1Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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2Novo Nordisk Pharmaceuticals Inc., Gentofte, Denmark
Correspondence to: Dr N S Key, Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota Medical School, MMC 480, 420 Delaware St SE, Minneapolis, MN 55455, USA
Acquired agency VII (FVII) absence in the absence of vitamin K deficiency, articulate anticoagulant therapy, constructed alarmist dysfunction, or DIC is rare, with abandoned a scattering of cases appropriately far reported. In the aeon from 1990 to 1996 we articular eight patients with acquired FVII deficiency, all of whom presented with assiduity of the prothrombin time (PT) in the aboriginal 2 weeks afterward axis corpuscle transplantation (SCT). The beggarly claret FVII array action (FVII:c) was 22% (range 8-35%) with an about agnate abridgement in FVII antigen (FVII:Ag) level. Beggarly claret levels of fibrinogen and factors II, V, IX, and X were normal. Protein C action was decidedly depressed in abandoned one of the three patients in whom it was measured. Several patients accomplished bleeding complications, and drain anon accounted for afterlife in two cases. Veno-occlusive ache of the alarmist developed in three patients. We accomplish that FVII absence should be advised in the cogwheel appraisal of abiding PT in patients who accept afresh undergone SCT. The apparatus of this acquired absence accompaniment charcoal to be defined.
Bone Bottom Transplantation (2002) 29, 403-408. DOI: 10.1038/sj/bmt/1703381
factor VII; axis corpuscle transplantation; hemorrhage; acquired deficiency; astute myelogenous leukemia
Factor VII is a vitamin K-dependent zymogen which back activated binds to tissue agency (TF), a transmembrane protein acerb bidding by beef in the adventitia of claret vessels. The TF-VII(a) circuitous activates both factors IX and X in the attendance of phospholipid and calcium, and catalyzes the auto-activation of added zymogen FVII. The TF-VII(a) alleyway is now accustomed to be the ascendant hemostatic apparatus in vivo.1
Isolated acquired FVII absence in the absence of vitamin K deficiency, coumadin therapy, constructed alarmist dysfunction, or credible DIC is rare, accepting been declared in abandoned a scattering of cases. Associated ache states accept included malignancy,2 aplastic anemia,3,4 and antiphospholipid antibodies.5,6 In axis corpuscle displace (SCT) patients, a bashful abridgement in FVII levels (in the 25 to 50% range) has been declared in the aboriginal 2 weeks afterward SCT.7,8,9 In these cases it has about been associated with deficiencies of added factors such as FXII or protein C.10 It has been adapted that the abatement in FVII and protein C levels in this ambience may be a augury of veno-occlusive ache of the alarmist (VOD).11
Bleeding afterwards SCT has been articular as a cogent accident agency affecting outcome.12,13,14 Commonly encountered sites of bleeding accommodate hemorrhagic cystitis, broadcast alveolar hemorrhage, and oro-mucosal and gastro-intestinal sources. Although thrombocytopenia is acutely a aloft accidental factor, added reasons, such as toxicity accompanying to the anterior regimen, infection, and graft-versus-host disease, accept all been cited. Acquired FVII deficiency, at atomic of the amount ahead reported, has not been active as a accident agency for drain afterward SCT.
In this communication, we call the analytic and class appearance of a alternation of patients with acquired FVII absence afterward SCT, who accept been managed at our institution. The abundance and severity of bleeding complications in these patients advance that this coagulopathy may accept contributed to adverse outcomes.
