Keywords acquired hemorrhagic disorder - autoimmune disease - anticoagulation factor autoantibody
- coagulation factor inhibitor - designated intractable disease
The clotting cascade involves approximately 10 coagulation factors ([Fig. 1 ]),[1 ]
[2 ] with von Willebrand factor (VWF) playing a crucial role in connecting subcutaneous
tissue and platelets, or multiple platelets, while also binding and stabilizing factor
VIII (FVIII).[3 ]
[4 ] Factor XIII (FXIII) serves to covalently connect fibrin molecules or fibrin and
antifibrinolytic factor α2 -plasmin inhibitor (α2 -PI) through cross-linking to stabilize platelet/fibrin clots and enhances their mechanical
strength and antifibrinolytic resistance.[5 ]
[6 ] VWF is present as a series of multimers to which various molecules are linked, whereas
FXIII exists in blood as a heterotetramer comprising a dimer of the FXIII-A subunit
and a dimer of the FXIII-B subunit.
Fig. 1 Coagulation pathways and autoantibodies against coagulation factors. Anticoagulation
factor autoantibodies against any coagulation factors can be produced. However, higher
molecular weight coagulation proteins, such as FVIII, FXIII, FV, and VWF, have wider
surfaces, and thus, they may have more epitopic sites, judging from the actual numbers
of the patients with AiF8D, AiF13D, AiF5D, and AiVWFD. Activated coagulation factors
are shown in red. α-F* Ab, anti-F* autoantibody; AiF5D, AiF8D, AiF13D, AiVWFD, and
AiF10D, autoimmune factor V, factor VIII, factor XIII, von Willebrand factor, and
factor X deficiencies, respectively; Fbg, fibrinogen; Fbn, fibrin; HWM-K, high molecular
weight-kininogen; P-PreKal, plasma prekallikrein; PL, phospholipid; PR, prothrombin;
TF, tissue factor; THR, thrombin; VWF, von Willebrand factor; XIII, factor XIII; XIIIa,
activated factor XIII; XL-, crosslinked.
Hereditary coagulation factor deficiency (CFD) arises from an inherited deficiency
of any of these coagulation factors; these deficiencies block the formation of platelet/fibrin
clots, resulting in impaired hemostasis and abnormal bleeding.[7 ]
[8 ]
[9 ] Acquired CFDs (acCFD) may also occur due to low production, increased consumption,
or increased elimination of coagulation factors. Although rare, autoantibodies against
coagulation factors may be generated ([Fig. 2 ]), resulting in severe bleeding disorders,[10 ]
[11 ]
[12 ]
[13 ] known as autoimmune acCFDs (AiCFDs).[14 ]
[15 ]
Fig. 2 Pathological mechanisms of anticoagulation factor antibodies (concept). Inhibitory
type antibodies bind to the active site, activation (cleavage) site(s), and/or substrate
binding site(s) of coagulation factors to inhibit these functions, whereas hyperclearance
type antibodies bind nonfunctional site(s) of coagulation factors and exclusively
enhance their elimination from the blood circulation. Some antibodies possess both
inhibitory and hyperclearance natures. There may also be harmless autoantibodies that
simply bind to coagulation factors (innocuous binding type).
We initiated a nationwide survey on autoimmune FXIII deficiency (AiF13D) in 2009 with
support from the Japanese Ministry of Health, Labor and Welfare (MHLW). Subsequently,
AiF13D was first established as a designated intractable disease (DID)-288. Following
this, autoimmune VWF deficiency (AiVWFD) and autoimmune FVIII deficiency (AiF8D or
acquired hemophilia) were added ([Table 1 ]). Later, autoimmune factor V (FV) deficiency (AiF5D) and autoimmune factor X (FX)
deficiency (AiF10D) were added, and patients with these five types of intractable
bleeding diseases became eligible to receive medical and financial support through
the Public Medical Expense Subsidy Program for MHLW-DIDs. While lupus anticoagulant-hypoprothrombinemia
syndrome[16 ]
[17 ] is also a disease subject to investigation by the Japanese Collaborative Research
Group (JCRG), it has not as yet been added to DID-288 by the Japanese MHLW.
Table 1
Summary of geographic characteristics of 5 Japanese Designated Intractable Diseases
Japanese DID code
288–1
288–2
288–3
288–4
288–5
Disease name
AiF13D
AiF8D
AiVWFD
AiF5D
AiF10D
Number of patients
125 (2021)
Not available
Not available
Not available
26 (2021)
Patients in Japan
87 (2021)
2,548 (estimated)
40 (2021)
201 (2021)
3 (2022)[26 ]
Incidence in Japan (mil/y[a ])
0.044
1.83
Not calculable
0.038
Not calculable
Age (mean, SD)
71.8, 12.6 y
66.2, 18.3 y
55.0, 19.0 y
71.9, 11.9 y
56.5, 22.7 y
Age (median)
73 y
73 y
60 y
74 y
59 y
Sex ratio (male/female)
1.77
1.50
0.86
2.81
2.71
Underlying disease
None (idiopathic); 51%
None (idiopathic); 56%
Autoimmune; 29%
None (idiopathic); 29%
None (idiopathic); 35%
Autoimmune; 17%
Autoimmune; 16%
MGUS; 26%
Cancer; 19%
Infection; 25%
Cancer; 13%
Malignancies; 12%
Multiple myeloma; 18%
Infection; 19%
Severe burn; 8%
Infection; 9%
Pregnancy; 4%
None (idiopathic); 3%
Autoimmune; 11%
Inf. bowel dis.; 8%
Bleeding sites/symptoms
(+ ; % of 71 events)
Intramuscular; 66%
Subcutaneous; 37%+
Epistaxis; 35%
Subcutaneous; 27%
Subcutaneous; 65%
Subcutaneous; 59%
Intramuscular; 30%+
Gastrointestinal; 30%
Urinary; 24%
Gastrointestinal; 62%
Postsurgical; 16%
Intracranial; 3%+
Oral; 28%
Gastrointestinal; 20%
Urinary; 52%
Retro-, intraperitoneal; 15%
Epistaxis; 1%+
Subcutaneous; 28%
Postsurgical; 11%
Oral; 31%
Intracranial; 8%
Intra-articular; 1%+
Intracranial; 0%
(Thrombosis; 5%)
−
Bleeding severity (grade)
Grade III (severe); 84%
Severe; 76%
Grade III (severe); 25%
Grade III (severe); 41%
Grade III (severe); 70%
Grade 0 (none); 0%
Grade 0 (none); 0%
Grade 0 (none); 15%
Grade 0 (none); 30%
Grade 0 (none); 8%
Factor activity (C); mean, SD
Median
FXIII:C; 7.2, 6.9%
FVIII:C; 2.5, 1.8%
VWF:RCo; 10.3, 9.7%
FV:C; 2.9, 2.9%
FX:C; 5.7, 6.5%
FXIII:C; 5%
FVIII:C; 2%
VWF:RCo; 6%
FV:C; 3%
FX:C; 3.5%
Factor antigen (Ag); Mean, SD
FXIII:Ag; 56.4, 49.3; 45.5 (median)%
FVIII:Ag; 47, 29%[33 ]
VWF:Ag; 31.2, 58.3%
FV:Ag; 75.4, 14.4%[33 ]
FX:Ag; 31.9, 44.1%
Specific activity (C/Ag); mean, SD
0.46, 0.64; 0.18 (median)
0.04, 0.03; 0.03 (median)[33 ]
1.0, 1.7; 0.7 (median)
0.08, 0.12; 0.03 (median)[33 ]
0.26, 0.17; 0.21 (median)
Associated abnormal test; mean
