Acquired Isolated Factor VII Deficiency in Plasma Cell

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1		Anna Furlan	--	2276	2023-10-11 22:33:51	\|
2	Reference format revised.	Lindsay Dong	Meta information modification	2276	2023-10-16 02:56:43	\|

This entry is adapted from the peer-reviewed paper 10.3390/jcm12185837

Acquired isolated factor VII (FVII) deficiency is a rare but important discovery in patients with plasma cell disorders with significant therapeutic and prognostic implications. The discovery of acquired FVII deficiency in a patient with multiple myeloma (MM) or monoclonal gammopathy of uncertain significance (MGUS) should prompt an evaluation for AL amyloidosis, particularly for amyloid hepatosplenic involvement, whenever not previously documented. Acquired FVII deficiency in patients with MM and AL amyloidosis is frequently associated with severe bleeding diathesis, also related to a number of concomitant predisposing factors, adversely affecting the outcome. The prompt institution of a rapidly acting therapy is crucial to prevent severe bleeding complications and positively impact outcome. Recombinant activated factor VII (rVIIa) may represent a useful supportive care measure, both in treating active bleeding and in the peri-procedural setting. However, further clinical experience is needed to optimize the therapeutic management of this rare disorder.

factor VII deficiency plasma cell disorders multiple myeloma recombinant activated factor VII

1. Introduction

Acquired bleeding conditions are often the result of the deficiency of several clotting factors. Acquired isolated defects of clotting factors are rare conditions. The most common and widely known is factor X (FX) deficiency, associated with AL amyloidosis. Systemic light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by the extracellular deposition of fibrils composed of monoclonal immunoglobulin light chains. It presents alone or in association with other plasma cell and related disorders such as MM or Waldenström macroglobulinemia. AL amyloidosis is associated with multi-system clinical and laboratory manifestations resulting from amyloid deposition in various organs and tissues, such as the heart, kidneys, liver, spleen, gastrointestinal tract, skin, and nerves.

Amyloidosis-associated FX deficiency has been hypothesized to be secondary to the rapid clearance of factor X from the circulating blood through the absorption and immobilization of the protein to amyloid fibrils in the vasculature, mainly in the liver and spleen ^[1]. Studies ^[2]^[3]^[4]^[5] have reported that 8.7 to 14% of patients with AL amyloidosis had factor X levels of less than 50% of the normal levels, and 56% of those with reduced levels had clinically significant bleeding episodes ^[2]. However, FX deficiency does not account entirely for coagulopathy and bleeding diathesis in AL amyloidosis. A larger proportion of amyloidosis patients, approximately one third, exhibit bleeding symptoms, and about half, overall, show abnormal clotting findings ^[3]. Coagulation abnormalities have been reported to be associated with advanced disease ^[4]^[5], liver involvement, and inferior outcomes ^[5]. FX deficiency, in particular, has been proven to correlate with higher disease stage, the involvement of more than one organ, liver, and cardiac involvement, and greater than 10% bone marrow plasma cells ^[5].

Acquired isolated FVII deficiency is rare, in contrast to congenital FVII deficiency, which is the most frequent disorder among the rare congenital coagulation defects ^[6]. FVII is a coagulation factor dependent on vitamin K and is synthesized in the liver. It is usually found in human plasma at concentrations of 0.5 mcg/mL, with a relatively short half-life of approximately 3–4 h in the circulation, although this may be shorter during a bleeding episode ^[7]. FVII is often found in the shape of an inactive single-chain zymogen, and it is present in the circulation at the rate of 1% in an activated form (FVIIa). Vascular injury results in the binding of FVII to tissue factor (TF). FVII bound to TF is activated to generate the active serine protease FVIIa and it is the TF–VIIa complex that, through limited proteolytic cleavage, activates factors X and IX and the subsequent coagulation cascade ^[6]^[8].

2. Characteristics of Patients with Acquired Isolated FVII Deficiency Associated with Plasma Cell Disorders

Seven cases of acquired isolated FVII deficiency associated with plasma cell disorders (MM/PCL and/or AL amyloidosis) are reported in the literature ^[9]^[10]^[11]^[12]^[13], including the two personal cases here described, and one patient with combined FVII and FX deficiency ^[14].

