Post-Transplant Complications Acquired Factor VII Deficiency In

Bone Marrow Transplantation (2002) 29, 403–408  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Post-transplant complications Acquired factor VII deﬁciency in hematopoietic stem cell transplant recipients

AA Toor1, A Slungaard1, U Hedner2, DJ Weisdorf1 and NS Key1

Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA; and 2Novo Nordisk Pharmaceuticals Inc., Gentofte, Denmark

Summary: Isolated acquired FVII deficiency in the absence of vitamin K deficiency, coumadin therapy, synthetic liver dys- Acquired factor VII (FVII) deficiency in the absence of function, or overt DIC is rare, having been described in vitamin K deficiency, oral anticoagulant therapy, syn- only a handful of cases. Associated disease states have thetic liver dysfunction, or DIC is rare, with only a included malignancy,2 aplastic anemia,3,4 and antiphospho- handful of cases thus far reported. In the period from lipid antibodies.5,6 In stem cell transplant (SCT) patients, a 1990 to 1996 we identified eight patients with acquired modest reduction in FVII levels (in the 25 to 50% range) FVII deficiency, all of whom presented with pro- has been described in the first 2 weeks following SCT.7–9 longation of the prothrombin time (PT) in the first 2 In these cases it has often been associated with deficiencies weeks following stem cell transplantation (SCT). The of other factors such as FXII or protein C.10 It has been mean plasma FVII clotting activity (FVII:c) was 22% suggested that the fall in FVII and protein C levels in this (range 8–35%) with an approximately equivalent setting may be a harbinger of veno-occlusive disease of the reduction in FVII antigen (FVII:Ag) level. Mean plasma liver (VOD).11 levels of fibrinogen and factors II, V, IX, and X were Bleeding after SCT has been identified as a significant normal. Protein C activity was significantly depressed in risk factor affecting outcome.12–14 Commonly encountered only one of the three patients in whom it was measured. sites of bleeding include hemorrhagic cystitis, diffuse Several patients experienced bleeding complications, alveolar hemorrhage, and oro-mucosal and gastro-intestinal and hemorrhage directly accounted for death in two sources. Although thrombocytopenia is clearly a major con- cases. Veno-occlusive disease of the liver developed in tributing factor, other reasons, such as toxicity related to three patients. We conclude that FVII deficiency should the preparative regimen, infection, and graft-versus-host be considered in the differential diagnosis of prolonged disease, have all been cited. Acquired FVII deficiency, at PT in patients who have recently undergone SCT. The least of the degree previously reported, has not been impli- mechanism of this acquired deficiency state remains to cated as a risk factor for hemorrhage following SCT. be defined. In this communication, we describe the clinical and lab- Bone Marrow Transplantation (2002) 29, 403–408. DOI: oratory features of a series of patients with acquired FVII 10.1038/sj/bmt/1703381 deficiency following SCT, who have been managed at our Keywords: factor VII; stem cell transplantation; institution. The frequency and severity of bleeding compli- hemorrhage; acquired deficiency; acute myelogenous leu- cations in these patients suggest that this coagulopathy may kemia have contributed to adverse outcomes.

