Official reprint from UpToDate®

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Acquired inhibitors of coagulation

Author: Steven Coutre, MD

Section Editor: Lawrence LK Leung, MD
Deputy Editor: Jennifer S Tirnauer, MD

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Nov 2016. | This topic last updated: Oct 26, 2015.

INTRODUCTION — Acquired inhibitors of coagulation are antibodies that either inhibit the activity
or increase the clearance of a clotting factor.

● Some disorders may be associated with antibodies to a variety of clotting factors. In systemic
lupus erythematosus, for example, antiphospholipid antibodies and antibodies directed
against factors II, VIII, IX, XI, XII, and XIII have been described [1]. (See "Hematologic
manifestations of systemic lupus erythematosus in adults", section on 'Antibodies to clotting
factors and phospholipids' and "Clinical manifestations of antiphospholipid syndrome".)

● Antiphospholipid antibodies represent a special problem; these antibodies prolong certain

clotting assays, but result in thrombosis rather than bleeding. The pathogenesis, diagnosis,
and treatment of conditions associated with antiphospholipid antibodies are discussed
elsewhere in UpToDate. (See "Pathogenesis of antiphospholipid syndrome" and "Clinical
manifestations of antiphospholipid syndrome" and "Treatment of antiphospholipid syndrome".)

A common clinical manifestation in affected patients is a hemorrhagic diathesis. Acquired

coagulation inhibitors that lead to bleeding will be reviewed here. The natural history and
management of these inhibitors are quite different from inhibition due to alloantibodies that occur
in patients with various inherited bleeding disorders (eg, congenital deficiencies of factors VIII, IX,
or XI) treated with factor replacement. The latter problem is discussed separately. (See "Factor VIII
and factor IX inhibitors in patients with hemophilia" and "Factor XI deficiency", section on 'FXI
inhibitors'.)

FACTOR VIII INHIBITORS — The most common autoantibodies that affect clotting factor activity
and lead to a bleeding disorder are directed against, and interfere with, the activity of factor VIII, a
condition also called acquired hemophilia A [2-6]. Although there are no large series describing the
immunoglobulin class of the factor VIII autoantibodies, most have been IgG antibodies that do not
bind complement.

The reasons for the production of factor VIII autoantibodies in a particular individual are not clear,
but may involve the presence of certain gene polymorphisms (eg, HLA, CTLA4) and/or
autoreactive CD4+ T lymphocytes [7].

An individual patient, either nonhemophilic or hemophilic, can produce antibodies of different IgG
subclasses directed against different epitopes on the factor VIII molecule [8-10]. However, the
production of multiple antibodies is much more common in patients with hemophilia [11]. Most of
these antibodies bind to the C2 or, less often, the A2 domain on factor VIII [11-13]. Loss of the C2
domain, which binds to the procoagulant phospholipid phosphatidylserine on activated platelets
and endothelial cells and to von Willebrand factor [14], leads to reduced procoagulant activity
[12,13]. (See "Biology and normal function of factor VIII and factor IX".)

A similar finding has been noted with factor V inhibitors that are associated with bleeding
manifestations; the antibodies are usually directed against the C2 domain of the protein (see
'Factor V inhibitors' below) [15,16], which is also responsible for binding to phosphatidylserine on
activated platelets and endothelial cells [17].

Epidemiology — Population-based unselected cohorts of patients seen in South and West Wales
and the United Kingdom have calculated an incidence of acquired factor VIII inhibitor of 1.3 to 1.5
cases per million population per year [18,19]. In another survey of 118 physicians likely to see
such patients, 215 were described over a 10-year period; the following characteristics were noted
[2]:

● Most of the patients were over age 50, except for women who were pregnant or postpartum.

● The major identifiable causes were pregnancy or the postpartum period, rheumatoid arthritis,
malignancy, systemic lupus erythematosus, and drug reactions (each responsible for 5 to 10
percent). However, in almost one-half of the patients no underlying disorder was present.

A meta-analysis of series and surveys of patients with acquired factor VIII inhibitors, including the
author's own experience, and comprising 249 patients, has been published [20]. Median age was
64 (range: 8 to 93); 55 percent were female. Median inhibitor and factor VIII levels were 10
Bethesda units (range: 0.9 to 32,000) and 2 percent (range: 0 to 30), respectively. The most
common associated conditions were malignancy, post-partum status, and autoimmune disorders.
On multivariate analysis, factors predicting for improved overall survival were attainment of
complete remission, age <65, and post-partum status. Although treatment data appeared to suffer
from publication bias, the highest rates of complete remission and lowest rates of disease-specific
mortality were noted in patients treated with cyclophosphamide.

● Postpartum – Several retrospective studies and reviews of acquired factor VIII inhibitors
associated with pregnancy have come to similar conclusions regarding the course and
prognosis of these inhibitors [2,3,21,22]. The inhibitors are typically diagnosed within two to
three months postpartum. Most cases were associated with the first pregnancy (ie, in
primigravidas) [21]. The survival of patients with pregnancy associated factor VIII inhibitors is
nearly 100 percent, substantially better than that of patients with these inhibitors not
associated with pregnancy. This excellent survival might reflect the younger age, overall
better health, and reversibility of the condition that provoked the development of the inhibitor
[22]. (See 'Natural history' below.)