FXIII:C of 1:1 mixing; 20.9%
Inhibitor titer; 47.0 BU/mL
Inhibitor titer; 3.5 BU/mL
Inhibitor titer: 46.3 BU/mL
Inhibitor titer: 1.6 BU/mL
Inhibition potential; 37.9%[34 ]
Prolonged aPTT; 91.2 s
Reduced FVIII act; 18.6%
Prolonged PT; 56.3 s
Prolonged PT; 74.6 s
Reduced XL-α2 -PI; 7.6%
–
Prolonged aPTT; 62.6 s
Prolonged aPTT; 145.8 s
Prolonged aPTT; 86.4 s
–
–
Prolonged BT; 13.3 min
–
–
Abnormal test; % of total
(of tested)
–
–
–
Mixing test (+); 85%
Mixing test (+); 83%
–
–
–
Normotest (−); 89%
–
–
LA positive; 6%[33 ]
Reduced large multimer; 53% (91%)
Unmeasurable LA; 4% (54%)[33 ]
Unmeasurable LA; 4%
Autoantibody positive (of tested)
Anti-FXIIIA; 79%, anti-FXIIIB; 13%[23 ]
Anti-FVIII; 100%[33 ]
Anti-VWF; 68% (93%)
Anti-FV; 18% (90%)
Anti-FX; 35% (82%)
Inhibitory type (of tested)
87%[40 ]
100%[33 ]
80% (94%)
85% (92%)
75% (56%)[25 ]
[26 ]
Non-neutralizing type[b ] (of tested)
13% (7%, type B)[40 ]
0%[33 ]
5% (6%)
15% (8%)
25% (44%)[25 ]
[26 ]
Note
–
Unprolonged PT
Unestablished anti-VWF Ab detection assay
Cooccurrence of LA
–
–
–
–
Inhibitor (−) and auto-Ab (+) cases
–
References
[14 ]
[18 ]
[19 ]
[20 ]
[23 ]
[34 ]
[40 ]
[41 ]
[42 ]
[21 ]
[33 ]
[24 ]
[43 ]
[22 ]
[33 ]
[15 ]
[25 ]
[26 ]
Abbreviations: Ab, antibody; AiF5D, AiF8D, AiF13D, AiVWFD, and AiF10D, autoimmune
factor V, factor VIII, factor XIII, von Willebrand factor, and factor X deficiencies;
aPTT, activated partial thromboplastin time; BT, bleeding time; Inf. bowel dis., inflammatory
bowel disease; LA, lupus anticoagulant; MGUS, monoclonal gammaglobulinemia with undetermined
significance; PI, plasmin inhibitor; PRT, prothrombin; PT; prothrombin time; SD, standard
deviation; XL, cross-linked.
a Million people/year.
b Predominantly hyperclearance type.
Compared with “nonimmune” acCFDs, AiCFDs are very rare, posing diagnostic and therapeutic
challenges even to hematologists. Given this rarity, disease-specific tests have not
become generally available, making definitive diagnosis and initiation of optimal
treatment difficult. Diagnosis of AiCFD is not possible based on bleeding symptoms
alone; unless unique disease-specific tests are performed, patients will be diagnosed
with a “bleeding disorder of unknown cause.”
In this review, we aim to summarize the results of our surveys and studies conducted
on five AiCFDs in Japan and compare their characteristic clinical features, laboratory
findings, and treatment methods.[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] This evidence-based comprehensive review may contribute to facilitating earlier
diagnosis and treatment of AiCFDs.
Clinical Features and Diagnosis
Clinical Features and Diagnosis
Number and Frequency of Autoimmune Coagulation Factor Deficiency Cases
AiF8D is the most common among all AiCFDs. Deriving an estimate from the number of
patients diagnosed with AiF8D in “G prefecture” (population: 1.93 million; as of October
1, 2021), we inferred that approximately 2,550 people were affected in Japan (population:
∼126 million; as of October 1, 2021)[21 ] ([Table 1 ]).
For AiCFDs other than AiF8D, the actual numbers of affected patients are known, as
confirmed by our research group (JCRG), and are all smaller than the number of patients
with AiF8D. By the end of December 2021, a total of 201 and 87 cases of AiF5D[22 ] and AiF13D,[14 ]
[18 ]
[19 ]
[20 ]
[23 ] respectively, and 40 cases of AiVWFD were identified.[24 ] As only three cases of AiF10D in Japan were reported,[26 ] we conducted a comprehensive literature search on AiF10D patients worldwide and
discussed all 26 cases reported.[15 ]
[25 ] In Japan, the estimated annual incidence of AiF8D, AiF13D, and AiF5D was 1.83 (G
prefecture only),[21 ] 0.044, and 0.038 cases per million people/year,[23 ] respectively.
The target antigens of the autoantibodies directly responsible for AiF13D, AiVWFD,
AiF8D, and AiF5D are FXIII, VWF, FVIII, and FV, respectively. The molecular weights
of these proteins are much higher than that of other proteins such as FX, which are
typically in the range of tens of kilodaltons, suggesting that these proteins have
a larger surface area and therefore potentially more target sites (epitopes) for antibodies
to bind to.
Age and Sex
The number of diagnosed AiCFD cases is gradually increasing, parallel with the increased
aging of the population.[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] The median age at diagnosis of AiF13D, AiF8D, and AiF5D was in the 70s.[21 ]
[22 ]
[23 ] Approximately 50% of AiF13D and AiF8D were idiopathic, suggesting aging itself as
a contributing factor to onset. For AiVWFD and AiF10D, the median age at diagnosis
was in the 60s,[15 ]
[24 ] approximately 13 years younger than that of the other three AiCFDs. The reason for
this age difference is unknown. AiVWFD often occurs in myelo- and lymphoproliferative
diseases and multiple myeloma,[24 ] whereas AiF10D includes young patients with infections and severe burns,[15 ] which may be contributing factors. Additionally, AiF8D includes pregnancy-related
cases,[21 ] and thus, one of the characteristics is a small peak in the age of onset of this
disease in young women of childbearing age.[27 ] AiF5D and AiF10D are three times more common in men than in women[15 ]
[22 ]; however, the underlying cause for this sex-related disparity is unknown.
Etiology
More than half of AiF13D[23 ] and AiF8D[21 ] cases and approximately 30% of AiF5D[22 ] and AiF10D[15 ] cases are idiopathic, whereas idiopathic AiVWFD cases are extremely rare.[24 ] Other autoimmune diseases (e.g., 13 cases with systemic lupus erythematosus among
a total 379 AiCFD cases) similar to AiCFD are observed in 10 to 30% of individuals
with all AiCFDs except AiF10D.[15 ] Malignant tumors/cancers are observed in 10 to 20% of individuals with AiF13D, AiF8D,
and AiF5D but not in those with AiVWFD[24 ] and AiF10D[15 ]
[25 ]; plasma cell neoplasms (monoclonal gammopathy of undetermined significance, multiple
myeloma) occur in 43% of individuals with AiVWFD.[24 ] Regarding AiF10D, 25% of individuals have infections.[15 ]
[25 ] A single pregnant young woman was found to have AiF8D,[21 ] as previously mentioned.
