Acquired Factor V Inhibitors: A Review of Literature

Boland F¹* and Shreenivas AV²

¹Department of Medicine, Icahn School of Medicine, New York

²Division of Hematology-Oncology, Icahn School of Medicine, USA

*Corresponding author: Boland F, Department of Medicine, Icahn School of Medicine, Mount Sinai St. Luke’s and Mount Sinai West, New York

Received: June 20, 2017; Accepted: August 08, 2017; Published: August 30, 2017

Abstract

Objective: The implications of inhibitor formation can vary from an asymptomatic prolonged APTT and PT to a life threatening hemorrhage. We are still trying to understand why there are such variable clinical phenotypes and how we might best risk stratify patients. The focus of this review is to dissect the literature on this topic and offer recommendations to managing this rare affliction in the clinical setting.

Evidence Review: We conducted a search on PubMed, Scopus, web of science from 2010 until 2016 using different combinations of the following terms ‘’factor V inhibitors’’, ‘’factor V autoantibodies’’, ‘’FV inhibitors’’, ‘’Factor V and spontaneous inhibitors’’. We cross referenced the bibliographies for additional reports. 47 cases were included in final review.

Findings: The most common bleeding presentations included hematuria 23% (n=11) and gastrointestinal bleed 21% (n=10). 23% (n=11) of patients were asymptomatic at the time of presentation. 34% of cases were associated with infection and 31% with drugs. The median inhibitor titer and FVa (Factor V activity) was 9 Bethesda units and 2% respectively. The median PT and aPTT at presentation was 50 and 100 seconds respectively. To eliminate the inhibitor, steroids were generally used a first line therapy. 88% who received steroids alone for immunosuppression achieved remission. Other agents used included rituximab, IVIG, plasmapheresis, thalidomide and cyclophosphamide. The time for inhibitor disappearance was documented in 22 cases with a median time of 3.5 weeks.

Conclusion: Diagnosis and treatment of factor V inhibitors remains a challenge for clinicians. Because of its rare presentation and expertise required in diagnosing this disorder at present there are no trials to compare treatment options to analyze both acute bleeding control and inhibitor eradication.

Keywords: Factor V inhibitors; Factor V deficiency

Introduction

Factor V inhibitor is one of the rare forms of factor inhibitors and is an infrequent cause of factor V deficiency. Factor V is an integral part of the coagulation cascade. Synthesized in the liver, it acts as a cofactor in the prothrombinase complex. It is cleaved by thrombin into a 2-chain molecule and serves to activate prothrombin. It also has important anticoagulant properties by participating in the inactivation of factor VIII (FVIII). The first case was documented in 1955 in Germany [1]. The development of inhibitors against Factor V is an extremely rare occurrence with an estimated incidence of 0.09- 0.023 for 1 million persons per year, based on studies in Singapore and Australia [2]. There are five incidences when FV inhibitors develop: following exposure to bovine proteins, post-operatively in those not exposed to bovine proteins, inhibitors associated with other medical conditions, in congenital factor deficiency after replacement therapy and idiopathic formation of FVI. Historically FVI occurred most commonly due to bovine proteins. During surgical procedures topical bovine preparations were often used. This initiated the production of autoantibodies against bovine proteins including bovine FV which cross reacted with human FV. Though bovine thrombin has since been replaced by human and recombinant thrombin formulation which exhibit less antigenicity, there is still an association with surgical procedures and the formation of autoantibodies against FV. This may be due to prior exposure to bovine proteins causing a low titer of these antibodies which may then be stimulated by human or recombinant thrombin. Although 3 mechanisms, namely spontaneous autoantibodies, alloantibodies, and cross-reacting anti bovine factor V antibodies, have been hypothesized, the precise mechanisms of inhibitor development remain unknown. Normally, factor V acts by binding to the procoagulant phospholipid -phosphatidylserine -on activated platelets and endothelial cells through its C2 domain of its light chain. This complex binds to von Willebrand factor and enhances the coagulation process by acting as a cofactor to activated factor X, which cleaves prothrombin to thrombin. Factor V inhibitors are polyclonal IgG antibodies that attack the C2 domain of light chain of factor V resulting in loss of function, by decreasing the procoagulation effect of factor V [3].