Methods Factor VII is a vitamin K-dependent zymogen which when activated binds to tissue factor (TF), a transmembrane protein strongly expressed by cells in the adventitia of blood Patients vessels. The TF–VII(a) complex activates both factors IX We conducted a retrospective chart review of eight patients and X in the presence of phospholipid and calcium, and known to have developed acquired FVII deficiency during catalyzes the auto-activation of more zymogen FVII. The SCT at the University of Minnesota between 1990 and TF–VII(a) pathway is now known to be the dominant 1996. The transplants were carried out using a myeloabl- 1 hemostatic mechanism in vivo. ative regimen, followed by allogeneic or autologous hematopoietic SCT (using bone marrow or peripheral blood stem cells). Post-transplant care consisted of GVHD prophylaxis, Correspondence: Dr NS Key, Department of Medicine, Division of Hema- tology, Oncology, and Transplantation, University of Minnesota Medical anti-microbial prophylaxis and therapy as needed, School, MMC 480, 420 Delaware St SE, Minneapolis, MN 55455, USA nutritional support, and transfusion support with red cell Received 24 October 2000; accepted 12 October 2001 and platelet products. Routine parenteral vitamin K supple- Factor VII deficiency following SCT AA Toor et al 404 mentation was administered to all patients. Daily blood reagent referred to above; (2) APTT-FSL reagent (Sigma counts were obtained and coagulation tests were performed Diagnostics, St Louis, MO, USA); (3) Dade Actin FS if clinically indicated, eg in patients with bleeding, septice- (Dade-Behring Inc); and (4) Organon Teknika (Durham, mia, or suspected DIC. In non-bleeding patients, platelets NC, USA) automated APTT reagent. When a prolonged were transfused to keep the platelet counts greater than 10– APTT was detected with one or more reagents, a 1:1 mix 20 ϫ 109/l. Hemoglobin was routinely maintained at Ͼ8.0 of patient and normal pooled plasma was performed, and G/dl. These parameters were revised upwards for patients the APTT repeated using that same reagent(s). Failure of with clinically overt bleeding. Coagulopathy was assessed the mixing study to correct led to the performance of the initially by a battery of tests that included prothrombin time platelet neutralization procedure16 (with one or more (PT), activated partial thromboplastin time (APTT), throm- reagents) to confirm the diagnosis of a lupus inhibitor. After bin time (TT), Clauss fibrinogen, and fibrin(ogen) degra- converting our procedure to include the dilute Russell viper dation product titer. In the event of a clotting time being venom time (dRVVT), with mix and confirm steps, sub- prolonged, a 1:1 mix with normal plasma was performed sequent to 1996, we were able to determine that the mul- to differentiate the presence of a coagulation inhibitor from tiple APTT screening approach used in this study was a a factor deficiency. This was followed by specific factor very specific, if somewhat less sensitive technique for assays if indicated. At the discretion of the attending phys- screening for lupus anticoagulants. ician, coagulopathy was treated with fresh frozen plasma (FFP), and/or cryoprecipitate infusions with a therapeutic FVII antibody screening methods goal of clinical hemostasis (in the case of clinical bleeding) and/or normalization of laboratory parameters of coagu- Two separate methods were used to screen for the presence lation. In some cases, additional doses of parenteral vitamin of an auto-antibody to FVII. Firstly, we used a previously K were also administered. None of the patients were receiv- described ELISA method in which patient plasma was ing any form of anti-thrombotic therapy nor anti-platelet screened for the presence of anti-FVII(a) IgG.17 Reference agents, such as aspirin or non-steroidal anti-inflammatory ranges and cut-off limits were established by screening agents. multiple normal donors. Secondly, in order to screen for a neutralizing antibody to FVII, we used a plasma mixing Factor assays assay. Specifically, FVII:c was measured in patient and standard (pooled normal) plasma, which were then mixed Measurement of specific clotting factor activity was in all in equal proportions. FVII:c was assayed both immediately cases performed by a one-stage clotting assay (PT-based after mixing and following a 1 h incubation at 37°C. A assay for factors II, VII and X, and APTT-based assay for positive result (ie presence of an inhibitory antibody) was FIX), using a mixture of the appropriate factor-deficient suspected if the FVII:c in the mixed sample (either at time substrate plasma and test plasma. All factor assays were zero or after 1 h incubation) was approximately 15% or performed at 1/10, 1/20, 1/40, and 1/80 dilutions. The more below the expected value. This arbitrary cut-off value results are expressed as a percentage, with 100% equivalent was chosen taking into account the fact that FVII:c in the to the appropriate factor level in pooled plasma samples mix sample might be slightly less than expected – in the from 40 normal volunteers. Reference ranges for factor lev- absence of an inhibitor – simply due to the reproducibility els were established as the mean Ϯ 2 s.d. of 40 normal of the factor VII assay. In order to minimize artifactual loss individuals. Prior to January 1993, rabbit brain thrombo- of activity of labile clotting factors (such as FVIII) in the plastin (Thromboplastin C, Dade Laboratories, Deerfield, mix, a 1 h incubation is routinely used in our laboratory to IL, USA) was used in our laboratory for PT and PT-based screen for possible coagulation factor inhibitory antibodies. factor assays. The stated International Sensitivity Index The exception to this is in the case of suspected FVIII (ISI) of this reagent was 2.71. Subsequently, all PT assays inhibitors, where a 2 h incubation, as described in the ori- were performed using recombinant re-lipidated tissue factor ginal18 (and subsequently modified19) Bethesda assays, is (Innovin, Dade) with an ISI of 1.0. APTT was performed used. using an in-house reagent in which 0.075% aluminum silicate was used as an activator, and the chloroform extract Statistical analysis of acetone-dried rabbit brain thromboplastin as the phospholipid source.15 The immunoreactive level of factor VII Significance testing of the differences observed between antigen was measured using a commercial ELISA kit clotting factor levels seen in our patients was performed (Diagnostica Stago, Asnieres, France). using a two-tailed, paired Student’s t-test, using Microsoft Plasma fibrinogen was assayed by the Clauss method. Excel Version 5.0 software. Mean and standard error of Protein C activity was assayed using a commercially avail- mean were calculated using standard methods. able kit (COAMATIC Protein C; Chromogenix, Milan, Italy), according to the manufacturer’s instructions. Results Lupus inhibitor screen Between 1990 and 1996, during which period 1443 stem A screening test for lupus inhibitor was performed by per- cell transplants were performed, eight patients with forming an APTT on the patient plasma with four different acquired FVII deficiency of a moderately severe degree APTT reagents, namely: (1) the in-house aluminum silicate were retrospectively identified. These individuals came to

