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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in Arthritis
- Sprache: Englisch
Frontiers in Arthritis is an ebook series devoted to publishing the latest advances in arthritis medicine and research. Each volume brings forth contributions on topics relevant to the diagnosis, management and treatment of arthritis. The ebook series is essential reading for rheumatologists and orthopedic surgeons involved in clinical research and practice.
This volume presents comprehensive information about the pathology, diagnosis and treatment of haemophilic arthropathy. Readers will find information about knee, hip, elbow, foot and ankle surgery in patients affected by haemophilia as well as special topics (microsurgery and postoperative rehabilitation and health risks). The broad range of information presented in this volume makes it the definitive handbook on arthritis in haemophiliac cases and the management of related complications.
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Seitenzahl: 518
Veröffentlichungsjahr: 2017
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Frontiers in Arthritis
(Volume 2)
(The Management of the Haemophilc Arthropathy)
Edited by
Christian Carulli
BENTHAM SCIENCE PUBLISHERS LTD.
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FOREWORD
This book is the result of 20 years of clinical activity in the management of the haemophilic arthropathy. It is based on the personal experience and on the cultural and professional aspects shared with active scientists involved in the study and treatment of Haemophilia.
My personal experience started in the ‘90s as a consultant at the Florence Haemophilic Service, at that moment in the vanguard as a haematologic department; however, it lacked a modern orthopaedic approach to this disease, that was then introduced. Arthroscopic and prosthetic surgery were at the beginning focused on knees and hips; subsequently other surgeons in my hospital joined and shared with me their experience in elbow, hand, and ankle surgery. Moreover, I progressively and successfully applied in haemophilic patients several principles of the regenerative medicine when indicated, in particular in cases of important bone loss.
The high expertise of eminent haematologists as Dr. Morfini initially, and Dr. Castaman later with their equipes allowed us to safely perform complex surgical procedures without complications.
Subsequently, non-operative approaches as hyaluronic acid injections and chemical synoviorthesis were largely used, and physical therapy strategies increasingly promoted.
The local health service punctually granted financial resources, and enabled me to perform surgery in patients with inhibitors too.
In addition to clinical and surgical aspects, the book offers a detailed overview of the general aspects of Haemophilia and the haemophilic arthropathy: from the definition and features of the disease to the pathogenesis of arthropathy; from the pharmacokinetics of the most important drugs to the laboratory perspective. A chapter is dedicated to the radiological findings, lifestyle recommendations, and postoperative rehabilitation. A section on the nursing of such patients is also considered.
I think that anyone wishing to approach haemophilic patients and to treat the haemophilic arthropathy will find in this volume a useful and complete guide.
PREFACE
Haemophilia is one of the most common rare diseases, characterized by bleedings and haemorrhages related to an inherited deficiency of coagulative factors. For decades it has been associated with higher rates of mortality and morbidity, until clotting factor concentrates were diffused, significantly limiting most of the complications. A dramatic raise of morbidity and mortality after blood transfusions was reported when HIV and Hepatitis infections were discovered. The development of recombinant concentrates, the modern prophylactic treatment, and the multidisciplinary approach to this disease lead over the years to the reduction of such complications and improvements in the management of the related clinical settings.
Then, why another book on the management of the haemophilic arthropathy? Simply because arthropathy may be to date considered the most frequent complication of Haemophilia.
Since childhood, the first falls in the physiological development of gait ability and the high frequency of impacts during games and sports activity may induce bleedings in muscles and joints. While a haematoma in muscles usually shows a self-resolution, blood in some joints, named “target joints”, may induce early negative effects, producing the so-called “arthropathy”. Such degenerative and inflammatory condition finally results in a mild to severe irreversible damage, that nowadays represents not a cause of mortality but rather a source of severe disability.