Purpose of study

The implications of inhibitor formation can vary from an asymptomatic prolonged APTT and PT to a life threatening hemorrhage. We are still trying to understand why there are such variable clinical phenotypes and how we might best risk stratify patients. Therefore, the recognition, work up, diagnostics and management of this condition is of extreme importance. The focus of this review is to dissect the literature on this topic and offer recommendations to managing this rare affliction in the clinical setting.

Search methods

To focus this review specifically on inhibitors to FV, we examined the literature for recent review articles on this topic. A comprehensive systematic review on acquired factor V inhibitors was carried out by Franchini and Lippi in 2011 which analyzed data from 74 cases up to 2010. To avoid redundancy, we conducted a search on PubMed, Scopus, Web of Science from 2010 until 2016 using different combinations of the following terms ‘’factor V inhibitors’’, ‘’factor V autoantibodies’’, ‘’FV inhibitors’’, ‘’Factor V and spontaneous inhibitors’’. We cross referenced the bibliographies for additional reports. Only articles in English were included.

Literature Results and Discussion

94 cases of AFVD were documented in the literature. As illustrated in Figure 1, 47 cases were excluded. Cases in which inhibitors formed secondary to bovine thrombin were excluded given this less clinically relevant. A case series conducted by the Mayo clinic in which patients with MPN (myeloproliferative neoplasm) were found to have low levels of Factor V was excluded given there were no inhibitors detected, though it was noted that 3 out of the 33 patients did have clotting studies suggestive of an inhibitor though none was detected, which was also discovered in 2 of our case reports [4]. This is an interesting caveat when establishing a diagnosis of acquired factor V deficiency due to an inhibitor, which we shall discuss further on. An additional 2 cases were associated with congenital factor V deficiency which was excluded given the different mechanism of action of inhibitors in this setting. These patients given their history of bleeding disorder undergo a different specialized approach which will not be discussed in this review. The 47 remaining cases were reviewed which is outlined in Table 1.

Table 1: Case reports of Acquired Factor V inhibitors.




  
    First    author, year
    G
    Age
    Hemorrhagic    symptoms
    Reported    association
    Inhibitor    titer
    FVa
    Treatment
    Normalization    of FVa
    Time^*
  
  
    Tessier-Marteau, 2010 [18]
    M
    74
    DIC
    Sepsis, β-lactam, CPX 
    9
    <3
    FFP, PLTs, rFVIIa 
    Y
    <3
  
  
    Teh,    2010 [19]
    F
    88
    GI    Bleed
    CPX
    4
    6
    FFP,    PLTs CRYO, rFVIIa
    N
    -
  
  
    Nakamura,    2010 [20]
    M
    74
    GI    Bleed (provoked)
    Rectal    Surgery, rectal cancer
    -
    -
    PLTs,    plasmapheresis, rFVIIa
    N
    -
  
  
    Wu,    2010 [21]
    M
    71
    GI    Bleed, hematuria
    CPX
    6.6
    6.2
    FFP,    PLTs, steroids, CYP
    N
    3
  
  
    Shanmugam, 2010 [22]
    M
    69
    none
    Bacterial infection 
    17.6
    <1
    FFP, VK 
    Y 
    8 
  
  
    Bobba,    2011 [23]
    M
    79
    Hematoma    from surgical site (provoked)
    Surgery (Rt hip arthroplasty), CPX 
    3
    15
    Steroids, CYP, RTX 
    Y
    -
  
  
    Imashuku,    2011 [24]
    M
    88
    Hematuria
    Hashimotos
    4.3
    <1
    Steroids
    Y
    <2
  
  
    Guglielmone, 2011 [25]
    F
    27
    GI    Bleed (provoked)
    Liver    transplant (AIH T2)
    -
    <1
    FFP,    PC, PCC, rFVIIA,tacrolimus, steroids, IVIG
    Y
    <5
  