Methods
Patients
We conducted a attendant blueprint appraisal of eight patients accustomed to accept developed acquired FVII absence during SCT at the University of Minnesota amid 1990 and 1996. The transplants were agitated out application a myeloablative regimen, followed by allogeneic or autologous hematopoietic SCT (using cartilage bottom or ambiguous claret axis cells). Post-transplant affliction consisted of GVHD prophylaxis, anti-microbial prophylaxis and appraisal as needed, comestible support, and admixture abutment with red corpuscle and platelet products. Accustomed parenteral vitamin K supplementation was administered to all patients. Daily claret counts were acquired and agglomeration tests were performed if clinically indicated, eg in patients with bleeding, septicemia, or doubtable DIC. In non-bleeding patients, platelets were alloyed to accumulate the platelet counts greater than 10-20 ´ 109/l. Hemoglobin was commonly maintained at >8.0 G/dl. These ambit were revised upwards for patients with clinically credible bleeding. Coagulopathy was adjourned initially by a array of tests that included prothrombin time (PT), activated fractional thromboplastin time (APTT), thrombin time (TT), Clauss fibrinogen, and fibrin(ogen) abasement artefact titer. In the accident of a array time actuality prolonged, a 1:1 mix with accustomed claret was performed to differentiate the attendance of a agglomeration inhibitor from a agency deficiency. This was followed by specific agency assays if indicated. At the acumen of the accessory physician, coagulopathy was advised with beginning arctic claret (FFP), and/or cryoprecipitate infusions with a ameliorative ambition of analytic hemostasis (in the case of analytic bleeding) and/or normalization of class ambit of coagulation. In some cases, added doses of parenteral vitamin K were additionally administered. None of the patients were accepting any anatomy of anti-thrombotic appraisal nor anti-platelet agents, such as aspirin or non-steroidal anti-inflammatory agents.
Factor assays
Measurement of specific array agency action was in all cases performed by a one-stage array appraisal (PT-based appraisal for factors II, VII and X, and APTT-based appraisal for FIX), application a admixture of the adapted factor-deficient substrate claret and appraisal plasma. All agency assays were performed at 1/10, 1/20, 1/40, and 1/80 dilutions. The after-effects are bidding as a percentage, with 100% agnate to the adapted agency akin in affiliated claret samples from 40 accustomed volunteers. Advertence ranges for agency levels were accustomed as the beggarly ± 2 s.d. of 40 accustomed individuals. Above-mentioned to January 1993, aerial academician thromboplastin (Thromboplastin C, Dade Laboratories, Deerfield, IL, USA) was acclimated in our class for PT and PT-based agency assays. The declared International Sensitivity Index (ISI) of this reagent was 2.71. Subsequently, all PT assays were performed application recombinant re-lipidated tissue agency (Innovin, Dade) with an ISI of 1.0. APTT was performed application an centralized reagent in which 0.075% aluminum silicate was acclimated as an activator, and the chloroform abstract of acetone-dried aerial academician thromboplastin as the phospholipid source.15 The immunoreactive akin of agency VII antigen was abstinent application a bartering ELISA kit (Diagnostica Stago, Asnieres, France).
Plasma fibrinogen was assayed by the Clauss method. Protein C action was assayed application a commercially accessible kit (COAMATIC Protein C; Chromogenix, Milan, Italy), according to the manufacturer's instructions.
Lupus inhibitor screen
A screening appraisal for lupus inhibitor was performed by assuming an APTT on the accommodating claret with four altered APTT reagents, namely: (1) the centralized aluminum silicate reagent referred to above; (2) APTT-FSL reagent (Sigma Diagnostics, St Louis, MO, USA); (3) Dade Actin FS (Dade-Behring Inc); and (4) Organon Teknika (Durham, NC, USA) automatic APTT reagent. Back a abiding APTT was detected with one or added reagents, a 1:1 mix of accommodating and accustomed affiliated claret was performed, and the APTT again application that aforementioned reagent(s). Failure of the bond abstraction to actual led to the achievement of the platelet abatement procedure16 (with one or added reagents) to affirm the appraisal of a lupus inhibitor. Afterwards converting our action to accommodate the adulterate Russell viper acidity time (dRVVT), with mix and affirm steps, consecutive to 1996, we were able to actuate that the assorted APTT screening admission acclimated in this abstraction was a actual specific, if somewhat beneath astute address for screening for lupus anticoagulants.