Even the powerful efficacy of bleeding prophylaxis, musculoskeletal alterations are still yet highly represented. Thus, the management of the haemophilic arthropathy has gained importance being to date one of the most essential goals of the modern approach to Haemophilia. Lifestyle modifications, selected sports activity, periodic evaluations by the multidisciplinary team (haematologist, orthopaedic surgeon, skilled nurse, radiologist, physiotherapist, lab personnel, and several other figures), and tailored prophylactic treatments represent the best way to prevent articular degenerative changes or to delay the progression of the arthropathy. In cases of fair results with this approach, it is possible to adopt conservative therapies, as braces, physical therapy, and articular injections with several substances and different indications. This would mean to avoid the early recourse to surgical procedures that until a decade ago was the only choice to ensure an acceptable quality of life in young symptomatic patients. On the other hand, a significant number of patients still now found no improvements with these strategies. In such cases, surgery is mandatory. With respect to the past, knee arthroplasty, ankle fusions, and arthroscopy are not the only orthopaedic procedures useful to address a joint arthropathy. Elbow and ankle arthroscopy, hip, ankle, and elbow arthroplasty are gaining popularity given the good outcomes and high reproducibility, simultaneously with the development of modern implants and devices, less invasive techniques, and biomaterials with better tribology and performance. Nowadays, it is possible to delay a joint replacement by a minimally invasive surgery, and also to achieve a long-term survival of implant after an arthroplasty. Joint fusions are unfrequently indicated, mostly after failure of the above mentioned procedures. Amputations are to date very uncommon, and proposed only in difficult cases when no limb salvage procedures are feasible. As expected, joint replacements in young haemophilic patients will fail, and revision arthroplasty often associated with reconstructive and plastic surgery will progressively arise. Thanks to modern modular revision implants, also such challenging conditions have been well addressed. Finally, no orthopaedic procedures may produce a good result without a valid and tailored rehabilitative protocol: specific approaches under control of the multidisciplinary team now ensure an effective functional recovery, and a better feeling referred by the operated patients.
Our future target will be the prevention of arthropathy by a multimodal and multidisciplinar approach, in order to make Haemophilia an early diagnosis but no more a source of disability. In specific challenging cases, as patients with inhibitors, the goal will eventually be the limitation of the natural history of arthropathy by all conservative or minimally invasive means that are now available, more than surgical procedures.
This textbook represents an updated overview on all aspects related to Haemophilia and its orthopaedic complications; it may be considered the most multidisciplinary textbook on this topic, focusing on this disease from the bench to the surgical room.
List of Contributors
Pathogenesis of the Haemophilic Arthropathy
Daniela Melchiorre1,*,Silvia Linari2,Fabrizio Matassi3,Giancarlo Castaman2Abstract
Joint damage due to recurrent bleedings in Haemophilia is the cause for long-term disabilities. The pathogenetic mechanism of haemophilic arthropathy is multifactorial and includes inflammatory synovium-mediated and degenerative cartilage-mediated phenomenons, in addition to neoangiogenesis and bone loss. Free blood in the joint has a direct effect on cartilage and synovium, and the deposit of iron appears to play a pivotal role. Iron may promote the apoptosis of chondrocytes by catalyzing the formation of oxygen metabolites. Iron may also act on the synovial membrane by favouring its proliferation through the induction of proto-oncogenes involved in cellular proliferation and stimulation of inflammatory cytokines. Such degenerative and inflammatory processes occur concomitantly, but also independently. A reduction of bone mineralization is usually present as a part of the articular damage associated to a multifactorial mechanism: it seems that the molecular triad (osteoprotegerin/Receptor activator of nuclear factor kB/Receptor activator of nuclear factor kB ligand) probably plays a major role, inducing osteoclastic differentiation and maturation. These processes finally result in a fibrotic and irreversible altered joint, feature of haemophilic arthropathy.