Bone Marrow Transplantation Factor VII deficiency following SCT AA Toor et al 405 our attention because of an unexplained prolongation of the normal reference range in all patients (Table 1). Notably PT, which was usually seen 9–12 days following SCT. also, when measured more than once over a period of a Clinical data are summarized in Table 1. The mean patient week or more, the levels of these factors remained stable, age in this series was 33 years (range 10–43). All patients without any progressive decline, suggesting that there was were recipients of bone marrow or peripheral blood SCT not a generalized loss of hepatic clotting factor synthetic for a variety of hematologic disorders or solid tumors. Four activity. Protein C chromogenic activities (performed on patients received an allogeneic sibling transplant, while two the same samples as FVII levels shown in Table 1) were received autologous and two received unrelated donor obtained in three patients; the level was borderline in two transplants. Five patients underwent conditioning therapy and frankly low in patient No. 2 (P ϭ 0.3). Like factor VII, with cytoxan (Cy) and total body irradiation (TBI), one protein C has a relatively short half-life in plasma, and any received a regimen of busulfan, Cy, anti-thymocyte globu- pathophysiologic mechanism affecting factor VII levels lin and TBI (patient No. 5). The two patients undergoing (such as proteolysis, enhanced clearance, or biosynthesis) autologous SCT were conditioned with carboplatin, eto- might also be reflected in reduced protein C levels. How- poside and melphalan. ever, despite the fact that protein C was measured in only At the time of diagnosis all patients were receiving rou- three individuals, the results tend to suggest a relatively tine parenteral vitamin K supplements, and did not have more selective decrease in factor VII. apparent DIC or synthetic liver dysfunction. PT prior to Six patients were screened for the presence of a lupus SCT was normal in all cases. In the two patients who sur- inhibitor, either because of a mild prolongation of the vived the acute phase of SCT or chemotherapy, recovery APTT, or because of a clinical suspicion that the PT pro- to a normal PT was seen coincident with engraftment longation and/or low FVII:c might be due to an associated (patient Nos 3 and 7). In evaluating the cause of the PT inhibitor. Four were found to be positive. In two patients prolongation, it was found that FVII:c levels were reduced with a positive lupus inhibitor study, an IgG and IgM anti- in all patients, with a mean value of 22% (range 8–35%). cardiolipin antibody screen was negative. Nevertheless, the In the cases where FVII:c levels were repeated, from 1 to presence of these lupus anticoagulants raised the possi- 6 days later, similarly low values were obtained. Therefore, bilities that (1) PT prolongation was also due to a lupus it is possible that the mean nadir value for FVII:c would anticoagulant, or (2) that there existed an associated auto- have been even lower. In the three patients tested, a close antibody to FVII; analogous auto-antibodies to other vit- correlation between FVII:c and FVII:Ag levels was noted amin K-dependent coagulation factors that are capable of (not shown), indicating that the reduced FVII:c was not due binding to phospholipid have been described in association to synthesis of a dysfunctional FVII molecule, such as with lupus anticoagulants.20 With respect to the former could occur with vitamin K deficiency. possibility, a PT mixing study was performed in two The mean plasma FVII:c was significantly decreased patients (Nos 6 and 8), demonstrating full correction in both compared to mean FII:c (P Ͻ 0.01), FV:c (P Ͻ 0.01), cases. Furthermore, FVII:c assays were performed at sev- FIX:c (P Ͻ 0.01), and FX:c (P Ͻ 0.01). Fibrinogen levels eral dilutions in all patients, with no observed difference were also well preserved, remaining within or above the in the measured FVII level, suggesting that there was no