Autoimmune diseases, neoplastic diseases, infectious diseases, and pregnancy cause
chronic, acute, and recurrent disturbances in immune and inflammatory responses, which
may lead to the breakdown of immune tolerance. In AiF13D and AiF8D, involvement of
human leucocyte antigen (or histocompatibility)-related genes has been reported,[28 ]
[29 ] indicating the importance of genetic factors. Immune- and tumor-related inflammatory
markers are correlated to AiF13D and AiF8D, which has been demonstrated by proteomic
analysis of patient plasma specimens,[30 ] suggesting that both environmental and genetic factors contribute to the onset of
AiF13D and AiF8D. Consequently, AiF13D and AiF8D are considered to be a multifactorial
disease.
Bleeding Symptoms, Sites, and Severity
Bleeding is the main symptom of all AiCFDs; although there are no distinct bleeding
symptoms or bleeding sites specific to a particular disease, each has some specific
characteristics that can help with diagnosis.[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] For example, the proportion of intramuscular hemorrhage was higher in AiF13D and
AiF8D (66 and 30%, respectively) than in other AiCFDs. In contrast, subcutaneous hemorrhage
was observed in a high proportion of AiF10D and AiF13D (65 and 59%, respectively);
however, this symptom is nonspecific, because it occurs in approximately 30% of other
AiCFDs.
Epistaxis was observed in 35% of AiVWFD cases,[24 ] but not in AiF8D (1%)[21 ] or other AiCFDs and is a relatively specific symptom for AiVWFD. In AiVWFD and AiF10D,
gastrointestinal and oral hemorrhages are common (mucocutaneous hemorrhages are predominant).[15 ]
[24 ] Gross hematuria including kidney hemorrhage was observed in 52 and 24% of AiF10D
and AiF5D cases,[15 ]
[22 ] respectively. Conversely, intra-articular hemorrhage was rarely observed, even in
AiF8D,[21 ]
[27 ] aiding in distinguishing it from (hereditary) hemophilia A. Fatal central nervous
system hemorrhage and peritoneal/retroperitoneal hemorrhage were associated with AiF13D
and AiF8D, requiring caution.[14 ]
[21 ]
The following proportions of severe bleeding (Grade III: defined as “spontaneous major
bleeding: hematomas [hospitalization required], hemarthrosis, central nervous system,
gastrointestinal and umbilical cord bleeding) were observed as per the bleeding severity
classification of the International Society on Thrombosis and Haemostasis-Scientific
and Standardization Committee[31 ]: AiF13D (84%), AiF8D (76%), AiF10D (70%), AiF5D (41%), and AiVWFD (25%). AiF5D and
AiVWFD are therefore considered moderate to mild bleeding disorders. Notably, AiF10D
had a higher bleeding severity than “hereditary” F10D.[15 ] In contrast, the proportion of bleeding-free (grade 0) cases was 0% for AiF13D and
AiF8D,[14 ]
[21 ] whereas 8, 15, and 30% of AiF10D, AiVWFD, and AiF5D, respectively, were diagnosed
without bleeding symptoms (cases were “captured” due to abnormal laboratory findings
identified by attending physicians).
In AiF5D, thrombosis was observed to occur in 5% of cases,[22 ] but other AiCFDs such as AiF13D also had such complications[32 ]; therefore, attention toward possible thrombosis risk should be paid to AiF5D in
addition to other AiCFDs. Presumably, administration of activated coagulation factor
preparations (such as recombinant activated factor VII [rFVIIa] and activated prothrombin
complex concentrates [APCC]) and/or inhibition of anticoagulant properties by anticoagulation
factor autoantibodies (e.g., activated protein C cofactor function of FV inhibited
by anti-FV autoantibodies) and/or a coexisting vascular disorders were involved in
the cause of thrombosis.
Abnormal Laboratory Findings Important for Diagnosis
A critical item in the diagnosis of AiCFD was the result of the clotting/coagulation
test. A drastic decrease in any coagulation factor results in bleeding and a definitive
diagnosis can be reached by searching for abnormalities in the coagulation cascade
according to the algorithm described later ([Fig. 3 ]).
Fig. 3 Algorithm for laboratory tests and diagnosis of AiCFDs. When physicians meet new
patients with bleeding who have no family and past histories of hemorrhagic tendency,
or excessive anticoagulation, the activities (as well as antigen levels, if possible)
of coagulation factors should be measured. When patients' coagulation factor activities
are unexplainably low, detailed functional and immunological examinations are highly
recommended to definitively diagnose AiCFDs. Orange lines indicate options for the
detection of patients with non-neutralizing coagulation factor antibodies. It is important
to understand that autoantibodies to coagulation factors and autoantibodies to phospholipids
(e.g., LA) can simultaneously coexist in one patient and may interfere with each other.
If the attending physician of a patient with unexplained bleeding follows the pink,
green, and blue lines, he or she may arrive at a diagnosis of AiF13D and AiVWFD, AiF5D
and AiF10D, and AiF8D, respectively. * (with a large red triangle), aPTT is often
prolonged in patients with AiVWFD. AiCFD, autoimmune coagulation factor deficiencies;
F2, 5, 7, 8, 9, 10, 11, and 13, factor II, V, VII, VIII, IX, X, XI, and XIII; aPTT,
activated partial thromboplastin time; DIC, disseminated intravascular coagulopathy;
DOAC, direct oral anticoagulants; LA, lupus anticoagulant; N, normal; PAI-I, plasminogen
activator inhibitor type I; PT, prothrombin time; VWF, von Willebrand factor; XMT,
cross-mixing test.
The coagulation factor activity (F*:C), the “core test” that represents the direct
cause of bleeding in each AiCFD, was markedly decreased without exception ([Table 1 ]).[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] Additionally, the amount of coagulation factor antigen (F*:Ag) was often reduced
by varying degrees. As a result, specific activity, defined as the ratio of coagulation
factor activity to the amount of coagulation factor antigen (F*:C/F*:Ag), was also
reduced by varying degrees in most cases because F*:C often decreases more severely
than F*:Ag due to inhibitory type antibodies ([Fig. 2 ]).[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ] For example, in AiF8D[21 ] and AiF5D,[22 ] coagulation factor activity (F*:C) were markedly decreased compared with the slight
decrease in antigen amount (F*:Ag),[33 ] resulting in remarkably low specific activity ([Fig. 2 ]; Inhibitory type antibody).
However, depending on the characteristics of autoantibodies against the coagulation
factor, elimination (clearance) of the coagulation factor itself may be predominantly
or selectively promoted ([Fig. 2 ]; Non-Inhibitory-Hyperclearance type antibody and Inhibitory-Hyperclearance type
antibody). Consequently, the coagulation factor antigen level and activity may decrease
in parallel at the same time. As a result, specific activity often remains normal,
i.e., approximately 1.0 (such as in AiVWFD,[24 ]
[Table 1 ]).
As FVIII is an intrinsic coagulation factor and FV and FX act in the common clotting
pathway, their decreased activity was confirmed by isolated prolongation of activated
partial thromboplastin time (aPTT) for AiF8D and concomitant prolongation of aPTT
and prothrombin time (PT) for AiF5D and AiF10D.