● Rheumatic disease – Among the rheumatic diseases, factor VIII inhibitors have primarily
been described in patients with rheumatoid arthritis and systemic lupus erythematosus
[1,2,23-25]. In occasional patients, these antibodies coexist with antiphospholipid antibodies
[26].

● Malignancy – Anti-factor VIII antibodies are a rare complication of solid tumors. In a review of
27 analyzable cases, there was a close temporal relationship between detection of the
inhibitors and diagnosis of the tumor [27]. There was no association with a specific tumor; the
possible causative role of treatment with immunomodulatory agents (eg, interferon,
fludarabine, ipilimumab) is unclear [28-32].
 In a second review of 41 patients identified through the available literature, there were 25 with
solid organ tumors and 16 with hematologic malignancies [33]. Adenocarcinomas comprised
64 percent of the solid tumors, with the most common sites being prostate and lung. Chronic
lymphocytic leukemia was the most common of the hematologic malignancies. The median
age was 70 and 68 percent of the subjects were men. Treatment of the inhibitor led to a
complete response (CR) in 70 percent of patients. Patients achieving CR were more likely to
have early stage tumors and a lower median inhibitor titer at the time of presentation,
compared with nonresponders.

● Drug-induced – Anti-factor VIII antibodies have been associated some medications (eg,
penicillin, sulfamides, phenytoin) and immunomodulatory agents such as interferon and
fludarabine [4,34]. These antibodies often resolve following cessation of the offending drug.

Clinical features — The hallmark of acquired factor VIII antibodies is bleeding that, in some
cases, is first noted after a surgical procedure. Symptomatic patients often present with large
hematomas, extensive ecchymoses or severe mucosal bleeding, including epistaxis,
gastrointestinal bleeding, and gross hematuria. Spontaneous hemarthroses, which are common in
hereditary factor VIII deficiency, are unusual in those with acquired disease (table 1).

The range of bleeding manifestations can be illustrated by observations in women with postpartum
factor VIII inhibitors. Soft tissue bleeding was most common (29 of 51 patients), followed by
muscle, vaginal, joint bleeding, and hematuria (13 to 18 patients) [3]. There were no episodes of
intracerebral bleeding.

Bleeding is often severe, constituting a medical emergency. In the above survey of 215 patients,
87 percent experienced major bleeding and 22 percent died from complications attributed directly
or indirectly to the inhibitor [2]. In the United Kingdom cohort, bleeding was the cause of death in 9
percent and remained a risk until the inhibitor had been eradicated [19].

Diagnosis — The sudden presence of large hematomas or extensive ecchymoses in an elderly

individual without significant trauma or known bleeding disorder should always raise the clinical
suspicion of an acquired factor VIII inhibitor.

Coagulation tests — In addition to the clinical features, factor VIII inhibitors are characterized
by a prolonged activated partial thromboplastin time (aPTT) and a normal prothrombin time (PT).
The differential diagnosis of this profile in a patient with a bleeding diathesis includes deficiencies
of factors XI, IX or VIII, von Willebrand disease, inhibitors of these factors, and the use of
heparin (table 2). A prolonged aPTT is also seen in the antiphospholipid antibody syndrome, but
these patients present with thrombosis rather than bleeding episodes. (See "Clinical
manifestations of antiphospholipid syndrome".)

A reasonable first step is to exclude the use of heparin as a cause of the patient's bleeding and/or
prolongation of the aPTT. In addition to a review of the patient's medications, the presence of
heparin in the blood sample can be suspected via one of the following (see "Clinical use of
coagulation tests", section on 'Activated partial thromboplastin time (aPTT)'):

● The simplest approach is to redraw a blood sample using an uncontaminated peripheral vein.
If the repeat aPTT is normal, the original sample was probably contaminated with heparin

● If a prolonged aPTT or thrombin time is normalized after the addition of protamine or a

commercially available ion exchange resin (Heparsorb), heparin or a heparin-like material is
present.
 ● Perform a thrombin time and a reptilase time. Heparin is present if the thrombin time is
prolonged and the reptilase time is normal.

Inhibitor screen (mixing test) — The primary initial diagnostic test for a factor VIII inhibitor is
the mixing test or inhibitor screen. In this assay, varying amounts of patient plasma and pooled
normal plasma are mixed and the aPTT measured. After mixing, measurement of the aPTT should
be performed not only immediately but also after incubation at 37ºC for one to two hours. The
second measurement is necessary to detect factor VIII inhibitors with slow reaction kinetics [35].
(See "Clinical use of coagulation tests".)

Correction of the prolonged aPTT suggests a factor deficiency or VWD, while persistent
prolongation of the aPTT indicates the presence of an inhibitor. The mixing test will establish
whether an inhibitor is present but will not identify the inhibitor's specificity.

The next step is adding a source of phospholipid to the mixed plasma. Correction of the aPTT
suggests the presence of antiphospholipid antibodies. If the aPTT does not correct, the Bethesda
assay is performed. The Bethesda assay both establishes the diagnosis of a factor VIII inhibitor
and quantifies the antibody titer [36]. By standardizing the strength of factor VIII inhibitors, this
assay also permits comparison between different treatment regimens.