FVII antibiotic screening methods
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Two abstracted methods were acclimated to awning for the attendance of an auto-antibody to FVII. Firstly, we acclimated a ahead declared ELISA adjustment in which accommodating claret was buried for the attendance of anti-FVII(a) IgG.17 Advertence ranges and absolute banned were accustomed by screening assorted accustomed donors. Secondly, in adjustment to awning for a acrid antibiotic to FVII, we acclimated a claret bond assay. Specifically, FVII:c was abstinent in accommodating and accustomed (pooled normal) plasma, which were again alloyed in according proportions. FVII:c was assayed both anon afterwards bond and afterward a 1 h evolution at 37°C. A absolute aftereffect (ie attendance of an inhibitory antibody) was doubtable if the FVII:c in the alloyed sample (either at time aught or afterwards 1 h incubation) was about 15% or added beneath the accustomed value. This approximate absolute amount was called demography into annual the actuality that FVII:c in the mix sample adeptness be hardly beneath than accustomed - in the absence of an inhibitor - artlessly due to the reproducibility of the agency VII assay. In adjustment to abbreviate artifactual accident of action of labile array factors (such as FVIII) in the mix, a 1 h evolution is commonly acclimated in our class to awning for accessible agglomeration agency inhibitory antibodies. The barring to this is in the case of doubtable FVIII inhibitors, area a 2 h incubation, as declared in the original18 (and afterwards modified19) Bethesda assays, is used.
Statistical analysis
Significance testing of the differences empiric amid array agency levels credible in our patients was performed application a two-tailed, commutual Student's t-test, application Microsoft Excel Version 5.0 software. Beggarly and accustomed absurdity of beggarly were affected application accustomed methods.
Results
Between 1990 and 1996, during which aeon 1443 axis corpuscle transplants were performed, eight patients with acquired FVII absence of a moderately astringent amount were retrospectively identified. These individuals came to our absorption because of an alien assiduity of the PT, which was usually credible 9-12 canicule afterward SCT. Analytic abstracts are abbreviated in Table 1. The beggarly accommodating age in this alternation was 33 years (range 10-43). All patients were recipients of cartilage bottom or ambiguous claret SCT for a array of hematologic disorders or solid tumors. Four patients accustomed an allogeneic affinity transplant, while two accustomed autologous and two accustomed altered donor transplants. Bristles patients underwent conditioning appraisal with cytoxan (Cy) and absolute anatomy betterment (TBI), one accustomed a dieting of busulfan, Cy, anti-thymocyte globulin and TBI (patient No. 5). The two patients adeptness autologous SCT were conditioned with carboplatin, etoposide and melphalan.
At the time of appraisal all patients were accepting accustomed parenteral vitamin K supplements, and did not accept credible DIC or constructed alarmist dysfunction. PT above-mentioned to SCT was accustomed in all cases. In the two patients who survived the astute appearance of SCT or chemotherapy, accretion to a accustomed PT was credible ancillary with engraftment (patient Nos 3 and 7). In evaluating the account of the PT prolongation, it was begin that FVII:c levels were bargain in all patients, with a beggarly amount of 22% (range 8-35%). In the cases area FVII:c levels were repeated, from 1 to 6 canicule later, analogously low ethics were obtained. Therefore, it is accessible that the beggarly base amount for FVII:c would accept been alike lower. In the three patients tested, a abutting alternation amid FVII:c and FVII:Ag levels was acclaimed (not shown), advertence that the bargain FVII:c was not due to amalgam of a abortive FVII molecule, such as could action with vitamin K deficiency.
The beggarly claret FVII:c was decidedly decreased compared to beggarly FII:c (P < 0.01), FV:c (P < 0.01), FIX:c (P < 0.01), and FX:c (P < 0.01). Fibrinogen levels were additionally able-bodied preserved, actual aural or aloft the accustomed advertence ambit in all patients (Table 1). Notably also, back abstinent added than already over a aeon of a anniversary or more, the levels of these factors remained stable, afterwards any accelerating decline, suggesting that there was not a ambiguous accident of hepatic array agency constructed activity. Protein C chromogenic activities (performed on the aforementioned samples as FVII levels credible in Table 1) were acquired in three patients; the akin was ambiguous in two and bluntly low in accommodating No. 2 (P = 0.3). Like agency VII, protein C has a almost abbreviate half-life in plasma, and any pathophysiologic apparatus affecting agency VII levels (such as proteolysis, added clearance, or biosynthesis) adeptness additionally be reflected in bargain protein C levels. However, admitting the actuality that protein C was abstinent in abandoned three individuals, the after-effects tend to advance a almost added careful abatement in agency VII.
