 74.8% (77/103) on evaluable episodes. The success rate for bleeding was higher when adhering to a tentatively defined “optimal regimen” (80 μg/kg at 2.5 h intervals for at least three doses) derived from the earlier Canadian pilot study84 compared with other regimens (77%, 24/31 vs. 47%, 19/40; χ 2 ¼ 0.010). Two other findings of interest are: (1) rFVIIa by continuous infusion while effective in preventing bleeds (as in surgical prophylaxis), was less effective (failing six of seven treatments) and potentially less safe than bolus injections in treating bleeds; and (2) Patients given maintenance doses had significantly fewer recurrences compared with those not given any. Two serious adverse events possibly related to rFVIIa use include one clotting in a ureter and one venous thromboembolic event.86,87,93 Based on these data, in 2004 the EMA (European Medicines Agency) approved the use of rFVIIa in the European Union

Factor VIIa

(EU) for GT patients with antiplatelet antibodies and a history of platelet refractoriness. Glanzmann Thrombasthenia Registry (GTR). A requirement for the EMA to approve the use of rFVIIa for GT with platelet antibodies and history of platelet refractoriness in EU was the establishment of an international postmarketing pharmaco-vigilance study. This was to assess the efficacy and safety of rFVIIa and other systemic hemostatic agents (including platelet transfusion and antifibrinolytics) in GT patients with or without platelet antibodies or platelet refractoriness for the treatment and prevention (surgical prophylaxis) of bleeding. Treatment was based on local clinical practice rather than a set protocol. Treatment data on 218 patients (from 45 centers in 15 countries, including 75 with platelet antibodies and/or platelet refractoriness, entered from May 2007 to December 2011, were reported in 2015.113,114 This is the largest GT data collection to date, and includes treatments of 829 bleeding episodes (148 patients) and 206 procedures (97 patients). Efficacy of the treatment of nonsurgical bleeds and surgical prophylaxis in patients with and without platelet antibodies and/or history of platelet refractoriness, using different hemostatic agents (rFVIIa  antifibrinolytics [AF], platelets  AF, rFVIIa + platelets  AF, and AF alone), are shown in Table 63.1. Several observations can be made from the table.

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(1) Effectiveness of rFVIIa  AF compared to that of platelets  AF (a) For patients without platelet antibodies/platelet refractoriness, rFVIIa  AF is as effective as platelets  AF for both treatment of bleeding (91.4% [128/140]) for rFVIIa  AF vs. 83.3% [25/30] for platelets  AF) and for surgical prophylaxis (100% [48/48] for rFVIIa  AF vs. 100% [16/16] for Platelets  AF) (b) For patients with platelet antibodies/refractoriness, rFVIIa  AF is somewhat more effective than platelets  AF for both treatment of bleeding (80.2% [69/ 86] for rFVIIa  AF vs. 63.9% [23/36] for platelets  AF) and surgical prophylaxis (87.1% [74/85] for rFVIIa  AF vs. 70.6% [12/17] for platelets  AF). The decrease in effectiveness of platelets  AF in bleeding patients is contributed mainly by those with severe bleeding (72.2% [26/36] for rFVIIa  AF vs. 59.4% [19/32] for platelets  AF). It is not clear from the data which type of surgery (major or minor) contributed more to the decreased effectiveness of platelets  AF in these patients. Compared to rFVIIa  AF, effectiveness of platelets  AF was slightly higher in major surgery (100% [7/7] for platelet  AF vs. 84.6% [11/13] for rFVIIa  AF), but the number for both were small.

TABLE 63.1 Glanzmann Thrombasthenia Registry

Patient Groups

rFVIIa ± AF Number Effective/ Total Number (%)

(A) BLEEDING MANAGEMENT Severe bleeds 26/36 (72.2) (n ¼ 214) Moderate bleeds 171/190 (90.0) (n ¼ 605) No AB/refractoriness 128/140 (91.4) (n ¼ 511) 69/86 (80.2) AB and/or refractoriness (n ¼ 308) (B) SURGICAL PROPHYLAXIS Major procedures 11/13 (84.6) (n ¼ 35) Minor procedures 111/120 (92.5) (n ¼ 168) No AB/refractoriness 48/48 (100) (n ¼ 88) 74/85 (87.1) AB and/or refractoriness (n ¼ 115)

P ± AF Number Effective/ Total Number (%)

rFVIIa + P ± AF Number Effective/ Total Number (%)

AF Number Effective/ Total Number (%)

Overall Number Effective/ Total Number (%)

19/32 (59.4)

39/47 (83.0)

80/99 (80.8)

164/214 (76.6)

29/34 (85.3)

144/169 (85.2)

165/212 (77.8)

509/605 (84.1)

25/30 (83.3)

145/172 (84.3)

143/169 (84.6)

441/511 (86.3)

23/36 (63.9)

38/44 (86.4)

102/142 (71.8)

232/308 (75.3)

7/7 (100)

8/12 (66.7)

3/3 (100)

29/35 (82.9)

21/26 (80.8)

11/13 (84.6)

5/9 (55.6)

148/168 (88.1)

16/16 (100)

10/13 (76.9)

7/11 (63.6)

81/88 (92.0)

12/17 (70.6)

10/12 (83.3)

1/1 (100)

96/115 (83.5)

(A) Treatment of bleeding episodes and (B) prophylaxis of surgical procedures, rated effective stratified according to bleeding/surgical category and to the presence of platelet antibodies and/or platelet refractoriness ((A) n ¼ 829 in 184 patients; (B) n ¼ 206 in 97 patients). (A) Out of 829 episodes, effectiveness rating was missing for 10 (two treated with rFVIIa only, three with rFVIIa + AF, three with AF, one with P  AF, and one with rFVIIa + P  AF). rFVIIa usage for bleed treatment in median (interquartile range): Severe bleeding: 90 (90–105) μg/kg every 3 (3–7) h  5 (3–9) doses. Moderate bleeding: 90 (90–90) μg/kg every 3 (2–7) h  2 (1–3) doses. (B) Out of 206 procedures effectiveness outcome was missing for 3 (one minor surgical procedure treated with rFVIIa  AF, two major surgical procedures, one treated with AF and one with rFVIIa  P  AF). rFVIIa usage for surgical prophylaxis in median (interquartile range): Major surgery: 90 (90–92) μg/kg every 3 (2–6) h  11 (3–21) doses. Minor surgery: 100 (90–110) μg/kg every 2 (2–3) h  2 (2–3) doses. Abbreviations: AB: platelet antibodies; AF: antifibrinolytic agent(s); P: platelets; refractoriness: platelet refractoriness; rFVIIa: recombinant human activated factor VII. (Summarized from Di Minno et al. and Poon et al.113,114)