Table 1 Clinical characteristics and coagulation proﬁles of FVII deﬁcient patients

Patient Age/Sex Diagnosis and type I II V VII IX X Protein of SCT (mg/dl) (%) (%) (%) (%) (%) C (%)

1 41/F Myeloﬁbrosis 780 86 73 11 – 145 56 Allogeneic PBSCT 2 40/M AML 280 ND 74 35 ––24 URD BMT 3 31/F CML 540 78 88 27 91 121 66 Allogeneic PBSCT 4 10/M Rhabdomyosarcoma 350 84 57 15 ––– Autologous BMT 5 32/M Wiskott–Aldrich 490 62 78 16 97 117 – URD BMT 6 43/F ALL 470 65 54 8 – 82 – Allogeneic BMT 7 7/F Ewing’s sarcoma 460 58 121 31 108 –– Autologous BMT 8 34/M PNH/BM aplasia 980 102 – 30 ––– Allogeneic BMT

AML ϭ acute myelogenous leukemia; CML ϭ chronic myeloid leukemia; PNH ϭ paroxysmal nocturnal hemoglobinuria; PBSCT ϭ peripheral blood stem cell transplant; URD ϭ unrelated donor; Sib ϭ sibling donor. ND ϭ not done. In all cases, PT was normal at baseline. Reference ranges for individual factors were as follows: ﬁbrinogen (factor I) ϭ 170–370 mg/dl; factors II, V, VII, X, and protein C ϭ 70–130%; factor IX ϭ 75–135%.

Bone Marrow Transplantation Factor VII deﬁciency following SCT AA Toor et al 406 Table 2 FVII antibody screening results of FVII deﬁcient patients 1.75

Patient Lupus FVII mixing FVII antibody inhibitor study (by ELISA)

1 ϩ ND Ϫ 1.5 2NDNDϪ 3 ϩϪϪ 4NDϪ ND 5 ϪϪND a 6 ϩϪND 1.25

7 Ϫ ND ND INR 8 ϩϪa ND

ND ϭ not done. aMixing study in which PT (rather than FVII levels) was measured. 8 1