FXIII acts on the fibrin cross-linking reaction after clotting occurs, whereas VWF
acts on the platelet aggregation reaction; specific measurements, such as transglutaminase
activity in AiF13D and Ristocetin cofactor activity (VWF:RCo) in AiVWFD, are decreased
respectively, in almost all cases.[24 ]
[34 ] In AiF13D, a test that mixes plasma specimens of patients and healthy controls in
a ratio of 1:1 (mixing test, MXT), demonstrated that inhibition (inhibitor) is detected
based on decrease in residual FXIII:C in the mixed samples. In addition, the strength
of the inhibitor was confirmed by the degree of inhibition, and reduction in FXIII:C
was also indirectly confirmed by a reduction in the amount of cross-linked α2 -PI.[34 ]
[35 ]
In AiF8D, aPTT was significantly prolonged owing to the decrease in FVIII:C, and residual
FVIII:C was markedly decreased when patient samples diluted in various ratios were
mixed with control plasma samples (Bethesda inhibitor assay), indicating a high inhibitory
potency.[33 ] In AiVWFD, a secondary FVIII:C decrease, consequent prolongation of aPTT, and absence/decrease
in high-molecular-weight VWF multimers were observed.[24 ] In particular, AiVWFD is characterized by prolonged bleeding time, a decrease in
VWF:RCo, and low VWF:Ag.
In AiF5D and AiF10D, simultaneous prolongation of aPTT and PT, positive MXT, and high[22 ] and low[15 ]
[26 ] titers, respectively, in the Bethesda assay are common abnormal findings. However,
AiF5D is characterized by a normal Normotest (Hepaplastintest; Complex factor H“Kokusai” , Sysmex Corp., Kobe, Japan).[22 ]
[36 ]
[37 ] Approximately 4% of patients with AiF5D reported unmeasurable for lupus anticoagulant
(LA)[22 ] because of extremely prolonged clotting times,[33 ] thereby requiring diagnostic caution.[38 ] For example, 8 out of 13 (54%) of AiF5D patients had a diluted Russell viper venom
time (dRVVT) of more than 200 and 130 seconds (T1 without excess phospholipid and
T2 with excess phospholipid, respectively) measured by a commercial laboratory service
(SRL Ltd., Hachioji, Japan) using the LA Test Gradipoa (MBL, Ina, Japan; reference
range of T1/T2, <1.3). In contrast, all 18 AiF8D patients showed a T1 of dRVVT between
35.8 and 82.7 seconds and a T2 of dRVVT between 35.3 and 75.4 seconds (mean and standard
deviation of T1/T2; 1.15 and 0.11).[33 ]
Laboratory Findings Essential for Definitive Diagnosis
Anti-coagulation factor autoantibody positivity is a requirement for a “definite”
diagnosis, and coagulation factor inhibitor positivity is a requirement for a “probable”
diagnosis of AiCFDs[14 ]
[22 ]
[24 ]
[39 ] ([Table 1 ]).
Autoantibodies were positive in most cases tested for detection. Specifically, in
AiF13D, autoantibodies for FXIII-A subunit (FXIII-A), autoantibodies for FXIII-B subunit
(FXIII-B), and autoantibodies for native FXIII-A (Aa type) and autoantibodies against
activated FXIII-A (Ab type) were positive, all of which were detected using published
methods.[40 ]
[41 ]
[42 ] An autoantibody detection test performed at our laboratory using a commercial kit
(Zymutest Anti-FVIII IgG MonoStrip, Hyphen BioMed, Neuville sur Oise, France) was
positive in all AiF8D.[33 ] Autoantibodies detection methods for AiF5D and AiVWFD, although not standardized,[43 ] were positive in most cases.[24 ]
[33 ] The autoantibodies detection method for AiF10D, immunological laboratory tests that
are not commercially available (e.g., enzyme-linked immunosorbent assay [ELISA], radioimmunoassay,
western blotting, and/or crossed immune electrophoresis),[26 ]
[44 ]
[45 ] showed a positive rate of 82% (9 of 11 patients).
For coagulation factor inhibitors, indirect cross-MXTs using aPTT or PT (aPTT- or
PT-based cross-MXT) and factor-specific cross-MXTs using individual coagulation factor
activity assays or Bethesda assay-like titration have been performed.
In AiF13D, 87% of autoantibody positives were inhibitory, whereas 13% were noninhibitory
when tested using 1:1 MXT or five-step dilution cross-MXT[23 ]
[34 ]
[40 ]; Anti-FXIII autoantibodies that cause this disease are classified into three types:
type Aa inhibits the heterotetramer assembly and activation of FXIII; type Ab inhibits
the enzymatic activity of activated FXIII; and type B enhances the elimination of
FXIII from the blood.[40 ] Type B autoantibodies were 4%, and the remaining 9% were considered to be of the
noninhibitory hyperclearance type ([Fig. 2 ]).
AiVWFD was also tested with factor-specific MXT, and 6% of autoantibody-positive results
were of the “non” inhibitory type.[24 ]
AiF8D and AiF5D had high antibody titers (mean: 47 and 46.3 BU/mL, respectively) in
functional assays,[21 ]
[22 ] whereas AiVWFD and AiF10D had low titers (mean: 3.5 and 1.6 BU/mL, respectively)
in functional assays.[15 ]
[24 ]
In AiCFDs other than AiF8D, noninhibitory autoantibodies were also detected (44% in
AiF10D[25 ]
[26 ]); therefore, autoantibodies for each coagulation factor should be measured whenever
possible to prevent oversight.
Laboratory Testing and Diagnostic Algorithm
Laboratory Testing and Diagnostic Algorithm
The following steps are performed when diagnosing patients with unexplained bleeding
symptoms (especially older individuals) ([Fig. 3 ]; [Table 2 ]):
Table 2
Comparison of 5 Japanese Designated Intractable Diseases among autoimmune coagulation
factor deficiencies
Japanese DID code
288–1
288–2
288–3
288–4
288–5
Disease name
AiF13D
AiF8D
AiVWFD
AiF5D
AiF10D
Occurrence
Rarely
Not rarely
Very rarely
Rarely
Extremely rarely
Peak age
Early 70's
Later 60's
Mid 50's
Early 70's
Mid 50's
Sex difference
Male-dominant tendency
No sex difference
No sex difference
Male-dominant
Male-dominant
Underlying disease
Often idiopathic
Often idiopathic
Often plasma cell neoplasms
Not uncommon idiopathic
Not uncommon idiopathic
Not rarely autoimmune,
Not rarely cancer
Not rarely autoimmune,
Not rarely malignancies
Not uncommon autoimmune
Not rarely cancer,
Not rarely infection,
Not uncommon infection
–
Rarely pregnancy-related
Very rarely idiopathic
Not rarely autoimmune
Rarely severe burn
Bleeding sites/symptoms
Often intramuscular,
Often subcutaneous
Not uncommon subcutaneous, not uncommon intramuscular
Not uncommon epistaxis,
Not uncommon gastrointestinal
Not uncommon subcutaneous,
Not uncommon urinary
Often subcutaneous,
Often gastrointestinal
Not rarely retroperitoneal,
Not rarely intraperitoneal
Very rarely epistaxis,
Very rarely intra-articular
Not uncommon oral,
Not uncommon subcutaneous
Not rarely gastrointestinal
Often urinary
Rarely intracranial
–
Very rarely intracranial
Rarely thrombosis
Not uncommon oral
Bleeding symptoms
Mostly severe
Mostly severe
Not uncommon severe
Not uncommon severe
Often severe
No none-bleeding
No none-bleeding
–
Not uncommon none-bleeding
Rarely none-bleeding
Factor activity (C)
Always severely reduced
Always severely reduced
Always variably reduced
Always severely reduced
Always severely reduced
Factor antigen (Ag)
Mildly ∼ severely reduced
Mildly ∼ severely reduced
Mildly ∼ severely reduced
Mildly ∼ modestly reduced
Mildly ∼ modestly reduced
Specific activity (C/Ag)
Mostly reduced
Always severely reduced
Often variably reduced
Always reduced
Often variably reduced
Associated abnormal test (*; defined in ref. 34)
Mostly factor XIII 1:1 mixing test (+)
Always Severely Prolonged aPTT
Often low inhibitor titer
Always prolonged PT,
Always prolonged aPTT
Always prolonged PT,
Always prolonged aPTT
Mostly increased inhibitory potential*
Always mixing test (+)
Mostly high inhibitor titer
Often reduced large multimer
Mostly mixing test (+),
Mostly high inhibitor titer
Mostly mixing test (+),
Mostly low inhibitor titer
Often reduced XL-α2 -PI
(Often type II inhibitor)
Often reduced FVIII:C, often prolonged aPTT
Mostly hepaplastin test (−)
–
–
Rarely LA (+)
Mostly prolonged BT
Often unmeasurable LA
–
Autoantibody detection
Mostly anti-F13A (+), not rarely anti-F13B (+)
Always (+)
Often ∼ mostly (+)
Not rarely (+)
Not uncommon (+)
Inhibitor detection
Mostly (+)
Always (+)
Mostly (+)
Mostly (+)
Mostly (+)
Diagnostic criterion
JMHLW and ISTH/SSC
JMHLW
JMHLW
JMHLW
JMHLW
Definite diagnosis
Always antibody (+)
Always antibody (+)
Always antibody (+)
Always antibody (+)
Always antibody (+)
Probable diagnosis
Mostly inhibitor (+)
Mostly inhibitor (+)
Mostly inhibitor (+)
Mostly inhibitor (+)
Mostly inhibitor (+)
Differential diagnosis
Hereditary FXIII deficiency
Hereditary FVIII deficiency
von Willebrand disease
Hereditary FV deficiency (FVD)
Hereditary FX deficiency (FXD)
DIC (AAA, cancer, etc.)