Six patients were buried for the attendance of a lupus inhibitor, either because of a balmy assiduity of the APTT, or because of a analytic suspicion that the PT assiduity and/or low FVII:c adeptness be due to an associated inhibitor. Four were begin to be positive. In two patients with a absolute lupus inhibitor study, an IgG and IgM anti-cardiolipin antibiotic awning was negative. Nevertheless, the attendance of these lupus anticoagulants aloft the possibilities that (1) PT assiduity was additionally due to a lupus anticoagulant, or (2) that there existed an associated auto-antibody to FVII; akin auto-antibodies to added vitamin K-dependent agglomeration factors that are able of bounden to phospholipid accept been declared in affiliation with lupus anticoagulants.20 With account to the above possibility, a PT bond abstraction was performed in two patients (Nos 6 and 8), demonstrating abounding alteration in both cases. Furthermore, FVII:c assays were performed at several dilutions in all patients, with no empiric aberration in the abstinent FVII level, suggesting that there was no artifactual dimunition of the agency VII akin due to a circulating inhibitor. With account to the achievability of a acrid FVII-specific inhibitor, we were clumsy to ascertain any cogent change in FVII:c levels afterwards a 1 h evolution of a mix of accustomed and accommodating claret from three individuals (Nos 3, 4, 5) with acquired FVII deficiency. Furthermore, the achievability of either a acrid or non-neutralizing inhibitor to FVII in three patients (Nos 1, 2, 3) is about afar by the abrogating allegation with a accurate ELISA which detects IgG antibodies directed to FVII(a) (Table 2).
The all-embracing analytic aftereffect in this accumulation of patients was dismal, with six patients dying aural the aboriginal ages afterward SCT (Table 3). Bleeding complications were common in this accumulation of patients (Table 3) and anon accounted for two deaths (from gastrointestinal and pulmonary hemorrhage, in patients 6 and 8, respectively). These contest occurred admitting advancing platelet and FFP backup therapy. FVII levels did not arise to advance as accustomed anon afterwards ample aggregate FFP infusions in two patients, one of whom is illustrated in Figure 1. In one added accommodating (No. 3), a claret barter about agnate to a audible claret aggregate (3.5 l), application beginning arctic claret as the backup fluid, was performed above-mentioned to debridement of the maxillary sinuses for invasive fungal sinusitis. The incremental acceleration in claret FVII:c akin was abundant beneath than advancing (11% pre-exchange, ascent to abandoned 19% anon afterward the procedure). As a result, the planned anaplasty was deferred. There was a bit-by-bit adulteration in the FVII akin over the advance of the abutting 4 canicule (19% to 12% over 4 days).
Previous studies adapted that a abatement in FVII levels in SCT patients is a augur of VOD of the liver; in this series, three patients (Nos 3, 4 and 6) developed analytic appearance of this complication. Their beggarly FVII:c akin (17%) was not decidedly altered back compared to the added bristles patients (mean = 25%).
Discussion
We present analytic abstracts from a attendant alternation of eight patients who developed a coagulopathy characterized by a low claret FVII akin with about accustomed levels of added agglomeration factors afterward myelo-ablative chemotherapy and SCT. Because of the rather astringent abridgement in FVII:c levels, this may represent a audible analytic entity. Admitting the usually amiable advance of affiliated FVII absence of an agnate degree, FVII absence afterwards SCT appears to accept a addiction to be accompanied by a variably astringent hemorrhagic diathesis that was anon amenable for the afterlife of two patients, and was a accidental agency to afterlife in two others. The birthmark was analogously adverse to parenteral vitamin K supplementation, to massive FFP beverage (in two patients) and, in one case, to claret barter with FFP replacement. However, we would like to accent the actuality that this case alternation is a attendant appraisal based on analytic observations fabricated over a continued aeon of time. Due to accessible anamnesis bias, and conceivably because of a addiction to under-diagnose this action afterwards accustomed PT checks (which were not performed), we cannot appraisal the accurate accident of this affection afterward SCT. Indeed, afterwards the acceptance of this analytic entity, one added accommodating adeptness consecration chemotherapy for AML was diagnosed with acquired FVII absence (FVII:c 18%) with accustomed levels of added agglomeration factors and protein C. His analytic advance was complicated by epistaxis and gastrointestinal bleeding acute admixture support. However, his prothrombin time normalized aloft entering remission, with accretion of his claret counts. Therefore, this affection may not be bound to SCT alone, but rather may additionally affect patients adeptness accelerated chemotherapy.
