Case report:
Isolated acquired factor VII deficiency: Report of
Two Cases and Review of the Literature
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2
Sylvie MN Mulliez, Pharm , Anna Vantilborgh, PhD and Katrien MJ Devreese, MD, PhD
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2
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Coagulation Laboratory, Ghent University Hospital, Ghent, Belgium
Department of Hematology, Ghent University Hospital, Ghent, Belgium
Case report
Case 1
A 54-year-old man was admitted with sudden onset of headache with vomiting and diarrhoea without
neurological failure. Computer tomography (CT-scan) confirmed the diagnosis of a subarachnoid bleeding.
Cerebral angiography could not show an aneurysm or other cause of bleeding.
During the admission period a spontaneous International Normalized Ratio (INR) elevation was seen. Over a
period of 7 days the prothrombin time (PT) decreased from 70% towards 37% (normal range, 70-120%),
unresponsive to two doses of intravenous vitamin K (5 mg and 20 mg) (Figure 1). The activated partial
thromboplastinn time (aPTT) was normal. The nature of the deregulated PT was further investigated by clotting
factor dosage. Factor assays revealed normal factor levels of FII, FV, FIX and FX, but a low FVII (8%). In de
diagnostic work-up, we performed a mixing study that showed a correction of the PT, suggesting the presence
of factor deficiency. The Bethesda assay could not demonstrate a neutralizing inhibitor. Lupus anticoagulant
(LA) testing was positive in the dilute Russel’s Viper Venom Test (dRVVT) (LA screen, Life Diagnostics, DSRV,
Clarkstons, USA), the mixing test and confirmation test (LA confirm, Life Diagnostics) and negative in the aPTT
system (PTT-LA, Diagnostica Stago, Asnières, France).
These results were compatible with an acquired FVII deficiency without inhibitory antibodies. Causes of
FVII deficiency were ruled out: vitamin K deficiency, liver disease and diffuse intravascular coagulation (DIC). In
this patient no underlying associated disease could be identified, the patient showed no signs of infection (Creactive protein (CRP) of 4.7 mg/L, normal range <5 mg/L) and malignancy was excluded.
The patient was initially transfused with 2 units fresh frozen plasma. After 20 days the PT normalized
spontaneously to 76% and LA disappeared after one month. FVII slowly normalized to 41% after 20 days, 60%
after three months and 78% after seven months.
Figure 1. Prothrombin time (PT) of case 2 during hospital admission. The arrows
indicate the moments of vitamin K administration, first time 5 mg and the second
time 20 mg, without any response in PT
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Case 2
In September 2014, a 78-year-old man presented to the emergency department with red blood loss per
anum. Since four days he had melena and complained of low-grade fever, sweats, generalized malaise since a
few weeks and 5 kg weight loss during the last months. He had a medical history of rheumatoid arthritis
treated with methotrexate and folic acid. In 2012 he was diagnosed with prostate cancer with solitair bone
metastasis, followed by prostatectomy with lymphadenectomy and radiotherapy. In August 2014, PET-CT and
PSA results (<0.03 µg/L) showed no relapsed prostate cancer. At administration, a physical examination
revealed an enlarged axillary lymph node on the right side and multiple other lymphadenopathies supra- and
infra-diaphragmatic. A lymph node biopsy was taken.
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At presentation the complete blood count revealed a white cell count (WBC) of 1.52*10 /L (normal range,
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3.65-9.30*10 /L), platelet count of 148*10 /L (normal range, 149-319*10 /L) and haemoglobin value of 118 g/L
(normal range, 129-173 g/L). The coagulation results showed normal aPTT of 35.1 sec (normal range, 28.9-38.1
sec) and normal PT of 77% (normal range, 70-120%) with an INR of 1.18 (normal range, 0.9-1.1). Lymph node
biopsy results were consistent with the diagnosis of classical Hodgkin’s lymphoma, type mixed cellularity.
During the admission period a deterioration of the coagulation results was seen. Two days after admission a
PT of 62% and an aPTT of 46 sec was observed. Factor assays revealed normal level of FV, FVIII, FIX, FXI and
FXII, FII and a borderline normal value of FX (65%), FVII was reduced (35%). The reduced FVII was confirmed in
a second sample (30%). The mixing study showed a correction of the PT, suggestive for the presence of a factor
deficiency. Lupus anticoagulant (LA) testing was only positive in the aPTT system (screen and mix with PTT-LA
and confirm with Staclo-LA® assay (Diagnostica Stago, Asnières, France)), and negative in the dRVVT system (LA
screen and LA confirm). On the moment of LA testing, the CRP was 63.5 mg/L, therefore the LA testing should
be interpreted with care since Staclot-LA® can be false positive if CRP is elevated [3]. Twelve days later LA was
negative.