AiVWFD
Other acquired VW syndrome
Nonimmune acquired FVD
AL-amyloidosis
Leukemia
–
–
Hereditary FX, PRT deficiency
Secondary FXD including DIC
–
Other AiCFDs
Other AiCFDs
Antiphospholipid syndrome
Other AiCFDs
Abbreviations: AAA, abdominal aortic aneurysm; AiCFD, autoimmune coagulation factor
deficiencies; AiF5D, AiF8D, AiF13D, AiVWFD, and AiF10D, autoimmune factor V, factor
VIII, factor XIII, von Willebrand factor, and factor X deficiencies; aPTT, activated
partial thromboplastin time; BT, bleeding time; DIC, disseminated intravascular coagulation;
ISTH/SSC, International Society on Thrombosis and Hemostasis; JMHLW, Japanese Ministry
of Health, Labor, Welfare; LA, lupus anticoagulant; PI, plasmin inhibitor; PRT, prothrombin;
PT; prothrombin time; XL, cross-linked.
Note: Order of frequency: always > mostly > often > not uncommon > not rarely > rarely > very
rarely > extremely rarely > no. (+), positive; (−), negative.
Confirm no prior history of abnormal bleeding, no family history, and no history of
administration (especially overdose) of anticoagulants/antiplatelets.
Check for any prolongation of PT and aPTT, and if there is no abnormality, examine
platelet count, FXIII:C, α2 -PI, plasminogen activator inhibitor type-1, and VWF:RCo. If any of these items are
abnormal, proceed to their specific evaluation in the next steps.
In case of prolongation of PT and aPTT, plasma samples of the patient and healthy
controls are mixed in several ratios to measure PT and aPTT (aPTT- and PT-based cross-MXTs)
and to determine whether the prolongation of PT and aPTT is corrected (normalized).
Simultaneously, prolonged clotting times should be classified into three types: PT
(extrinsic pathway) only, aPTT (intrinsic pathway) only, and both (common pathway).
The amounts of antigens of coagulation factors should be measured, because it is useful
for diagnosis.
If prolonged PT and aPTT was not corrected by MXT, the residual activity of the coagulation
factor whose activity was specifically decreased should be measured by mixing the
plasma samples of patients and healthy controls in a ratio of 1:1 or other ratios
(factor-specific MXT or cross-MXT) to determine the presence/absence of inhibition.
Inhibitor titer is measured by Bethesda (-like) assay, and if it is ≥ 0.5 (or 1.0
for AiF8D) BU/mL, the patient is determined to have a “probable” diagnosis of AiCFD.
Regardless of the presence or absence of inhibitors, anticoagulation factor autoantibodies
are tested, and if positive, a “definite” diagnosis of AiCFD is made.
Even if PT and aPTT are normal in the search in Step 2, follow the orange (and pink)
arrows ([Fig. 3 ]), and if a decrease in FXIII:C or VWF:RCo is observed in Step 4, check for them
in Step 5 (and hopefully in Step 6).
Differential Diagnosis
[Table 2 ] summarizes the characteristics of each aforementioned AiCFD. If the attending physician
proceeds with the “coagulological” examination according to the algorithm, the five
types of hemorrhagic DIDs can be delineated.
For all AiCFDs, hereditary CFD should be excluded based on conditions such as age
of onset, past history, family history, and lack of recovery of coagulation factor
after treatment.
Attention should be paid to AiF13D[14 ] because chronic disseminated intravascular coagulation is associated with aortic
aneurysms and malignant tumors,[46 ]
[47 ] which increase with age and result in decreased activity based on sustained consumption
of FXIII. However, even if an exclusion diagnosis can be made, it is often difficult
to cure the primary disease and control bleeding, especially in older individuals.
Decreased FXIII activity is also observed in leukemia but often not severe.
In AiF8D, characteristic intra-articular hemorrhage observed in hereditary hemophilia
A is absent,[21 ] and differentiation from AiVWFD is based on a severe decrease in FVIII:C with no
epistaxis and no decrease in VWF activity. It is important to distinguish AiVWFD from
“nonimmune” acquired von Willebrand syndrome—secondary to various causes and pathologies.
Testing to detect VWF autoantibodies is essential for a definitive diagnosis.[24 ] Since there is no standardized assay for detecting anti-VWF autoantibodies, we deemed
it positive if the results of two or more immunological test methods for detection
of anti-VWF autoantibodies (e.g., an ELISA using plasma-derived purified VWF and that
using recombinant VWF) matched.[43 ]
In AiF5D, the clotting time is markedly prolonged, and LA is often unmeasurable,[33 ] making differential diagnosis difficult. Irrespective of the presence of LA, a positive
diagnosis of AiF5D is confirmed if the anti-FV autoantibody is positive. Measurement
of antiphospholipid antibodies is also useful in differentiation.[22 ]
A low FX level may be secondary to AL-amyloidosis and should be considered as a differential
to AiF10D, as FX:C reduction is common in both.[15 ]
[48 ]
[49 ] In AiF10D, abnormal fibrinolytic parameters based on bleeding symptoms, especially
increased fibrin/fibrinogen degradation products (FDP) and D-dimer released from hematoma
clots, are also observed; the presence or absence of FX inhibitors and anti-FX autoantibodies
is decisive.[26 ] Absence of amyloid deposition on biopsy also contributes to the exclusion of AL-amyloidosis.
Treatment and Prognosis
All AiCFD treatments are centered on immediate cessation of bleeding by hemostatic
therapy and eradication therapy for autoantibodies that cause bleeding ([Table 3 ]). Radical therapy is essential when the underlying disease is clear; however, it
is often difficult to implement this therapy in older individuals.