Bethesda assay — In the Bethesda assay, serial dilutions of patient plasma are incubated with
pooled normal plasma at 37ºC for two hours; factor VIII activity is then measured using a clotting
assay as one would in a patient with hereditary factor VIII deficiency. The reciprocal dilution of
patient plasma that results in 50 percent factor VIII activity is defined as one Bethesda unit (BU).
The stronger the inhibitor, the greater the dilution required to allow for factor VIII activity.

Other testing — Initial, limited information has been presented on an immunoassay for anti-
factor VIII antibodies [37].

TREATMENT OF FACTOR VIII INHIBITORS — Initial treatment of acquired factor VIII inhibitors
consists of two separate steps [38-40]:

● Control of bleeding and

● Elimination of the inhibitor

As with any other bleeding disorder, actions that might provoke bleeding (eg, intramuscular
injections, invasive procedures, use of antiplatelet agents) should be avoided or minimized [41].

Control of active bleeding — Treatment strategies to control active bleeding include the use of
desmopressin (dDAVP), factor VIII concentrates, activated prothrombin complex concentrates
(aPCCs; eg, anti-inhibitor coagulant complex, FEIBA, Autoplex T), recombinant human factor VIIa,
and recombinant porcine factor VIII [4,38,39,42-49].

The decision regarding initial treatment should be made based upon the severity of bleeding and
the titer of the inhibitor [50].

● Non-life-threatening bleeding – For patients with non-life-threatening bleeding and low

inhibitor titers, DDAVP at a dose of 0.3 mcg/kg subcutaneously per day given for three to five
days may be sufficient for control of bleeding or for hemostatic coverage of invasive
procedures [41,51,52].

● Severe bleeding, low titer inhibitor – For bleeding associated with a low titer inhibitor (ie, <5
Bethesda units) we suggest the use of human factor VIII product (recombinant factor VIII or a
 factor VIII concentrate) at high doses, rather than another product such as a prothrombin
complex concentrate, recombinant factor VIIa, or porcine factor VIII. A typical dose of human
factor VIII is 20 international units/kg intravenously for each Bethesda unit of the inhibitor, plus
an additional 40 international units/kg, with monitoring of factor VIII activity 10 minutes
following bolus injection, and repeat intravenous bolus dosing if the incremental recovery is
not adequate [41].

● Severe bleeding, high titer inhibitor – For patients with higher titer factor VIII inhibitors (ie,
≥5 Bethesda units) and/or severe bleeding, we suggest the use of an activated prothrombin
complex concentrate (aPCC; eg, factor VIII inhibitor bypassing activity [FEIBA]) or
recombinant human factor VIIa [45,46]. Human factor VIII products generally cannot be given
in high enough amounts to overcome the inhibitor. Recombinant porcine (pig) factor VIII,
approved by the US Food and Drug Administration (FDA) in October 2014, is also available
[53].

There are no comparative trials to determine whether an aPCC or rfVIIa is more effective in
the setting of a high titer inhibitor and active bleeding. Results from an uncontrolled European
registry in 501 patients with acquired factor VIII deficiency suggest that the two agents have
similar efficacy [49]. Thus, the choice between FEIBA and rfVIIa should be guided by local
experience and cost considerations.

Recommended doses for FEIBA and rfVIIa are similar to those employed in hemophilia
patients with inhibitors (eg, typical FEIBA dose 75 units/kg; rfVIIa median starting dose 90.4
mcg/kg, range 45 to 181 mcg/kg). (See "Factor VIII and factor IX inhibitors in patients with
hemophilia", section on 'Agents other than factor VIII'.)

Porcine (pig) factor VIII has protein sequence differences from human factor VIII, and may
thus be less inactivated by factor VIII inhibitors. In a study using a previously available porcine
factor VIII product, the inhibitor titer to porcine factor VIII was only 5 to 10 percent of the titer
against human factor VIII [54]. A recombinant porcine factor VIII product engineered to lack
the B domain (OBI-1, Obizur) became available in 2014 [53]. In a prospective study in 28
patients with an acquired factor VIII inhibitor and severe bleeding, this product controlled
bleeding in 24 individuals (86 percent) [55]. Efficacy was greater in those who received OBI-1
as primary therapy versus those who received another hemostatic agent first (94 versus 73
percent). Patient comorbidities included a variety of underlying conditions such as malignancy
or rheumatologic disease; 16 had no underlying etiology for acquired factor VIII inhibitor
identified. Dosing was initiated at 200 units/kg and titrated according to clinical bleeding and
factor VIII activity level. All individuals also received immunosuppressive therapy with a
glucocorticoid and/or another agent (eg, rituximab, cyclophosphamide). Five patients
developed new inhibitors to the porcine product. There were no serious adverse events.
Additional evidence for the efficacy and safety of this product is awaited.

Recombinant ovine (sheep) factor VIII is also being investigated [56].

Eliminating the inhibitor — Elimination of the factor VIII inhibitor requires the use of
immunosuppressive modalities which are described below. Of importance, some inhibitors will
regress spontaneously (see 'Natural history' below).

There are no convincing data from randomized trials that one immunosuppressive regimen is
better than another or that the choice of regimen should be based upon the inhibitor titer or factor
VIII level [40]. The lack of definitive data from non-randomized studies was shown in a
retrospective analysis of the outcomes of various immunosuppression regimens in 331 subjects
enrolled in the European Acquired Hemophilia Registry [57].