INTRODUCTION
Haemophilia A and B are rare X-linked recessive bleeding disorders characterized by the absence or functional defect of clotting factor VIII (FVIII) or factor IX (FIX) respectively. The hallmark of such disease is represented by musculoskeletal bleedings, particularly haemarthrosis, leading to orthopaedic complications. Joint bleeding is the most common and potentially most disabling manifestation of severe Haemophilia (i.e. plasma FVIII or FIX <1U/dL) [1]. In
nearly half of all children affected by severe Haemophilia, the initial haemartrosis occurs during the first year of life [2], and 90% of patients experience at least a joint bleeding before the age of 4.5 years [3]. Eighty per cent of joint bleedings involve knees, elbows, and ankles [4], and patients often develop multiple “target” joints. Although blood is rapidly cleared from the joint space also by the replacement with the missing factor, the pathologic process still continues, resulting in both clinical and radiographic changes. Recurrent bleedings cause an irreversible joint damage with progressive functional impairment [5], chronic pain [6], and heavy impact on quality of life [7]. Haemarthrosis can be prevented or controlled by the prophylactic administration of clotting factor concentrates. Compared with an on-demand treatment strategy, a primary prophylactic treatment (i.e. the regular continuous treatment initiated in the absence of documented osteochondral joint disease and started before the second clinically evident large joint bleed in children >3 years) leads to better musculoskeletal outcomes, as clearly established [8-11]. [8]. However despite such strategy, joint bleedings and related damages may recur and the haemophilic arthropathy (HA) may realize, as confirmed by the radiographic evidence by the age of 6 in some subjects who had no bleeding or few subclinical haemarthroses [11].
The mechanism of the progressive joint damage in patients with Haemophilia is still relatively unclear, but recurrence and persistence of blood into the joint cavity is the key factor responsible for synovial and cartilage changes [12, 13]. Increasing evidences of a close relationship between the type of mutation (“null” and/or “missense” mutations), bleeding, inflammatory process, and neoangiogenesis are emerging and suggesting that iron, cytokines, and neoangiogenic factors can initiate synovial and early cartilage damages with molecular changes and perpetuation of a chronic inflammatory condition [14].
From Bleeding to Synovial and Cartilage Damage
Bleeding into a joint exposes synovial cells to blood and its components including iron that plays a pivotal role in joint damage [15] (Fig. 1). The progressive accumulation over time of iron as haemosiderin (normally removed from the by synovial macrophages) represents the trigger for synovial inflammation [16]. Haemosiderin deposits are crucial in the early stages of HA, triggering synoviocyte hypertrophy (resulting in “villi”), neoangiogenesis, and release of hydrolytic enzymes from synovial cells. Iron up-regulates the expression of proinflammatory cytokines, as interleukin-6 (IL-6), IL-1alpha, IL-1beta and tumor necrosis factor-alpha (TNF-alpha) in synovial cells and induces the regulator genes c-myc and MDM2 expression, resulting in synovial proliferation [17, 18]. Another effect of haemosiderin is the lymphocytes infiltration of the synovial membrane with subsequent inflammatory changes. Moreover, different proinflammatory cytokines released by synovial cells may inhibit the formation of human cartilage matrix [15]. Synovitis is one of the earliest macroscopic effect of a target joint and it is not always easily distinguishable from a clinical point of view from haemarthrosis. Synovitis is an inflammatory process involving synovial tissue, characterized by hypertrophy, migration of inflammatory cells, and a high degree of neoangiogenesis [18-22].
Fig. (1)) Mechanisms of blood-induced joint damage in Haemophilia: the role of iron (Fe2+) interacting with Hydrogen peroxide (H202), macrophages’activation (Mo/Mö), matrix metalloproteinases (MMPs), and involvement of several cytokines.Recurrent bleedings and synovitis rapidly evolving into joint damage can be considered two different aspects of HA. Intense, chronic effusion of the affected joint after one or several haemarthrosis typically occurs in the early stages of HA [23, 24]. Synovitis can lead to further bleedings with transformation of an acute process in a chronic disease.
Also the presence of free blood in a target joint has a direct harmful effect on cartilage, resulting in adverse changes in chondrocyte activity [25]. Moreover, these alterations may occur before the synovial inflammation becomes evident. Human articular cartilage consists of a relatively small number of chondrocytes embedded in a relatively large amount of extracellular matrix that consists mainly of collagen and proteoglycans. There is a continuous turnover of these components, with a delicate balance between synthesis and breakdown [26].
