Bleeding disorders Management of patients with acquired Von Willebrand syndrome and acquired hemophilia A
A.B. Federici 1 ABSTRACT U. Budde 2 Acquired von Willebrand syndrome (AVWS) and acquired hemophilia A (AHA) are two rare bleeding A. Tiede 3 disorders caused by acquired mechanisms. AVWS is characterized by clinical and laboratory features similar to inherited von Willebrand disease (VWD) and occurs mainly in patients with underlying lym - phoproliferative, cardiovascular, myeloproliferative and immunological disorders. In most instances, 1 Hematology and Transfusion AVWS is identified because of bleeding complications; in fact more than 80% of the patients are Medicine, L. SACCO University active bleeders. Recurrent bleeding episodes occur in approximately 20-33% of patients with AVWS, Hospital, Department of Clinical especially following major trauma and surgery. Because of the heterogeneous mechanisms of AVWS, Sciences and Community Health, more than one therapeutic approach is often required to prevent or treat acute bleedings. Acquired University of Milan, Milan, Italy; 2Haemostaseology Medilys hemophilia A (AHA) is an autoimmune disease caused by an autoantibody against Factor VIII. Laborgesellschaft mbH, Asklepios Incidence of AHA increases with age, being more frequent in the elderly. Rapid and accurate diagnosis Klinil Altona, Hamburg, Germany; is necessary for correct therapy of acute bleeding episodes that are often life-threatening. Activated 3Department of Hematology, prothrombin complex concentrates and recombinant activated Factor VII are the mainstay of treat - Hemostasis, Oncology and Stem Cell ment of these bleedings. Eradication of the inhibitor by immunosuppressive agents such as steroids Transplantation, Hannover Medical and cytotoxic agents can be obtained. As a second option, rituximab has been used with success in School, Hannover, Germany some cases. Learning goals Correspondence: Augusto B. Federici At the conclusion of this activity, participants should be able to: E-mail: [email protected] - identify patients with bleeding caused by AVWS and AHA; - select appropriate tests to confirm suspected cases of AVWS and AHA; - start different treatment options depending on the age of patients and on the underlying Acknowledgment: conditions associated with AVWS and AHA. We would like to thank all the col - leagues who participated in the International Registry on AVWS. We thank also Luigi Ghilardini who pre - pared the figures and tables. Introduction other very rare AHI have been reported against Factor V, VII, IX, X, XI, XII and XIII. 1 The Hematology Education: The acquired hemostatic inhibitors (AHI) management of patients with AVWS, AHA the education program for the are relatively rare forms of acquired hemosta - and other AHI is difficult and costly, and the annual congress of the European attention of an experienced hematologist con - Hematology Association tic defects but they should be immediately diagnosed because of their severe bleeding sultant is always required. 1 2014;8:53-60 tendency. These AHI are circulating antibod - ies (mainly immunoglobulin) that specifically Definition and epidemiology of acquired neutralize the activity of the various hemosta - von Willebrand syndrome tic proteins and result in a deficiency state. They may develop in the plasma of individuals whose hemostatic mechanisms were previous - Acquired von Willebrand syndrome i s an ly normal. In this scenario, the immunoglobu - acquired bleeding disorder, first reported in 1968, with clinical and laboratory features lin (IG) is designated as autoantibody 3 inhibitor, in contrast to alloantibody inhibitors, similar to inherited von Willebrand disease. which arise in individuals with congenital fac - This rare bleeding disorder occurs mainly in tor deficiencies as a consequence of replace - patients with underlying lymphoproliferative, ment therapy. 1 The most well-characterized cardiovascular, myeloproliferative and inhibitor is directed against Factor VIII immunological disorders. However, abnor - (FVIII) and occurs with a prevalence of 15- malities in the levels, structure and function of circulating von Willebrand factor (VWF) can 30% in patients with inherited hemophilia A 4,5 (alloantibody). The clinical condition caused be found in many other clinical conditions. by the autoantibodies is named acquired Among hematologic diseases, monoclonal hemophilia A (AHA). 2 The other acquired gammopathies of uncertain significance hemostatic defect involving the complex (MGUS) and essential thrombocythemia (ET) FVIII/von Willebrand factor (VWF) is known are considered to be the most frequent condi - as acquired von Willebrand syndrome tions associated with AVWS, but other (AVWS) to be distinguished from the inherited acquired VWF defects can also be found in defects of VWF defined as von Willebrand many other chronic and acute lympho- and disease (VWD). 2 Besides AVWS and AHA, myeloproliferative disorders. 6-8 In most Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 53 | 19 th Congress of the European Hematology Association