Table 3
Summary of managements and outcomes of 5 Japanese Designated Intractable Diseases
(DIDs)
Japanese DID code
288–1
288–2
288–3
288–4
288–5
Disease name
AiF13D
AiF8D
AiVWFD
AiF5D
AiF10D
Diagnostic criterion
JMHLW and ISTH/SSC
JMHLW
JMHLW
JMHLW
JMHLW
Hemostatic therapy
None; 10%
None; 32%
None; 28%
None; 14%
None; 9%
Plasma-derived FXIII conc.; 80%
rFVIIa; 64%
FVIII/VWF conc.; 40%
Fresh frozen plasma; 42%
Fresh frozen plasma; 83%
Fresh frozen plasma; 19%
APCC; 12%
DDAVP; 32%
Platelet conc.; 15%
Vitamin K; 48%
–
(FVIII; 0%)
Cryoprecipitate; 8%
Vitamin K; 14%
PCC; 30%
(Antifibrinolytic; 27%)
–
(Antifibrinolytic; 12%)
PCC; 4%
rFVIIa; 13%
Antibody eradication
Therapy (not approved)
Prednisolone; 81%
Prednisolone; 96%
Prednisolone; 53%
Prednisolone; 73%
Prednisolone; 48%
(Cyclophosphamide; 27%)
(Rituximab; 16%)
(Cyclophosphamide; 3%)
(Steroid pulse; 14%)
(Steroid pulse; 22%)
(Rituximab; 18%)
Cyclophosphamide; 12%
(Rituximab; 3%)
(Cyclophosphamide; 5%)
(Rituximab; 13%)
(Steroid pulse; 14%)
–
(Chemotherapy; 13%)
–
(Cyclophosphamide; 9%)
None; 10%
None; 4%
None; 13%
None; 17%
None; 13%
Autoantibody reduction
Therapy
Plasma exchange; 4%
Plasma exchange; 0%
Plasma exchange; 3%
Plasma exchange; 17%
Plasma exchange; 35%
Immunoadsorption; 0%
–
–
–
–
Miscellaneous therapy
High-dose IVIG; 4%
High-dose IVIG; 0%
High-dose IVIG; 9%
High-dose IVIG; 0%
High-dose IVIG; 43%
Outcomes/prognosis
Recovery; 36%
Remission; 88%
Remission; 74%
Recovery; 74%
Recovery; 90%
Under treatment; 41%
Relapse; 12%
Relapse; 18%
(Spontaneous rec.; 11%)
(Spontaneous rec.; 0%)
–
–
–
Relapse; 11%
–
Death; 19%
Death; 28%
Death; 6%
Death; 15%
Death; 10%
Cause of death (% of death)
Hemorrhage; 14% (57%)
Hemorrhage; 0%
Hemorrhage; 0%
Hemorrhage; 7%
Hemorrhage; 5%
Infection; 9% (30%)
Infection; 28%
Aspiration pneumonia; 3%
Infection; 4%
Infection; 5%
Underlying disease; 1% (4%)
–
Underlying disease; 3%
Respiratory failure; 2%
–
Day to recovery
Not available
57.5 d
51.7 d
40.8 d
26.5 d
Note (not approved)
(rec. FXIII product)
Bispecific antibody preparation; Emicizumab
(Two rec.VWF products)
(rec. FV product)
(rec. FX product)
Therapy-resistant cases
–
–
–
(Plasma-der FX product)
References
[14 ]
[18 ]
[19 ]
[20 ]
[23 ]
[34 ]
[40 ]
[41 ]
[42 ]
[21 ]
[33 ]
[24 ]
[43 ]
[22 ]
[33 ]
[15 ]
[25 ]
[26 ]
Abbreviations: APCC, activated prothrombin complex concentrates; conc., concentrates;
DDAVP, 1-desamino-8-D-arginine vasopressin; IVIG, intravenous immunoglobulin; PCC,
prothrombin complex concentrates; rFVIIa, recombinant activated factor VII.
Hemostatic Therapy
In the case of severe bleeding or bleeding in vital organs, a preparation containing
a large amount of the deficient coagulation factor is immediately administered to
reduce pain caused by bleeding, symptoms of organ ischemia, anxiety, and other conditions.
Given the high possibility of exacerbation of symptoms by stimulating the production
of antibodies against the relevant coagulation factors, it is desirable to administer
preparations that bypass the deficient coagulation factors (bypass agents); however,
some products are not commercially available and/or cannot be obtained. In principle,
an immunosuppressive drug should be administered in tandem with the relevant coagulation
factor-containing drug.
Frozen fresh plasma (FFP) is used in emergencies when coagulation factor preparations
are not readily available; however, the amount of each coagulation factor contained
is 1 unit/mL or less, and a large amount of such blood products cannot be administered
as to avoid excessive circulating blood volume. It is not uncommon for patients with
mild bleeding to be followed up without hemostatic treatment (9–32%).
In AiF13D, purified FXIII concentrates derived from human plasma were used in 80%
of cases, and when they were not readily available, FFP was administered in 19% of
emergencies. Overall, 27% of AiF13D were treated with antifibrinolytics, as in AiF13D,
“FXIII with antifibrinolytic activity” is markedly reduced.[34 ]
rFVIIa and APCC are “bypass agents” often used to treat AiF8D. As bypass agents are
available, FVIII products are rarely administered.[21 ] It is also because the administered FVIII preparations are easily overwhelmed by
high-titer anti-FVIII autoantibodies, and hemostatic effects are rarely observed.
Recently, plasma-derived FX/FVIIa[50 ]
[51 ] and a so-called bispecific antibody preparation (Emicizumab; Hemlibra, Chugai Pharmaceutical
Co., Tokyo, Japan)[52 ] have been marketed and covered by health insurance for AiF8D.
In AiVWFD, FVIII/VWF concentrates derived from human plasma and desmopressin acetate
(DDAVP [1-desamino-8-D-arginine vasopressin]), which stimulate the release of VWF
from endothelial cells, were administered in 40 and 32% of cases,[24 ] respectively, probably because no clear bypass agents exist. In the past, cryoprecipitates
rich in macromolecular proteins such as VWF were sometimes used; however, these are
now limited to emergency cases where FVIII/VWF concentrates are unavailable.
In AiF5D, FFP was administered in 42% of cases[22 ]; FV is unstable, its concentrate is not commercially available, and a concentrated
platelet solution was used in 15% of cases. We recommend administration of the concentrated
platelet solution, because the granules of platelets contain a large amount of FV.[53 ] Vitamin K and prothrombin complex concentrates (PCC) are administered for emergency
treatment for serious bleeding; this is unavoidable, because it is often “before”
a definitive diagnosis.
In AiF10D, FFP was administered in 83% of cases, followed by vitamin K (48%) and PCC
(30%).[15 ] rFVIIa was administered in 13% of cases. FX, which is downstream to FVII in the
coagulation cascade, is drastically reduced; therefore, the use of recently marketed
plasma-derived FX/FVIIa concentrates is reasonable,[50 ]
[51 ]
[54 ] although not covered by insurance.