● The most commonly employed initial immunosuppressive regimens were glucocorticoids

alone (n = 142), glucocorticoids plus cyclophosphamide (n = 83), and glucocorticoids plus
rituximab (n = 28).

● Complete remissions (ie, undetectable inhibitor levels, factor VIII levels >70 International
units/mL, and immunosuppression stopped) were noted in 48, 70, and 59 percent of those
treated with glucocorticoids alone, glucocorticoids plus cyclophosphamide, and
glucocorticoids plus rituximab, respectively.

● The median times to complete remission were approximately five weeks for the use of
glucocorticoids with or without cyclophosphamide; rituximab-based regimens required
approximately twice as long. Immunoglobulin administration did not improve outcome.

● Adverse events were common in all three treatment groups, and were reported in 25, 41, and
37 percent, respectively.

● Second-line therapy was successful in approximately 60 percent of cases that failed first-line
therapy; outcome was not affected by the choice of first-line therapy.

Although patients were more likely to respond to glucocorticoids plus cyclophosphamide than with
other regimens, outcome at final follow-up was not affected by the choice of first-line therapy. Data
were insufficient to adjust the immunosuppression regimen based upon factor VIII levels and/or
the inhibitor titer.

Prednisone and cyclophosphamide — A prospective randomized trial evaluated the efficacy

of prednisone, cyclophosphamide, and the combination of both drugs in 31 nonhemophilic patients
with factor VIII antibodies [58]. All patients initially received prednisone (1 mg/kg per day PO) for
three weeks; if the antibody persisted, the patients were randomly assigned to continuation of
prednisone for another six weeks, tapering of prednisone and initiation of cyclophosphamide (2
mg/kg per day orally), or continuation of prednisone with the addition of cyclophosphamide. The
antibody disappeared in 10 of the 31 subjects (32 percent) during the initial course of prednisone.
Twenty of the 21 nonresponding patients were then randomly assigned to further treatment, with
the following results [58]:

● The antibody disappeared in three of the four subjects randomly assigned to receive
continued prednisone alone, making the overall response to prednisone alone 42 percent.

● The antibody disappeared in three of six randomly assigned to receive cyclophosphamide

alone.

● The antibody disappeared in 5 of 10 randomly assigned to receive prednisone plus

cyclophosphamide.

The antibody titer was significantly lower in responders than nonresponders, but seven patients
with titers >5 Bethesda units had complete remissions. The authors concluded that all patients
should receive initial prednisone therapy and that cyclophosphamide was effective second-line
therapy in many patients who were steroid-resistant.

This conclusion was supported by results of a non-randomized retrospective analysis of 88

patients from a UK cohort study [19]. No significant difference was found in the proportion of
patients achieving complete remission or in the time to complete remission following treatment
with steroids alone versus those treated with steroids plus cytotoxic therapy (usually
cyclophosphamide). Of interest, all four patients with rheumatoid arthritis responded to treatment
with steroids alone, in contrast to reports that suggested such patients are resistant to treatment
with steroids alone and do better when treated with cyclophosphamide [23,24].

Similar findings have been noted in patients with postpartum disease. In the above retrospective
series of 51 patients, prednisone did not appear to be more effective than no therapy, but a shorter
time to complete response was noted in patients treated with cyclophosphamide, azathioprine, or
6-mercaptopurine [3]. The overall outcome was quite favorable, with 97 percent survival at two
years and almost 100 percent probability of complete remission by 30 months.

Other options — Another option for the therapy of acquired factor VIII inhibitors is the
administration of intravenous immune globulin (IVIG) [25,41,59]. In a prospective study, 19
patients were treated with IVIG (1 g/kg IV for two days or 400 mg/kg IV for five days) [59]. Two
patients had a decline in inhibitor titer within several days, and four patients responded over weeks
to months. Because only some patients respond to IVIG and multiple courses are often required,
and given the excellent results obtained with prednisone and cyclophosphamide, we suggest that
IVIG not be used as initial therapy.

Utility of the anti-CD20 antibody rituximab, alone or with cyclophosphamide and/or prednisone,
has been demonstrated in a number of patients with acquired factor VIII inhibitors [60-69]. Highly
anecdotal information suggests that subjects with high inhibitor titers (eg, >100 BU) may require
the use of all three agents [41,62,63,65,69].

Anecdotal information indicates that some patients resistant to all of the above therapies have
responded to cyclosporine [70-73] or to cladribine [74]. In the rare patient not responding to the
above measures, the use of extracorporeal plasmapheresis with an immunoadsorption column to
absorb the autoantibody can be tried [50,75-77].

Pregnancy — Management of a factor VIII inhibitor during pregnancy is similar to non-pregnant

individuals. The most relevant aspect of management is prevention and/or control of bleeding.
Immunosuppression with prednisone may be used. Other agents are generally avoided unless
maternal health is critically dependent on their use. (See "Use of antiinflammatory and
immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)

The efficacy of therapy is monitored similarly to non-pregnant individuals. (See 'Monitoring

response to treatment' below.)

Monitoring response to treatment — The primary goal of treatment for an acquired factor VIII
inhibitor is cessation of bleeding, followed ultimately by a decrease in the titer of the inhibitor. The
former is monitored via the usual clinical and laboratory observations (eg, observable blood loss,
blood in urine or stool, repeated blood counts). Since inhibitor titers drop very slowly following
successful treatment, it is neither necessary nor advisable to check the patient’s aPTT or inhibitor
titer more often than every two to four weeks once immunosuppressive therapy has been started.