instances, AVWS is identified because of bleeding compli - frequently in lymphoproliferative disorders (LPD). A cations. In fact, more than 80% of the patients with this reduced activity/antigen ratio (VWF:RCo/Ag or syndrome are active bleeders. Recurrent bleeding episodes VWF:CB/Ag) can indicate structural or functional disor - occur in approximately 20-33% of patients with AVWS, ders, even if the absolute activity is within normal limits. especially following major trauma and surgery. 4 Because A loss or decrease of HMW multimers can be quantified of the heterogeneous mechanisms of AVWS, more than using densitometry. However, these methods are not avail - one therapeutic approach is often required to prevent or able in many laboratories and have not yet been standard - treat acute bleedings. Remission from some forms of ized. Moreover, pre-analytical variables can contribute to AVWS can be obtained when the underlying disorders are the losses of HMW multimers. A decrease of HMW mul - treated. It has been challenging to collect data on AVWS timers can sometimes be observed in patients with normal as even large centers do not have sufficient numbers of VWF:RCo and VWF:CB and even normal VWF:RCo/Ag patients with AVWS to comprehensively evaluate this rare and VWF:CB/Ag ratios. 11 The assessment of VWF bleeding disorder and there have been no large prospective propeptide (known previously as VWF:Ag II) has been studies of AVWS. Consequently, the actual prevalence of suggested to improve diagnosis of AVWS because it rep - AVWS in the general population is somewhat uncertain. resents a marker of VWF biosynthesis. An increased Between 1998 and 1999, a retrospective survey was con - propeptide/VWF:Ag ratio reflects accelerated clearance of ducted and published as an official communication of the VWF from the plasma. However, the same has been found Scientific and Standardization Committee (SSC) of the in a subset of patients with VWD type 1, indicating accel - 13 International Society on Thrombosis and Hemostasis erated clearance of VWF as a reason for their condition. (ISTH), which described cases in the ISTH-SSC registry. 4 Therefore, propeptide/VWF:Ag ratio may not always dis - Since then, a few additional reports on AVWS cases have criminate between AVWS and VWD, and cannot for the 10 been published by single institutions. 9,10 The prevalence of moment be recommended for routine use. AVWS is probably underestimated because few physi - Autoantibodies play a role in the pathogenesis of some cians search for VWF abnormalities among patients with patients with AVWS, in particular those with LPD. The hematologic, cardiovascular and immunological disor - presence of autoantibodies appears to be associated with a 8 ders. The distribution of the AVWS-associated disorders is more severe bleeding tendency. In a minority of patients, changing according to the most recent reports (Figure 1). inhibitory (neutralizing) antibodies can be detected in A significant increase in the number of cases associated mixing studies of VWF:RCo or VWF:CB. In contrast to with cardiovascular disorders has been observed. 11 AHA, where FVIII inhibitors are virtually always detectable with standard laboratory assays, the frequency of inhibitor detection in AVWS is low. 4 In patients with Pathogenesis of acquired von Willebrand syndrome AVWS, inhibitors are sometimes saturated in complexes In contrast to inherited VWD, VWF is synthesized in normal or even increased quantity in most patients with AVWS. Low plasma levels of VWF can result from accel - erated VWF removal from the plasma by three main path - ogenic mechanisms: a) specific or non-specific autoanti - bodies that form circulating immune complexes with, and inactivate, VWF (these complexes are cleared by cells bearing Fc-receptors that bind immunoglobulin G (IgG)); b) adsorption of VWF by malignant cell clones; and c) loss of high-molecular-weight (HMW) VWF multimers under conditions of high shear stress. A pictorial representation of these mechanisms is shown in Figure 2. Compared with AHA (which is always caused by autoantibodies against FVIII), AVWS has more heterogeneous pathogenic mech - anisms. None of the proposed mechanisms appear to be disease-specific, and the same mechanism can be respon - sible for AVWS in different underlying disorders associat - ed with the syndrome. Additionally, in some patients, the basic mechanism is unknown. 4-10 Another important mech - anism of the acquired VWF defects that is sometimes for - gotten is the increased VWF proteolysis by specific pro - teases that cleave the VWF HMW forms. 12
Diagnostic tests
Figure 1. Relative distribution of the underlying disorders The tests used to assess AVWS are the same as for VWD (cardiovascular, hematologic, others) associated with and the differential diagnosis between AVWS and VWD acquired von Willebrand syndrome (AVWS). From left to can sometimes be difficult (Table 1). Bleeding time and right those of the literature, of the registry, 4 of the German 9 and of the Hannover 10 groups. From the bottom to the top activated partial thromboplastin time (APTT) are not very of each histogram the number of AVWS cases associated useful. FVIII:C, VWF:Ag, VWF:RCo and collagen-bind - with these 3 underlying disorders are shown. ing activity (VWF:CB) are sometimes decreased, most