Some antecedent studies,11 but not others,21 accept assured that a falling FVII akin afterward SCT is a augury of VOD of the liver. In this series, three of the eight patients in our alternation did, in fact, advance analytic allegation of VOD. While this is a cogent admeasurement of the total, it is additionally bright that VOD is not accordingly associated with acquired FVII deficiency. It has been ahead acclaimed that in abiding alarmist disease, FVII levels may be decidedly low back compared to factors II and X.22 We cannot, therefore, absolutely exclude the achievability that the acquired and acutely careful FVII absence that we empiric is artlessly a appearance of alarmist dysfunction, whether due to VOD or some added etiology. Overall, however, several analytic appearance point to the achievability of accelerated approval rather than constructed dysfunction as the apparatus for FVII deficiency. Specifically, these include: (1) the abridgement of acknowledgment in FVII levels to acutely able backup appraisal with FFP in several patients, and a abounding claret barter in one other; and (2) the canning of added agency levels in claret on again follow-up.
In the cases of abandoned acquired FVII absence that accept been declared previously, an inhibitory antibiotic to FVII has been declared in abandoned a few instances. In casual cases,5,6,23 a acrid auto-antibody could be approved in vitro. The analytic common award of a lupus inhibitor in our patients added acute the achievability that FVII absence may accept been due to development of an associated auto-antibody to FVII.5 The ascertainment that new lupus inhibitors may advance afterwards SCT has been ahead arise from this institution.24 However, accepting bootless to authenticate a acrid antibiotic to FVII by bond experiments, we acclimated ELISA to chase for auto-antibodies to FVII(a). Such antibodies adeptness not be detected by bond experiments, yet they could abide able of accelerating approval of FVII/anti-FVII allowed complexes. This was an adorable antecedent accustomed the antecedent affirmation of this apparatus in addition accommodating with acquired FVII deficiency.4 However, in three patients who were buried by ELISA none had a credible titer of antibiotic to FVII(a). Although our ELISA absolutely activated anchored FVIIa (which may alter conformationally from built-in FVII) to abduction circulating immunoglobulin, we doubtable that this did not accommodation our adeptness to ascertain an antibiotic to zymogen FVII.
The credible abridgement of affirmation for an auto-immune apparatus does not avert added accessible affidavit for accelerated FVII clearance. An acquired anatomy of FVII absence actual agnate to that declared herein has been acclaimed in patients with sepsis, in whom the proposed apparatus was break of FVII by granulocyte-derived proteases.25 Furthermore, a agnate alien abatement in claret FVII:c (and FVIIa) levels has been empiric afterward the administering of endotoxin to accustomed volunteers.26 In the absence of a acutely authentic mechanism, one can brainstorm about an another account for the credible accident of FVII, namely added bounden to its arch ligand, tissue agency (TF). TF is a cell-associated trans-membrane glycoprotein that is predominantly,27 although not exclusively,28 localized to beef in the extravascular alcove in vivo. We brainstorm that high-dose chemo-radiotherapy, by inducing a accompaniment of added vascular permeability, enhances admission of intravascular FVII to a ample basin of extravascular TF, sequestering FVII in the added vascular compartment. However, affidavit of this antecedent would crave anxiously advised FVII approval studies in vivo.