Natural history — In terms of eliminating the inhibitor, most patients have been treated with
immunosuppressive drugs. Although these drugs hasten the time to complete remission, there is
an appreciable incidence of spontaneous recovery. In the survey of 215 nonhemophilic patients
noted above, 31 received no therapy other than supportive transfusions or factor concentrates; the
inhibitor disappeared spontaneously in 11 (36 percent) at an average duration of 14 months [2].
Similar findings were noted in a report of 16 patients who received little or no therapy for an
average of 31 months [78]. There were no spontaneous hemarthroses, two died from
retroperitoneal bleeding, and five (31 percent) had spontaneous disappearance of the inhibitor.
Given the continued risk of bleeding, not treating with immunosuppressive therapy should be an
informed decision made by the patient, since these therapies are usually successful.

The relapse rate after a first complete remission has been estimated at about 20 percent; 70
percent of such relapsing patients achieve a second complete remission [19,38].

The relapse rate of pregnancy-associated factor VIII inhibitors appears to be lower [79]. Relapse of
pregnancy-associated acquired factor VIII inhibitors may rarely occur in subsequent pregnancies;
the antibody may affect fetal factor VIII levels, resulting in life-threatening hemorrhage in a
subsequent fetus because of transplacental transfer of IgG antibodies [21,38,80,81]. Patients with
low antibody titers (ie, <5 Bethesda units) tend to have remissions within months, whereas those
with higher titers may have antibody persistence for years [21].

In at least one case, treatment of the underlying condition (eg, malignancy) has resulted in
disappearance of the inhibitor [82].

OTHER COAGULATION FACTOR INHIBITORS — Autoantibodies can be directed against a

variety of clotting factors other than factor VIII, with variable clinical manifestations [83]. These will
be described below, with the exception of antibodies to von Willebrand factor, which are discussed
separately. (See "Classification and pathophysiology of von Willebrand disease", section on
'Acquired von Willebrand disease'.)

Prothrombin (factor II) inhibitors — Antibodies to prothrombin are most often detected in
patients with antiphospholipid antibodies [84,85]. The prothrombin antibodies, which can cause
significant clinical bleeding, usually bind to a nonactive portion of the molecule, resulting in
accelerated clearance of prothrombin [84]. Laboratory testing (ie, screening for an inhibitor) is
most consistent with a factor deficiency rather than an inhibitor, since the functional activity of
prothrombin is not impaired in a clotting assay when additional prothrombin is added. (See
"Clinical manifestations of antiphospholipid syndrome".)

The possible presence of prothrombin antibodies should be suspected if a patient with

antiphospholipid antibodies develops bleeding rather than the expected thrombotic events [85,86].
An autoantibody directed against prothrombin has been well characterized in one patient who did
not have a lupus anticoagulant [87]. It bound to a different epitope on the prothrombin molecule
than described above, but still led to depletion of prothrombin without affecting prothrombin
function.

Specific immunochemical measurement of the prothrombin concentration is required to establish

the diagnosis.

Treatment of active bleeding consists of the use of fresh frozen plasma (FFP) to increase
prothrombin levels. The recommended dose of FFP is 15 to 20 ml/kg, with a target prothrombin
level >30 percent.

The modalities used to treat factor VIII inhibitors also may apply to patients with prothrombin
inhibitors [85-88]. (See 'Treatment of factor VIII inhibitors' above.)

Thrombin (factor IIa) inhibitors — Inhibitors specific for human thrombin are quite rare as one
might expect, given the multiple important functions of this enzyme. (See "Overview of
hemostasis".) The majority of antibodies directed against thrombin are detected incidentally in the
absence of clinical bleeding because of prolongation of the thrombin clotting time (thrombin time,
TT) and other clot-based anticoagulation assays performed for some other reason.

Thrombin antibodies typically arise after exposure to bovine thrombin found in topical thrombin or
fibrin-glue preparations used in surgery [89-92]. These antibodies do not cause clinical bleeding
unless they crossreact with human thrombin or, more often, when antibodies are also present
against factor V, a common contaminant in bovine thrombin preparations [90-93]. (See "Fibrin
sealant".)

In these patients the thrombin time is prolonged when using bovine reagent thrombin and is
normal when the thrombin reagent is of human origin. The aPTT is prolonged and the prothrombin
time is increased if factor V antibodies are also present [90,92]. The availability of human, rather
than bovine, thrombin for fibrin sealant and topical thrombin preparations should decrease the
incidence of thrombin antibody formation. (See "Clinical use of coagulation tests", section on
'Thrombin time (TT)'.)

Thrombin antibodies have also been described in several patients without exposure to exogenous
thrombin. Most of these patients had a comorbid condition such as lupus erythematosus,
rheumatoid arthritis, or monoclonal gammopathy [94-96]; however, one patient had no obvious
underlying disease [97]. These inhibitors may cause severe bleeding [95,97]. Anecdotal treatment
approaches include immunosuppression with prednisone or cyclophosphamide and plasma
exchange [97]. Given the severity of bleeding that can occur in this setting, aggressive initial
management including plasma exchange is probably warranted.