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On the contrary, the effectiveness of rFVIIa  AF was slightly higher in minor surgery (92.5% [111/120] vs. 80.8% [21/26]) but again the number of patients using platelets  AF was relatively small. (2) Use of rFVIIa + Platelets  AF One of the questions raised in the 2004 survey93 was whether a combination of rFVIIa + platelets  AF would represent an advantage over rFVIIa ( AF) or platelets ( AF) by themselves. The current data do not appear to provide an answer. In fact, the effectiveness of the combination appears to be lower particularly for major procedures (66.7% [8/ 12]) when compared with rFVIIa  AF (84.6% [11/13]) and platelets  AF (100% [7/7]). It is possible that those treated with all three agents were more challenging patients in whom treatment probably started with one or two agents and then, the second and/or the third were/was added when the initial regimens were not successful. (3) Use of AF alone. In the GTR, AF appears to have relatively good efficacy in the treatment of bleeding (71.8%–84.4%) and in 12 surgical procedures (55.6%–100%). In these instances. AF was probably the first-line treatment in anticipation of adding rFVIIa or platelet when available or if AF would turn out to be ineffective. However, use of AF alone as a first-line treatment for severe bleeding and for major procedures is not recommended.

Acquired Platelet Function Disorders rFVIIa has been used effectively for acute bleeding in a limited number of patients with acquired platelet functional disorders: one 76-year-old man with myelodysplastic syndrome and persistent small intestinal bleeding after laparotomy,126 a 12year-old girl with uremia and pulmonary bleeding complicating cytomegalovirus pneumonitis following a renal transplant,124 and a 69-year-old woman patient with essential thrombocythemia and uncontrolled gynecological surgical bleeding.34 The first two patients were refractory to desmopressin and all three were refractory to platelet transfusion. All the bleeding responded promptly to one dose of rFVIIa at 40–90 μg/kg, but maintenance doses were given to the third patient. A 24-yearold female with massive GI bleeding after receiving aspirin for postsurgical reactive thrombocytosis was apparently successfully rescued with two doses of rFVIIa at 90 μg/kg after failing blood products, desmopressin, and tranexamic acid.127 rFVIIa has also been used to cover extraction of six teeth in a 9-year-old boy with acquired storage pool disorder and a mild thrombocytopenia (platelet count 75  109/L) associated with myelodysplastic syndrome. He was covered successfully with two doses of rFVIIa, one pre- and one postoperatively.75

Summary In GT patients with platelet antibodies, particularly those with platelet refractoriness, there is now a collection of published data, including those from the recent GTR, suggesting that rFVIIa would be a safe and effective agent for management of bleeding and for surgical prophylaxis. Currently, rFVIIa is approved in a number of countries (including the EU, USA, and Canada) for this indication. Many investigators also prefer the off-label use of rFVIIa in nonimmune/nonplatelet refractory GT patients especially those with severe mutations (e.g., Type I GT with absent αIIbβ3 expression) to prevent platelet antibody development. This is particularly important for affected women of reproductive age and prepubertal girls, given that anti-αIIbβ3 has the potential to cross the placenta during pregnancy, resulting in fetal/neonatal thrombocytopenia and

bleeding.128–133 Similar arguments may also be made for patients with Bernard-Soulier syndrome.133–135 It may also be argued that avoidance of platelet exposure prevents alloimmunization in these patients with severe mutations, allowing platelet transfusions to be used subsequently in life/limbthreatening bleeding or major surgeries.

ADVERSE EVENTS Thromboembolic Adverse Events of rFVIIa Use in Platelet Disorders rFVIIa when used in patients with platelet disorders appears to be safe. In the International Survey,93 one patient with GT developed thrombus in the right renal pelvis and ureter after gynecologic surgery covered with rFVIIa by continuous infusion (25 μg/ kg/h tapered gradually to 12 μg/kg/h) for 4 days, and antifibrinolytics.86 This patient likely had trauma to the kidney during surgery with bleeding and clotting in the renal pelvis and ureter that did not lyse. A 72-year-old woman with GT developed deep vein thrombosis and pulmonary embolism after bowel resection surgery covered with rFVIIa.87 She received a bolus of 90μg/kg rFVIIa followed by high-dose continuous infusion at 30 μg/kg/ h for 16 days. The thrombotic event occurred 6 days after rFVIIa was discontinued. In the GTR, only one deep venous thrombosis occurred in an adult woman with platelet refractoriness treated with a combination of rFVIIa, platelets and antifibrinolytics after an emergency surgery for an ovarian cyst and hematoma with bilateral ureteral compression.113,114 Among patients with other platelet disorders receiving rFVIIa, thrombotic events in one patient with Bernard-Soulier syndrome and one with uremic platelet dysfunction have been reported to the US Food and Drug Administration (FDA) MedWatch Pharmacovigilance Program.136 As indicated in the section on “rFVIIa in the Treatment of Thrombocytopenia”, ischemic stroke was observed in one of 24 patients with hematologic malignancies-associated thrombocytopenia treated for bleeding with rFVIIa.38 In the prospective placebo-controlled trial on 100 patients treated for bleeding in thrombocytopenic patients following marrow transplantation,78 six episodes of thromboembolic complications occurred in the rFVIIa treated group, compared to zero in the placebo group, although with no statistical significance. In a recent review on the safety of rFVIIa used across four approved indications (Glanzmann thrombasthenia, congenital hemophilia with inhibitors, acquired hemophilia and factor VII deficiency) between January 1, 1996 and December 31, 2013,137 eight GT patients with a total of 12 known thromboembolic events (seven venous and five mixed venous and arterial) after receiving rFVIIa either alone or in combination with other hemostatic drugs were identified. Two of these thromboembolic events were fatal, but the comorbidity and clinical circumstances surrounding these events were not described. Thus, the prevalence of thrombotic events in patients with platelet disorders receiving rFVIIa appears to be low, but experience is still limited.