A pivotal role in the whole process is played by the high-weight molecular complex called “inflammasome”. The inflammasome controls the maturation and the secretion of IL-1beta by means of the activation of caspase 1. The inflammasome constituents are the pattern-recognition receptors (PRRs), including the Toll-like receptors (TLRs) and lectins (CTLs), which analyze the extracellular environment and are associated with pathogen-associated molecular patterns (PAMPs). PRRs also include the intracellular NOD-like receptors (NLR) which recognize both PAMPs that harmful signals caused by danger associated molecular patterns (DAMPs) as demonstrate by Mendonça et colleagues [27].
In vitro studies have shown that a relatively short exposure (4 days, the expected natural evacuation time of blood from a human joint) of human cartilage to whole blood in concentrations up to 50% (blood concentration during haemarthroses are expected to approach 100%) induces long-lasting damaging effects [28]. The marked inhibition of matrix formation (proteoglycan synthesis) and increased breakdown, i.e. release of matrix components (proteoglycan release) result in a progressive loss of matrix, caused by the induction of apoptosis of chondrocytes by hydroxyl radicals formed upon exposure to blood [29]. Hydroxyl radicals are formed when hydrogen peroxide production by chondrocytes is increased upon stimulation by pro-inflammatory cytokines, such as IL-1beta, originating from activated blood monocytes/macrophages present in the blood within the joint. Hydrogen peroxide reacts with haemoglobin-derived iron from damaged and phagocytosed red blood cells close to chondrocytes. This triggers the formation of radicals that induce apoptosis and consequently an irreversible inhibition of cartilage matrix synthesis [25, 29, 30]. Canine in vivo studies have corroborated these findings [31] and demonstrated that immature cartilage is more susceptible to blood-induced damage than mature cartilage [32]. Joint bleeding leads to initially independent adverse changes in synovial tissue, articular cartilage, and consequently subchondral bone. Taken together, the mechanism of blood-induced joint damage includes both degenerative (cartilage-mediated) and inflammatory (synovium-mediated) components. Although influencing each other, these processes also occur independently [33].
Neoangiogenesis
Neoangiogenesis associated with the recruitment of bone marrow-derived progenitors is a critical, independent mechanism involved in the development and maintenance of HA. Neoangiogenesis is also implicated in tumor growth and inflammatory arthritis [14, 34, 35]. The proangiogenic vascular endothelial growth factor (VEGF) is the principal signaling molecule in angiogenesis and can be induced by hypoxia and different cytokines through interaction with its receptors, VEGFR1 and 2. Similarly to other joint diseases, sharing histological similarities with HA, the synovial pannus has enhanced oxygen demand with evidence of de novo blood vessel formation of the synovium. A four-fold elevation in different proangiogenic factors as VEGF, stromal cell-derived factor-1 (SDF-1), and metalloproteinase 9 (MMP-9) has been recorded. Also pro-angiogenic macrophage/monocyte cells (VEGF+/CD68+ and VEGFR1+/CD11b+ and VEGF/CD68+) in synovium and peripheral blood of haemophilic subjects were observed. A significant increase of VEGFR2/AC133+ endothelial progenitor cells and CD34/ VEGFR1+ haemopoietic progenitors cells was also demonstrated [34, 36]. Human synovial cells, when incubated with haemophilic sera, up-regulated hypoxia-inducible factor 1alpha (HIF1A) mRNA, implicating hypoxia in the neoangiogenesis process [36]. Moreover, an increased microvessels density has been shown by immunofluorescence in synovial cells from patients with end-stage HA [34]. This suggests that also late stages of HA can be characterized by an active neoangiogenesis.
From Bleeding to Osteoporosis
Osteoporosis is a disorder characterized by decreased bone mass and microarchitectural deterioration, resulting in loss of bone strength and fragility fractures [37]. Such condition has been recently recognized as a severe comorbidity in Haemophilia [38, 39].