  
    Gartrell, 2011 [26]
    F
    80
    None
    Unknown 
    17
    3
    PLTs,    prednisone
    Y
    <2
  
  
    Lipshitz,    2012 [27]
    F
    60
    GI    Bleed, oral cavity, hematuria
    Unknown
    6
    <1
    FFP,    VK, rFVIIa, PLTs, PCC, steroids
    Y
    3
  
  
    Ciang, 2012 [28]
    M
    70
    Epistaxis,    intracerebral hemorrhage
    MPA,  β-lactam
    -
    0
    FFP,    plasmapheresis
    N
    -
  
  
    Shreenivas, 2012 [29]
    M
    80
    Epistaxis
      Hematuria
      Pulmonary    hemorrhage
    Amiodarone
      Bioprosthetic    valve replacement (bovine valve)
               32                  
    3.3
    Steroids,CYP
    Y
    6
  
  
    Navarrete, 2012 [30]
    F
    72
    Hematoma
    Unknown
    -
    <2
    Steroids,    CYP, rituximab
    N
    -
  
  
    Navarrete,    2012 
    M
    51
    Hematuria,    oral cavity
     
    17
    <3
    PLTs,    steroids, CYP, azathioprine, RTX
    N
    -
  
  
    Higuchi,2012 [31]
    F
    82
    DVT,    hematoma
    Unknown 
    4
    2
    Steroids
    Y
    2
  
  
    Motwani, 2013 [32]
    M
    84
    Hematoma
    Rifaximin
    50
    undetectable
    FFP,    VK, Cryo, DDAVP, FVIII inhibitor bypass agent, IVIG, CYP
    Y
    -
  
  
    Ahmadinejad, 2013 [33]
    M
    82
    GI    bleed, epistaxis. hematuria
    Esophageal    SCC
    16
    2
    FFP,    steroids
    Y
    <1
  
  
    Kang,    2013 [34]
    M
    79
    Hematoma,    hematuria
    Unknown
    <1
    <1.5
    FFP,    rFactor VIIa, CYP
    Y
    6
  
  
    Kitamura, 2013 [10]
    M
    62
    Intracranial    hemorrhage
    Membranous    nephropathy
    2.5
    4.4
    Steroids
    Y
    -
  
  
    Ashizawa, 2013 [35]
    M
    65
    Unknown
    Unknown
    3
    <3
    FFP,    steroids
    Y
    6
  
  
    Khalafallah, 2013 [36]
    M
    85
    Purpura
     β-lactam 
    11
    <2
    FFP,    VK, PCC, Steroids
    Y
    4
  
  
    Sosa,    2013 [37]
    F
    64
    None
    Unknown
    ND
    1
    FFP,    Steroids, IVIG
    N
    -
  
  
    Yamanda,    2014 [38]
    M
    61
    Pulmonary    hemorrhage
    Bacterial infection,  β-lactam, lung surgery 
    83
    <3
    Steroid,    RTX
    Y
    -
  
  
    Siekańska-Cholewa, 2014 [39]
    F
    67
    Hematuria,    Mucosal bleeding (epistaxis)
    Surgery    (aortic aneurysm surgery)
    7.75
    <5
    FFP,    steroid
    N
    -
  
  
    Van den Berg, 2014 [40]
    M
    29
    None
    Infection    (appendiceal abscess), antibxs, CPX
    1
    25
    VK,    PCC
    Y
    1
  
  
    Sun,    2014 [41]
    M
    54
    GI    bleed (provoked)
    Liver    transplant (hep B cirrhosis)
    9
    0.6
    FFP,    PC, PCC, rFVIIA,IVIG
    Y
    -
  
  
    Sekiguchi,    2014 [42]
    M
    90
    Purpura
    DEM 
    4
    <3
    Steroid
    Y
    -
  
  
    Kinjo, 2014 [43]
    M
    85
    None
    Antibiotic
    -
    -
    VK
    Y
    -
  
  
    AlJohani, 2014 [44]
    M
    64
    Hematuria
    Mantle    cell lymphoma
    80
    <0.01
    Steroids
    Y
    <8
  