Thromboembolic Adverse Events in Other Approved Indications for rFVIIa Use rFVIIa has been used more extensively in hemophilia with inhibitors, and thrombotic complications are rare except in unusual circumstances.9,136 Neufeld et al.137 documented a total of 84 thromboembolic events in 73 hemophilia patients with inhibitors (nine fatal) and 54 thromboembolic events in 50 acquired hemophilia patients (19 fatal) associated with FVIIa use. There were also 45 thromboembolic events in 38 patients with FVII deficiency (none fatal); during the study period between January 1, 1996 and December 31, 2013,

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4 million standard doses of rFVIIa (each equivalent to 90 μg/kg  40 kg) have been used. An earlier review by Abshire et al.9 suggested most of patients with thromboembolic events apparently had co-morbid or predisposing factors, such as diabetes mellitus, coronary artery disease, atherosclerosis, hypertension, obesity, advanced age, or indwelling catheter.

Thromboembolic Adverse events in rFVIIa Off-Label and Investigational Use rFVIIa has also been used on an investigational (off-label) basis in patients without hemophilia, FVII deficiency, thrombocytopenia or platelet function disorders for diverse bleeding situations such as: GI, intracranial and postoperative bleeds, bleeding after trauma, after bone marrow/stem cell or organ transplantation, as well as in patients with von Willebrand disease or factor XI deficiency, etc. Thirty-eight thrombotic events (including cerebrovascular thrombosis, myocardial infarction, deep vein thrombosis/pulmonary embolism, disseminated intravascular coagulation [DIC] and others) related to off-label treatments were reported spontaneously to the FDA MedWatch Pharmacovigilance Program, or as published case reports during the period April 1999 to June 2002.136,138 O’Connell et al.139 reviewed adverse events related to rFVIIa use reported to the US FDA Adverse Event Reporting system from March 25, 1999 to December 31, 2005. They found 220 reports on 246 thromboembolic events (23 reports in hemophilia and 197 reports in off-label indications) that included 129 (52%) arterial events (nonhemorrhagic intracranial cerebrovascular accident, acute myocardial infarction, other arterial thromboembolism), 100 (41%) venous thromboembolism, 15 (6%) device occlusion and two (1%) with sites not stated. Forty-three of the 67 deaths were probably related to thromboembolic events. In all series, the contribution of patient factors relative to rFVIIa in these adverse events was not clear and the true incidence remains unknown. Retrospective cohort studies report mixed results. Some did not show excess thromboembolic events following rFVIIa use compared to rFVIIa nonuse controls140,141 while some did.142,143 In a Phase IIb clinical trial on 309 patients with intracranial hemorrhage receiving placebo or rFVIIa (120 or 160 μg/kg), venous thrombotic events in patients receiving rFVIIa (2%, 5/ 303) was similar to those in patients receiving placebo (2%, 2/96), but arterial thrombosis was significantly higher in the rFVIIa group (5%, 16/303 vs. 0%, 0/96).144 A follow-up phase III trial on another 841 patients with intracranial hemorrhage, using a lower dosage of rFVIIa also show a higher arterial thrombosis rate in the group receiving rFVIIa 80 μg/kg (46%) compared to the group receiving placebo (27%) or rFVIIa 20 μg/kg (26%) (P ¼ .04).145 A rFVIIa dose-dependent thromboembolic complication rate was also reported in cardiac surgical patients supported by left ventricular assist device (LVAD).146 The incidence of thromboembolic events was 36.7% in the group receiving rFVIIa at 30–70 μg/kg compared to 9.4% in those receiving 10–20 μg/kg (P  0.001). Levi et al.147 conducted a systematic review to determine the thromboembolic safety of rFVIIa used on an off-label basis to treat life-threatening bleeding in 35 randomized placebo-controlled clinical trials (26 on patients and nine on health volunteers), that included the two stroke studies indicated earlier.144,145 Of 4468 patients (4119 patients, 349 heathy volunteers) analyzed, 401 (9.0%) had thromboembolic events. They confirmed the excess arterial thrombotic rate in those receiving rFVIIa compared to those on placebo (5.5% vs. 3.2%, P ¼ .003) particularly in the older age groups (age >65 year, 9.0% vs. 3.8%, P ¼ .003; age >75 year, 10.8% vs. 4.1%, P ¼ .02), but not for venous thromboembolic rate (5.3% vs.

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5.7%). Among subjects who received rFVIIa, 2.9% (vs. placebo 1.1%) had coronary arterial thromboembolic events.

Summary It is expected that correction of the hemostatic defect may predispose a patient with bleeding disorder to thrombosis if predisposing factors are present. Thus, caution should be exercised when using rFVIIa in patients with underlying conditions that may predispose them to arterial or venous thrombosis or DIC, and in patients of advanced age, particularly for off-label use.