6 Units FFP artifactual dimunition of the factor VII level due to a circulating inhibitor. With respect to the possibility of a neutraliz- 4 ing FVII-specific inhibitor, we were unable to detect any 0.75 significant change in FVII:c levels after a 1 h incubation of 2 a mix of normal and patient plasma from three individuals (Nos 3, 4, 5) with acquired FVII deficiency. Furthermore, 0 -50 5 101520253035 the possibility of either a neutralizing or non-neutralizing inhibitor to FVII in three patients (Nos 1, 2, 3) is essentially Days post BMT excluded by the negative findings with a validated ELISA Figure 1 Time course of the coagulopathy due to FVII deficiency and which detects IgG antibodies directed to FVII(a) (Table 2). its refractoriness to FFP infusions in patient No. 1. The INR returned to The overall clinical outcome in this group of patients normal as the patient engrafted. was dismal, with six patients dying within the first month following SCT (Table 3). Bleeding complications were frequent in this group of patients (Table 3) and directly ual decay in the FVII level over the course of the next 4 accounted for two deaths (from gastrointestinal and pul- days (19% to 12% over 4 days). monary hemorrhage, in patients 6 and 8, respectively). Previous studies suggested that a fall in FVII levels in These events occurred despite aggressive platelet and FFP SCT patients is a predictor of VOD of the liver; in this replacement therapy. FVII levels did not appear to improve series, three patients (Nos 3, 4 and 6) developed clinical as expected immediately after large volume FFP infusions features of this complication. Their mean FVII:c level in two patients, one of whom is illustrated in Figure 1. In (17%) was not significantly different when compared to the one other patient (No. 3), a plasma exchange approximately other five patients (mean ϭ 25%). equivalent to a single plasma volume (3.5 l), using fresh frozen plasma as the replacement fluid, was performed prior to debridement of the maxillary sinuses for invasive fungal Discussion sinusitis. The incremental rise in plasma FVII:c level was much less than anticipated (11% pre-exchange, rising to We present clinical data from a retrospective series of eight only 19% immediately following the procedure). As a patients who developed a coagulopathy characterized by a result, the planned surgery was deferred. There was a grad- low plasma FVII level with essentially normal levels of

Table 3 Major clinical outcomes in FVII-deﬁcient patients

Patient Hemorrhage/Thrombosis Outcome/Cause of death

1 None Fungemia – day 23 2 Oral mucosal hemorrhage (intubation) ARDS – day 15 3 Sub-dural (2), oral mucosal and vaginal bleeding, DVT-PE, VOD CML relapse 3 months post transplant 4 Hematuria and VOD Hepatorenal syndrome – day 30 5 GI (severe) and pulmonary hemorrhagea Sepsis, GVHD – day 22 6 GI (severe), renal and pituitary hemorrhage, SAH, DVT (subclavian) and VODa GI bleeding – day 18 7 Vaginal bleeding Alive 8 ARDS, pulmonary and GI (severe) hemorrhage, hemorrhagic cystitisa Pulmonary hemorrhage – day 17

aAt autopsy SAH ϭ sub-arachnoid hemorrhage.

