Abstract
Introduction
Isolated acquired Factor VII deficiency is a rare coagulation disorder which is independent of vitamin K deficiency. The exact pathophysiological basis of this condition is unclear. We present a series of cases highlighting different clinical scenarios where this condition was encountered.
Case series
The first case presented with intra-abdominal sepsis. The second was a patient admitted with acute kidney injury and subsequently diagnosed with myeloma. The final case presented with microangiopathic haemolytic anaemia and was suspected of having atypical Haemolytic Uraemic Syndrome. In each case, there was no family or personal history of a bleeding disorder. Follow-up Factor VII levels after recovery from illness was normal in all three cases.
Conclusion
Acquired Factor VII deficiency is an uncommon but important finding which should be considered in the general medical setting when an isolated prolonged prothrombin time is detected.
Keywords
Introduction
Factor VII (FVII) deficiency is a rare bleeding disorder characterised by either a quantitative or qualitative defect in coagulation FVII. FVII deficiency results in a bleeding diathesis with a heterogeneous phenotype. Patients can present with mucocutaneous, gastrointestinal, genitourinary, soft tissue or joint bleeding. Congenital FVII deficiency is an autosomal recessive disorder with an estimated prevalence of 1 in 500,000. 1 Acquired FVII deficiency can be seen in various clinical contexts including coumarin therapy, sepsis, malabsorptive disorders, and malignancy. It typically occurs in these situations as a result of vitamin K deficiency, where there are accompanying reductions in other vitamin K dependent coagulation factors (II/IX/X). More rarely, acquired FVII deficiency can occur in isolation and independent of vitamin K deficiency.
We present a case series of three patients, admitted over a period of 18 months, found to have isolated acquired FVII deficiency whilst inpatients. The first case demonstrates FVII deficiency while being treated for intra-abdominal sepsis post Endoscopic retrograde cholangiopancreatography (ERCP). The second demonstrates a case of FVII deficiency in a newly diagnosed myeloma patient admitted to medical HDU with acute kidney injury. The third details a patient who presented with acute kidney injury due to atypical Haemolytic Uraemic Syndrome (aHUS) and was found to have FVII deficiency. Each of these patients was acutely unwell and had normal levels of other vitamin K dependent factors. FVII levels completely normalised once the patients had recovered from their acute illness.
Case presentation
Case 1
A 52-year-old woman was admitted to the general surgery unit and treated for a bowel perforation following ERCP. She developed an intra-abdominal collection which required the insertion of a retroperitoneal drain. A coagulation screen showed a prolonged prothrombin time (PT) of 19.9 s (normal range 10.0–12.6 s) and prolonged activated partial thromboplastin time (APTT) of 38.5 s (normal range 22.5–31.0 s). Her FVII level using a functional assay was reduced at 30% (normal range 50–200%). Her FIX level was 128% (normal range 50–200%) and FX was 62% (normal range 50–200%). FII was not checked as this would involve forwarding the sample to a reference laboratory, and the likelihood of vitamin K deficiency was low, given normal levels of FIX and FX. She had a reactive thrombocytosis of 585 × 109/l (normal range 140–400 × 109/l) and her fibrinogen level was raised at 9.5 g/l (normal range 2.5–5.5 g/l) making a consumptive coagulopathy such as disseminated intravascular coagulation (DIC) unlikely. Her liver function tests showed only a mild-moderate rise in the alkaline phosphatase (160 U/l, normal range 30–130 U/l) and gamma GT (82 U/l, normal range 6–35 U/l) but these abnormalities were present from two months earlier. Liver dysfunction was therefore excluded as a cause for the low FVII, as the other measured coagulation factors would typically also be reduced.
She had a normal coagulation screen one month earlier, and in the past had undergone several surgical procedures including cholecystectomy, appendicectomy, salpingectomy and two caesarean sections. None of these surgical procedures had haemorrhagic complications. This history supported an acquired factor deficiency. Insertion of the retroperitoneal drain was covered with recombinant FVII (Novoseven) and there were no issues with bleeding.
Repeat FVII levels at three and six months were normal (83% and 101%, respectively). She had a lupus anticoagulant (LA) detectable which is the most likely reason for her prolonged APTT at the time of her initial admission. Anticardiolipin IgG was checked and this was negative. The LA was not repeated as the APTT was normal when checked after the patient had recovered from this illness and it was assumed to be a transient phenomenon in the context of acute illness.
Case 2
A previously well 73-year-old man was admitted as an emergency with acute kidney injury. Two days after admission he developed pulmonary haemorrhage which necessitated admission to medical High Dependency Unit for high-flow nasal oxygen. Serum immunoglobulins were checked and he was found to have panhypogammaglobulinemia. His IgG level was 3.4 g/l (normal range 6.0–16.0 g/l), IgA 0.2 g/l (0.8–4.0 g/l) and IgM < 0.2 g/l (0.5–3.0 g/l). Electrophoresis detected a lambda light chain, and serum free light chain assay identified a very high lambda quantitation of 8405 mg/l (normal range 5.71–26.30 mg/l) with a low-normal kappa light chain. Bone marrow aspirate showed an infiltrate of plasma cells, thereby confirming a diagnosis of light chain myeloma. The patient was commenced on protease inhibitor-(Bortezomib) based anti-myeloma treatment.
A coagulation screen was checked which showed a prolonged PT of 15.0 s and normal APTT (19.5 s). His FVII activity was reduced at 34% (normal range 50–129%), but his other vitamin K dependent factors were normal. FIX level was 122.7% (normal range 65–150%) and FX level was 102% (normal range 77–131%). He had a normal platelet count of 152 × 109/l and a normal fibrinogen (3.0 g/l) making DIC unlikely. His liver function tests were normal.