MECHANISMS OF ACTION High-Dose FVIIa-mediated Thrombin Generation: TF-dependent and TF-independent Models, and Effects on Fibrin Clot Structure The mechanisms of high-dose rFVIIa’s enhancement of thrombin generation was originally studied in patients with hemophilia. van’t Veer et al.148 showed that at a physiologic ratio of FVII (10 nM) to FVIIa (100 pM), FVII competed with FVIIa for TF binding, resulting in downregulation of thrombin generation. High-dose rFVIIa could overcome the FVII inhibition and in hemophilia patients, FVIIa at 10 nM (attained by therapeutic rFVIIa doses) normalized the thrombin generation profile to that observed in the presence of FVIII and normal concentrations of FVII (10 nM) and FVIIa (100 pM),148,149 suggesting the role of the TF-dependent mechanism of thrombin generation. High-dose FVIIa also supports hemostasis via a TFindependent mechanism. High-dose rFVIIa binds with a low affinity (Kd
100 nM) to negatively charged phospholipid surface exposed on activated platelets,150 enhanced by the platelet membrane GPIb-IX-V complex.151 At high concentration, FVIIa on the platelet surface can activate FX and mediate thrombin generation sufficiently to effect hemostasis in the absence of FVIII or FIX, independent of TF. It is likely that both the TF-dependent and TF-independent mechanisms contribute to thrombin generation in hemophilia patients treated with high-dose rFVIIa. Butenas et al.149 showed that in a synthetic mixture corresponding to hemophilia B and “acquired hemophilia B” blood produced in vitro by an anti-FIX antibody, the delay in thrombin generation in the presence of 5 pM TF could be normalized in the presence of 10 nM rFVIIa and 6–8  108 activated platelets. TF, rFVIIa and activated platelets were all required, as thrombin generation was abolished by omitting TF, and was substantially decreased in the absence of either rFVIIa or activated platelets in the mixture. Enhanced thrombin generation by rFVIIa in patients with hemophilia (and with GT) also improves fibrin clot structure152,153 and decreases fibrinolysis through activation of the thrombin activatable fibrinolytic inhibitor (TAFI),154 further contributing to hemostasis. The improvement of fibrin clot structure (decreasing clot permeability and tightening of the fibrin network demonstrated by confocal 3D microscopy) when rFVIIa (5 μg/mL final concentration, equivalent to plasma concentration attained at dosage of
250 μg/kg) was added to plasmas from normal control, hemophilia patients, and from one patient with GT, required the presence of frozen-thawed platelets.155 A substantial effect was observed even at a low platelet count of 10–20  109/L for both normal and GT platelets, and the response increased with increasing platelet counts up to 150  109/L. The effects of rFVIIa in this system could be blocked by the addition of annexin V (capable of covering the platelet phospholipid coagulant surface), and naïve platelets

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were not effective. These observations confirm that exposure of phosphatidylserine on the frozen-thawed platelet membrane surface is required for thrombin generation mediated by high concentration of rFVIIa and that the quantity of phospholipids in GT platelet membranes was normal despite the lack of integrin αIIbβ3 on the platelet surface.

High-Dose FVIIa in Thrombocytopenia Kjalke et al.156 used their cell based in vitro model to study the effect of high-dose rFVIIa on thrombocytopenia using unactivated platelets and TF-bearing monocytes in the presence of physiologic concentration clotting factors and natural inhibitors. In this model, decreasing platelet density resulted in a dose-dependent decrease in the rate of thrombin generation, prolongation of time to maximal thrombin generation, and a lower peak level of thrombin formed, together with a decreased rate of platelet activation as monitored by CD62P (P-selectin) expression. A high concentration of rFVIIa at 50–100 nM (at low platelet density) increased the initial rate of thrombin generation (Fig. 63.2A) and shortened the lag phase of platelet activation (Fig. 63.2B) without influencing the time to

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The mechanism of action of high-dose factor VIIa in platelet function disorders has been more extensively studied in GT patients, who are deficient in integrin αIIbβ3 with impaired thrombin generation.159 The data suggest a predominance of TF-independent mechanisms of high-dose rFVIIa-mediated thrombin generation that results in GT platelet activation, adhesion and aggregation (Fig. 63.3).

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maximal thrombin generation or the peak level of thrombin (Fig. 63.2A). Kjalke et al.156 therefore proposed that high-dose rFVIIa may ensure hemostasis in thrombocytopenic patients by increasing initial thrombin generation, resulting in faster platelet activation (and thereby compensating for the lower number of platelets). Improved thrombin generation represented by enhanced fibrin deposition, was also observed in an in vitro model of Galán et al.,157 perfusing thrombocytopenic blood through an annular chamber containing damaged vascular segments with high-concentration rFVIIa, even though there was no improvement of platelet deposition. Subsequently, Lisman et al.158 did show that high concentration rFVIIa (1.2 μg/mL) in the presence of factors X (10 μg/mL) and II (20 ng/mL) significantly increased adhesion of platelets (but not thrombus height) to type III collagen or fibrinogen coated slides perfused with washed red cells and platelets (platelet concentrations from 10 to 200  109/L). This platelet adhesion was prevented by the omission of rFVIIa or addition of thrombin inhibitor, hirudin, confirming that it is a result of thrombin generation mediated by high-dose rFVIIa. Platelet activation was enhanced during platelet adhesion as evident by calcium fluxes and enhanced expression of negatively charge procoagulant phospholipids (reported by annexin A5 binding). They also demonstrated binding of FITC-labeled rFVIIa to the deposited platelet surface. They suggested that enhanced generation of procoagulant phospholipid surface would further facilitate enhancement of thrombin and fibrin generation mediated by the bound rFVIIa in a TF-independent manner.158

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Fig. 63.2 The effect of high-dose rFVIIa on thrombin generation and platelet activation. Unactivated platelets at various concentrations were mixed with factors V, VIII, IX, X, and XI, prothrombin, antithrombin, tissue factor pathway inhibitor, calcium, and various concentrations of rFVIIa and added to tissue factor-expressing monocytes. Aliquots were removed and analyzed for thrombin generation by amidolytic activity (A) and for platelet activation, measured as P-selectin-positive cells by flow cytometry (B). (A) depicts thrombin generation over a 120-min assay, with the first 10-min assay shown in the insert, whereas (B) depicts platelet activation over a 10-min assay. Solid circles, normal platelet count with rFVIIa at 0.2 nM; open circles, low platelet count with rFVIIa at 0.2 nM; open triangles, low platelet count with rFVIIa at 50nM. (Adapted from Poon.42 Original figure by Dr. Marianne Kjalke, Department of Hemostasis Biology, Novo Nordisk A/S, Maaloev, Denmark.)