Five out of nine cases are associated with AL amyloidosis (+/− MM). Interestingly, all amyloidosis patients presented with liver and/or spleen involvement. Overall, in six out of nine cases, including the three personal cases reported here, hepatosplenomegaly has been documented, in two cases evolving to splenic rupture. Accordingly, the analysis by Abdallah et al. revealed that, compared with AL amyloidosis patients with normal PT, patients with a prolonged PT were more likely to have liver involvement (33% vs. 15%) ^[5]. In four cases of MM/PCL and FVII deficiency, the association with AL amyloidosis has not been excluded or reported and is strongly suspected in the two cases of PCL here described in view of the presence of hepatosplenomegaly, ALP, and NT-proBNP elevation. The majority of patients with amyloidosis had multi-organ involvement.

3. Type and Severity of Clinical Manifestations and Outcome for Patients with Acquired Isolated FVII Deficiency Associated with Plasma Cell Disorders

Reported factor VII levels varied from 18% to 46% of normal; PT, measured in seconds, varied from 14 to 46. With the exception of two patients with a mild deficiency (FVII levels of 44% and 46% of normal levels, respectively) who showed no or mild bleeding tendency, the majority of cases (five patients) have been reported to be associated with severe bleeding, including delayed post-procedural bleeding (neck and retroperitoneal hematoma, and oral mucosal bleeding after a dental procedure) and spontaneous bleeding (nasal bleeding, pulmonary hemorrhage, and intracranial hemorrhage). Overall, there were three fatalities. Bleeding was the direct cause of death in two cases (intracranial hemorrhage in the context of interstitial pneumonia, upper GI bleeding; one patient died from infective complications after achieving hematological remission and correction of the clotting defect. Conversely, Girolami et al. reported that 8 of 29 patients with acquired FVII deficiency from any etiology had no bleeding tendency and that in the remaining patients, the entity of bleeding was variable and distributed between mild or moderate (8 cases) and severe (13 cases) and often out of proportion with the entity of the defect ^[15].

It is important to emphasize that in patients with plasma cell disorders, bleeding tendency may be enhanced compared to acquired isolated factor VII deficiency from other underlying conditions and due to inherited defects due to a number of concomitant factors: thrombocytopenia and platelet dysfunction (secondary to bone marrow insufficiency and/or chemotherapy), hyperfibrinolysis, hyperviscosity, vascular fragility, impaired vasoconstriction, renal failure, and thromboprophylaxis ^[16].

Both in patients with an acquired defect from any etiology, including transplant patients, and particularly in plasma cell disorders, a decrease in FVII activity seemed to be associated with a poor prognosis ^[15]^[17]. In AL amyloidosis, FVII deficiency, without reference to whether it was isolated or combined, has been reported to be an independent predictor of death, similar to FX deficiency and prolonged PT ^[5]. The unfavorable outcome may be related not only to the risk of bleeding, but also to advanced disease and multi-organ involvement ^[4]^[5].

Although limited in size, the series reported here suggests that in patients affected by plasma cell dyscrasias, bleeding tendency might correlate with the activity of the factor tested as a percentage of normal activity levels. The correction of PT and factor VII deficiency after chemotherapy, surgery, or supportive measures corresponded, in fact, to a clinical response in terms of bleeding control.

4. Potential Mechanisms Underlying Acquired Isolated FVII Deficiency Associated with Plasma Cell Disorders

FVII is disproportionately lower in chronic liver disease than other vitamin-K-dependent factors, probably due to its short half-life. However, none of the cases reported here showed signs of liver dysfunction at detection of factor VII deficiency and/or at onset of bleeding diathesis. Liver function tests were normal or near-normal in all patients, at least at the time of diagnosis of the clotting disorder, apart from an increase in ALP in patients with documented or suspected hepatic amyloidosis. PTT and the other vitamin-K-dependent (II, IX, and X) and -independent (V, VIII, XI, and XII) coagulation factors were also preserved when evaluated on repeated follow up.