We empiric astringent hemorrhagic complications in several of our patients, which in some cases contributed anon to their demise. It is difficult to apperceive to what admeasurement acquired FVII absence may accept contributed to these complications, abnormally back complete FVII absence at levels of 10-15% is about not associated with a bleeding tendency.29 However, it may be that lesions that adeptness contrarily accept airish a accessory hemostatic claiming to an complete agglomeration system, drain catastrophically in the attendance of both sub-optimal circulating FVII levels and thrombocytopenia afterward SCT. Backup appraisal with FFP and platelets bootless to advance FVII:c levels or accomplish hemostasis in several of our cases. Atypical therapies such as rFVIIa, conceivably accumulated with anti-fibrinolytic agents, may aftereffect in bigger outcomes, decidedly in appearance of contempo abstracts documenting the ability of rFVIIa in both FVII-deficient and thrombocytopenic patients.30,31,32
In conclusion, we call an aberrant anatomy of acquired coagulopathy arising as a aggravation of high-dose chemotherapy and SCT, which contributed to the aboriginal annihilation of several patients adeptness this therapy. Added studies are bare to acutely annotate the apparatus of this coagulopathy and whether patients with associated bleeding adeptness be candidates for appraisal with atypical hemostatic agents.
Acknowledgements
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We would like to acknowledge Luke Dandelet and Marie Johannessen for their abstruse contribution, and Carol Taubert for advice in alertness of the manuscript.
1 Semeraro N, Colucci M. Tissue agency in bloom and disease. Thromb Haemost 1997; 78): 759-764. MEDLINE
2 de Raucourt A, Dumont M, Tourani J et al. Acquired FVII absence associated with pleural liposarcoma. Claret Coag Fibrinol 1994; 5: 833-836.
3 Fischer M, Lechner K, Hinterberger W et al. Absence of fibrinogen and FVII afterward appraisal of astringent aplastic anemia with antithymocyte globulin and aerial dosage methyl prednisolone. Scand J Haematol 1985; 34: 312-316. MEDLINE
4 Weisdorf D, Hasegawa D, Fair D. Acquired FVII absence associated with aplastic anemia: alteration with cartilage bottom transplantation. Br J Haematol 1989; 71: 409-413. MEDLINE
5 Kimka Ndimbie O, Raman K, Saeed S. Lupus anticoagulant associated with specific inhibition of FVII in a accommodating with AIDS. Am J Clin Pathol 1989; 91: 491-493. MEDLINE
6 Delmer A, Horellon M, Andreu G et al. Life aggressive intra-cranial bleeding associated with attendance of an anti-factor VII auto-antibody. Claret 1989; 74: 229-232. MEDLINE
7 Bazzarbachi A, Scrobohaci M, Gisselbrecht C et al. Changes in protein C, agency VII and endothelial markers afterwards autologous SCT: accessible affiliation in the pathogenesis of VOD. Nouv Rev Fr Hematol 1993; 35: 135-140. MEDLINE
8 Collins P, Roderick A, O'Brien D et al. Agency VIIa and added haemostatic variables afterward cartilage bottom transplantation. Thromb Haemost 1994; 72: 28-32. MEDLINE
9 Vannuchi A, Rafanelli D, Longo G et al. Aboriginal hemostatic alterations afterward SCT: a -to-be study. Haematologica 1994; 79: 519-525. MEDLINE
10 Kaufman P, Jones R, Greenberg C, Peters W. Auto SCT and FXII, FVII and protein C deficiency. Report of a new affiliation and its accessible accord to endothelial corpuscle injury. Cancer 1990; 66: 515-21. MEDLINE
11 Scrobohaci M, Drouet L, Monem-Mansi A et al. Alarmist VOD afterwards cartilage bottom transplantation, changes in agglomeration ambit and endothelial markers. Thromb Res 1992; 63: 509-519.
12 Nevo S, Enger C, Swan V et al. Astute bleeding afterwards allogeneic cartilage bottom transplantation: affiliation with affix against host ache and aftereffect on survival. Transplantation 1999; 67: 681-689. MEDLINE
13 Price KJ, Thall PF, Kish SK et al. Prognostic indicators for claret and bottom displace patients accustomed to an accelerated affliction unit. Am J Resp Crit Affliction Med 1998; 158: 876-884. MEDLINE
14 Nevo S, Swan V, Enger C et al. Astute bleeding afterwards cartilage bottom transplantation - accident and aftereffect on survival. A quantitative appraisal in 1402 patients. Claret 1998; 91: 1469-1477. MEDLINE
15 Edson J, Vogt J, Hasegawa D. Abnormal prothrombin beyond immuno-electrophoresis in patients with lupus inhibitors. Claret 1994; 64: 807-816.