In an in vitro perfusion model160 in which washed red cells and platelets deficient in αIIbβ3 (from GT patients or normal platelets treated with αIIbβ3 inhibitors) were perfused over an extracellular matrix of stimulated human umbilical vein endothelial cells or type III collagen, adhesion of these defective platelets to the matrix was significantly increased by high concentration of rFVIIa (1.2 μg/mL) in the presence of factors X (10 μg/mL) and II (20 ng/mL). This improvement in adhesion required the participation of the von Willebrand factor-GPIb interaction as it could be blocked by anti-GPIb and anti-von Willebrand factor antibodies. Thrombin generation on the activated platelet surface mediated by bound rFVIIa was responsible for the improvement in adhesion, as adhesion was blocked by hirudin, and by annexin V, and FITC-labeled rFVIIa was demonstrated on the activated platelet surface. The TF-independent mechanism was further confirmed as improvement of platelet adhesion was not affected by anti-TF.

Aggregation of Glanzmann Thrombasthenia Platelets Mediated by High-Dose FVIIa GT platelets are deficient in integrin αIIbβ3, the primary binding site for fibrinogen important for aggregation of normal activated platelets for primary hemostatic plug formation (see Chapter 12). However, in the in vitro model of GT blood

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Fig. 63.3 Schematic tissue factor-independent, platelet-dependent model of primary hemostatic plug formation in Glanzmann’s thrombasthenia (GT) platelets deficient in integrin αIIbβ3 (GPIIb-IIIa). FVIIa-tissue factor (TF) complex on TF-bearing cells at the site of vascular injury activates FX to FXa. FXa-FVa on the TF-bearing cells initiates generation of a small amount of thrombin (FIIa) that is insufficient to provide fibrin formation but sufficient to activate the GT platelets, causing degranulation and release of FV. FVIIa binds to activated platelets weakly, and at high concentration (attained by high-dose rFVIIa therapy) it can directly activate FX to FXa to mediate generation of a high concentration of thrombin (thrombin burst). The augmented thrombin generation results in an increased number of activated platelets deposited (adhesion) to the wound site and increased available platelet procoagulant surface to facilitate more thrombin generation and more platelet activation. The augmented thrombin generated also converts fibrinogen to fibrin. GT platelets lack the fibrinogen receptor (integrin αIIbβ3) and these platelets therefore cannot utilize fibrinogen for aggregation. However, binding of fibrin/polymeric fibrin to an unidentified platelet surface receptor can mediate aggregation of the GT platelets at the wound site (albeit less potently than fibrinogen-mediated aggregation of normal platelets), resulting in primary hemostatic plug formation.

perfusing through an annular chamber containing damaged vascular segments, high-concentration of rFVIIa improved thrombin generation, increased fibrin deposition, and partially restored platelet aggregation.157 A number of studies have also demonstrated that fibrin, particularly polymeric fibrin could, independently of fibrinogen, mediate agglutination of GT platelets, or platelets with αIIbβ3 inhibited.161–163 Lisman et al.164 further showed that high-dose rFVIIa could mediate fibrin-mediated agglutination of GT platelets via a TF-independent thrombin generation. When washed GT platelets were activated with collagen or the thrombin receptoractivating peptide SFLLRN, full aggregation did not occur until high concentration rFVIIa (1.2 μg) was present together with FX (10 μg/mL), FII (20 ng/mL) and fibrinogen (0.5 mg/mL). The platelet aggregation phase was not abolished by anti-TF, but was partially dependent on platelet activation, formation of thromboxane A2, secretion of ADP, activation of proteaseactivated receptor 1 (PAR-1), as well as binding of thrombin to GPIb,164 which has been shown in normal platelets to mediate binding of fibrin to an as yet unidentified platelet receptor.165 Thrombin generation and fibrin formation are both required in this rFVIIa-mediated platelet aggregation, as the time course of the aggregation phase correlated with the generation of FII F1+ 2 as well as fibrinopeptide, and aggregation could be abolished by the addition of hirudin or omission of any of the clotting factors (FX, FII, fibrinogen). Electron microscopy of the αIIbβ3-deficient platelet aggregates showed platelet packing and immunogold identifiable fibrin(ogen) present at some platelet-platelet contact sites, albeit less so than that in similarly prepared normal platelet aggregates. Fibrin appeared

to participate actively to mediate platelet agglutination partly in a receptor-mediated manner, as opposed to being passively trapped during platelet aggregation, since aggregation was less efficient if viable platelets were replaced with fixed platelets.

FVIIa ANALOGS IN CLINICAL DEVELOPMENT One major drawback of the current rFVIIa is its short T1/2 requiring frequent dosing for the management and prevention of bleeding. Improvements in biotechnology has allowed the development of (1) “longer-acting” FVIIa, and (2) FVIIa molecules with enhanced enzymatic activity, or higher affinity to activated platelets for FX activation (and hence thrombin generation). Preclinical in vitro and animal studies have identified a number of promising molecules showing advantages over regular FVIIa by virtue of improving half-lives, or increased activities or both. Of the analogs reviewed in the previous edition,166 the clinical development of three had been discontinued. The long acting N7-GP (GlycoPEGylated FVIIa) was discontinued because of insufficient efficacy advantage in a phase III trial.167 Two analogs with modified sequence by site directed mutagenesis were discontinued because of the development of antidrug antibodies when studied in hemophilia patients with inhibitors. These include the higher potency vatreptacog alfa activated (NN1731, with V158D, E296V, M298Q modifications) after a phase III trial,168 and the more active and longer acting Bay86-6150 (Bay7, with P10Q, K32E, A34E, R36E, T106N,V253N modifications) after a phase I clinical trial.169

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Nevertheless, there are a few analogs showing promise in preclinical studies positioning for clinical trials.