| 54 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014 with VWF, preventing detection unless the complex is dis - AVWS who are seen before undergoing procedures that sociated by heating or other methods. Non-neutralizing are associated with a high risk of bleeding. 4,11 The treat - VWF-binding antibodies can be detected by ELISA and ment goals in AVWS are: to control acute bleeds, to pre - have been reported to occur in patients with LPD but also vent bleeding in high-risk situations, and to obtain long- other underlying disorders. 14 However, no standardized term remission. The strategies utilized to obtain these assays are available yet for detecting these. Plasma- goals depend on the underlying disease mechanisms derived VWF contains AB0 blood group antigen and (Table 2). Whenever possible, treatment should address should not be used as an antigen for ELISA, since the the underlying disorder, which can treat the AVWS as presence of isoagglutinins may cause false-positive well. However, it is not always possible to treat the under - results. Recombinant human VWF expressed in cultured lying disorder. The available evidence for efficacy and animal cells is currently under investigation as a reagent safety of the commonly used hemostatic treatments is that may potentially resolve this issue. 11 summarized below according to single therapeutic approach. Desmopressin: desmopressin (DDAVP) is a synthetic General therapeutic approaches to acquired von analog of vasopressin. It can be used to prevent and con - Willebrand syndrome trol bleeding in some patients with AVWS. DDAVP is usu - m ally administered in doses of 0.3 microgram ( g)/kilogram There are two main clinical situations in which the diag - (kg) of body weight, given intravenously over 30 min, nosis of AVWS should be considered: i) bleeding patients once or twice daily. In the only prospective clinical trial of whose laboratory finding suggests abnormalities of VWF; DDAVP therapy in 10 patients with monoclonal gam - and ii) patients known to have a disorder associated with mopathy of uncertain significance (MGUS), all subjects
Figure 2. Pictorial representation from the bottom to the top of the main mechanisms causing acquired von Willebrand syndrome (AVWS) partially modified from previous report. 7 (Bottom) The VWF protein is normally synthesized and released from endothelial cells: all the high molecular weight (HMW) VWF multimers are present in circulation after the cleavage of the pro-peptide. (Middle) The normal structure and function of the VWF can be modified by 3 mechanisms causing AVWS. Specific and non-specific auto-antibodies (a); absorption of the VWF onto abnormal or malignant cell clones; loss of the HMW VWF multimers under conditions of high-shear stress in heart valve abnormalities. (Top) The effects of the 3 different mechanisms of AVWS induce reduction of the VWF activities with very low levels of VWF: (a) and preferential removal of HMW VWF multimers (b and c).
Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 55 | 19 th Congress of the European Hematology Association had improved VWF levels 30 min after treatment, whereas and measures need to be taken to prevent fluid overload VWF levels were close to baseline by 4 h after DDAVP and hyponatremia, which are the most common adverse treatment. 4 Therefore, VWF:Ag and VWF:RCo, along effects of DDAVP. with FVIIIC, should always be closely monitored when VWF/FVIII concentrates: these can be used for replace - DDAVP is used for prophylaxis and treatment of bleeds. ment therapy. In clinical practice, doses of between 30 and Caution must be exercised with this therapy in patients 100 VWF:RCo units/kg are recommended, depending on who have cardiovascular disorders and/or who are elderly, the patient’s residual VWF activity, the severity of bleed -
Table 1. Differential diagnosis between AVWS and VWD. 11
Aspect In favor of AVWS In favor of VWD Limitations Personal history Late onset of bleeding Early onset of bleeding Variable penetrance of VWD Uneventful surgery before onset of bleeding No uneventful surgery or no previous high-risk situations Family history Negative Positive Variable penetrance of VWD AVWS-associated disorder Present Absent Coincidental presence of highly prevalent disorders, e.g. MGUS in the elderly Laboratory evaluation Presence of inhibitor or VWF gene mutation Low frequency of detectable VWF-binding antibodies inhibitors in AVWS Alloantibodies in rare cases of VWD type 3 Treatment response Remission after treatment of Normal recovery and half-life of Cannot be assessed before treatment underlying disorder VWF-containing concentrate Response to IVIG in IgG Sustained response to MGUS associated AVWS desmopressin Short-lived response to VWF containing concentrates or desmopressin AVWS: acquired von Willebrand syndrome; VWD: von Willebrand disease; MGUS: monoclonal gammopathy of uncertain significance; IgG: immunoglobulin G.