Vitamin K deficiency could be ruled out because of the isolated decrease of FVII. There was no evidence for
DIC (high fibrinogen levels). Aspartate– and alanine aminotransferase (AST and ALT) were slightly elevated,
respectively 51 U/L (normal range, 0-37 U/L) and 43 U/L (normal range, 7-40 U/L), but did not correlate with
the PT prolongation during the hospitalisation.
We concluded to an acquired FVII deficiency without inhibitor associated with Hodgkin’s lymphoma. He was
treated accordingly with methylprednisolone and chemotherapy with ABVD (doxorubicin, bleomycin,
vinblastine and dacarbazine). After two weeks the PT normalised.
Discussion
We describe two patients diagnosed with an isolated acquired factor (F) VII deficiency, without inhibitor.
We report what is currently known about the pathogenesis, clinical features, diagnosis, treatment and
prognosis of acquired FVII deficiency. After a literature search we found 22 individual cases reported in the
literature (between 1980 and Juli 2014). Besides, Toor et al. identified eight patients with acquired FVII
deficiency within two weeks following hematopoietic stem cell transplantation and Biron et al. reported eleven
cases of acquired FVII deficiency associated with severe systemic sepsis [1,2].
Pathogenesis
In a minority of the cases of acquired FVII deficiency (nine patients) an inhibitory antibody to FVII has been
described [4-12]. In these cases the PT remained prolonged after mixing of the patient plasma with normal
pooled plasma. The inhibitor antibody was of the immunoglobulin G (IgG) type, with features of IgG1 with κ
and λ-light chains inhibiting the procoagulant activity of activated FVII (FVIIa) by interaction with the light chain.
They also suggested that the antibody recognizes the calcium-dependent conformation in or near the Gla
domain having the ability to inhibit the interaction between FVIIa and tissue factor (TF) or phospholipid
membranes [7,9,11,13].
In the cases where no neutralizing auto-antibody could be demonstrated in vitro different
pathophysiological hypothesis have been suggested. An IgG autoantibody without inhibitory activity may
enhance in vivo clearance of FVII by formation of immune complexes or FVII could be absorbed from blood by
binding to either the antibody-producing lymphoid cells or to tissue deposits or the antibody may bind to cells
secreting factor VII and thereby down regulating its synthesis by feedback mechanism [14-15]. In the context
of sepsis, FVII consumption is suspected due to tissue factor (TF) overexpression by monocytes and endothelial
cells or a enzymatic degradation of FVII by proteases (cathepsin G and human leucocyte elastase) released
from activated granulocytes in sepsis have been postulated [2]. An alternative explanation for the apparent loss
of FVII after stem cell transplantation was speculated: high-dose chemo-radiotherapy induces an increased
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vascular permeability enhancing access of intravascular FVII to a large pool of extravascular TF capturing FVII in
the extravascular compartment [1]. In malignancy, the possibility that FVII is eliminated from the circulation by
abnormal fixation to tumor cells was assumed [16-18].
In 33 out of 41 cases described in the literature, information about LA is lacking. In six out of eight cases
from whom information was reported, LA was present [1,4,10]. In one of our reported cases LA testing was also
positive. The precise role of the lupus inhibitor remains unclear.
Patient’s characteristics
Considering all cases (n=43), at disease onset the median age was 38 years (range: 2.8 – 80 years). Four out
of these 43 cases were described in the pediatric age group (9%)[1,21,22].
The disease affects males more often than females, with an overall male: female ratio of 2.3:1 (30 men and
13 women) [1,4-12,14-27].
Underlying diagnosis
The most frequently associated diseases of acquired FVII deficiency are severe systemic sepsis (16 cases),
malignant diseases (8 cases) (solid tumors, acute leukemia and lymphoproliferative malignancies) and stem
cell transplantation (8 cases) [1-2,5,7,11,15-22,25-26].
Clinical features
Bleeding occurred in 47% (20 out of 43) cases. Most cases (19 of 20 cases) experienced severe bleeding,
including vaginal bleeding, pulmonary and digestive tract hemorrhage, hematuria and intracerebral hematoma
[1,4,6-8,10,12,14,15,20,24,29].