FVIIa Analogs With Prolonged T1/2 (1) FVIIa fused to albumin or monomeric Fc portion of IgG are protected from catabolism by utilizing the MHC-related neonatal Fc receptor (FcRn) that mediates the pathway for IgG and albumin recycling.170–174 Albumin and IgG (together with their linked proteins) pinocytosed by cells in the extravascular compartment are transported to acidic endosomes where they bind FcRn and are thereby diverted from the lysosomal degradation pathway.171,174 They are then exocytosed intact and are free to circulate again, thus extending their T1/2. The binding of albumin and IgG-Fc portion is independent of one another by distinctive mechanisms and to different surfaces of FcRn.172 The T1/2 extension of rFVIIa fused to albumin (rVIIa-FP) and to monomeric Fc of IgG (rFVIIaFc) have been demonstrated in animal studies.174,175 A phase 1 clinical trial on healthy volunteers has been completed on rVIIa-FP, and showed a good tolerability profile up to 1000 μg/kg with prolonged T1/2 to 8.5 h (3–4 times that of regular FVIIa).176,177 Human trials on rFVIIaFc have not yet been performed.

FVIIa Analogs With Enhanced Enzymatic Activity and Prolonged T1/2 (1) FVIIa has been modified with a platelet-targeting motif either to activated αIIbβ3 (on activated platelets) or to both activated αIIbβ3 and GPIb (on activated and nonactivated platelets) for improved platelet binding and enhanced thrombin generation while fused to Fc (for longer T1/2).174,178 (2) CB813d (PF.05280602) is a modified rFVIIa molecule with unknown details, although its patent application suggested modifications were targeted in the same general domain as in vatreptacog alfa activated and BAY 866150.179 Preclinical study suggested that variant CB813D has a 3–5 fold increase in duration of activity in hemophilic mice180 and a 7-fold increase in catalytic activity in dogs.181 A phase 1 single ascending dose (4.5, 9, 18, 30 μg/kg) cohort study on 24 hemophilia A and B patients with or without inhibitors showed a T1/2 of 3.5 h across all dose groups with significant improvement (6–9-fold) in potency and duration of effects. The drug was well tolerated with no dose limiting toxicity or immunogenicity.182 (3) X-TEN is a hydrophobic and unstructured polypeptide that will increase the radius of the protein it links to and interferes with the renal and receptor clearance mechanism.183 FVIIa recombinantly linked to XTEN sequence of 288 amino acids (FVIIa-XTEN288) has an increased T1/ 2 by 8-fold to
9 h in hemophilic mice, but the activity in whole blood ROTEM was lower than regular FVIIa. Incorporating scFv derived from a monoclonal antibody that specifically recognizes human platelet receptor αIIbβ3 into FVIIa-XTEN288 resulted in increased binding to platelets with no detectable effect on platelet activation and platelet clearance in vitro and in vivo. This platelet targeted rFVIIa-XTEN fusion protein has significant increase in clotting activity as measured by thrombin generation assay and ROTEM in addition to a prolongation of T1/2.183 (4) CTP technology involves fusion of the C-terminus peptide of human chorionic growth hormone (hCG) to one or both ends of the target protein resulting in an enhanced T1/2 of the protein. rFVIIa-CTP-hCG has a 5-fold increase

in T1/2 and 3.5-fold increase in the area under the curve and appears to have improved activity based on a thrombin generation assay. Studies on FVIII/ mice showed improved survival following tail-vein transection and reduced intensity and duration of bleeding in tail-clip studies.184

Subcutaneous (SC) Preparations Development Both CB813d and FVIIa-CTP-hCG also have programs to develop preparations for more convenient SC administration. SC injection of CB813d in hemophilia A dogs resulted in decreased whole blood clotting time for
20–40 min.182 SC injection of FVIIa-CTP-hCG in hemophilic mice showed prolonged TEG correction.184

Challenges in FVIIa Analog Development Development of FVIIa analog with increased T1/2 and/or increased enzymatic activities are principally targeted for management of hemophilia with inhibitors and these analogs must have safety and efficacy advantage or administration convenience over the current rFVIIa molecule in these patients. This is amply illustrated by the discontinuation of development of N7-GP (due to insufficient efficacy) as well as vatreptacog alfa activated and Bay86-6150 due to the development of antidrug antibodies.168,169 The latter also suggest that a minor modification of FVIIa sequence or conformation structure may result in immunogenicity not necessarily predicted by preclinical immunogenicity modeling. FVIIa analogs also face competition by other innovative products including the factor VIII mimetics (emicizumab)185 and agents that will increase thrombin generation by decreasing endogenous concentration of natural inhibitors of coagulation, such as antithrombin targeting RNAi (fitusiran)186 and anti-TFPI (concizumab).187

CONCLUSIONS Available data suggest rFVIIa is an attractive alternative to platelet transfusion for the treatment of patients with platelet disorders. There is, however, a major need for clinical studies, particularly clinical trials to formally assess efficacy, safety, and optimal treatment regimens in patients with thrombocytopenia and in patients with congenital and acquired platelet function disorders. The data need to be stratified according to mild/moderate and severe bleeding episodes, as well as minor and major surgical procedures. The mechanisms of actions of rFVIIa need to be clarified in the different types of platelet function disorders (GT, Bernard-Soulier syndrome, platelet-type von Willebrand disease, and other congenital and acquired platelet disorders) given that they have different pathophysiologies, and the efficacy, safety, and optimal treatment regimen for each may not necessarily be the same. A number of FVIIa analogs with longer T1/2 and/or higher potency are under development, but their development is not without challenges. REFERENCES 1. Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, et al. Clinical practice guidelines from the AABB: red blood cell transfusion thresholds and storage. JAMA 2016;316 (19):2025–35. 2. Katus MC, Szczepiorkowski ZM, Dumont LJ, Dunbar NM. Safety of platelet transfusion: past, present and future. Vox Sang 2014;107(2):103–13. 3. Stramer SL, Hollinger FB, Katz LM, Kleinman S, Metzel PS, Gregory KR, et al. Emerging infectious disease agents and their