Factor V inhibitors — As with thrombin inhibitors, the majority of factor V inhibitors are
autoantibodies that arise from exposure to topical fibrin glues or bovine thrombin preparations that
are contaminated with bovine factor V [90-92,98]. One review evaluated 105 published cases of
acquired factor V inhibitors [93]. The following results were noted:

● Forty-six (44 percent) were associated with bovine thrombin exposure. In the only prospective
study that has evaluated this relationship, such exposure led to the generation of factor V
inhibitors in 11 of 24 patients after cardiac surgery and 2 of 10 patients after neurosurgery, for
a combined incidence of 38 percent [92]. Repeated exposure appeared to lead to more potent
inhibitors.

● Twenty-four patients (23 percent) developed inhibitors following surgery without known
exposure to bovine proteins. These antibodies showed specificity for human factor V, but can
crossreact with bovine factor V. They do not prolong the thrombin time, in contrast to patients
exposed to bovine thrombin.

● Other associated conditions included malignancy, autoimmune disease, the postpartum state,
and congenital factor V deficiency. Nineteen had apparently idiopathic disease.

In one series of 12 patients (with and without bovine thrombin exposure), only the antibodies from
patients with hemorrhagic manifestations inhibited factor V activity [15]. These antibodies usually
recognize the C2 domain of the protein. Loss of this domain, which binds to the procoagulant
phospholipid phosphatidylserine on activated platelets and endothelial cells [17], results in loss of
procoagulant activity [16]. As noted above, some factor VIII antibodies are directed against the C2
domain on that protein [12,13].
A case of acquired factor V inhibitor after exposure to topical human thrombin has also been
reported [99].

Clinical manifestations — The hemorrhagic manifestations associated with factor V inhibitors

are variable, ranging from asymptomatic to life-threatening bleeding [15,90,91,93]. In the large
review cited above, bleeding occurred in one-third of patients with inhibitors following exposure to
bovine proteins, compared with two-thirds of other cases [93].

At least two factors contribute to this variability. First, bleeding is primarily associated with
antibodies directed against the C2 domain of the protein [15]. Second, functionally important factor
V is concentrated on platelets. One patient who did not have a severe bleeding disorder had an
inhibitor that neutralized plasma factor V but not the less accessible platelet factor V [100]. Platelet
factor V may be more important for assembly of the prothrombinase complex than circulating
factor V [101]. (See "Overview of hemostasis".)

Diagnosis — The presence of a factor V inhibitor should be suspected in a patient with

prolongation of the aPTT and PT but a normal thrombin time [91]. However, the thrombin time may
be prolonged in patients with bovine thrombin exposure and the production of antibodies to
thrombin as well as to factor V. As described for factor VIII inhibitors, mixing studies should
confirm the diagnosis and the inhibitor titer can be determined using the Bethesda assay.

Treatment — Acute severe bleeding due to a factor V inhibitor may be life-threatening. For
those patients who survive the acute bleeding episode, the prognosis is generally excellent [93].
Most inhibitors disappear within a period of months; it is not clear if immunosuppressive therapy
accelerates this response.

Treatment modalities for acutely bleeding patients include platelet transfusions, plasma exchange
[92,93], and intravenous immune globulin (IVIG) [102,103]. For serious bleeding, we suggest the
use of platelet transfusions and plasma exchange; such patients should also receive
immunosuppressive therapy with prednisone and cyclophosphamide, as described above in
patients with factor VIII inhibitors; rituximab has also been used successfully in a few patients with
acquired factor V inhibitors refractory to other therapy [104] (see 'Treatment of factor VIII inhibitors'
above).

Factor VII inhibitors — Antibodies directed against factor VII are rare and only a small number of
cases have been reported [105-108]. As expected, the PT is prolonged but the aPTT is normal,
since factor VII is not involved in either the intrinsic coagulation pathway or the final common
pathway (table 2). Mixing studies will confirm the presence of an inhibitor; a low level or absence
of residual factor VII activity, especially after prolonged incubation (one hour) is necessary to
confirm the diagnosis.

The clinical manifestations in the few reported cases have ranged from minor bleeding to life-
threatening events such as intracranial hemorrhage [107,108]. One such patient did not improve
after IVIG but was successfully treated with cyclophosphamide, corticosteroids, and plasma
exchange [107]. This response is similar to that described for severe bleeding with other acquired
inhibitors.

Factor IX inhibitors — Acquired antibodies directed against factor IX in the absence of

hemophilia B are also very rare; two cases have been reported in the postpartum period [109-112].
The natural history is similar to factor V inhibitors. The role of immunosuppressive therapy is
uncertain, but one child seemed to respond to IGIV and dexamethasone [110].
Factor X inhibitors — Only three patients have been described with documented inhibitors
against factor X [113-115]. Other patients have presented with the sudden onset of bleeding,
prolonged PT and aPTT measurements, and transient, severe deficiency of factor X. There was
often an antecedent acute respiratory infection, and inhibitors were not conclusively demonstrated.

Amyloidosis can lead to deficiency of factor X due to binding of the protein to amyloid fibrils [116-
118]. In this disorder, other hemostatic defects probably also contribute to the bleeding [119]. (See
"Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL)
amyloidosis (primary amyloidosis)", section on 'Clinical presentation'.)