In view of the pulmonary haemorrhage, the patient received Novoseven. Once the patient had recovered from this acute illness, he had a repeat FVII checked approximately one month later and this showed recovery of FVII to a normal level of 70%.
Case 3
A 64-year-old man had eight months previously been found to have an IgG paraprotein of 2.8 g/l (normal range 6.0–16.0 g/l) but no evidence of related end organ dysfunction, in keeping with a monoclonal gammopathy of unknown significance. He subsequently noted progressive oedema over a period of six months. Urea and electrolytes checked in primary care showed acute kidney injury and urgent admission was arranged. The patient was oliguric with gross peripheral and pulmonary oedema, and was commenced on haemodialysis. He also had evidence of microangiopathic haemolytic anaemia (MAHA) raising the possibility of aHUS. The patient had a mild thrombocytopenia (78 × 109/l) consistent with a MAHA syndrome. A renal biopsy was scheduled but it was noted on his coagulation screen that he had an isolated prolonged PT of 14.3 s which persisted despite intravenous vitamin K replacement. Repeat PT measurements were 14.2 s and 15.8 s. The liver function tests showed only a minor rise in his gamma GT of 49 U/l. His FVII level was measured as mildly reduced at 46%. The other vitamin K dependent factors were not checked as he had a normal APTT. His fibrinogen was normal at 2.8 g/l making DIC unlikely. His renal biopsy was covered with Novoseven and the biopsy showed features consistent with aHUS. The patient received Eculizumab but did not recover renal function.
He was reviewed in the haematology department several months later. At this stage, his coagulation screen showed the PT to be consistently normal when checked three times over a four-month period. A repeat FVII level was also normal at 75%.
Discussion
FVII is a protein involved in the initiation of the extrinsic coagulation pathway. FVII binds tissue factor (TF) at the site of blood vessel injury and subsequently activates Factor X, ultimately leading to thrombin generation. 2 Acquired FVII deficiency is typically seen in the context of vitamin K deficiency or malabsorption. Treatment with coumarin anticoagulant is another common cause. FVII also becomes disproportionately low in chronic liver disease owing to its short half-life. Other reported causes of this rare entity include severe sepsis, aplastic anaemia, pleural liposarcoma, stem cell transplant, liver cirrhosis and the presence of antiphospholipid antibodies.3,4 Acquired FVII deficiency has also been reported in association with diseases such as myeloma and underlying malignancy, secondary to use of penicillins, cephalosporins, anti-thymocyte globulin and interleukin-2.5,6 However, in the majority of these situations, there is an accompanying reduction in the other vitamin K dependent coagulation factors.
Acquired defects of a single clotting factor are rare. 7 Of those encountered in clinical practice, acquired Haemophilia A (Factor VIII) and acquired von Willebrand Syndrome (von Willebrand factor) are the most common, although the incidence of these conditions is still very low at approximately 1.5/million/year. 8 Isolated acquired FVII deficiency is extremely rare and the exact mechanism underlying the condition is ill defined. There are at least five possible mechanisms which could give rise to acquired isolated coagulation factor deficiency. These include decreased synthesis; accelerated consumption or catabolism; neutralisation via antibodies; abnormal adsorption by tumour mass and synthesis of abnormal, hypoactive or labile forms. 6
Decreased synthesis of a single clotting factor is something which has never been suspected or reported in acquired bleeding disorders. Consumption or catabolism of coagulation factor has been proposed, especially in cases where a large amount of TF becomes available, for instance as a result of capillary leakage in sepsis. Proteases secreted by leucocytes may also lead to catabolism and degradation of clotting factors, potentially another mechanism for transiently low levels of FVII. 9 Antibodies against FVII have also been demonstrated in several cases.10,11 FX deficiency is well recognised in amyloidosis and may potentially be secondary to adsorption of FX by amyloid deposits. However, no such mechanism has ever been proven for other clotting factor deficiencies. It is important to remember that a combination of the above mechanisms may result in an acquired FVII deficiency.
Clinical manifestations of this rare entity are varied – recorded reports range from no symptoms to life-threatening haemorrhage. 5 In our case series, recombinant FVII was used to treat bleeding as well as secure haemostasis prior to invasive procedures. In contrast to congenital bleeding disorders, the severity of bleeding can be unpredictable in acquired factor deficiencies and does not always correlate with the measured levels. 7 Hence, Novoseven was given to the patients undertaking procedures despite only a mild reduction in the FVII level.
In summary, we present a case series of acquired FVII deficiency which demonstrates that this can occur in isolation and independent of vitamin K deficiency. It may be encountered in various clinical circumstances and the presence of a persistently prolonged PT should alert the clinician to testing for this, even if the individual has no personal or family history of bleeding. Furthermore, follow-up testing should be offered, as genetic analysis for previously undiagnosed congenital FVII deficiency needs to be considered for patients with persistently reduced FVII levels outwith the context of acute illness.
Conclusion with learning points
Isolated acquired FVII deficiency is rare but should be considered in patients with no prior personal or family history of a bleeding diathesis and a persistently prolonged PT without any alternative explanation. Repeat testing once the acute phase of illness is over should be considered to document the recovery of FVII. Genetic testing for congenital FVII deficiency should be offered if FVII fails to recover to normal level after the patient has recovered from the initial illness.
Footnotes
Authors’ contributions
All authors have significantly contributed to the drafting and review of the manuscript. Two of the cases are now deceased but verbal informed consent was obtained from the living case.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.