  
    Hervent,    2014 [45]
    M
    82
    None
    Bioprosthetic    valve replacement (bovine valve)
    16
    <1
    None
    Y
    -
  
  
    Schmidt,    2015 [46]
    M
    84
    None
    intracranial surgery 
    212
    <5
    PLTs,    PCC
    Y
    -
  
  
    Donohoe, 2015 [7]
    F
    71
    None
    Topical    human thrombin, CPX, Otolaryngeal surgery, malignancy (hemangiopericytoma)
    1.4
    1
    VK,    FFP, PCC
    Y
    -
  
  
    Cui,    2015 [47]
    M
    59
    None
    CPX
    10
    2
    FFP,    PCC, Steroids
    Y
    1
  
  
    Leung,    2015 [48]
    M
    53
    Hematuria,    pulmonary hemorrhage
    ECMO, legionella 
    6
    1
    FFP, IVIG, plasmapheresis, RTX 
    Y
    1
  
  
    Ma, 2015 [49]
    M
    87
    GI    bleed (provoked)
    Surgery    (gastrectomy), gastric cancer
    2.2
    2.2
    IVIG,    plasmapheresis, PTLs, RTX
    Y
    7
  
  
    Rief, 2016 [50]
    M
    58
    None
    Surgery,    (nasal)
    2.65
    <8
    Steroids,    RTX
    N
    -
  
  
    Niwa, 2016 [9]
    M
    82
    Hematuria
    Unknown/ESRD    on HD
    2.8
    7
    Steroids
    Y
    <10
  
  
    Hirai, 2016 [51] 
    F
    79
    Hematoma
    Unknown
    18
    <3
    VK,    FFP, steroids
    N
    -
  
  
    Kitazawa, 2016 [8]
    (M
    72
    GI    bleed
    Unknown/ESRF,
    6
    <3
    FFP,    steroids
    Y
    6
  
  
    Patel, 2016 [17]
    F
    74
    Oral    cavity (provoked), retroperitoneal
    Teeth    extractions
    15
    <10
    rFVIIIa,    FEIBA, Steroids, RTX
    N 
    -
  
  
    Cadamuro, 2016 [52]
    M
    -
    Hematoma
     β-lactam 
    50
    <5
    PCC,    VK, FFP, EC,
    N 
    -
  
  
    Olson, 2016 [53]
    F
    76
    Intracranial    hemorrhage
    Antibiotics
    70
    -
     
    N
    -
  
  
    Gavva, 2016 [54]
    F
    64
    DVT
    ESRD,  β-lactam, CFX, sepsis
    5
    2
    Steroids
    Y
    <3
  
  
     
    F
    75
    Purpura
    HCV, β-lactam , MPGN on    HD
    21
    <1
    Steroids
    Y
    3
  
  
    Wang, 2016 [55]
    M
    64
    Hematuria
    Urinary    tract infection
    1.9
    2
    Steroids
    Y
    -
  
  
    Yen, 2016 [11]
    F
    83
    GI    Bleed
    Unknown/ESRD    on HD
    -
    5
    FFP,    plts, steroids, plasmapheresis
    N
      Death    (sepsis)
    -
  
  
    Cortier, 2016 [56]
    F
    76
    none
    Sepsis, β-lactam, surgery    (4 limb amputation)
    -
    6
    none
    Y
    <1
  
  
    ^*Time to inhibitor    disappearance (wks); G:Gender;MPA:Microscopic polyangiitis;CFX:Ciprofloxacin; CPX: Cephalosporin;    ECMO: Extracorporeal Membrane    Oxygenation; ESRF:End Stage    Renal Failure; DEM: Dabigatran    Etexilate Methanesulfonate;CRYO:Cryoprecipitate; FFP:Fresh Frozen Plasma;PLTs:Platelets;VK:Vitamin K;PCC:Prothrombin Complex    Concentrate;EC:Erythrocyte Concentrate;rFVIIa:Recombinant Factor VIIa;RTX:Rituximab;CYP:Cyclophosphamide;AIHT2:Autoimmune Hepatitis    Type 2;SCC:Squamous Cell Carcinoma;FEIBA:Factor VIII Inhibitor bypass Activity;    ND:Not detected



Table 1: Case reports of Acquired Factor V inhibitors.