The pathogenesis of low bone mineral density in subjects with Haemophilia is multifactorial. Primary key factors include: prolonged immobilization [38-40]; lack of weight-bearing exercises and failure to achieve an optimal strength during growth [41]; excessive bone resorption resulting in loss of bone mass and failure to replace the lost bone due to defects in bone formation [42, 43]. Other factors such as Human Immunodeficiency Virus (HIV) or hepatitis C virus (HCV) infections, and their treatments, may be independently associated with decreased bone mineral density [38, 42, 44]. The mechanism and pathways by which blood in the joint cavity causes bone quality and quantity depletion have not been to date fully elucidated [45, 46]. However, members of the TNF receptor superfamily probably play a major role. Effectively, the molecular triad osteoprotegerin/Receptor activator of nuclear factor kB/Receptor activator of nuclear factor kB ligand (OPG/RANK/RANKL) that tightly controls the bone turnover is a crucial parameter of bone biology [47, 48]. RANKL is a transmembrane ligand mainly expressed on osteoblasts/stromal cells in the bone microenvironment. RANKL exists either as a cell-bound form or a truncated ectodomain variant derived by enzymatic cleavage of the cellular form (soluble RANKL, sRANKL). It binds to its receptor RANK expressed at cell surface of osteoclast precursor, possibly of the macrophage lineage, and induces osteoclastic differentiation and maturation, leading to bone resorption. In synovial membrane, RANKL is expressed by fibroblast-like synoviocytes (synoviocytes type B), and by activated T cells and may induce osteoclastogenesis, through a mechanism enhanced by several cytokines (TNF-alpha, IL1, and IL17) that promote both inflammation and bone resorption [49, 50]. OPG, also a member of the TNF receptor family, acts as a decoy receptor for RANKL, and competes for binding of RANKL to RANK [51-53]. By this mechanism, OPG negatively regulates osteoclast differentiation, activity, and survival both in vivo and in vitro [48, 50, 53, 54]. RANKL inhibits osteoclast apoptosis whereby OPG acts as antagonist [49]. OPG is predominantly found in macrophages of the intimal synovial lining and in endothelial cells, where is complexed with von Willebrand factor within the Weibel-Palade bodies [54]. Variations in the balance between OPG and RANKL leads to pathological bone changes. Osteoclasts precursors (OCPs) are derived from haemopoietic (monocyte) progenitors in the spleen and liver migrating from blood into bone where they fuse with one another to form multinucleated osteoclasts. Blood neutrophils in the joint create an inflammatory environment that produces IL-1, IL-6, RANKL, and TNF-alpha [55, 56]. TNF increases the proliferation and differentiation of OPCs [57]. TNF also inhibits the production by bone marrow stromal cells of stromal cell-derived factor 1, which, in turn, increases the release of OPCs from the bone marrow [58]. RANKL synthesized by reactive lymphocytes in the joint binds to RANK stimulating osteoclasts to resorb bone (Fig. 2).
Fig. (2)) The role of the molecular triad osteoprotegerin/RANK/RANKL in bone remodelling.As key regulators of bone remodeling, serum levels of OPG/RANKL were analysed in a wide population of patients with haemophilia, together with the expression of the triad OPG/RANK/RANKL in synovial tissue of adult patients with Haemophilia, undergoing to knee replacement surgery [59]. OPG levels in all Haemophilia A patients were decreased and a strong expression of RANK and RANKL was found. A strict correlation between instrumental findings and severity of HA, according to the World Federation of Haemophilia orthopaedic joint scale (WFH score) [60], Petterson [61], and ultrasound score [62] was also observed. The biochemical markers of bone turnover in the synovial tissue of haemophiliacs indicate an osteoclastic activation, not counteracted by OPG. In fact, RANK and RANKL were found to be strongly expressed in the synovium. Instead, the expression of OPG was dramatically reduced in synovial tissue. The absence of OPG in synovial tissue suggests that the balance is shifted versus osteoclastic activity. In conclusion, osteoclastogenesis seems to be activated in synovial tissue of haemophilic patients, and it may be mediated by an inflammatory milieu (Fig. 3).