Autoantibody Eradication Therapy
As AiCFD is an autoimmune disease, it is rarely completely cured; to ameliorate the
deficiency of the coagulation factor, treatments aimed at stopping the production
of autoantibodies and eradicating them are essential. AiCFDs are mainly caused by
the breakdown of the maintenance mechanism of autoimmune tolerance; therefore, immunosuppressive
drugs are administered to suppress excessive immune reactions to self-coagulation
factors. In total, 96 and 81% of patients with AiF8D and AiF13D,[21 ]
[23 ] respectively, received regular doses of prednisolone, followed by 73, 53, and 48%
of patients with AiF5D, AiF10D, and AiVWFD, respectively.[15 ]
[22 ]
[24 ]
Steroid pulse therapy, a short-term high-dose prednisolone administration, was also
administered in 22 to 14% of AiF10D, AiF5D, and AiF13D cases.[15 ]
[22 ]
[23 ] However, prednisolone is not covered by insurance if the dosage is high. Cyclophosphamide
or rituximab was administered when normal doses of prednisolone did not achieve remission.
Cyclophosphamide was administered to 27% of patients with AiF13D, who often became
resistant to treatment,[14 ]
[39 ] and only 5 and 3% of patients with AiF5D and AiVWFD, respectively. Underlying plasma
cell neoplasms are common in AiVWFD,[24 ] and chemotherapy was performed in 13% of cases, and they reported improvement in
AiVWFD, confirming that the treatment of underlying disorders is the principle for
all AiCFDs.
Corticosteroids may not be administered in conditions such as infection, comorbid
diabetes, possible adverse events such as thrombosis, or asymptomatic cases; patients
in these cases may be followed up without treatment (10–17%). For AiF8D, 4% of the
patients were untreated.[21 ]
Autoantibody Reduction Therapy
Plasma exchange was performed in 35 and 17% of AiF10D and AiF5D cases,[15 ]
[22 ] respectively, to quickly reduce the autoantibody levels (antibody reduction therapy).
For these diseases, no concentrates of the relevant coagulation factors are available;
instead of factor replacement therapy, plasmapheresis can be used as it reduces antibodies
and makes it possible to replenish the relevant coagulation factors (as a large volume
of normal plasma is administered). In AiF13D, AiF8D, and AiVWFD, where coagulation
factor concentrates are available, plasma exchange is performed only in 0 to 4% of
cases.[14 ]
[21 ]
[24 ]
Antibody adsorption therapy—in which immunoglobulin (Ig), including autoantibodies,
is adsorbed to column beads to reduce levels quickly—has been practiced in some parts
of Europe and the United States, but not in Japan.
Antibody reduction therapy does not suppress autoantibody production but provides
a temporary reduction in autoantibody levels; however, it has the advantage of completing
the hemostatic process in the meantime.
Intravenous immunoglobulin (IVIG) therapy (intravenous administration of large doses
of Ig) has been performed in 43 and 9% of patients with AiF10D and AiVWFD,[15 ]
[24 ] respectively; however, no reports are available on its implementation in other AiCFDs.
It is assumed to block the Ig receptors on the cell surfaces of the reticuloendothelial
system and inhibit the removal of immune complexes.[55 ] IVIG has been reported to increase the plasma level of administered VWF for weeks.[56 ]
Treatment Results and Prognosis
Remission/recovery of AiCFD was good at 74 to 90%. However, with AiF13D, recovery
was noted in only 36% of patients, and 41% of patients have been under treatment for
more than a year.[14 ]
[39 ] Although the cause of this treatment resistance is unknown, FXIII-A is originally
an intracellular protein, and its antigenicity and antibody-inducing ability may differ
from those of other plasma proteins (FVIII, VWF, FV, and FX).
The time to remission/recovery was the longest for AiF8D (57.5 days),[21 ] shortest for AiF10D (26.5 days),[15 ] and intermediate for AiVWFD and AiF5D. In AiF13D, more patients remained under treatment
than who recovered, and the time to remission/recovery was not calculated.
In AiVWFD, AiF8D, and AiF5D, relapse/recurrence occurred in 18, 12, and 11% of cases,[21 ]
[22 ]
[24 ] respectively, necessitating long-term close follow-up. As most autoantibodies are
IgG, and the amount and ratio of subtypes IgG1 to IgG4 vary depending on the case,
the autoantibody IgG subtype may be related to inhibitor titer,[57 ] underlying diseases,[57 ]
[58 ] clinical course/symptoms,[57 ]
[59 ] and outcomes.[57 ]
The mortality rates of AiF8D, AiF13D, and AiF5D were 28, 19, and 15%, respectively,[21 ]
[22 ]
[23 ] a condition with a mortality rate of >10% qualifies as a “fatal disease.” AiF10D
and AiVWFD have mortality rates of 9.5 and 6%,[15 ]
[24 ] respectively. Every AiCFD requires a strict treatment protocol.
The mortality rate due to the primary disease was not high, at 3 and 1% for AiVWFD
and AiF13D, respectively. AiCFD reportedly undergoes remission after removal of the
underlying malignant tumor, confirming that treatment of the primary disease is crucial.
Cause of Death
Regarding the cause of death in AiCFDs, hemorrhagic death was the most common in AiF13D
at 14% (57% of all deaths),[14 ] followed by AiF5D and AiF10D at 7 and 4% in Japan, respectively. Conversely, AiF8D
and AiVWFD had no hemorrhagic deaths.[21 ]
[24 ] The hemorrhagic death rate for AiF8D substantially differs from that (50%) 10 years
ago,[60 ] suggesting progress in clinical practice.
Since nearly 40% of deaths in closely followed AiF13D cases occur early after onset
(within 3 months) owing to bleeding, bleeding control in the acute stage is critical
([Fig. 4 ]). Regarding recent deaths due to bleeding, because there were no cases marked “patient
dead on arrival of plasma sample[14 ]
[20 ]” and the recent hemorrhagic death rate was 42%[23 ] in 2022, lower than the previously reported rate of 71%[20 ] in 2015, early diagnosis and early treatment have seemingly become widely implemented
at least for AiF13D.
Fig. 4 Survival rate and cause of death in AiF13D cases. In total, 37 cases were followed
up closely, and the average period from onset to death was 24.1 (median = 41) months
for the 19 patients (51%) who died: 7 of 19 patients (37%) had died by 3 months, primarily
from bleeding (5/7, 71%). Three patients died 20, 41, and 112 months after onset owing
to gastrointestinal bleeding, intracranial + splenic bleeding, and intracranial bleeding,
respectively, after relapse. The causes of death in the remaining nine patients were
sepsis (5 patients), cancer (2 patients), intestinal rupture of unknown cause (1 patient),
and acute myocardial infarction (1 patient). Red oval, early death; brown oval, later
death.
All deaths in AiF8D (28% of patients) were due to infection,[21 ] compared with the 9 to 4% in other AiCFDs. This may be attributed to the adverse
effects of the immunosuppressive drugs used in almost all cases (96%) for autoantibody
eradication therapy, necessitating optimization of autoantibody eradication therapy.
Discussion, Limitations, and Residual Issues
Discussion, Limitations, and Residual Issues
Concept of Anticoagulation Factor Autoantibodies
The following are the causes of decreased coagulation factor activity ([Fig. 2 ]): (1) autoantibodies bind to coagulation factor proteins and complexes of the coagulation
factor proteins and autoantibodies (immune complexes) are rapidly removed from the
blood (hyperclearance type); (2) autoantibodies bind to the site involved in the activity
of the coagulation factors and inhibit their activity (inhibitor type); and (3) combination
of both of these (hyperclearance and inhibitor type).
Since autoantibodies are generally polyclones,[61 ]
[62 ] these three types are present in varying proportions in a single patient plasma;
some may be predominant, or the proportion may change over time, requiring physicians'
attention. In blood, coagulation factor-bound (complexed) and -unbound (free) autoantibodies
exist. The bound autoantibodies do not inhibit further coagulation factor activity,
but the unbound autoantibodies usually do.