Demographics and etiology

Of the 47 cases analyzed, 31 (66%) were male and 16 (34%) female. The median age was 74 years (range 29-90). The predisposition towards males and the broad age range is in keeping with a review carried out by [6] Ang, et al. in 2009 and signifies the need to be aware of this condition developing in any patient presenting with a bleeding diathesis. With this rare condition we rely heavily on the data from case reports to guide us to the causation behind these inhibitors. Over 200 case reports have been documented based on this review and in the literature [5,6]. The associations implicated in our review are noted in Table 2. Surgical procedures were associated with 22% of cases. For some patients it is not clear if they had been exposed to bovine thrombin in the past. One such case postulates that prior formed antibodies from bovine thrombin from a previous surgery were stimulated by exposure to human thrombin [7]. The majority of patients that underwent a surgical procedure also had other possible causations such as underlying malignancy or autoimmune disorder or concurrent antibiotic use perioperatively. This of course makes the association extremely difficult to establish. Likewise, infection (bacterial or viral), was an associated etiology in 34%, however 17% had also received antibiotics prior to discovery of the FVI. In fact, 30% of patients had more than one associated condition or drug. A large proportion of cases were found to have no underlying trigger. In this review this was the case for 25% of patients. This may be partly due to inability to uncover an underlying pathology or establish causation. In 2 cases there is a noted association with eosinophilia, renal failure and FV inhibitors suggesting an underlying immunoallergic process [8,10]. It is also observed that 2 cases where no causation is found, both patients were undergoing hemodialysis [9,11]. However, again causation is difficult to prove and it is hard to confirm that these patients did not have an underlying autoimmune disease or were exposed to a medication not commonly known to trigger autoantibody production. When combining this review with that of Franchini’s [5], the most common causation is antibiotics which was associated with 38% of cases (48/125). Next most common are surgery followed by infection at 29% and 27% respectively.

Table 2: Etiology implicated.




  
    Reported    Association^*
    Number    of cases (%)
  
  
    Infection
    16    (34)
  
  
    Surgery
    12    (25)
  
  
    Antibiotics^#
                      β-lactam 
                      Cephalosporin 
                      Not specified  
    15    (31)
       8 (17)
       6 (13)
       4 (8)
  
  
    Malignancy 
    4    (8)
  
  
    Autoimmune    disorder
    3    (6)
  
  
    Unknown
    12    (25)
  
  
    ^*several pts with    more than one association
      ^#some patients    receiving both β-lactams    and cephalosporins



Table 2: Etiology implicated.