Fig. (3)) Expression of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) in synovial tissue from patients with Haemophilia A and osteoarthritis. Representative microphotographs of tissue sections subjected to immunoperoxidase staining for RANK, RANKL, and OPG (brownish-red color) and counterstained with hematoxylin are shown.Arthropathy in Haemophilia A and B: Some Differences
Haemophilia A and B are considered clinically indistinguishable, sharing recurrent joint bleeds as hallmark of a severe disease. However some evidences suggest that Haemophilia B may be less severe than Haemophilia A [1, 63-65]. In a recent study, a large population of patients with Haemophilia A and B was evaluated by using clinical, imaging, and biochemical markers [66]. WFH score and US score were significantly worse in patients with Haemophilia A than the others, matched for age, even with similar frequency of haemarthroses. Notwithstanding the equivalent degree of clotting deficiency, the number of haemarthroses was significantly less in Haemophilia B patients. The lower serum OPG and sRANKL levels in Haemophilia A are in keeping with more severe forms of arthropathy and clinical outcomes. Similar significance can be attributed to the reduced expression of OPG with the marked expression in the synovial tissue of RANK and RANKL in Haemophilia A. Moreover, the histological analysis in synovial tissue of patients affected by Haemophilia B underlines the differences of the expression of RANK/RANKL/OPG triad with respect to Haemophilia A. Effectively, the increased expression of OPG and the lower number of patients undergoing arthroplasty confirm that the arthropathy may be less severe.
CONCLUDING REMARKS
Joint bleeding is the most common and potentially most important long-term disabling manifestation of severe Haemophilia. Recurrent joint bleedings cause irreversible articular damages with progressive functional impairment. The subsequent release of iron from destroyed red cells has a direct pathogenetic effect on cartilage, synovium, and bone. Different cytokines play a crucial role in blood-induced arthropathy inducing an overreaction and leading to irreversible damages independent from the bleeding. These processes finally result in an altered, restructured, and not functional joint, with risk of ankylosis, feature of the classic haemophilic arthropathy that tends to be more severe in Haemophilia A than in Haemophilia B.
CONFLICT OF INTEREST
The authors confirm that they have no conflict of interest to declare for this publication.
ACKNOWLEDGEMENTS
Declared none.
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Giancarlo Castaman*,Maria Chiara SusiniAbstract
Pharmacokinetic (PK) has improved our knowledge about the most appropriate dosing and timing of administration of FVIII/FIX concentrates in patients with Haemophilia. However, although several studies have recently addressed the relevance of PK of clotting factors, usual practice is still mostly based on empiric approaches since individual PK estimation is difficult to obtain unless the patient is formally enrolled in a study. In fact, several plasma samples collected over several hours and/or days are required to establish a half-life curve confidently and this may be a relevant problem, especially in children. Recently however population PKs has emerged as an important tool to overcome this drawback. Targeted prophylaxis could take advantage of knowing the individual response to factor concentrate administration. On the clinical ground, age and body weight (BW) are roughly used to guide dosing because usually in vivo recovery is lower and clearance is faster in children than in adults.
INTRODUCTION
Replacement treatment with clotting factor concentrates (factor VIII – FVIII or factor IX – FIX) has dramatically improved Haemophilia care and prognosis [1]. In conjunction with the evolution of products and therapeutic regimens, the important role of pharmacokinetics (PK) has been also increasingly recognized. Methods for PK evaluation have been developed, progressively becoming more and more accurate. From the 1970s, it has been clearly shown that three times per week treatment was much better than once-weekly for prevention of bleeding [2, 3]. Subsequent careful PK studies showed the benefits of PK plotting and implementation in Haemophilia prophylaxis providing hints to a personalized
prophylaxis in an attempt to strengthen efficacy without increasing the costs [4, 5]. Substitutive treatment for haemophilia is expensive, but inadequate treatment worsens quality of life by increasing morbidity and late sequelae and eventually increasing the associated costs. As in most fields of medical treatment, variability in response among patients is critical and thus tools to optimize clotting factor usage should be always pursued. The required dose should be administered according to the clinical setting (treatment of acute bleeding, surgical prophylaxis or regular prophylaxis), the degree of the factor deficiency, the site and severity of bleeding. On this basis the application of pharmacokinetic analysis would provide the clinicians with more accurate information to tailor patient treatment [6-9].
