How to identify and treat acquired coagulation factor deficiency based on the "four coagulation factors"

Author: Blue whale Xiaohu This article is the author's permission NMT Medical publish, please do not reprint without authorization.

Autoimmune processes can induce the production of functional inhibitors of coagulation factors, which are autoantibodies.

Congenital coagulation factor deficiency, for example, the inhibitor produced in patients with hemophilia A is the same kind of antibody, and its target is exogenous coagulation factor.

Coagulation factor autoantibodies are polyclonal, mainly IgG1 and IgG4, but IgA and IgM have also been reported [1].

The above two inhibitors can bind to the functional epitopes of a single coagulation factor, neutralize the activity or promote the removal of the targeted coagulation factor from the blood, prolong the clotting time, and can lead to bleeding disorders [2].

In contrast, lupus anticoagulant is an antiphospholipid antibody that targets a complex of phospholipids and clotting factors, rather than a single clotting factor.

Although lupus anticoagulants can also cause prolonged clotting time, they usually have prothrombotic activity and are associated with thrombosis or pregnancy complications.

This article summarizes the classification and diagnosis and treatment of acquired inhibitors of anticoagulation factors (autoantibodies) in the coagulation cascade, and aims to provide references for clinicians to identify and treat acquired coagulation factor deficiency in clinical work.

1 Epidemiology.
Autoantibodies against all coagulation factors have been reported, but the most common is autoantibodies against coagulation factor VIII (FVIII), also known as "acquired hemophilia A" [3].

Unlike congenital hemophilia A, which is an X-linked recessive genetic disease, acquired hemophilia A occurs in both men and women.

The incidence of acquired hemophilia A is about 1.
5/100 million/year, and it increases with age.
It is estimated that the rate is 0.
045/1 million/year for children under 16 years old, and 14.
7%/1 million for people over 85 years old.
/year. The median age for the diagnosis of acquired hemophilia A is 70 years, but due to pregnancy-related cases, young women between the ages of 20-40 also have a small peak of incidence.

Autoantibodies to other coagulation factors (such as FV, ​​XI, XII, XIII, and vitamin K-dependent proteins) are rare.

2 Classification and pathogenesis Table 1 lists the coagulation factor deficiency in the coagulation cascade associated with clinical bleeding tendency, and the reported autoimmune antibodies to the coagulation factor.

About 50% of patients with acquired hemophilia A have related underlying diseases, including autoimmune diseases, malignant tumors, pregnancy, drug induction, and skin diseases [4].

The underlying disease reported in patients with autoantibodies to other coagulation factors is similar to that of patients with acquired hemophilia (Table 1).

Table 1.
Classification and characteristics of anti-coagulation factor autoantibodies in the coagulation cascade related to bleeding tendency [4] In addition, it has been previously observed that coagulation factor V (FV) is produced after exposure to bovine thrombin in a surgical environment Of acquired inhibitors.

Bovine thrombin preparations often contain "contaminated" bovine protein (such as FV).
Bovine FV may act as a potent immune stimulant against bovine FV inhibitors, and then cross-react with human FV [5].

It has been described in the literature that acquired inhibitors of coagulation factors, especially FV and thrombin inhibitors, are produced after local exposure to bovine thrombin during or after surgery, leading to coagulation dysfunction.

The pathogenesis of autoantibodies to these coagulation factors remains unclear.

In some studies of acquired hemophilia A, the combined effect of genetic and environmental factors and the decline of immune function in the elderly may lead to the destruction of immune tolerance and the production of anti-FVIII autoantibodies.

The complex interaction of different CD4+ subgroups (such as Th1, Th2 and Th3) can control the production of antibodies by B cells, which may be the reason for the production of FVIII autoantibodies.

3 Clinical manifestations Acquired hemophilia A is usually an acute attack.
Most patients need emergency blood transfusion and hemostasis due to severe or life-threatening bleeding, and the mortality rate is high.
It is a serious bleeding disease. Bleeding episodes are usually spontaneous, and the common bleeding site is subcutaneous or muscle, which is different from joint bleeding in congenital hemophilia A.

A small number of patients with acquired hemophilia A (approximately 6%) do not bleed, and only occasionally find that the activated partial thromboplastin time (APTT) is prolonged [6].

Autoantibodies to coagulation factors other than FVIII are rare, and the clinical manifestations of patients vary greatly.

4 Diagnosis For patients with unexpected bleeding symptoms in the near future, platelet count, prothrombin time (PT) and APTT should be screened.

For patients with a normal platelet count but prolonged PT or APTT, or both without personal and family bleeding history, after excluding lupus anticoagulant and heparin therapy, the presence of autoantibodies to clotting factors should be considered.

The patient's plasma and normal plasma were mixed 1:1 to perform a mixed test.

When coagulation factors are lacking or only weak inhibitors are present, the results of the previous APTT prolongation will be corrected.

On the contrary, if the APTT is still prolonged in the mixed experiment, it indicates the presence of inhibitors.

The interaction between inhibitors and FVIII is time- and temperature-dependent.
Therefore, the results of the mixed test immediately after incubation and 2h (or longer) should be compared to increase the sensitivity of detecting low-titer inhibitors.

The prolongation of APTT in the mixed test after 1-2 hours of incubation is a typical feature of FVIII autoantibodies.

Inhibitors of coagulation factors other than FVIII usually do not have this time dependence, and the inhibitors can be effectively identified immediately after mixing.