Notably, splenectomy after splenic rupture was reported to be beneficial in terms of the correction of factor deficiency and PT in two cases of amyloidosis ^[9]. Similarly, the resolution of FX deficiency has been described after splenectomy in patients with amyloidosis ^[18]^[19]. These observations suggest a similar etiology for these acquired clotting disorders, likely involving the binding of coagulation factors to splenic and hepatic amyloid deposits. However, a similar mechanism has not been proven to date for clotting factors other than FX.

Among other proposed mechanisms underlying an acquired FVII deficiency is an accelerated consumption where a massive, sudden availability of TF occurs, as in the case of increased leakage into surrounding tissue in patients who have undergone extensive chemotherapy, which is known to alter capillary permeability ^[17]. This may represent the mechanism underlying acquired FVII deficiency in patients undergoing SCT, as supported by the elevated incidence of veno-occlusive disease (VOD) of the liver in this clinical setting. The initial trigger for the development of VOD is thought to be the activation of liver sinusoidal endothelial cells and endothelial damage caused by toxic metabolites generated during conditioning regimens, with subsequent activation of the coagulation pathway ^[20].

FVII deficiency in plasma cell dyscrasias does not appear to be related to the presence and amount of serum and urine monoclonal protein. This condition has been described in one case of light chain MM with no intact monoclonal immunoglobulin production ^[13] and in one patient with amyloidosis detected in tissue biopsy samples with no monoclonal band on serum and urine electrophoresis ^[12].

PT mixing study with normal plasma, performed on one patients, corrected abnormal PT, indicating a simple clotting factor deficiency in the absence of an inhibitor. Notably, in the review by Girolami et al., the mixing study did not correct abnormal PT in 6 out of 25 cases that had been evaluated. An inhibitor was characterized in three of them. Underlying disorders associated with the presence of a FVII inhibitor included an autoimmune condition (aplastic anemia) in one case, and cancer, including one case of AML ^[15].

5. Therapeutic Considerations

As only few case reports exist in the literature, there is no consensus as to how patients with isolated acquired factor VII deficiency, and, more specifically, patients with underlying plasma cell disorders should be managed in terms of prophylactic and therapeutic measures. Previously published cases, similarly to the personal cases described here, report inadequate response to FFP administration even at high doses. FFP may not be an effective therapy to correct factor VII deficiency due to the low concentration of FVII in plasma and its short half-life. In patients with amyloidosis, accelerated clearance by absorption of the factor by the tissue amyloid may also play a role ^[1].

In support of this assumption, the administration of factor concentrates in a patient with MM and AL amyloidosis with an acquired combined deficiency of FVII and FX resulted in a transient increase in the factor levels followed by a fall to baseline values within 30 min ^[14]. In a different clinical setting of accelerated FVII consumption as is the case of chemotherapy/SCT, the defect was uniformly refractory to parenteral vitamin K supplementation, massive FFP infusion and, in one case, to plasma exchange with FFP replacement. With regard to the inherited FVII deficiency, on the other hand, plasma has been successfully used to manage patients undergoing surgery, either by itself or in combination with FVII concentrate ^[21]^[22]. The daily transfusion of high doses of FFP may be complicated by fluid overload, especially in patients with cardiac amyloid involvement.

The use of recombinant activated factor VII (rFVIIa) has been reported to be of value in patients with plasma cell disorders and acquired FVII deficiency who are actively bleeding ^[11]^[13]. rFVIIa is indicated for use in the congenital deficiency of factor VII and acquired hemophilia, and patients with acquired inhibitors to hemophilia A and B replacement products ^[23].

The use of prothrombin complex concentrate (PCC) has not been reported to date in patients with acquired isolated FVII deficiency from any cause ^[15], including patients with underlying plasma cell disorders. On the other hand, there are reports of the successful use of PCC for treatment and prophylaxis of bleeding, including the perioperative setting, in acquired FX deficiency associated with AL amyloidosis ^[24]^[25]. Among other therapeutic indications, PCC can be used for the treatment and prophylaxis of bleeding in congenital deficiency of any vitamin-K-dependent coagulation factors when purified specific products are unavailable.