Bone Marrow Transplantation Factor VII deficiency following SCT AA Toor et al 407 other coagulation factors following myelo-ablative chemo- search for auto-antibodies to FVII(a). Such antibodies therapy and SCT. Because of the rather severe reduction in might not be detected by mixing experiments, yet they FVII:c levels, this may represent a distinct clinical entity. could remain capable of accelerating clearance of Despite the usually benign course of inherited FVII FVII/anti-FVII immune complexes. This was an attractive deficiency of an equivalent degree, FVII deficiency after hypothesis given the previous demonstration of this mech- SCT appears to have a tendency to be accompanied by a anism in another patient with acquired FVII deficiency.4 variably severe hemorrhagic diathesis that was directly However, in three patients who were screened by ELISA responsible for the death of two patients, and was a con- none had a detectable titer of antibody to FVII(a). Although tributing factor to death in two others. The defect was uni- our ELISA actually utilized immobilized FVIIa (which may formly refractory to parenteral vitamin K supplementation, differ conformationally from native FVII) to capture circul- to massive FFP infusion (in two patients) and, in one case, ating immunoglobulin, we suspect that this did not compro- to plasma exchange with FFP replacement. However, we mise our ability to detect an antibody to zymogen FVII. would like to emphasize the fact that this case series is a The apparent lack of evidence for an auto-immune mech- retrospective review based on clinical observations made anism does not preclude other possible reasons for acceler- over a long period of time. Due to possible recall bias, and ated FVII clearance. An acquired form of FVII deficiency conceivably because of a tendency to under-diagnose this very similar to that described herein has been noted in condition without routine PT checks (which were not patients with sepsis, in whom the proposed mechanism was performed), we cannot estimate the true incidence of this cleavage of FVII by granulocyte-derived proteases.25 Fur- syndrome following SCT. Indeed, after the recognition of thermore, a similar unexplained fall in plasma FVII:c (and this clinical entity, one other patient undergoing induction FVIIa) levels has been observed following the adminis- chemotherapy for AML was diagnosed with acquired FVII tration of endotoxin to normal volunteers.26 In the absence deficiency (FVII:c 18%) with normal levels of other coagulation factors and protein C. His clinical course was compli- of a clearly defined mechanism, one can speculate about cated by epistaxis and gastrointestinal bleeding requiring an alternative explanation for the apparent loss of FVII, transfusion support. However, his prothrombin time nor- namely enhanced binding to its principal ligand, tissue fac- malized upon entering remission, with recovery of his tor (TF). TF is a cell-associated trans-membrane glyco- 27 28 blood counts. Therefore, this syndrome may not be limited protein that is predominantly, although not exclusively, to SCT alone, but rather may also affect patients under- localized to cells in the extravascular compartment in vivo. going intensive chemotherapy. We speculate that high-dose chemo-radiotherapy, by Some previous studies,11 but not others,21 have con- inducing a state of increased vascular permeability, cluded that a falling FVII level following SCT is a harbin- enhances access of intravascular FVII to a large pool of ger of VOD of the liver. In this series, three of the eight extravascular TF, sequestering FVII in the extra vascular patients in our series did, in fact, develop clinical findings compartment. However, proof of this hypothesis would of VOD. While this is a significant proportion of the total, require carefully designed FVII clearance studies in vivo. it is also clear that VOD is not inevitably associated with We observed severe hemorrhagic complications in sev- acquired FVII deficiency. It has been previously noted that eral of our patients, which in some cases contributed in chronic liver disease, FVII levels may be particularly directly to their demise. It is difficult to know to what extent low when compared to factors II and X.22 We cannot, there- acquired FVII deficiency may have contributed to these fore, fully exclude the possibility that the acquired and complications, especially since congenital FVII deficiency seemingly selective FVII deficiency that we observed is at levels of 10–15% is generally not associated with a simply a manifestation of liver dysfunction, whether due bleeding tendency.29 However, it may be that lesions that to VOD or some other etiology. Overall, however, several might otherwise have posed a minor hemostatic challenge clinical features point to the possibility of accelerated clear- to an intact coagulation system, bleed catastrophically in ance rather than synthetic dysfunction as the mechanism the presence of both sub-optimal circulating FVII levels for FVII deficiency. Specifically, these include: (1) the lack and thrombocytopenia following SCT. Replacement ther- of response in FVII levels to seemingly adequate replace- apy with FFP and platelets failed to improve FVII:c levels ment therapy with FFP in several patients, and a full plasma or achieve hemostasis in several of our cases. Novel ther- exchange in one other; and (2) the preservation of other apies such as rFVIIa, perhaps combined with anti- factor levels in plasma on repeated follow-up. fibrinolytic agents, may result in improved outcomes, parti- In the cases of isolated acquired FVII deficiency that cularly in view of recent data documenting the efficacy of have been described previously, an inhibitory antibody to rFVIIa in both FVII-deficient and thrombocytopenic FVII has been described in only a few instances. In 30–32 5,6,23 patients. occasional cases, a neutralizing auto-antibody could be In conclusion, we describe an uncommon form of demonstrated in vitro. The reasonably frequent finding of acquired coagulopathy arising as a complication of high- a lupus inhibitor in our patients further heightened the dose chemotherapy and SCT, which contributed to the early possibility that FVII deficiency may have been due to demise of several patients undergoing this therapy. Further development of an associated auto-antibody to FVII.5 The studies are needed to clearly elucidate the mechanism of observation that new lupus inhibitors may develop after this coagulopathy and whether patients with associated SCT has been previously reported from this institution.24 However, having failed to demonstrate a neutralizing anti- bleeding might be candidates for therapy with novel hemo- body to FVII by mixing experiments, we used ELISA to static agents.

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