Page 2279 - Hematology_ Basic Principles and Practice ( PDFDrive )

2026 Part XII Hemostasis and Thrombosis

Amino acids 2303-2332
inhibit binding to FIX 55

Amino acids 2248-2312
inhibit binding to vWF 143

Amino acids 351-365
inhibit binding Amino acids 2181-2243
144
to FX 140,141 inhibit binding to VWF

Amino acids 1804-1819
inhibit binding to FIX 63

A1 a1 A2 a2 B a3 A3 C1 C2

Amino acids 2170-2327
inhibit binding to PL
and VWF 54

Amino acids 484-508 Amino acids 2218-2307
inhibit binding to FIXa 59 slow release from VWF 56

Amino acids 2253-2270
inhibit binding to FX
and cleavage by FX 142

Fig. 136.1 FACTOR VIII DOMAINS AND BINDING SITE BY AMINO ACID LOCATION AND
EFFECT ON FACTOR VIII. Intensity of color reflects the frequency of inhibitors to the epitope. 170–174
FIX, Factor IX; FIXa, activated factor IX; FX, factor X; PL, phospholipid; vWF, von Willebrand factor.

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an inhibitor. This polyclonal antibody response can result in the investigated SNPs in more than 1000 genes in a cohort of 833 HA
inhibition of FVIII function via diverse clotting impairing mecha- patients for the association with inhibitor occurrence, and identified
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nisms because the epitopes may be different. It is important to note 53 polymorphisms significantly associated with the risk of developing
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that inhibiting antibodies to FVIII have an up to 100-fold higher inhibitors. This study highlighted the complexity of the mechanisms
affinity for FVIII than those in patients without inhibitors or healthy that are involved in the antibody formation against FVIII and FIX.
individuals. 67 In support of the polygenic nature of inhibitor formation, evidence
The weak association between MHC II phenotypes and FVIII is emerging that the regulatory T cell (Treg) lymphocyte system
inhibitor formation is dependent on the availability of “risk” MHC downmodulates the immune reaction to FVIII and plays a role in
class I/II alleles. 68,69 T-lymphocyte involvement in inhibitor forma- ITI induction. 74
tion is manifested by the isotype switching and the somatic hyper- FVIII exists as a heterodimer, with a heavy chain containing the
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mutation of the B cells. There are several FVIII epitopes against A1, A2, and B domains connected to a light chain containing the
+
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which CD4 T cells react strongly. In addition, non–FVIII-associated A3, C1, and C2 domains (Fig. 136.1). Short intervening acidic
gene polymorphisms can exert a protective influence on inhibitor regions (a1, a2, and a3) aid in FVIII binding to factor X and serve
development—for example, the C→T single-nucleotide polymor- as important sites for FVIII proteolysis by thrombin and factor Xa
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phism (SNP) at position –318 in the promoter region of the gene (FXa). By serving as a cofactor for FIX in the intrinsic tenase
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encoding for cytotoxic T-lymphocyte–associated protein-4 (CTLA4). complex, FVIIIa promotes the conversion of FX to FXa, which
This polymorphism “downregulates” the effects of the co-stimulatory together with factor Va forms the prothrombinase complex on the
signal of the B7-CD28 complex, which mediates T-cell immune activated platelet surface. This complex then converts prothrombin
responsiveness to infused FVIII. The MIBS study group reported an to thrombin, which in turn amplifies the coagulation system (see
OR of 0.3 for inhibitor formation among a cohort of severe hemo- Chapter 122). 76,77
philiacs with the T allele SNP despite their risk for inhibitors related Normally, when FVIII is secreted, it is noncovalently bound to
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to a FVIII intron 22 gene inversions. MIBS also identified poly- vWF via the light chain, particularly through interactions with the
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morphisms in the IL-10 cytokine gene that are associated with A3 and C2 domain. Upon thrombin activation, FVIIIa dissociates
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inhibitor formation in severe hemophiliacs. The same group from vWF and via the C2 domain, which is no longer linked to vWF,