Clinical presentations and laboratory results

The most common bleeding presentations as highlighted in Table 2 included hematuria (n=11), gastrointestinal bleed (n=10) and hematoma (n=7) and least common was intracranial hemorrhage (n=3) and pulmonary hemorrhage (n=2). 23% (n=11) of patients were asymptomatic. Given Factor V participates in both procoagulant and anticoagulant pathways, it is not surprising that thrombosis occurred in some of patients (n=3). The laboratory findings were extremely variable, though of course, all documented cases were consistent with having a prolonged PT and aPTT. On mixing studies, 91% of cases were not fully correctable on 1:1 mixing studies with pooled normal plasma. The four cases that fully corrected, represents a rare entity which contradicts the basic principle that we use to work up these abnormal coagulation studies. In one such case by Lipshitz [24], the patient has a proven factor inhibitor, despite mixing studies showing complete correction. In this case, it is hypothesized that factor V inhibition may be time dependent. Another such case, [34] demonstrated another diagnostic dilemma, in that no inhibitor was found, yet it also seemed that this was not a production problem. It was suggested, there may be an antibody present which is escaping detection by ELISA and rapidly removing FV without the selective binding of FV to tissues or neutralizing its activity. A case documented in 2014, was unable to confirm the presence of an inhibitor but did notice a pattern consistent with phospholipid dependence but most significantly affecting FV [40]. This is due to either FV in the presence of lupus anticoagulant (LA), or a FV with phospholipid dependence, or may have been a LA with more pronounced factor V inhibition. With the potential for these unusual laboratory findings, clinicians need to be persistent with a thorough investigation to prove evidence of FV inhibitors. Though the PT and PTT were consistently prolonged, these values were extremely variable, with a median PT and APTT at presentation of 50 and 100 seconds respectively. A wide range of inhibitor titres and Factor V activity was also notable. The median inhibitor titer and FVa (Factor V activity) was 9 Bethesda units and 2% respectively. In contrast with other coagulation factor inhibitors, the level of factor V inhibitors does not correlate with the degree of clinical bleeding. In addition, the risk of bleeding does not seem to correlate with prolongation of prothrombin time or activated partial thromboplastin time, factor V activity, factor V inhibitor levels, or the duration of presence of factor V inhibitor. This brings up two relevant questions. Firstly, that the incidence of FVI is likely underestimated given almost 1 in 4 of the patients were asymptomatic. This is similar to the review by [6] Ang, et al. where 32% of cases demonstrated no bleeding. Analyzing the coagulation profiles and FVa (Factor V activity) in the asymptomatic patients (Table 4) and those who experienced fatal hemorrhage (Table 5) showed no apparent association between FVa, inhibitor titer and derangement of aPTT and PTT. This makes the approach to the asymptomatic population trickier as it is unpredictable which patients may be at higher risk of a bleeding event.

Reported Association^*	Number of cases (%)
Infection	16 (34)
Surgery	12 (25)
Antibiotics^# β-lactam Cephalosporin Not specified	15 (31) 8 (17) 6 (13) 4 (8)
Malignancy	4 (8)
Autoimmune disorder	3 (6)
Unknown	12 (25)
^*several pts with more than one association ^#some patients receiving both β-lactams and cephalosporins

Bleeding site	N (%)
Mucosal Gastrointestinal Genitourinary Upper airway/oral cavity	10 (21) 12 (25) 3 (6)
Intracerebral	3 (6)
Hematoma	7 (14)
Skin	3 (6)
Lungs	3 (6)
Asymptomatic	11 (23)

Suspected Etiology	Inhibitor Titre (BU)	FVa	APTT	PT/INR	Outcome/ (time to inhibitor disappearance in wks)
infection	17.6	<1	48.7		Remission (8w)
unknown	17	3	150	54.6/5.8	Death 2/2 sepsis
unknown	not detected	1	94.4	36	Persistent (no inhibitor found)
infection, CPX	1	25	38.3	25.8	Spontaneous resolution (1wk)
antibiotics	-	-	-	-	Remission
bioprosthetic valve replacement (bovine valve)	16	<1	141	-	Death 2/2 renal failure
intracranial surgery	212	<5	-	-	Remission
topical human thrombin, antibiotics, surgery, malignancy	1.4	1	49.5	14.9	Remission
CPX	10	2	200	68.3	Remission (1w)
surgery	2.65	<8	67.7	37	Persistent
infection, β-lactam, surgery	-	6	72	24.9	Remission (<1wk)

Bleeding site	Suspected Etiology	Inhibitor Titre (BU)	FVa	APTT	PT/INR	Treatment	Site of fatal hemorrhage
GI	CPX	4	6	173	50.7/-	FFP, PLTs CRYO, rFVIIa	Gastrointestinal
GI Bleed, hematuria	CPX	6.6	6.2	100	50/-	FFP, PLTs, steroids, CYP	Gastrointestinal
Epistaxis, intracerebral hemorrhage,	MPA, β-lactam	-	-	120	-/8	FFP, plasmapheresis	Intracerebral
Hematuria, epistaxis	Surgery (aortic aneurysm surgery)	7.75	<5	-	-	FFP, steroids	Intracerebral
Hematoma	Unknown	18	<3	120	60/-	VK, FFP, steroids	Intracerebral
Hematoma	β-lactam	50	<5	150	-/5.7	PCC, VK, FFP, EC	Not specified
Intracranial hemorrhage	Antibiotics	70	-	160	59.1/-		Intracerebral