Table 2. Therapeutic options in AVWS according to underlying disorder. 11
Underlying disorder Causal treatment Additional treatment options Autoimmune disorders Systemic lupus erythematosus Steroids, cyclophosphamide IVIG (only IgG-MGUS or anti-VWF IgG), plasmapheresis or immunoadsorption, antifibrinolytics, VWF-containing concentrate, rFVIIa Lymphoproliferative disorders MGUS Usually untreated Lymphoma, multiple myeloma Chemotherapy according to entity Cardiovascular Aortic valve stenosis and other Corrective surgery VWF-containing concentrate, antifibrinolytic anomalies with increased sheer stress Dysfunctional heart valve prosthesis, LVAD Corrective surgery if applicable Reduce or withdraw anticoagulation, VWF-containing concentrate Myeloproliferative neoplasia Essential thrombocythemia Cytoreductive therapy, chemotherapy or stem cell transplantation in case of progression Polycythemia vera Phlebotomy, cytoreductive therapy Withdraw aspirin (if applicable), desmopressin, chemotherapy or stem cell antifibrinolytics, VWF-containing concentrate transplantation in case of progression Chronic myeloid leukemia Tyrosine kinase inhibitors, stem cell transplantation
IVIG: intravenous gammaglobulin; AVWS: acquired von Willebrand syndrome; VWD: von Willebrand disease; MGUS: monoclonal gammopathy of uncertain significance; IgG: immunoglobulin G; rFVIIa: activated recombi - nant Factor VII; LVAD: left ventricular assist device.
| 56 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014
How to manage acute bleeds? ing and the presence of inhibitors. Similar to DDAVP, the half-life of infused VWF can be very short in AVWS, in Desmopressin or VWF-containing concentrates typical - particular in patients with AVWS associated with MGUS 4 ly result in short-lived improvements in VWF. Therefore, or inhibitors. Close monitoring of the clinical response, these treatments require close monitoring and may some - with measurements of VWF activities, are needed for tai - times be ineffective. Patients with IgG autoantibodies and . loring doses and dose intervals paraproteins usually respond well to IVIG. Improvement Intravenous gammaglobulin: intravenous gammaglobu - of VWF measurements is typically observed after 12-72 h lin (IVIG) were assessed in an open-label crossover study and lasts for several days or weeks. 6 IVIG has been recom - in patients with AVWS associated with MGUS of the IgG mended for second-line treatment in patients unresponsive class (IgG-MGUS). Doses of 1 gram/kg body weight per to DDAVP or VWF-containing concentrates. Since IVIG . day were used for two days An increase of VWF and is not immediately effective, simultaneous use of DDAVP FVIII, and shortening of the bleeding time, were observed or VWF-containing concentrates can be necessary in the the day after the second infusion, with levels reaching first few days. Patients with paraproteins of the IgM class their maximum after four days and slowly returning to 4 6 do not respond to IVIG. Plasmapheresis combined with baseline within 21 days. IVIG was not effective in AVWS VWF-containing concentrates has been reported to be patients with MGUS of the immunoglobulin M (IgM- effective in a few cases. 11 MGUS) class. Repeated doses of IVIG every three weeks are effective to induce long remission from AVWS, but How to induce long-term remission? lower doses (0.5-0.75 mg/kg) are not sufficient to correct these VWF defects. 6 Treatment of the underlying disorder should be consid - Activated recombinant factor VII: activated recombi - ered whenever possible. MGUS usually remains untreated nant Factor VII (rFVIIa) as a hemostatic agent has also in asymptomatic patients. If it becomes symptomatic due been used in patients with AVWS and VWD type 3, par - to AVWS, an effective long-term therapy would be highly ticularly in those who have significant bleeding manifes - warranted, but unfortunately has not been established. tations and alloantibodies against VWF . rFVIIa is usually Therefore, for the moment, IVIG (for IgG-MGUS) and m administered at a dose of 90 g/kg body weight (range 40- plasmapheresis (for IgM-MGUS) remain the only treat - m 150 g/kg), for a median of 3 doses (range 1-54). ment options. For patients with B-cell lymphomas or mul - Treatment is usually effective, with responses reported in tiple myeloma, successful chemotherapy (combined with 96% of patients. Thromboembolic complications are rare rituximab if appropriate) can result in remission of AVWS among hemophilia patients receiving rFVIIa, but it is with an overall success rate of 35-70%. Steroids, other unclear if this is also true for patients receiving this thera - immunosuppressive drugs, and IVIG (for IgG VWF-bind - ing antibodies) should be considered in autoimmune dis - py for AVWS or VWD. Caution should be exercised, par - 11 ticularly when treating elderly patients and others at orders but only few data are available. increased risk for thromboembolism. 