One well-characterized case of an acquired inhibitor involved the spontaneous appearance of an

autoantibody in an elderly man who presented with hemoptysis, hematuria, and bleeding into the
thigh after an intramuscular injection [115]. The patient was successfully treated with steroids with
disappearance of the inhibitor within two weeks. It is unclear if the inhibitor would have resolved
spontaneously had such therapy not been given.

Factor XI inhibitors — Factor XI autoantibodies not occurring in patients with congenital factor XI
deficiency are often associated with lupus erythematosus [120,121]. Affected patients usually have
little or no bleeding despite a prolonged aPTT that does not fully correct in a mixing study. The
relative lack of bleeding, which is also noted in congenital factor XI deficiency, probably reflects the
tertiary role for factor XI in factor X activation, although bleeding can occur under certain
circumstances. (See "Overview of hemostasis" and "Factor XI deficiency", section on 'FXI
inhibitors'.)

Factor XIII inhibitors — Activated factor XIII stabilizes and crosslinks overlapping fibrin strands.
Factor XIII inhibitors, which are exceedingly rare, can act by one of several mechanisms: inhibition
of activation of factor XIII; interference with enzymatic function; or prevention of binding to fibrin
[122,123]. (See "Overview of hemostasis", section on 'Continuation of the coagulation cascade'.)

The clinical hallmark of a factor XIII inhibitor is delayed bleeding after surgery or an invasive
procedure, since the initial clot which does form is mechanically weak and unstable. Large
spontaneous hematomas or intracranial hemorrhage can occur. Most patients are over age 50,
and death from bleeding is not uncommon [122,124]. As an example, in a review of 33 cases, nine
died of hemorrhage [124].

Factor XIII inhibitors can be associated with immune dysregulation. In one review, development of
an anti-factor XIII antibody was associated with systemic lupus erythematosus in a third of cases
[125]. Other associated conditions include other autoimmune disorders, lymphoid malignancies,
and some drugs [124,125].

Factor XIII inhibitors produce a unique pattern on coagulation testing. The PT and aPTT, which
measure fibrin generation, are normal, but the clot stability assay is abnormal, since the absence
of fibrin crosslinking causes the clot to lyse much more rapidly in 5 molar urea, 2 percent acetic
acid, or 1 percent monochloroacetic acid. In one review, clot solubility testing was used to make
the diagnosis in half of the patients, with the remainder diagnosed by a variety of other tests (eg,
Berichrom FXIII, which is a photometric assay for quantitative measurement of FXIII level) [124].
(See "Approach to the adult patient with a bleeding diathesis", section on 'Urea clot solubility'.)

Management typically involves immunosuppression; most patients have received

immunosuppressive therapies, including prednisone, cyclophosphamide, plasma exchange, IVIG,
rituximab, and/or infusion of factor XIII concentrates [126-130]. Reviews of patients with acquired
factor XIII antibodies have reported eventual disappearance of the antibodies in up to half of cases
[122,124].

SUMMARY AND RECOMMENDATIONS

● Acquired hemophilia results from the development of autoantibodies to the coagulation

factors. Antibodies to factor VIII are the most common, and their treatment has been more
extensively studied than that of other acquired inhibitors. (See 'Factor VIII inhibitors' above.)

● Acquired antibodies to the clotting factors are often diagnosed by mixing studies, in which
addition of patient plasma to normal plasma causes the relevant clotting test to become
abnormal due to the antibody. The clotting tests affected by each type of inhibitor are
discussed above.

● The most common conditions associated with the development of acquired factor VIII
inhibitors are rheumatic diseases, the postpartum period, malignancy, and some drugs. (See
'Epidemiology' above.)

● For patients with a low titer factor VIII inhibitor (eg, <5 Bethesda units) and active bleeding,
we suggest initial control of active bleeding using a human factor VIII product (recombinant
factor VIII or a factor VIII concentrate) rather than another product (Grade 2C). A typical dose
is 20 international units/kg intravenously for each Bethesda unit of the inhibitor, plus an
additional 40 international units/kg, with monitoring of factor VIII activity 10 minutes following
bolus injection, and repeat intravenous bolus dosing if the incremental recovery is not
adequate. (See 'Control of active bleeding' above.)

● For patients with a high titer factor VIII inhibitor (eg, ≥5 Bethesda units) and active bleeding,
we suggest using an activated prothrombin complex concentrate (aPCC; eg, factor VIII
inhibitor bypassing activity [FEIBA]) or recombinant human factor VIIa (rfVIIa) rather than a
human factor VIII product (Grade 2C). Human factor VIII generally cannot be given in high
enough amounts to overcome the inhibitor. Recombinant porcine factor VIIIa is also an option.
The choice of product depends on availability, initial or previous responses, and clinician
preference. (See 'Control of active bleeding' above.)

● To eliminate factor VIII inhibitors we recommend the use of prednisone at an initial oral dose
of 1 mg/kg per day in all patients (Grade 1B). Based upon weak evidence from the literature
and our own experience, we suggest that oral cyclophosphamide (2 mg/kg per day) be added
to the initial prednisone treatment regimen (Grade 2C). (See 'Eliminating the inhibitor' above.)

● Inhibitors of prothrombin are frequently associated with antiphospholipid antibodies.