If the results of the mixed test are prolonged, a thrombin time (TT) test should be performed to exclude the wrong type of specimen, such as ethylenediaminetetraacetic acid (EDTA) anticoagulated plasma and serum.

If TT is prolonged, perform TT in the patient/normal plasma mixture and perform a heparin neutralization test to exclude or confirm the presence of heparin or other anticoagulants [8].

After finding that the clotting time is prolonged and performing a mixed test, the type of possible inhibitors should be considered based on the clinical history and test results, and the titers of coagulation factor inhibitors should be quantitatively detected by the Bethesda or Nijmegen method [10].

However, FVIII autoantibodies may exhibit complex and nonlinear type 2 kinetics, and the Bethesda method may not be able to estimate the true antibody titer.

The diagnostic laboratory testing procedures compiled according to recently published literature to identify inhibitors of coagulation factors in the coagulation cascade are shown in Figure 1.

*Correct: Exceeding the normal mixed plasma ≤5s (or extending ≤15%) or within the normal laboratory reference range; *Not correcting: Exceeding the normal mixed plasma >5s (or extending >15%) or higher than the laboratory normal reference range Figure 1.
Laboratory testing process for identifying coagulation factor inhibitors based on abnormal coagulation indicators [4,8] 5 Treatment options Compared with congenital hemophilia, patients with coagulation factor autoantibodies are rare.

The clinical bleeding symptoms of this disease vary greatly, ranging from mild or no bleeding tendency to life-threatening bleeding, and the bleeding manifestations are inconsistent with laboratory findings.

The management of patients with acquired hemophilia A includes immediate control of acute bleeding and immunosuppressive therapy to remove FVIII autoantibodies.

For patients with active severe bleeding, regardless of the inhibitor titer and residual FVIII activity, hemostatic therapy should be started.

Bypass preparations (activated prothrombin complex concentrate [APCC] and recombinant activated FVII [rFVII]) are the most commonly used and recommended first-line treatments.

Only in the absence of bypass therapy, is it recommended to use alternative treatments aimed at increasing circulating FVIII levels, such as recombinant or plasma-derived human FVIII concentrate or desmopressin [11].

In patients with high titers of autoantibodies and severe bleeding, in vitro plasma exchange or immunoadsorption can rapidly reduce the titer of inhibitors, and then immediately initiate replacement therapy with human FVIII concentrates [11].

All patients with acquired hemophilia A should receive immunosuppressive therapy after diagnosis.

The recommended first-line treatment is steroids alone or combined with cyclophosphamide, which can achieve complete remission in 70%-80% of patients.

If the first-line treatment fails or there are contraindications, the anti-CD20 monoclonal antibody rituximab is recommended as a second-line treatment [11].

Neutropenia-related infections and sepsis are important side effects of immunosuppressive therapy, especially in elderly patients with underlying diseases.

Therefore, immunosuppressive therapy should balance the risks and benefits, and should also be adjusted according to individual patient status [11].

The additional benefit of high-dose intravenous immunoglobulin on the basis of immunosuppressive therapy has not been confirmed, so it is not recommended [12].

References: 1.
Franchini M, Lippi G, Favaloro EJ.
Acquired inhibitors of coagulation factors: part II.
Semin Thromb Hemost 2012;38:447–53.
2.
Dardikh M, Meijer P, van der Meer F, Favaloro EJ, Verbruggen B Acquired functionalcoagulation inhibitors: review on epidemiology, results of a wet-workshop on laboratory detection, and implications for quality of inhibitor diagnosis.
Semin Thromb Hemost 2012;38:613–21.
3.
Collins PW, Hirsch S, Baglin TP, Dolan G, Hanley J, Makris M, et al.
Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation.
Blood 2007;109:1870–7.
4.
Chang HH, Chiang BL.
The diagnosis and classification of autoimmune coagulopathy: an updated review.
Autoimmun Rev.
2014;13(4-5):587-90.
5.
Savage WJ, Kickler TS, Takemoto CM.
Acquired coagulation factor inhibitors in children after topical bovine thrombin exposure.
Pediatr Blood Cancer 2007;49:1025–9.
6.
Knoebl P, Marco P, Baudo F, Collins P, Huth-Kuhne A, Nemes L, et al.
Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).
J Thromb Haemost 2012;10:622–31.
7.
Lu Ting, Yang Chengde, Cheng Xiaobing.
The clinical significance of autoantibodies to clotting factors in autoimmune diseases[J].
Journal of Science, 2017, 21(12): 852-855.
8.
Thrombosis and Hemostasis Group of Hematology Branch of Chinese Medical Association, Chinese Hemophilia Cooperative Group.
Chinese Guidelines for Diagnosis and Treatment of Coagulation Factor Ⅷ/Ⅸ Inhibitors (2018 Edition )[J].
Chinese Journal of Hematology,2018,39(10):793-799.
9.
Karimi M, Peyvandi F, Naderi M, Shapiro A.
Factor XIII deficiency diagnosis: Challenges and tools.
Int J Lab Hematol.
2018;40 (1):3-11.
10.
Kershaw G, Favaloro EJ.
Laboratory identification of factor inhibitors: an update.
Pathology 2012;44:293–302.
11.
Huth-Kuhne A, Baudo F, Collins P, Ingerslev J, Kessler CM, Levesque H, et al.
International recommendations on the diagnosis and treatment of patients with acquired hemophilia A.
Haematologica 2009;94:566–75.
12.
Collins P, Baudo F, Knoebl P, Levesque H, Nemes L, Pellegrini F, et al.
Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).
Blood 2012;120:47–55.
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