11 Plasmapheresis: plasmapheresis can be used to reduce Acquired von Willebrand syndrome associated with the levels of autoantibodies and paraproteins of any myeloproliferative neoplasms immunoglobulin class, although the treatment is more effective in reducing the levels of IgM antibodies. Acquired von Willebrand syndrome associated with Plasmapheresis has been reported as therapy for patients myeloproliferative neoplasia (MPN) primarily results with AVWS due to IgM-MGUS . When this treatment is from adsorption of VWF to transformed blood cells, in given, fresh frozen plasma replacement should be used, 14-16 particular platelets. It has been reported in essential instead of albumin, to prevent depletion of fibrinogen and thrombocythemia (ET) and polycythemia vera (PV), but other coagulation factors. When the treatment is used for also in chronic myelogeneous leukemia (CML), primary managing severe bleeding, the restoration of VWF levels myelofibrosis (PMF). and sometimes in acute leukemia. In can be accelerated by concurrent treatment with VWF- 11 a prospective study by Mohri et al., AVWS was diagnosed containing concentrate or DDAVP. in 14 of 125 (11 %) consecutive patients with MPN. 11 What determines the risk of bleeding? Acquired von Willebrand syndrome associated with lymphoproliferative and autoimmune disorders Although risk factors for bleeding in MPN have not been well described, most studies concluded that a very high ¥ 9 15-17 Lymphoproliferative disorders (LPD) account for a sig - platelet count (>1500 10 /L) is a significant risk factor. nificant proportion of cases with AVWS, both in the liter - Indeed, an inverse relationship between the platelet count ature (30%) and in the International Society on and the VWF:RCo/Ag or VWF:CB/Ag ratio in patients with Thrombosis and Haemostasis (ISTH) registry (48%). 4 MPN has been reported. 17 However, in the prospective series Other immune disorders, such as systemic lupus erythe - by Mohri et al., 8 the median platelet count of patients with ¥ 9 matosus, mixed connective tissue disease and graft- ver - MPN and AVWS was only 638 10 /L (range 120-1305). It, sus -host disease have been reported less frequently. The therefore, appears likely that additional risk factors such as bleeding risk in these patients seems to be higher than in platelet function defects are likely to contribute to bleeding. patients with cardiovascular disorders (CVD). 4 It should The relationship between platelet count, AVWS, platelet be noted, however, that bleeding may not only result from function defects and the risk of bleeding deserves further AVWS. In patients with Waldenström’s disease or IgM- study. For the time being, according to the recommendations MGUS, for instance, bleeding may also result from hyper - by experts, bleeding patients with MPN should be screened viscosity. for both AVWS and platelet function defects. 11
Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 57 | 19 th Congress of the European Hematology Association
How to treat bleeding patients with MPN? rates of 10%. 4 Moreover, DDAVP can be contraindicated in patients with congestive heart failure, coronary artery Cytoreductive therapy was reported to result in remis - sion of AVWS in patients with MPN and should be consid - disease or advanced age (≥65 years). Response rates of 11 VWF-containing concentrates ranged between 10% and ered in bleeding patients. However, treatment is usually 4 not immediately effective and additional treatments can be 70%, probably reflecting different dosing regimens and required in actively bleeding patients. In theory, DDAVP concentrate characteristics. should be a preferred treatment because newly released How to manage antithrombotic therapy in bleeding VWF from endothelial cells contains very large HMW patients with AVWS? multimers, larger than those contained in plasma-based concentrates. However, the reported success rate in In AVWS patients with severe bleeding, usually the 4 patients with MPN has been only 21%. VWF concen - antithrombotic medications should be stopped; reversal of trates are more expensive and have not been reported to VKA or anti-platelet therapy should be used in emergency 4 result in higher success rates; higher doses (e.g. 50-80 situations according to published guidelines. 11 The throm - IU/kg 2 or 3 times daily) sometimes result in better treat - boembolic risk of bileaflet mechanical aortic valve pros - ment results. Alternatively, repeated doses of rFVIIa may thesis appears to be low enough to reduce or stop anti- be considered for severe bleeding refractory to other treat - 11 platelet or anticoagulants in patients with bleeding disor - ment modalities. ders. However, such a decision can be much more difficult How to address thrombotic risks in these patients? in high-risk situations, e.g. in patients with mitral valve prostheses or left ventricular assist device (LVAD). Until There is a consensus that cardiovascular risk factors evidence-based guidelines are available, the competing should be addressed. Primary prophylaxis with aspirin is risks of bleeding and thrombosis must be balanced care - generally recommended in PV and ET unless contraindi - fully for the individual patient, and experience should be 11 cated. The main contraindications are intolerance and collected in prospective registries. bleeding: maybe the presence of the AVWS should be also considered. 11 In asymptomatic patients with very high ¥ 9 Definition: epidemiology and clinical features of platelet counts (>1500 10 /L), where AVWS appears to be acquired hemophilia A particularly common, aspirin should be postponed until cytoreductive therapy has lowered the platelet count to ¥ 9 less than 1000 10 /L. If thromboembolic events occur in The acquired hemophilia A (AHA) is a potentially life- patients with asymptomatic AVWS, antithrombotic drugs threatening bleeding disorder occurring in patients without a should be administered in the same way as in the general previous personal or family history of bleeding caused by the immune-mediated development of acquired FVIII population. Usually, this includes anti-platelet drugs for 2 arterial events and anticoagulants for venous events. 