Diagnosis
Acquired factor VII deficiency is most often diagnosed in patients with discordance between a prolonged PT
and a normal aPTT. Occasionally the aPTT can be prolonged in the presence of LA (six cases described)[1,4]. As
a diagnostic step, coagulation factor activity should be determined and an isolated decrease of FVII level should
be confirmed. The median FVII level reported in the case studies was 17% (range <1%-50%) [1,4-7,9-12,14-26].
To further investigate the FVII deficiency, mixing study should be performed. If the PT remains prolonged after
mixing of patient plasma with normal pooled plasma, a factor inhibitor is suspected. The Bethesda assay may
confirm the presence of a specific FVII inhibitor.
Treatment & outcome
The treatment and outcome reported in respectively 32 and 29 out of 43 cases is summarized in Table 1.
Currently, there are no standardized guidelines for the treatment of acquired FVII deficiency. The initial
therapeutic choice must be made based on the biological features and clinical severity of bleeding. Besides, the
underlying disorder which might be associated has to be treated. When antibodies are present and persist,
immunosuppression is recommended to eradicate the inhibitor.
The overall clinical outcome of FVII deficiency is poor, complete remission was seen in only 17 out of 29
patients (59%) [1,6,7,14,15,17,19-25,29]. Bleeding complications were the direct cause of death in four patients
(intracranial, gastrointestinal and pulmonary hemorrhage) (13%) [1,8,12].
Table 1. Treatment and outcome reported in 33 cases of acquired FVII deficiency.
In 3 cases only information about treatment is available, no information about outcome
First autor (year)/Ref
Vit K
Case 1/PR
Treatment
Outcome
CR after 7 months
Case 2/PR
Methylprednisolone
CR after 24 days
Anoun (2014)/[12]
FFP (10ml/kg for 2 days)
Death, cause of death: intracranial
hemorrhage on day 15
Bidet (2009)/[19]
Vit K
CR when infection disappeared
Granger (2009)/[22]
Vit K and FFP (15 ml/kg) before surgery
CR 5 days after surgery
Lim (2006)/[4]
Meaudre (2005)[23]
Zili (2005)[18]
1.
2.
1.
2.
Vit K, FFP (15ml/kg), tranexamic acid Death, cause of death: progressive
multiorgan failure
rFVIIa
Vit K and FFP -> unresponsive;
CR after 14 days
FVII (FVII-LFB®) during 10 days
FFP (1ml/kg) (before and after surgery)
ND
3
Huang (2004)/[24]
Mullighan (2004)/[15]
Aguilar (2003)/[5]
1.
2.
3.
Vit K, FFP
rFVIIa
CR after 48 days
rFVIIa restarted on day 10 due to
new focus of hemorrhage
1. Vit K, FFP (3 U every 8h), aminocaproic
acid (1g/h IV after loading dose of 5g) CR
2. rFVIIa before and after surgery
Death, cause of death: cardiorespiratory
Tranexamic acid and methylprednisolone
failure on day 15
Death, cause of death: fungemia on day
23
Death, cause of death: ARDS on day 15
CR
Toor (2002)/[1]
All eight patients: vit K
Two patients: FFP
One patient: plasma exchange with FFP
replacement
Death, cause of death: hepatorenal
syndrome on day 22
Death, cause of death: sepsis and GVHD =
cause of death on day 22
Death, cause of death: GI bleeding on day
18
CR
Death, cause of death: pulmonary
hemmorhage on day 17
Okajima (1999)/[6]
1. FFP ineffective
2. Methylprednisolone (1g for 3 days
followed by tapering doses)
CR
Ranchère (1999)/[17]
FVII-LFB®
CR
White (1999)/[20]
rFVIIa
CR after 8 weeks
Muleo (1998)/[25]
rFVIIa and antifibrinolytic therapy
CR after chemotherapy
Brunod (1998)/[7]
de Raucourt
(1994)/[16]
Mehta (1992)/[8]
1. Blood transfusion, FFP, FVII-LFB®
2. Methylprednisolone (1mg/kg/day) and CR after 8 days
heparin
1. Vit K
2. FVII concentrate before surgery, no
Death, patient died from disease
bleeding complications occured,
progression 6 weeks later
3. IVIg (0.4 g/kg/day for 5 days)
Death, cause of death: intracerebral
FFP (800 ml)
haemorrhage and large haematoma in
the wall of the larynx on day 2
Alsar (1990)/[26]
Vit K
Death
Delmer (1989)/[9]
1. FFP (2 Units)
2. IVIg (0.4 g/kg/day for 5 days)
3. Cyclophosphamide (1.5 g in bolus IV
1. Relapse 1 month later, but no plasma
for 1 day) and corticosteroids
inhibitory activity was evidenced at
(methylprednisolone 500 mg/day for 2
that time
days, following by prednisolone 100
mg/day)
2. CR
4. Plasma exchanges with FFP
replacement, FVII concentrate and
antitrombin III before surgery
5. Tapering prednisolone
4
Weisdorf (1989)/[14]
After relapse: prednisolone (0.5
mg/kg/d) and azathioprine (100 mg/d)
1. Vit K, platelet concentrates, FFP,
cyclophosphamide and total lymphoid
irradiation befor BMT
2. Corticosteroids (GvHD)
CR
Koeberlé (1988)/[21]
FFP (2 Units) during surgery
CR (1 month afther FVII=100%)
Ndimbie (1988)/[10]
No therapy
ND
Campbell (1980)/[11]
No therapy
ND
PR, present report; ND, not documented; CR, complete remission; vit K, vitamin K therapy; FFP, fresh frozen plasma; F, factor;
IVIg, intravenous immunoglobulin therapy; BMT, bone marrow transplantation; GvHD, graft versus host desease.