The treatment or removal of the underlying cause, if this can be identified, is clearly important in all cases of acquired FVII deficiency ^[15]. More specifically, in the case of plasma cell dyscrasias, resolution of the bleeding disorder invariably requires treatment of the plasma cell clone by means of rapidly acting regimens, i.e., cyclophosphamide, bortezomib, and dexamethasone +/− daratumumab. The administration of immunomodulatory drugs (lenalidomide and thalidomide) in patients with MM may be challenging due to the contraindication to thromboprophylaxis in patients with a concomitant bleeding disorder.

6. Conclusions

The treatment of the underlying plasma cell disorder is the mainstay of coagulopathy management and a rapidly effective therapy targeting the plasma cell clone should be instituted promptly in order to prevent severe bleeding complications. The introduction of anti-CD138 monoclonal antibodies in the treatment of MM and, more recently, amyloidosis ^[26]^[27], both in the first line and in the relapsed/refractory setting, represents a viable tool for achieving rapid plasma cell clearance and preventing further amyloid deposition in tissues which may be responsible for FVII sequestration. Monoclonal antibodies that bind to amyloid light chain fibrils promoting the clearance from affected tissues represent a potential option in a future perspective, but data need to be collected in this specific clinical setting ^[28]. Splenectomy has been reported to correct the clotting defect in patients with hepatosplenic amyloidosis. FFP replacement has been demonstrated to be ineffective in correcting acquired FVII deficiency and in preventing or treating bleeding complications. Published data, although on a limited number of cases, suggest that rVIIa may represent a useful supportive care measure, both in treating active bleeding and in providing effective hemostasis in the pre- and perioperative settings, including splenectomy.