11 autoantibodies. The demographic characteristics, the clini - cal presentations, the management of bleeding episodes, as well as the eradication of autoantibodies with immune ther - Acquired von Willebrand syndrome associated with apies have all been extensively investigated in the European cardiovascular disorders Acquired Hemophilia (EACH2) Registry. 25-27 The incidence of AHA has been reported to be between 1.3 and 1.5/mil - The number of cases of AVWS associated with cardio - lion/year and has a biphasic age distribution: a small peak vascular disorders (CVD) has increased during the last ten occurs in 20- to 40-year old patients with a female predom - 18-24 years following the observations of several authors. inance due to the high prevalence of the post-partum period Normal or increased VWF:Ag, VWF:RCo, and VWF:CB and a large peak in patients aged over 65 years with an inci - 11 are very common in AVWS associated with CVD. dence of 14.7/million/year in people aged over 85. Clinical Therefore, these tests cannot be used to rule out AVWS. presentation of patients with AHA is quite different from that Consideration of the VWF:RCo/Ag and VWF:CB/Ag of inherited HA. Patients usually present with subcutaneous ratios can improve sensitivity, but is still insufficient to bleeds, which are often extensive. Soft tissue bleeds such as identify all patients. The implications of this characteristic muscle hematoma, retroperitoneal bleeds and intracranial feature are 2-fold: firstly, a multimer analysis is usually hemorrhage are also common, whereas joint bleeds are seen required before AVWS can be ruled out in this group of less commonly than in congenital HA. The muscle patients; secondly, VWF:Ag and VWF:RCo can most 11 hematomas can be very important with rapid and significant often not be used for treatment monitoring. reduction in HB levels (Figure 3). Gastrointestinal bleeding What are the therapeutic approaches in AVWS associated can be lifethreatening and hematuria may also occur. Some with CVD? patients are diagnosed with bleeding at the time of invasive procedures, while postpartum hemorrhage and bleeding fol - Treatment should aim at correcting the cardiac defect lowing Caesarian section is the usual presentation of AHA whenever possible. In aortic valve stenosis, valve replace - associated with pregnancy. Bleeding episodes are unpre - ment resulted in a remission of AVWS, 19 although recur - dictable and may be very severe: approximately 8% of AHA rence was noted in some patients, in particular those with patients have fatal bleedings. In contrast, approximately prosthesis malfunction; the malfunction of the prosthesis 25% of these patients have a relatively mild bleeding and do by echocardiography should be tested. not usually require hemostatic therapy. A general approach DDAVP has not been very successful, with response to the management of AHA has been recently published. 28
| 58 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) Milan, Italy, June 12-15, 2014
Diagnostic approach to patients with acquired and venous thrombosis, pulmonary embolisms and stroke. hemophilia A Recombinant or plasma-derived FVIII concentrates are rarely efficacious. Porcine plasma-derived FVIII concen - The diagnosis of AHA is often delayed but it should be trate has been used in the past with some success but there suggested by the recent onset of typical bleeding symptoms are few data about efficacy and safety. Some patients with and the finding of a prolonged activated partial thrombo - a low titer autoantibody inhibitor and measurable base- plastin time (PTT). AHA diagnosis is confirmed by the find - line FVIII may respond to a DDAVP infusion, therefore, ing of a reduced FVIII activity level and the presence of a this approach should be tested. The different therapeutic time- and temperature-dependent inhibitor. The kinetic of approaches are summarized in Table 3. this anti-FVIII inhibitor (autoantibody) is usually different (type 2 kinetic curve) from that of the alloantibody found in a patient with inherited HA (type 1 kinetic curve). After confirming the presence of an anti-FVIII inhibitor, the Bethesda assay with Nijmegen modification is used to eval - uate inhibitor titer levels; it is very important to know the levels of anti-FVIII inhibitors because patients with low (<5) or high (>5) inhibitor titers must be managed with dif - ferent therapeutic options. A lupus anticoagulant (LAC) can mimic an AHI, although typically the LAC should be differ - entiated from AHI in the laboratory by the absence of increasing neutralization of clotting factor activity after pro - longed incubation in mixing studies. In fact, lupus-like inhibitors decrease all factor levels measured in the PTT system (i.e. FVIII, FIX, FXI as well as FXII) while a spe - cific inhibitor predominantly decreases one single factor (FVIII in case of the AHA) for which it is specific. This is very important because specific inhibitors will often give Figure 3. Typical example of a very large hematoma in a false-positive LAC results in many commercial assays. Last patient with AHA. but not least, the LAC is not associated with the same type of extreme bleeding symptoms that characterizes AHA. A practical flow chart for diagnostic approach is shown in Figure 4.