Conclusion
We described two patients with acquired FVII deficiency followed by a literature search on case reports
presenting patients with acquired FVII deficiency. Acquired FVII deficiency is a rare disease, with only 41
patients reported in the literature so far, but the incidence might be underestimated. We found 22 individual
case reports, eight patients with acquired FVII deficiency following hematopoietic stem cell transplantation and
eleven cases associated with severe systemic sepsis. The exact pathogenesis of the disease is still unknown, but
different pathophysiological hypotheses have been suggested. Bleeding occurs in about half of the cases.
Patients without prior clinical evidence of bleeding were diagnosed based on coagulation abnormalities during
routine blood screening. The diagnose for this acquired hemorrhagic disorder should be suspected when an
isolated PT prolongation is seen. Although our two patients recoverd well, the overall complete remission is
poor (59%) and bleeding complication reported in literature was accounted for the death in 13% of patients.
References
1. Toor AA, Slungaard A, Hedner U, Weisdorf DJ, Key NS. Acquired factor VII deficiency in hematopoietic stem cell transplant
recipients. Bone marrow transplantation 2002; 29: 403-8.
2. Biron C, Bengler C, Gris JC, Schved JF. Acquired isolated factor VII deficiency during sepsis. Haemostasis 1997; 27: 51-6.
3. Schouwers SM, Delanghe JR, Devreese KM. Lupus Anticoagulant (LAC) testing in patients with inflammatory status: does Creactive protein interfere with LAC test results? Thrombosis research 2010; 125: 102-4.
4. Lim S, Zuha R, Burt T, Chacko J, Scott R, Mainwaring CJ. Life-threatening bleeding in a patient with a lupus inhibitor and
probable acquired factor VII deficiency. Blood coagulation & fibrinolysis : an international journal in haemostasis and
thrombosis 2006; 17: 667-71.
5. Aguilar C, Lucia JF, Hernandez P. A case of an inhibitor autoantibody to coagulation factor VII. Haemophilia 2003; 9: 119-20.
6. Okajima K, Ishii M. Life-threatening bleeding in a case of autoantibody-induced factor VII deficiency. International journal of
hematology 1999; 69: 129-32.
7. Brunod M, Chatot-Henry C, Mehdaoui H, Richer C, Fonteau C. Acquired anti-factor VII (proconvertin) inhibitor: hemorrhage
and thrombosis. Thrombosis and haemostasis 1998; 79: 1065-6.
8. Mehta J, Singhal S, Mehta BC. Factor VII inhibitor. The Journal of the Association of Physicians of India 1992; 40: 44.
9. Delmer A, Horellou MH, Andreu G, Lecompte T, Rossi F, Kazatchkine MD, et al. Life-threatening intracranial bleeding
associated with the presence of an antifactor VII autoantibody. Blood 1989; 74: 229-32.
10. Ndimbie OK, Raman BK, Saeed SM. Lupus anticoagulant associated with specific inhibition of factor VII in a patient with
AIDS. Am J Clin Pathol 1989; 91: 491-3.
11. Campbell E, Sanal S, Mattson J, Walker L, Estry S, Mueller L, et al. Factor VII inhibitor. The American journal of medicine
1980; 68: 962-4.