Treatment of active bleeding is done with fresh frozen plasma (FFP). Modalities associated
with factor VIII antibodies may also be useful. (See 'Prothrombin (factor II) inhibitors' above
and 'Treatment of factor VIII inhibitors' above.)

● Inhibitors of thrombin can develop in patients exposed to bovine thrombin, or in patients with
autoimmune diseases. Antibodies provoked by exposure to exogenous thrombin do not
always cause bleeding, while those associated with autoimmune disease can cause severe
bleeding. Although only anecdotal information is available for treatment, we suggest
immunosuppression and aggressive initial management including plasma exchange (Grade
2C). (See 'Thrombin (factor IIa) inhibitors' above.)
● Inhibitors of factor V tend to arise after exposure to exogenous clotting products such as
thrombin glue. The clinical phenotype can be quite variable. For serious bleeding, we suggest
the use of platelet transfusions and plasma exchange; such patients should also receive
immunosuppressive therapy with prednisone and cyclophosphamide (Grade 2C). (See 'Factor
V inhibitors' above.)

● Inhibitors of factors VII, IX, X, XI, and XIII are exceedingly rare. Suggested treatment for
these conditions includes cyclophosphamide, corticosteroids, and plasma exchange (Grade
2C). Infusion of coagulation factor concentrates, where available (eg, factor XI and factor XIII)
may also be helpful. (See 'Other coagulation factor inhibitors' above.)

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due to factor XIII deficiency". As many as 12 cases with haemorrhagic acquired factor XIII
deficiency due to its inhibitors were recently found in Japan. Thromb Haemost 2011;
105:925.

Topic 1305 Version 24.0

GRAPHICS

Clinical manifestations of bleeding disorders

Bleeding disorder

Bleeding Clotting factor

symptoms Platelet defects (qualitative or deficiencies (eg, factor
quantitative) VIII or factor IX
deficiencies)

Overview of Mucocutaneous bleeding Deep tissue bleeding

bleeding events (oral cavity, nasal, gastrointestinal, (including joints and
and genitourinary sites) muscles)

Excessive bleeding Yes Not usually

after minor cuts

Petechiae Common Uncommon

Ecchymoses Generally small and superficial; may be May develop large

significant, depending upon the defect or subcutaneous and soft tissue
degree of thrombocytopenia hematomas

Hemarthroses, Uncommon Common in severe

muscle hematomas deficiency states or in
association with injury in
those with mild to moderate
deficiency states

Bleeding with Often immediate, with degree of bleeding
invasive dependent upon the severity of the defect,
procedures, ranging from none (eg, mild degrees of
including surgery thrombocytopenia or mild platelet function
defect) to mild to severe (eg, Glanzmann
thrombasthenia)
May be associated either
with procedural bleeding or
delayed bleeding, depending
upon the type and severity
of the defect

Graphic 77834 Version 10.0

Causes of a prolonged prothrombin time (PT) and/or a prolonged
activated partial thromboplastin time (aPTT)

Test result
Causes of test result pattern
PT aPTT

Prolonged Normal Inherited

Factor VII deficiency

Acquired

Mild vitamin K deficiency

Liver disease

Warfarin administration*

Acquired inhibitor of factor VII

Lupus anticoagulant (more commonly causes isolated prolonged aPTT; may

be associated with thrombosis rather than bleeding)

Normal Prolonged Inherited

Deficiency of factors VIII, IX, or XI

Deficiency of factor XII, prekallikrein, or HMW kininogen (not associated

with a bleeding diathesis)

von Willebrand disease (variable)

Acquired

Heparin administration*

Inhibitor of factors VIII, IX, XI, or XII

Acquired von Willebrand disease

Lupus anticoagulant (may be associated with thrombosis rather than

bleeding)

Prolonged Prolonged Inherited

Deficiency of prothrombin, fibrinogen, or factors V or X

Combined factor deficiencies

Acquired

Liver disease

Disseminated intravascular coagulation

Supratherapeutic doses of anticoagulants

Severe vitamin K deficiency

Combined heparin and warfarin administration

Direct thrombin inhibitor administration (eg, argatroban, dabigatran)*

Direct factor Xa inhibitor administration (eg, rivaroxaban, apixaban,

edoxaban)

Fondaparinux administration (slight prolongation)

Inhibitor of prothrombin, fibrinogen, or factors V or X

Primary amyloidosis-associated factor X deficiency

Anticoagulant rodenticide poisoning

 Refer to UpToDate topics on use of coagulation tests and on evaluation of patients with bleeding or
specific inherited and acquired conditions for additional details.

PT: prothrombin time; aPTT: activated partial thromboplastin time; HMW: high molecular weight.
* The most common effects of the anticoagulants are shown. In principle, many anticoagulants affect
common pathway factors and can prolong both the PT and the aPTT if present at high enough levels. As
examples:
◾ Warfarin typically prolongs the PT alone, but at high levels warfarin can prolong both tests.
◾ Heparin typically prolongs the aPTT alone (because PT reagents contain heparin-binding agents that
block heparin effect), but at high levels heparin can prolong both tests.
◾ Direct thrombin inhibitors typically prolong both tests, but at low levels dabigatran may not prolong the
PT.

Graphic 79969 Version 8.0

Contributor Disclosures
Steven Coutre, MD Nothing to disclose Lawrence LK Leung, MD Nothing to disclose Jennifer
S Tirnauer, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements for
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