Management of acute bleeding episodes
Management of patients with AHA is complex and ide - ally should be always coordinated by an expert hematolo - gist with the help of other specialists according to the spe - cific clinical sites of bleedings. Treatment of AHA is directed at bleeding control, inhibitor eradication to pre - vent subsequent bleeding events, and treatment of any underlying causative disease. No randomized control clin - ical data are available to guide appropriate intervention and, therefore, selection of appropriate therapeutic approaches has been based primarily on expert opinion. Recent data from the European Acquired Hemophilia (EACH2) Registry have been used to prepare recommen - dations to guide selection of initial therapeutic interven - Figure 4. Suggested flow chart for the correct diagnosis of tion. 25-27 Optimal treatment involves protection of the a patient with AHA. patients against trauma; invasive procedure should not be undertaken unless unavoidable. Bleeds are usually treated acutely with FVIII bypassing agents such as activated pro - Table 3. Treatment strategies for acquired hemophilia A. thrombin complex concentrates (aPCC) or recombinant activated Factor VII (rFVIIa). The most widely used aPCC Bleeding control Inhibitor eradication is FVIII inhibitor bypassing agent (FEIBA) and the rFVIIa is NovoSeven. The safety and efficacy data of First-line treatment a PCC or rFVIIa Steroid ± cyclophosphamide FEIBA and NovoSeven was derived from congenital HA Second-line treatment Bypassing agent: Rituximab ± with alloantibody but numerous case reports and retro - Alternate Steroid spective analyses indicate that both FEIBA and rFVIIa are Sequential Cyclophosphamide safe and effective in controlling bleeding episodes in AHA Parallel Cyclosporine patients. However, these drugs are associated with poten - Immunoadsorption protocol AzathioprineCVP tially life-threatening side effects, such as myocardial rFVIIa: recombinant factor VIIa; aPCC: activated prothrombin complex concentrates; CVP: cyclophos - infarction, disseminated intravascular coagulation, arterial phamide, vincristine, prednisone.
Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1) | 59 | 19 th Congress of the European Hematology Association
How to obtain and monitor inhibitor eradication 6. Federici AB, Stabile F, Castaman G, et al. Treatment of acquired von Willebrand syndrome in patients with monoclon - al gammopathy of uncertain significance: comparison of three The inhibitor eradication therapy is necessary in patients different therapeutic approaches. Blood. 1998;92:2707-11. with AHA to reduce morbidity and mortality because the 7. Federici AB. Acquired von Willebrand syndrome: an under - diagnosed and misdiagnosed bleeding complication in patients risk of recurrent bleeding events still persists until the anti- with lymphoproliferative and myeloproliferative disorders. FVIII inhibitors are present. Eradication of the autoim - Semin Hematol. 2006;43:S48-58. mune inhibitor antibody with immunosuppression is indi - 8. Mohri H, Motomura S, Kanamori H, et al. Clinical signifi - cance of inhibitors in acquired von Willebrand syndrome. cated as soon as the diagnosis is confirmed and the bleed - Blood. 1998;91:3623-9. ing problems have been contained. Steroids, alone or com - 9. Budde U, Bergmann F. Michiesl JJ. Acquired von Willebramd bined with cytotoxic agents such as cyclophosphamide or Syndrome: experience from 2 years in a single laboratory compared with data from the literature and an international azathioprine, induce remission in approximately 70% of registry. Semin Thromb Haemost. 2012;28:227-38 patients. Current evidence does not support the use of 10. Tiede A, Priesack J, Werwitzke S, et al. Diagnostic workup of intravenous immunoglobulin (IVIG) to suppress the AHA patients with acquired von Willebrand syndrome: a retrospec - inhibitors, except perhaps for low titer autoantibody tive single-centre cohort study. J Thromb Haemost. 2008;6:569-76. (Table 3). 11. Tiede A, Rand JH, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome. Blood. 2011;117:6777-85. Current perspectives on acquired von Willebrand 12. Federici AB, Berkowitz SD, Lattuada A, Mannucci PM. syndrome and acquired hemophilia A Degradation of von Willebrand factor in patients with acquired clinical conditions in which there is heightened proteolysis. Blood. 1993;81:720-5. Acquired von Willebrand syndrome is a significant 13. Haberichter SL, Castaman G, Budde U, et al. Identification of under-recognized bleeding disorder occurring in several type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in different clinical situations. The diagnostic approach to the European study: molecular and clinical markers for the AVWS remains a challenge to the practising physician due diagnosis and management of type 1 VWD (MCMDM- to the variable clinical presentation and the many different 1VWD). Blood. 