12. Anoun S, Lamchahab M, Oukkache B, Qachouh M, Benchekroun S, Quessar A. Acquired factor VII deficiency associated with
acute myeloid leukemia. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 2014.
13. Kamikubo Y-i, Miyamoto S, Iwasa A, Ishii M, Okajima K. Purification and Characterization of Factor VII Inhibitor Found in a
Patient with Life Threatening Bleeding. Thrombosis and haemostasis 2000; 83: 60-4.
14. Weisdorf D, Hasegawa D, Fair DS. Acquired factor VII deficiency associated with aplastic anaemia: correction with bone
marrow transplantation. Br J Haematol 1989; 71: 409-13.
5
15. Mullighan CG, Rischbieth A, Duncan EM, Lloyd JV. Acquired isolated factor VII deficiency associated with severe bleeding
and successful treatment with recombinant FVIIa (NovoSeven). Blood coagulation & fibrinolysis : an international journal in
haemostasis and thrombosis 2004; 15: 347-51.
16. de Raucourt E, Dumont MD, Tourani JM, Hubsch JP, Riquet M, Fischer AM. Acquired factor VII deficiency associated with
pleural liposarcoma. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 1994; 5: 8336.
17. Ranchere JY, Menart C, Lienhart A, Attali O. [Factor VII deficiency and surgery]. Annales francaises d'anesthesie et de
reanimation 1999; 18: 772-5.
18. Zili M, Hammami S, Marghli A, Mechmech L, Boughnim L, Abid S, et al. [Acquired isolated factor VII deficiency and
bronchogenic carcinoma. A case report]. La Tunisie medicale 2005; 83: 363-5.
19. Bidet A, Boiteux-Vergnes C, Mouton C. [Acquired and repeated factor VII deficiency during two infectious episodes: a case
report]. Annales de biologie clinique 2009; 67: 587-9.
20. White B, Martin M, Kelleher S, Browne P, McCann SR, Smith OP. Successful use of recombinant FVIIa (Novoseven) in the
management of pulmonary haemorrhage secondary to Aspergillus infection in a patient with leukaemia and acquired FVII
deficiency. Br J Haematol 1999; 106: 254-5.
21. Koeberle P, Lemounaud P, Berry J. [An acquired isolated transitory factor VII deficiency]. Cahiers d'anesthesiologie 1988; 36:
471-2.
22. Granger J, Gidvani VK. Acquired factor VII deficiency associated with Wilms tumor. Pediatric Blood & Cancer 2009; 52: 3945.
23. Meaudre E, Kenane N, Kaiser E, Gaillard PE, Saillol A, Cantais E, et al. [Isolated acquired factor VII deficiency in patient with
severe head trauma: use of factor VII (factor VII-LFB]. Annales francaises d'anesthesie et de reanimation 2005; 24: 1383-6.
24. Huang WY, Kruskall MS, Bauer KA, Uhl L, Shaz BH. The use of recombinant activated factor VII in three patients with central
nervous system hemorrhages associated with factor VII deficiency. Transfusion 2004; 44: 1562-6.
25. Muleo G, Santoro R, Iannaccaro PG, Papaleo P, Leo F. The use of recombinant activated factor VII in congenital and acquired
factor VII deficiencies. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 1998; 9:
389-90.
26. Alsar MJ, Sedano C, Sanz Ortiz J, Zubizarreta A. [Acquired factor VII deficiency]. Medicina clinica 1990; 95: 557.
27. Sciascia S, Sanna G, Murru V, Roccatello D, Khamashta MA, Bertolaccini ML. Anti-prothrombin (aPT) and antiphosphatidylserine/prothrombin (aPS/PT) antibodies and the risk of thrombosis in the antiphospholipid syndrome. A
systematic review. Thrombosis and haemostasis 2014; 111: 354-64.
28. Giansily-Blaizot M, Verdier R, Biron-Adreani C, Schved JF, Bertrand MA, Borg JY, et al. Analysis of biological phenotypes from
42 patients with inherited factor VII deficiency: can biological tests predict the bleeding risk? Haematologica 2004; 89: 7049.
29. Delmer A, Andreu G, Horellou MH, Lecompte T, Samama M, Zittoun R. [Acquired factor VII inhibitor: treatment using highdose immunoglobulins, corticotherapy and plasma exchange]. Annales de medecine interne 1988; 139 Suppl 1: 48-50.
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