Pharmacokinetics: Basic Principles
The dose–response relationship for a drug is the result of dose, route of administration, patient characteristics and drug exposure that is defined by the PK of the drug. PK evaluates the rate of absorption, distribution, metabolism and excretion of a drug and its metabolite(s), commonly referred to as ADME. It can be broadly termed as what the body does to the drug and is essentially based on measurement of plasma concentrations. Pharmacodynamics (PD) is the other major component of the dose–response relationship and it can be defined as what the drug does to the body, that is the relationship between drug concentration at the site of action and a measurable effect. Jointly, pharmacokinetics and pharmacodynamics determine the necessary dose, dosing intervals and mode of administration [10, 11]. Typically, pharmacokinetic parameters are calculated on measurements of drug concentration serially taken over time or on measurable variations induced by the drug in plasma [6]. For coagulation products, PK differs from that of most pharmaceutical drugs since bioassays of coagulation factors are used to quantify the variation rather than on plasma immunological concentration [12]. Their concentrations in plasma are expressed as level of procoagulant activities of FVIII (FVIII:C) and FIX (FIX:C) in international units (IU) per milliliter or deciliter, rather than in molar units, as direct representations of the drug effects [10, 13].
Definitions and Applications of Pharmacokinetics
The pharmacokinetic parameters or definitions traditionally used in the study of coagulation products are summarized below together with how they are derived from the plasma concentration (or F:C) vs. time curve.
In vivo recovery (IVR)In vivo recovery (IVR) of a given clotting factor and its biological half-life, have been the standards to compare different clotting factor concentrates [7]. The percentage IVR is the measured peak plasma level relative to the expected peak plasma level, where the latter is defined as the dose divided by the plasma volume of the patient and calculated on either body weight (BW) or plasma volume. Body weight is usually preferred to calculate recovery because of the variability of plasma volume calculations according to the different results obtained with the methods of estimating plasma volume, even in the same patient [6, 12, 14]. Nowadays incremental IVR is usually reported as peak level divided by dose in U/kg.
Half-life (T½)It can be loosely defined as the time required for plasma factor level to decrease by half during the elimination phase. Unlike the plasma clearance value, which expresses only the ability of the body to eliminate the drug, half-life expresses the overall rate of elimination process of a given factor concentrate. This overall rate of elimination depends not only on drug clearance but also on the extent of drug distribution.
Area under the plasma concentration vs. time curve (AUC)AUC (the area under the plasma concentration vs. time curve) is a measure of drug exposure and bioavailability. It is calculated as the product of plasma drug concentration and time. The AUC is used to derive many other pharmacokinetic parameters.
Maximum plasma concentration (Cmax)Cmax is the maximum (“peak”) plasma concentration of a drug observed after its administration and before administration of a second dose. For an i.v. drug, this is usually assessed on plasma sample(s) taken very close to the end of infusion.
Clearance (CL)CL is the ability of the body to eliminate a substance and can be defined as the volume of plasma that is cleared of a drug in 1 min (or 1 hour). For an i.v. drug it is calculated as dose divided by AUC.
Volume of distribution (V, VD, Vss)Volume of distribution is the apparent volume in which a drug distributes in the body and it results from the relationship between the amount of drug in the body and the concentration of drug in plasma. Different ways to determine the volume of distribution are used and each may yield a different result, according to the drug. It can be calculated as the initial volume (VdArea), the terminal phase (Vz), or under steady-state conditions (Vss). Vss value is directly proportional to the distribution of the drug outside the plasma compartment.
Mean residence time (MRT)Distribution and clearance determine the mean residence time (MRT) of the drug, expressed as Vss divided by CL. After i.v. dosing, each drug molecule spends a different amount of time in the body, with some molecules being quickly eliminated after administration and others lasting longer. MRT describes the average lifetime for all the drug molecules in the body.
