Acquired Haemophilia A: A Review of What We Know

Figures & data

Table 1 Underlying Conditions Associated with Acquired Hemophilia A

Idiopathic	Dermatologic diseases  ● Psoriasis  ● Pemphigus
Postpartum/Abort/Pregnancy	Pulmonary diseases  ● Asma  ● EPOC
Autoimmune diseases  ● Systemic lupus erythematosus  ● Multiple sclerosis  ● Rheumatoid arthritis  ● Temporal arteritis  ● Sjogren’s syndrome  ● Autoimmune hemolytic anemia  ● Goodpasture syndrome  ● Myasthenia gravis  ● Graves disease  ● Autoimmune hypothyroidism  ● Inflammatory bowel disease  ● ITP	Diabetes
Drugs Penicillins and derivatives sulfonamides and quinolones, griseofulmin, Phenytoin, Chloramphenicol, methyldopa, Levodopa, alpha interferon, pegylated interferon, Fludarabine, BCG vaccine, Clopidogrel, Antidepressants (Thioxanthines, Flupenthixol, Fluphenazine), hydralazine acetaminophen	Infectious diseases HIV, HVB, HVC, SARS-CoV-2
Hematologic diseases  ● Chronic lymphocytic leukemia  ● Non-Hodgkin’s lymphoma  ● Multiple myeloma  ● Waldenstrom’s disease  ● Myelodysplastic síndrome  ● Myelofibrosis  ● Erythroleukemia	Solid tumors Prostate, Lung, Colon, Pancreas, Stomach, Bile duct, Head Neck, Cervix, Melanoma, Kidney

Figure 1 Mechanism of immune response to FVIII. FVIII is processed by the antigen-presenting cell (APC). Its function is to recognize and internalize it, giving rise to an endosome inside, which after merging with a lysosome leads to digestion of FVIII into peptide fragments that can bind to class II molecules of the major histocompatibility system. In case it is not assembled, the class II molecule will be degraded; otherwise, the complex will be transported to the surface of the APC, which presents it to the T cell receptor (TCR). The activation of T lymphocytes requires this union and the signals resulting from the interaction between various molecules such as CD28/B7 (pro-activation) or CTLA4/B7 (anti-activation). After this, there is an expansion of clone responsible for presenting FVIII to B lymphocytes. B lymphocytes (BL) are responsible for the production of specific antibodies (immunoglobulins [Ig]).

Figure 2 Kinetics of inhibition of FVIII activity by autoantibodies. The inhibition profile of FVIII activity which most often exhibit the autoantibodies characteristic in acquired haemophilia responds to a second order kinetics (triangles), in which a first phase of inhibition resulting from a linear pattern is followed by an equilibrium phase in which the inhibition rate slows markedly, a fact that allows the detection of residual FVIII activity in vitro. However, autoantibodies directed against FVIII rarely interact with this following a first-order kinetics (circles), in which the inhibition profile corresponds to a linear pattern and leads to the complete disappearance of FVIII activity, this being a more typical behavior of anti-FVIII alloantibodies that can occur in congenital haemophilia.

Figure 3 Examples of AHA bleeding profile. (A) Lingual and soft palate haematoma in patient with AHA. (B) Haemorrhagic infiltration of subcutaneous tissue due to abductor muscle bleeding in a patient with AHA.

Figure 4 Diagnostic algorithm for a prolonged APTT. Kasper test and Bethesda assay requires incubation 2 hours at 37°C of the mixing samples. (1) No evidence of correction is defined as a test time 8 seconds longer than the control time.

Abbreviations: BU, Bethesda units; DRVVT, dilute Russell viper venom test.

Table 2 Goals of AHA Treatment and Studies Recommended to Rule Out Underlying Conditions in Patients Suffering from AHA

Goals of AHA Treatment	Recommended Studies
Treat bleeding symptoms considering cardiovascular risk Treat underlying condition as soon as possible Individualize immunosuppressive treatment to prevent adverse events	Cervical and thoraco-abdominal CT Blood count Ferric metabolism and maturational factors Peripheral blood smear Biochemistry: basic, hepatic, renal and lipid profile Lactate dehydrogenase (LDH) Proteinogram Viral serology (herpes-virus, HIV, hepatotropic viruses) Thyroid tests Antinuclear antibodies and anti-DNA. Rheumatoid factor, RPC

Abbreviations: CT, computed tomography; DNA, deoxyribonucleic acid; HIV, human immunodeficiency virus; RPC, reactive protein C, TP, trough/peak ratio.

Table 3 Suggested Surgical Prophylaxis in Adults with Acquired haemophilia⁹⁴

Dental Extractions

APCC, 50 to 75 IU/kg/12 h, 2 to 3 doses, starting just before surgery rFVIIa, 90 to 120 μg/kg/2h, 3 to 4 doses, starting just before surgery minor surgery

Minor Surgery

APCC, 50 to 100 IU/kg/8–12 h, without exceeding 200 IU/kg/day. Start just before surgery. Treatment 3–7 days depending on evolution rFVIIa, 90 to 120 μg/kg/2–3 hours for 24 hours. Start just before surgery. Repeat dose every 4 to 6 hours for 3 to 7 days depending on evolution

Major Surgery

APCC, 75 to 100 IU/kg/8–12 hours on days 1 to 6, then every 12 hours on days 7 to 15, not to exceed 200 IU/kg/day. Start just before surgery. Adjust according to evolution rFVIIa, 90 to 120 μg/kg/2 hours for 24 hours, every 2 to 3 hours on day 2, every 4 hours on days 3 to 5, every 6 hours on days 6 to 15. Start just before surgery. Adjust according to evolution

Table 4 Outcomes of Immunosuppressive Treatment of Longest AHA Registries.^4–8,113

	Steroids		Steroids Plus Cyclophosphamide		Rituximab Plus Other Immunosuppressive Drug		Global Data (All Immunosuppressive Schemes)
	Complete Response Time to Response	Relapse	Complete Response	Relapse	Complete Response	Relapse	Complete Response	Time to Complete Response (Median)	Relapse	Time to Relapse
Collis et al^Citation113	48%	19%	77%	14%	59%	4%	65%	5 weeks	11%	137 days
Borg et al^Citation7	–	–	–	–	40%	–	87%	20 weeks	0% (12 months follow-up)	–
Tiede et al^Citation4	47% 32 days	–	80% 40 days	–	80% 65 days	–	61%	14 weeks (79 days)	–	–
Sun et al^Citation8	62%	22%	88%	7%	91%	5%	68%	7–10 weeks	9.4% (7 months follow up)	–
Mingot-Castellano et al^Citation5	68%	27%	89%	3.7%	88%	3.4%	84%	5–7 weeks	7.1% (13 months follow-up)	–
Schep et al^Citation6	35%	27%	80%	10%	63%	23%	46% with first line	10.7 weeks	25%	102 days

Table 5 Cause of Mortality in Longest AHA Registries.^4–8,113

Study Dead Patients/Total Patients Percentage of Death	Infections	Bleeds	Underlying Disease	Cardiac or Thrombosis
Collis et al^Citation113 89/287 31%	12.4%	3.3%	11.2%	–
Borg et al^Citation7 27/82 33%	37%	11%	–	15%
Tiede et al^Citation4 34/102 33%	47%	9%	9%	18%
Sun et al^Citation8 11/165 6.7%	27%	55%	18%	–
Mingot-Castellano et al^Citation5 36/151 23.8%	41.7%	13.9%	14%
Schep et al^Citation6 52/136 38%	19.2%	7.7%	13.5%	9.6%

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