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118. Palsson R, Vidarsson B, Gudmundsdottir BR, Larsen OH, Ingerslev J, Sorensen B, et al. Complementary effect of fibrinogen and rFVIIa on clotting ex vivo in Bernard-Soulier syndrome and combined use during three deliveries. Platelets 2014;25(5):357–62. 119. del Pozo Pozo AI, Jimenez-Yuste V, Villar A, Quintana M, Hernandez-Navarro F. Successful thyroidectomy in a patient with Hermansky-Pudlak syndrome treated with recombinant activated factor VII and platelet concentrates. Blood Coagul Fibrinolysis 2002;13(6):551–3. 120. Langendonck L, Appel IM. Modification of biological parameters after treatment with recombinant factor VIIa in a patient with thrombocytopathy due to storage pool disease. Pediatr Blood Cancer 2005;44(7):676–8. 121. Lohse J, Gehrisch S, Tauer JT, Knofler R. Therapy refractory menorrhagia as first manifestation of Hermansky-Pudlak syndrome. Hamostaseologie 2011;31(Suppl 1):S61–3. 122. Fressinaud E, Sigaud-Fiks M, Le Boterff C, Piot B. Use of recombinant factor VIIa (NovoSeven®) for dental extraction in a patient affected by platelet-type (pseudo-) von Willebrand disease. Haemophilia 1998;4:299. 123. Sanchez-Luceros A, Woods AI, Bermejo E, Shukla S, Acharya S, Lavin M, et al. PT-VWD posing diagnostic and therapeutic challenges—small case series. Platelets 2017;28(5):484–90. 124. Revesz T, Arets B, Bierings M, van den Bos C, Duval E. Recombinant factor VIIa in severe uremic bleeding [letter]. Thromb Haemost 1998;80(2):353. 125. Plews DE, Thomas AE. Novel uses of recombinant factor VIIa. Blood 1999;94(10 Suppl. 1):83b. 126. Meijer K, Sieders E, Slooff MJ, de Wolf JT, vdM J. Effective treatment of severe bleeding due to acquired thrombocytopathia by single dose administration of activated recombinant factor VII [letter]. Thromb Haemost 1998;80(1):204–5. 127. Vucelic D, Sabljak P, Pesko P, Stojakov D, Keramatollah E, Nenadic B, et al. The use of recombinant activated factor VII in the treatment of gastrointestinal bleeding following acetylsalicylic acid therapy in a surgical patient. Srp Arh Celok Lek 2008;136 (Suppl. 3):240–5. 128. Jallu V, Pico M, Chevaleyre J, Vezon G, Kunicki TJ, Nurden AT. Characterization of an antibody to the integrin beta 3 subunit (GP IIIa) from a patient with neonatal thrombocytopenia and an inherited deficiency of GP IIb-IIIa complexes in platelets (Glanzmann’s thrombasthenia). Hum Antibodies Hybridomas 1992;3(2):93–106. 129. Boval B, Bellucci S, Boyer-Neumann C, d’Oiron R, CiraruVigneron N, Audibert F, et al. Glanzmann thrombasthenia and pregnancy: clinical observations and management of four affected women. Thromb Haemost 2001;(Suppl). Abstract P1154. 130. Santoro C, Rago A, Biondo F, Conti L, Pulcinelli F, Laurenti L, et al. Prevalence of allo-immunization anti-HLA and anti-integrin alphaIIbbeta3 in Glanzmann Thromboasthenia patients. Haemophilia 2010;16(5):805–12. 131. Siddiq S, Clark A, Mumford A. A systematic review of the management and outcomes of pregnancy in Glanzmann thrombasthenia. Haemophilia 2011;17(5):e858–69. 132. Fiore M, Firah N, Pillois X, Nurden P, Heilig R, Nurden AT. Natural history of platelet antibody formation against alphaIIbbeta3 in a French cohort of Glanzmann thrombasthenia patients. Haemophilia 2012;18(3):e201–9. 133. Poon MC, d’Oiron R. Alloimmunization in congenital deficiencies of platelet surface glycoproteins: focus on Glanzmann Thrombasthenia and Bernard-Soulier Syndrome. Semin Thromb Hemost 2018;44(6):604–14. 134. Peng TC, Kickler TS, Bell WR, Haller E. Obstetric complications in a patient with Bernard-Soulier syndrome. Am J Obstet Gynecol 1991;165(2):425–6. 135. Peitsidis P, Datta T, Pafilis I, Otomewo O, Tuddenham EG, Kadir RA. Bernard Soulier syndrome in pregnancy: a systematic review. Haemophilia 2010;16(4):584–91. 136. Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2004;2(10):1700–8. 137. Neufeld EJ, Negrier C, Arkhammar P, Benchikh el Fegoun S, Simonsen MD, Rosholm A, et al. Safety update on the use of recombinant activated factor VII in approved indications. Blood Rev 2015;29(Suppl 1):S34–41.