Pharmacokinetics parameters are per se useful to evaluate the in vivo behavior of FVIII and FIX and their plasma level changes at any time and thus the dosing needed to obtain a predefined target level [13]. In addition the comparison between different preparations of coagulation factors can be based on PKs principles. Vss, CL and MRT are derived from a ‘model independent’ method because they do not depend on the one- or two-compartment pharmacokinetic model. In such model T½ is determined by curve-fitting while Vss, CL and MRT and IVR are calculated form the data points. Of note, the in vivo disappearance of FVIII:C, and especially of FIX:C, shows inner different half-lives, being characterized by an early phase related to distribution and a terminal phase due to elimination. This complicates calculations when comparing factor concentrates with different initial curve shaping or the dosing schedules and it should be emphasized that a few blood sampling, especially within a short period of time, may lead to erroneous PK results. The compartment methods are based on exponential functions which describe the decay of FVIII:C or of FIX:C over time. A simple one-compartment model (the molecule remains in plasma until eliminated from the body) corresponding to the terminal elimination can typically be used for FVIII:C, while for FIX:C bi-exponential functions (corresponding to a two-compartment model) must be used [7, 12, 13].
Pharmacokinetics of Factor VIII
FVIII is a 170-280 kDa protein circulating in plasma bound to the von Willebrand factor (VWF). VWF protects FVIII from early degradation by the activated protein C system and receptor-mediated clearance [13, 15, 16]. Thus, this interaction influences significantly the circulatory half-life of FVIII. In patients with Haemophilia A, infused FVIII rapidly binds to endogenous VWF and only a small fraction of this high molecular weight complex is distributed outside the plasma space. The binding of FVIII to VWF protects FVIII. When FVIII is infused to an adult patient, plasma FVIII:C levels on average rise by 0.020–0.025 U/mL for every U/kg administered [12]. Hence an infusion of 50 U/kg usually leads to a peak plasma level of 1.0-1.3 U/mL when basal FVIII:C is < 0.01 U/mL. The plasma disappearance pattern of FVIII:C is approximately monophasic for plasma derived-FVIII (pd-FVIII) concentrates, while for the recombinant products a biphasic pattern is observed because of a rapid initial fall. The peak value usually occurs 10–15 min after the end of infusion although sometimes it can occur later (within 1-2 hours at latest) [17-19]. Typical pharmacokinetic values of FVIII under non-bleeding status in adult patients with Haemophilia A after a single dose of 50 U/kg can be summarized as a peak plasma level of 1.0-1.3 U/mL; a CL of 3 mL/h/kg of body weight (ranging between 1.5 and 6 mL/h/kg); a Vss similar or slightly exceeding the plasma volume (0.04-0.06 L/kg) and an elimination T½ between 8 and 23 h [4, 5, 10, 12, 13, 17, 20-24]. In children, T½ is shorter, CL correlates negatively and T½ positively with age [7]. Several factors contribute to the inter-patient variability in haemophilia A, including age, weight, plasma volume, blood group, VWF level, the occurrence of an active bleed, polymorphisms of receptors involved in clearance, and the presence of inhibitors to FVIII [25]. Another source of variability of FVIII kinetics can result from variations in type of preparation, including the presence of other proteins, the size and protein-binding properties of the coagulation factor. There are no major differences between plasma-derived and recombinant FVIII concentrates, apart from long-lasting modified products [13]. These products are mainly on clinical trials, but they will become rapidly available and their PK compared to the “traditional” products. Even among the various recombinant FVIII concentrates PK differences are minor and clinically not significant [7, 26-30]. There is some variability in FVIII kinetics correlated to endogenous VWF, even when within the normal range and not only for patients with VWD lacking VWF, as a direct consequence of the VWF stabilizing effects and the mechanisms of clearance of both factors. A significant correlation between pre-infusion VWF levels and T½ was described not only with a B-domain deleted rFVIII, but also with plasma-derived and full-length rFVIII [23, 24, 31]. Furthermore the endogenous increase of VWF in the post-operative period, as a reactive parameter, may hypothetically clear up the lower CL of FVIII observed during continuous infusion after surgery [32, 33]. Blood group could also contribute as a further explanation of VWF levels variability, as persons with blood group O have on average lower levels of VWF [15, 16, 34]. In this regard Vlot et al. reported a significantly shorter T½ in patients with blood group 0 than in those with blood group A [35], persisting also when adjusted for VWF levels. On the other hand other studies [31, 36