16 Triplett DA, Brandt JT, Kaczor D, Schaeffer J. Class appraisal of lupus inhibitors: a allegory of the tissue thromboplastin inhibition action with a new platelet abatement test. Am J Clin Pathol 1983; 79: 678-82. MEDLINE
17 Nicolaisen EM, Hansen LL, Poulsen F et al. Immunological aspects of recombinant agency VIIa (rFVIIa) in analytic use. Thromb Haemost 1996; 76: 200-204. MEDLINE
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18 Kasper CK, Aledort LM, Counts RB et al. A added compatible altitude of agency VIII inhibitors. Thromb Diath Haemorrh 1975; 34: 869-872. MEDLINE
19 Verbruggen B, Novakova I, Wessels H et al. The Nijmegen modification of the Bethesda appraisal for agency VIII:c inhibitors: bigger specificity and reliability. Thromb Haemost 1995; 73: 247-251. MEDLINE
20 Galli M, Barbui T. Antiprothrombin antibodies: apprehension and analytic acceptation in the antiphospholipid syndrome. Claret 1999; 93: 49-57.
21 Park YD, Yasui M, Yoshimoto T et al. Changes in hemostatic ambit in hepatic veno-occlusive ache afterward cartilage bottom transplantation. Cartilage Bottom Displace 1997; 19: 915-920. MEDLINE
22 Mammen EF. Agglomeration defects in alarmist disease. Med Clin N Am 1994; 78: 545-554. MEDLINE
23 Okajima K, Ishii M. Life-threatening bleeding in a case of autoantibody-induced agency VII deficiency. Int J Hematol 1999; 69: 129-132. MEDLINE
24 Greeno EW, Haake R, McGlave P et al. Lupus inhibitors afterward cartilage bottom transplantation. Cartilage Bottom Displace 1995; 15: 287-291. MEDLINE
25 Biron C, Bengler C, Gris JC, Schved JF. Acquired abandoned agency VII absence during sepsis. Haemostasis 1997; 27: 51-56. MEDLINE
26 Li A, Morrissey J, Chang AKC et al. Factors VIIc and VIIa claret absorption are depressed afterward bolus bang of endotoxin into accustomed animal subjects. Claret 1996; 88 (Suppl. 1): 443a.
27 Drake TA, Morrissey JH, Edgington TS. Careful cellular announcement of tissue agency in animal tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol 1989; 134: 1087-1097. MEDLINE
28 Key NS, Slungaard A, Dandelet L et al. Whole claret tissue agency procoagulant action in patients with sickle corpuscle disease. Claret 1998; 11: 4216-4223.
29 Ingerslev J, Kristensen HL. Analytic account and appraisal strategies in agency VII deficiency. Haemophilia 1998; 4: 689-696. MEDLINE
30 Kristensen J, Killander A, Hippe E et al. Analytic acquaintance with recombinant agency VIIa in patients with thrombocytopenia. Haemostasis 1996; 26 (Suppl. 1): 159-164. MEDLINE
31 Hedner U. Recombinant activated agency VII as a accustomed haemostatic agent. Claret Coag Fibrinol 1998; 9 (Suppl. 1): S147-S152.
32 White B, Martin M, Kelleher S et al. Successful use of recombinant FVIIa (Novoseven) in the administration of pulmonary haemorrhage accessory to Aspergillus infection in a accommodating with leukaemia and acquired agency VII deficiency. Br J Haematol 1999; 106: 254-255. MEDLINE
Figure 1 Time advance of the coagulopathy due to FVII absence and its defiance to FFP infusions in accommodating No. 1. The INR alternate to accustomed as the accommodating engrafted.
Table 1 Clinical characteristics and agglomeration profiles of FVII amiss patients
Table 2 FVII antibiotic screening after-effects of FVII amiss patients
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Blood pharmacology - Dental | epistaxis vitamin k[/caption]
Table 3 Major analytic outcomes in FVII-deficient patients
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