138. Sallah S, Isaksen M, Seremetis S, Payne RL. Comparative thrombotic event incidence after infusion of recombinant factor VIIa vs. factor VIII inhibitor bypass activity–a rebuttal. J Thromb Haemost 2005;3(4):820–2. 139. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006;295(3):293–8. 140. Bucklin MH, Acquisto NM, Nelson C. The effects of recombinant activated factor VII dose on the incidence of thromboembolic events in patients with coagulopathic bleeding. Thromb Res 2014;133(5):768–71. 141. Martinez Lopez MC, Alcaraz Romero AJ, Martinez Lopez AB, Fernandez-Llamazares CM, Ramos Navarro C. Risk assessment of thrombotic events after the use of activated factor VII. An Pediatr (Barc) 2013;79(3):177–81. 142. Cooper JD, Ritchey AK. Response to treatment and adverse events associated with use of recombinant activated factor VII in children: a retrospective cohort study. Ther Adv Drug Saf 2017;8 (2):51–9. 143. Downey L, Brown ML, Faraoni D, Zurakowski D, DiNardo JA. Recombinant factor VIIa is associated with increased thrombotic complications in pediatric cardiac surgery patients. Anesth Analg 2017;124(5):1431–6. 144. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005;352(8):777–85. 145. Diringer MN, Skolnick BE, Mayer SA, Steiner T, Davis SM, Brun NC, et al. Thromboembolic events with recombinant activated factor VII in spontaneous intracerebral hemorrhage: results from the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Stroke 2010;41(1):48–53. 146. Bruckner BA, DiBardino DJ, Ning Q, Adeboygeun A, Mahmoud K, Valdes J, et al. High incidence of thromboembolic events in left ventricular assist device patients treated with recombinant activated factor VII. J Heart Lung Transplant 2009;28(8):785–90. 147. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010;363(19):1791–800. 148. van’t Veer C, Golden NJ, Mann KG. Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa. Blood 2000;95(4):1330–5. 149. Butenas S, Brummel KE, Bouchard BA, Mann KG. How factor VIIa works in hemophilia. J Thromb Haemost 2003;1(6):1158–60. 150. Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol 1997;99(3):542–7. 151. Weeterings C, de Groot PG, Adelmeijer J, Lisman T. The glycoprotein Ib-IX-V complex contributes to tissue factor-independent thrombin generation by recombinant factor VIIa on the activated platelet surface. Blood 2008;112(8):3227–33. 152. He S, Blomback M, Jacobsson Ekman G, Hedner U. The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX. J Thromb Haemost 2003;1(6):1215–9. 153. Dargaud Y, Prevost C, Lienhart A, Claude Bordet J, Negrier C. Evaluation of the overall haemostatic effect of recombinant factor VIIa by measuring thrombin generation and stability of fibrin clots. Haemophilia 2011;17(6):957–61. 154. Lisman T, Mosnier LO, Lambert T, Mauser-Bunschoten EP, Meijers JC, Nieuwenhuis HK. Inhibition of fibrinolysis by recombinant factor VIIa in plasma from patients with severe hemophilia A. Blood 2002;99(1):175–9. 155. He S, Ekman GJ, Hedner U. The effect of platelets on fibrin gel structure formed in the presence of recombinant factor VIIa in hemophilia plasma and in plasma from a patient with Glanzmann thrombasthenia. J Thromb Haemost 2005;3(2):272–9. 156. Kjalke M, Ezban M, Monroe DM, Hoffman M, Roberts HR, Hedner U. High-dose factor VIIa increases initial thrombin generation and mediates faster platelet activation in thrombocytopenia-like conditions in a cell-based model system. Br J Haematol 2001;114(1):114–20. 157. Galán AM, Tonda R, Pino M, Reverter JC, Ordinas A, Escolar G. Increased local procoagulant action: a mechanism contributing to the favorable hemostatic effect of recombinant FVIIa in PLT disorders. Transfusion 2003;43(7):885–92.

Factor VIIa 158. Lisman T, Adelmeijer J, Cauwenberghs S, Van Pampus EC, Heemskerk JW, De Groot PG. Recombinant factor VIIa enhances platelet adhesion and activation under flow conditions at normal and reduced platelet count. J Thromb Haemost 2005;3 (4):742–51. 159. Reverter JC, Beguin S, Kessels H, Kumar R, Hemker HC, Coller BS. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. Potential implications for the effect of c7E3 Fab treatment on acute thrombosis and “clinical restenosis”. J Clin Invest 1996;98(3): 863–74. 160. Lisman T, Moschatsis S, Adelmeijer J, Nieuwenhuis HK, De Groot PG. Recombinant factor VIIa enhances deposition of platelets with congenital or acquired alpha IIb beta 3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor-independent thrombin generation. Blood 2003;101(5):1864–70. 161. Niewiarowski S, Levy-Toledano S, Caen JP. Platelet interaction with polymerizing fibrin in Glanzmann’s thrombasthenia. Thromb Res 1981;23:457–63. 162. McGregor L, Hanss M, Sayegh A, Calvette JJ, Trzeciak MC, Ville D. Aggregation to thrombin and collagen of platelets from a Glanzmann thrombasthenic patient lacking glycoproteins IIb and IIIa. Thromb Haemost 1989;62(3):962–7. 163. Osdoit S, Rosa J-P. Polymeric fibrin interacts with platelets independently from integrin aIIbb3. Blood 2001;98 (Suppl):518a. 164. Lisman T, Adelmeijer J, Heijnen HF, de Groot PG. Recombinant factor VIIa restores aggregation of alphaIIbbeta3-deficient platelets via tissue factor-independent fibrin generation. Blood 2004;103(5):1720–7. 165. Soslau G, Class R, Morgan DA, Foster C, Lord ST, Marchese P, et al. Unique pathway of thrombin-induced platelet aggregation mediated by glycoprotein Ib. J Biol Chem 2001;276(24): 21173–83. 166. Poon MC, VIIa F. In: Michelson AD, editor. Platelets. 3rd ed. New York: Academic Press; 2013. p. 1257–74. 167. Ljung R, Karim FA, Saxena K, Suzuki T, Arkhammar P, Rosholm A, et al. 40K glycoPEGylated, recombinant FVIIa: 3-month, doubleblind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors. J Thromb Haemost 2013;11(7):1260–8. 168. Mahlangu JN, Weldingh KN, Lentz SR, Kaicker S, Karim FA, Matsushita T, et al. Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity. J Thromb Haemost 2015;13 (11):1989–98. 169. Mahlangu J, Paz P, Hardtke M, Aswad F, Schroeder J. TRUST trial: BAY 86-6150 use in haemophilia with inhibitors and assessment for immunogenicity. Haemophilia 2016;22(6):873–9. 170. Weimer T, Wormsbacher W, Kronthaler U, Lang W, Liebing U, Schulte S. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost 2008;99(4):659–67. 171. Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, et al. The major histocompatibility complexrelated Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med 2003;197(3):315–22. 172. Anderson CL, Chaudhury C, Kim J, Bronson CL, Wani MA, Mohanty S. Perspective-FcRn transports albumin: relevance to immunology and medicine. Trends Immunol 2006; 27(7):343–8.

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