Autoantibody Detection Methods
Presently, anti-FVIII and anti-FV antibody detection kits (Zymutest Anti-FVIII IgG
Mono Strip and Anti-FV IgG detection kit; both from Hyphen BioMed, Neuville sur Oise,
France) are commercially available[33 ]
[63 ] in Japan (and in Europe); however, commercial anti-FXIII, anti-VWF, and anti-FX
antibody detection kits are not. We have developed and implemented homemade detection
tests for these diseases.[26 ]
[40 ]
[41 ]
[42 ] Consequently, autoantibodies against each coagulation factor have been able to be
measured in most specimens. When AiCFD-suspected cases are referred to the JCRG by
attending physicians inside Japan, immunological workups are performed, and a diagnosis
can then be definitively made.[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[22 ]
[23 ]
[24 ]
[25 ]
The presence of non-neutralizing (noninhibitory) autoantibodies may often be overlooked,
as these autoantibodies are not measured unless their presence is suspected. This
underscores the importance of generalizing anticoagulation factor autoantibody detection
tests; sensitive autoantibody tests should be conducted promptly whenever AiCFD is
suspected. However, the positive detection rates of the various ELISA methods used
to detect anti-VWF autoantibodies vary from 0 to 80%.[24 ] Thus, no detection methods have yet been proven to be reliably sufficient. Confirmation
of the presence of anti-VWF autoantibodies is a requirement for a definite diagnosis
of AiVWFD,[24 ] and urgent standardization is needed.
We have developed a homemade anti-FXIII autoantibody detection method employing immunochromatography
as rapid point-of-care clinical testing[41 ]
[42 ]; however, it is not generally available, and its wider adoption is desired to address
missed AiF13D cases. Because “nonimmune” acquired F13D is extremely common,[64 ] anti-FXIII autoantibody detection is required to differentiate it from AiF13D.
Coagulation Factor Inhibitor Detection Methods
Globally, regular coagulation factor activity and its inhibitors are widely measured
using the one-stage clotting assay; however, the possibility of misdiagnosis due to
the detection of false LA in the functional coagulation test (false positive) cannot
be denied. Therefore, the presence of LA should be confirmed by immunologically testing
for antiphospholipid antibodies (other than LA) or by measuring coagulation factor
activity after diluting the sample.[33 ] When measuring coagulation factor activity, even after dilution, potent LA can still
interfere with the one-stage clotting assay. Therefore, we recommend the use of a
“synthetic substrate” method,[33 ] which is less susceptible to LA interference.[65 ]
[66 ] In Japan, activity measurement using the synthetic substrate method is covered by
health insurance only for FVIII and FIX (and FXIII in a sense), while those for other
coagulation factors such as FV and FX are undeveloped, unmarketed, and/or not covered.
If both the detection of anticoagulation factor autoantibodies and coagulation factor
inhibitors get insurance coverage, out-of-pocket costs for patients and medical institutions
will be reduced. By doing so, it is hoped that the current Public Medical Expense
Subsidy Program for MHLW-DIDs enacted by the Japanese MHLW will become even more useful.
Coagulation Factor Preparations in Hemostatic Therapy
Coagulation factor preparations, essential for AiCFD hemostatic therapy, are developed,
marketed, and covered by insurance for the treatment of hereditary CFDs. Currently,
human plasma-derived FXIII concentrate for AiF13D therapy, and rFVIIa, APCC, and the
“bispecific antibody preparation (Emicizumab)” for AiF8D therapy are covered by insurance.
Recombinant human coagulation factor preparations (rFXIII-A,[67 ] rVWF,[68 ] rFVIII, rFIX, etc.) are commercially available, however; they are not covered by
health insurance for AiCFD therapy in Japan ([Fig. 5A ]).
Fig. 5 Treatment strategies for hemostasis (A ) and autoantibody eradication (B ). (A ) Coagulation factor preparations used in hemostatic therapy. Solid lines indicate
a selection of formulations currently approved by public insurance, and dashed lines
indicate unapproved formulations. The formulations that the authors consider optimal
for hemostatic treatment of the respective AiCFD are shown in red. (B ) “ Bottom-up” therapy starts with a regular-dose oral corticosteroid, whereas “ top-down” therapy starts with a steroid pulse or rituximab. Upward and downward red
arrows indicate the selection order. AiCFD, autoimmune coagulation factor deficiencies;
APCC, activated prothrombin complex concentrates; conc., concentrates; CP, cyclophosphamide;
CS, cyclosporine; FFP, fresh frozen plasma; FVIIa, activated FVII; ITI, immune tolerance
induction; PCC, prothrombin complex concentrates; pd, plasma-derived; PSL; prednisolone;
Pulse; steroid pulse, r, recombinant; RTX; rituximab.
Although factor-specific replacement therapy is not presently available for AiVWFD,
and the only method is to administer nonfactor-specific blood preparations (i.e.,
FVIII/VWF concentrates), rVWF cannot be administered (despite being developed and
marketed) because it is not covered by public health insurance. Similarly, rFXIII-A
cannot be used for AiF13D, because it is not covered by public health insurance. Expanding
the indication of these clotting factor concentrates to the respective AiCFDs is desirable.
Immunosuppressants in Antibody Eradication Therapy (Including Cytotoxic Agents)
Regarding antibody eradication therapy for all AiCFDs, only corticosteroids such as
prednisolone are covered by insurance. Most recently, cyclophosphamide was approved
for use in public health insurance for the treatment of AiF8D, i.e., acquired hemophilia
A (since Feb. 27, 2023). In many cases of AiCFD, remission cannot be obtained with
prednisolone alone, whereas remission has been obtained in many cases with steroid
pulse therapy or additional drugs such as cyclophosphamide, rituximab, azathioprine,
and tacrolimus.[14 ]
[15 ]
[16 ]
[17 ]
[18 ]
[19 ]
[20 ]
[21 ]
[22 ]
[23 ]
[24 ]
[25 ]
We recommend expanding the indications to enable “step-up therapy,[14 ]” where prednisolone is the first-line drug and other drugs are gradually added or
switched ([Fig. 5B ]). Conversely, we also recommend implementing “top–down therapy,” in which steroid
pulses or rituximab are first administered to achieve rapid remission.
Administration of targeted coagulation factors to stimulate the proliferation of autoantibody-producing
B cells and increase their sensitivity to cytotoxic drugs may lead to success in subsequent
antibody eradication therapy against AiCFD, although further clinical trials are needed.
Long-Term Prognosis Survey
AiF13D is resistant to treatment, and as many patients are under long-term treatment,
accurate calculation of remission rate is not possible.[14 ] Some AiCFD cases were not in remission, recovery, or death during the observation
period, and accurate remission rates could not be determined. Several cases have not
been included in the follow-up investigations, owing to changes in residences or hospitals
or transfers of patients with AiCFD and/or their attending physicians.
Consequently, in February 2021, we launched a case registration system called the
“Designated Intractable Disease Database Platform.[69 ]” By increasing the number of diagnosed cases and accumulating a long-term database,
we hope to contribute to improvement in AiCFD medical care through research on the
effects of first- and second-line drugs and long-term prognosis.
Conclusion
The number of diagnosed cases of AiCFDs is gradually increasing, likely because of
the relatively high frequency of AiF8D and the nationwide research work of the authors
over 13 years. However, more research is still needed. We hope that this review article
will benefit physicians other than coagulation specialists, leading to early diagnosis
and initiation of appropriate treatment of more patients.