2008;111:4979-85. 14. Siaka C, Rugeri L, Caron C, Goudemand J. A new ELISA tests that have to be obtained to prove or rule out the diag - assay for diagnosis of acquired von Willebrand syndrome. nosis. Management requires consideration of the underly - Haemophilia. 2003;9:303-8. ing disorder and pathogenic mechanisms. Research in this 15. Budde U, Schaefer G, Mueller N, et al. Acquired von Willebrand's disease in the myeloproliferative syndrome. area has been limited by a number of difficulties, includ - Blood. 1984;64:981-5. ing the prolonged follow up required, the many confound - 16. Budde U, Scharf RE, Franke P, Hartmann-Budde K, Dent J, ing factors, and the increasingly documented clinical and Ruggeri ZM. Elevated platelet count as a cause of abnormal biological heterogeneity. Since prospective clinical studies von Willebrand factor multimer distribution in plasma. Blood. 1993;82:1749-57. are difficult to organize in this small and heterogeneous 17. Budde U, van Genderen PJ. Acquired von Willebrand disease group of patients, we encourage physicians to report their in patients with high platelet counts. Semin Thromb Hemost. experience in the up-dated version of the AVWS registry 1997;23:425-31. 18. Warkentin TE, Moore JC, Anand SS, Lonn EM, Morgan DG. promoted by the ISTH ( www.intreavws.com ), available at Gastrointestinal bleeding, angiodysplasia, cardiovascular dis - the end of 2014. As far as AHA is concerned, a lot of ease, and acquired von Willebrand syndrome. Transfus Med information has been collected by the European Registry. Rev. 2003;17:272-86. However, patients with AHA are still under- and misdiag - 19. Vincentelli A, Susen S, Le Tourneau T, et al. Acquired von Willebrand syndrome in aortic stenosis. N Engl J Med. nosed in hospitals where physicians are often not able to 2003;349:343-9. provide appropriate therapy during life-threatening bleed - 20. Uriel N, Pak SW, Jorde UP, et al. Acquired von Willebrand ings. The immediate consultation with hematologists Syndrome After Continuous-Flow Mechanical Device Support Contributes to a High Prevalence of Bleeding During expert in hemostasis is strongly recommended. More Long-Term Support and at the Time of Transplantation. J Am information about the correct eradication protocols, espe - Coll Cardiol. 2010;56(15):1207-13. cially for young women and elderly immune-compro - 21. Tsai HM, Sussman, II, Nagel RL. Shear stress enhances the proteolysis of von Willebrand factor in normal plasma. Blood. mised individuals, is also required. 1994;83:2171-9. 22. Wu T, Lin J, Cruz MA, Dong JF, Zhu C. Force-induced cleav - age of single VWFA1A2A3 tridomains by ADAMTS-13. References Blood. 2010;115:370-8. 23. Yoshida K, Tobe S, Kawata M, Yamaguchi M. Acquired and 1. Kessler CM, Acs P, Mariani G. Acquired disorders of coagu - reversible von Willebrand disease with high shear stress aortic lation: the immune coagulopathies. In: Colman RW, Marder valve stenosis. Ann Thorac Surg. 2006;81:490-4. VJ, Clowes AW, George JN, Goldhaber SZ (eds.) Hemostasis 24. Geisen U, Heilmann C, Beyersdorf F, et al. Non-surgical and Thrombosis: Basic Principles and Clinical Practice. 5th bleeding in patients with ventricular assist devices could be ed. Philadelphia, PA: Lippincott Williams & Wilkins; explained by acquired von Willebrand disease. Eur J 2006:1061-84. Cardiothorac Surg. 2008;33:679-84. 2. Collins P, Budde U, Rand JH, Federici AB, Kessler CM. 25. Knoebl P, Marco P, Baudo F, et al. Demographic and clinical Epidemiology and general guidelines of the management of data in acquired hemophilia A: results from the European acquired haemophilia and von Willebrand syndrome. Acquired Haemophilia Registry (EACH2). J Thromb Haemophilia. 2008;14:49-55 Haemost. 2011;10:622-31 3. Simone JV, Cornet JA, Abilgaard CF. Acquired von 26. Baudo F, Collins P, Huth-Kuhne A, et al. Management of Willebrand syndrome in systemic lupus erythematosus. bleeding in acquired hemophilia A: results from the European Blood. 1968;31:806-12 Acquired Haemophilia Registry (EACH2): Blood. 4. Federici AB, Rand JH, Bucciarelli P, et al. Acquired von 2012:120:39-46 Willebrand syndrome: Data from an international registry. 27. Collins P, Baudo F, Knoebl P et al. Immunosuppression for Thromb Haemost. 2000;84:345-9. acquired hemophilia A: results from the European Acquired 5. Veyradier A, Jenkins CS, Fressinaud E, Meyer D. Acquired Haemophilia Registry (EACH2). Blood. 2012:120:47-55 von Willebrand syndrome: from pathophysiology to manage - 28. Sborov DW, Rodgers GM. How I manage patients with ment. Thromb Haemost. 2000;84:175-82. acquired haemophilia A. Br J Haematol. 2013;161:157-65.
| 60 | Hematology Education: the education program for the annual congress of the European Hematology Association | 2014; 8(1)