References

Furie, B.; Voo, L.; McAdam, K.P.W.J.; Furie, B.C. Mechanism of Factor X Deficiency in Systemic Amyloidosis. N. Engl. J. Med. 1981, 304, 827–830.
Choufani, E.B.; Sanchorawala, V.; Ernst, T.; Quillen, K.; Skinner, M.; Wright, D.G.; Seldin, D.C. Acquired factor X deficiency in patients with amyloid light-chain amyloidosis: Incidence, bleeding manifestations, and response to high-dose chemotherapy. Blood 2001, 97, 1885–1887.
Mumford, A.D.; O’Donnell, J.; Gillmore, J.D.; Manning, R.A.; Hawkins, P.N.; Laffan, M. Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis. Br. J. Haematol. 2000, 110, 454–460.
Patel, G.; Hari, P.; Szabo, A.; Rein, L.; Kreuziger, L.B.; Chhabra, S.; Dhakal, B.; D’Souza, A. Acquired factor X deficiency in light-chain (AL) amyloidosis is rare and associated with advanced disease. Hematol. Stem Cell Ther. 2019, 12, 10–14.
Abdallah, N.; Muchtar, E.; Dispenzieri, A.; Gonsalves, W.; Buadi, F.; Lacy, M.Q.; Hayman, S.R.; Kourelis, T.; Kapoor, P.; Go, R.S.; et al. Coagulation Abnormalities in Light Chain Amyloidosis. Mayo Clin. Proc. 2021, 96, 377–387.
Perry, D.J. Factor VII Deficiency. Br. J. Haematol. 2002, 118, 689–700.
Lindley, C.M.; Sawyer, W.T.; Macik, B.G.; Lusher, J.; Harrison, J.F.; Baird-Cox, K.; Birch, K.; Glazer, S.; Roberts, H.R. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin. Pharmacol. Ther. 1994, 55, 638–648.
Peter, W.; Yale, N.; Hansen, L.L.; Finn, E.N.; Steven, G.; Ulla, H. Measurement of basal levels of factor VIIa in he-mophilia A and B patients. Blood 1992, 80, 25–28.
Uematsu, M.; Tsukaguchi, M.; Kinman, K.; Kitani, T.; Okuyama, M.; Kawasaki, T.; Satomi, T.; Hoshida, Y.; Hanai, J. Case of factor VII deficiency with systemic amyloidosis having a unique clinical course such as splenic rupture. Nihon Naika Gakkai Zasshi 1997, 86, 314–316.
Hu, H.; Wang, L.; Xu, H.; Peng, J.; Jia, Y. Clinical analysis of six cases of multiple myeloma first presenting with coagulopathy. Blood Coagul. Fibrinolysis 2014, 25, 553–556.
Nguyen, A.L.; Kamal, M.; Raghavan, R.; Nagaraj, G. Acquired factor VII deficiency causing severe bleeding disorder secondary to AL amyloidosis of the liver. Hematol. Rep. 2018, 10, 7235.
Dursun, F.E.; Akyar, E.; Uygun, G.; Baslar, Z.; Cobanoglu, B. Factor VII Deficiency in Systemic Primary Amyloidosis: A Rare Case. Case Rep. Intern. Med. 2018, 5, 29–32.
Zaidi, M.H.; Stanley, A.; Khan, M. Acquired Factor VII deficiency–A rare but important consideration. Scott. Med. J. 2019, 64, 119–122.
Elezović, I.; Djukanović, R.; Rolović, Z. Successful treatment of hemorrhagic syndrome due to an acquired, combined deficiency of factors VII and X in a patient with multiple myeloma and amyloidosis. Eur. J. Haematol. 1989, 42, 105–106.
Girolami, A.; Santarossa, C.; Cosi, E.; Ferrari, S.; Lombardi, A.M. Acquired Isolated FVII Deficiency: An Underestimated and Potentially Important Laboratory Finding. Clin. Appl. Thromb./Hemost. 2016, 22, 705–711.
Sucker, C.; Hetzel, G.; Grabensee, B.; Stockschlaeder, M.; Scharf, R. Amyloidosis and Bleeding: Pathophysiology, Diagnosis, and Therapy. Am. J. Kidney Dis. 2006, 47, 947–955.
Toor, A.; Slungaard, A.; Hedner, U.; Weisdorf, D.; Key, N. Acquired factor VII deficiency in hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2002, 29, 403–408.
Greipp, P.R.; Kyle, R.A.; Bowie, E.J.W. Factor X Deficiency in Primary Amyloidosis: Resolution after Splenectomy. N. Engl. J. Med. 1979, 301, 1050–1051.
Rosenstein, E.D.; Itzkowitz, S.H.; Penziner, A.S.; Cohen, J.I.; Mornaghi, R.A. Resolution of factor X deficiency in primary amyloidosis following splenectomy. Arch. Intern. Med. 1983, 143, 597–599.
Dalle, J.-H.; Giralt, S.A. Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment. Biol. Blood Marrow Transplant. 2016, 22, 400–409.
Greene, W.B.; McMillan, C.W. Surgery for Scoliosis in Congenital Factor VII Deficiency. Am. J. Dis. Child. 1982, 136, 411–413.
Doran, S.E.; Henry, T.R.; Bockenstedt, P.L.; Ross, D.A. Uncomplicated stereotactic and open neurosurgical procedures in patients with factor VII deficiency. Surg. Neurol. 1994, 42, 79–82.
European Medicines Agency. NovoSeven. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/novoseven (accessed on 4 August 2023).
Veneri, D.; Giuffrida, A.C.; Bonalumi, A.; Calabria, S.; Gandini, G.; Ambrosetti, A.; Minuz, P. Use of prothrombin complex concentrate for prophylaxis of bleeding in acquired factor X deficiency associated with light-chain amyloidosis. Blood Transfus. 2016, 14, 585–586.
Takabe, K.; Holman, P.R.; Herbst, K.D.; Glass, C.A.; Bouvet, M. Successful perioperative management of factor X deficiency associated with primary amyloidosis. J. Gastrointest. Surg. 2004, 8, 358–362.
Kastritis, E.; Palladini, G.; Minnema, M.C.; Wechalekar, A.D.; Jaccard, A.; Lee, H.C.; Sanchorawala, V.; Gibbs, S.; Mollee, P.; Venner, C.P.; et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N. Engl. J. Med. 2021, 385, 46–58.
Palladini, G.; Milani, P.; Malavasi, F.; Merlini, G. Daratumumab in the Treatment of Light-Chain (AL) Amyloidosis. Cells 2021, 10, 545.
Edwards, C.V.; Rao, N.; Bhutani, D.; Mapara, M.; Radhakrishnan, J.; Shames, S.; Maurer, M.S.; Leng, S.; Solomon, A.; Lentzsch, S.; et al. Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood 2021, 138, 2632–2641.

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