Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_104_библиотеки_им_акад_М_И_Перельмана
.pdf
Platelet disorders 263
https://t.me/med1917
Rosenberg, N., Lalezari, S., Landau, M. etal. (2007). Trp207Gly in plate-
let glycoprotein Ibα is a novel mutation that disrupts the connection
between the leucineture and causes Bernard–Soulier syndrome. J. Thromb. Haemost. 5:
378–386.
Vettore, S., Scandellari, R., Moro, S. etal. (2008). Novel point mutation
in a leucineWillebrand factor receptor, GPIb/IX/V, resulting in an inherited
dominant form of Bernard–Soulier syndrome affecting two unrelated families: the N41H variant. Haematologica 93: 1743–1747.
rich repeat domain and the disulfide loop struc-
rich repeat of the GPIbα chain of the platelet von
New GPIbβ mutations
Hadjkacem, B., Elleuch, H., Gargouri, J., and Gargouri, A. (2009).
Bernard–Soulier syndrome: novel nonsense mutation in GPIbβ gene
affecting GPIb–IX complex expression. Ann. Hematol. 88: 465–472.
Velocardiofacial syndrome
Liang, H.P., Morel- Kopp, M.C., Curtin, J. et al. (2007). Heterozygous
loss of platelet glycoprotein (GP)Ib- V- IX variably affects platelet
function in velocardiofacial syndrome (VCFS) patients. Thromb.
Haemost. 98: 1298–1308.
New GPIX mutations
Kunishima, S., Yamada, T., Hamaguchi, M., and Saito, H. (2006).
Bernard–Soulier syndrome due to GPIX W127X mutation in Japan
is frequently misdiagnosed as idiopathic thrombocytopenic purpura.
Int. J. Hematol. 83: 366–367.
Suva, L.J., Hartman, E., Dilley, J.D. etal. (2008). Platelet dysfunction
and a high bone mass phenotype in a murine model of plateletvon Willebrand disease. Am. J. Pathol. 172: 430–439.
type
Collagen receptor defects α2β1integrin
Joutsi- Korhonen, L., Smethurst, P.A., Rankin, A. etal. (2003). The low-
frequency allele of the platelet collagen signaling receptor glycoprotein VI is associated with reduced functional responses and
expression. Blood 101: 4372–4379.
Sarratt, K.L., Chen, H., Zutter, M.M. etal. (2005). GPVI and α2β1 play
independent critical roles during platelet adhesion and aggregate formation to collagen under flow. Blood 106: 1268–1277.
GPVI
Arthur, J.F., Dunkley, S., and Andrews, R.K. (2007). Platelet glycopro-
tein VI-
related clinical defects. Br. J. Haematol. 139: 363–372.
Dumont, B., Lasne, D., Rothschild, C. etal. (2009). Absence of collagen-
induced platelet activation caused by compound heterozygous GPVI
mutations. Blood 114: 1900–1903.
Gauer, J.S., Duval, C., Xu, R.-
interaction increases platelet procoagulant activity and impacts clot
structure. J. Thromb. Haemost. 21: 667–681.
Hermans, C., Wittevrongel, C., Thys, C. etal. (2009). A compound het-
erozygous mutation in glycoprotein VI in a patient with a bleeding
disorder. J. Thromb. Haemost. 7: 1356–1363.
Hughan, S.C., Senis, Y., Best, D. etal. (2005). Selective impairment of
platelet activation to collagen in the absence of GATA1. Blood 105:
4369–4376.
G. et al. (2023). Fibrin- glycoprotein VI
Variant forms
Balduini, A., Malara, A., Pecci, A. etal. (2009). Proplatelet formation in
heterozygous Bernard–Soulier syndrome type Bolzano. J. Thromb.
Haemost. 7: 478–484.
Vettore, S., Scandellari, R., Scapin, M. etal. (2008). A case of Bernard–
Soulier syndrome due to a homozygous four bases deletion (TGAG)
of GPIbα gene: lack of GPIbα but absence of bleeding. Platelets 19:
388–391.
Dib, F., Quéméner, A., Bayart, S. etal. (2022). Biological, clinical fea-
tures and modelling of heterozygous variants of glycoprotein Ib
platelet subunit alpha (GP1BA) and glycoprotein Ib platelet subunit
beta (GP1BB) genes responsible for constitutional thrombocytopenia. Br. J. Haematol. 199: 744–753.
Platelet- type von Willebrand disease
Matsubara, Y., Murata, M., Sugita, K., and Ikeda, Y. (2003). Identification
of a novel point mutation in platelet glycoprotein Ibα Gly to Ser at
residue 233, in a Japanese family with platelet- type von Willebrand
disease. J. Thromb. Haemost. 1: 2198–2205.
Nurden, P., Lanza, F., Bonnafous- Faurie, C., and Nurden, A. (2007). A
second report of platelet- type von Willebrand disease with a Gly233Ser
mutation in the GPIBA gene. Thromb. Haemost. 97: 319–321.
Othman, M., Notley, C., Lavender, F.L. etal. (2005). Identification and
functional characterization of a novel 27- bp deletion in the
macroglycopeptide- coding region of the GPIBA gene resulting in
platelet- type von Willebrand disease. Blood 105: 4330–4336.
Glanzmann thrombasthenia overview
Fang, J., Hodivala- Dilke, K., Johnson, B.D. et al. (2005). Therapeutic
expression of the platelet- specific integrin, αIIbβ3, in a murine
model for Glanzmann thrombasthenia. Blood 106: 2671–2679.
French, D.L. (1998). The molecular genetics of Glanzmann’s thrombas-
thenia. Platelets 9: 5–20.
Jayandharan, G., Nelson, E.J., Baidya, S. etal. (2007). A new multiplex
PCR and conformationmutation detection in the platelet glycoprotein αIIb and β3 genes.
J.Thromb. Haemost. 5: 206–209.
Manickam, N., Sun, X., Li, M. etal. (2008). Protein disulphide isomer-
ase in platelet function. Br. J. Haematol. 140: 223–229.
Nurden, A.T., Pillois, X., Fiore, M. etal. (2015). Expanding the mutation
spectrum affecting αIIbβ3integrin in Glanzmann Thrombasthenia:
screening of the ITGA2B and ITGB3 genes in a large international
cohort. Hum. Mutat. 36: 548–561.
Nurden, A. (2021). Profiling the genetic and molecular characteristics
of Glanzmann Thrombasthenia: can it guide current and future therapies? J. Blood Med. 12: 581–599.
sensitive gel electrophoresis strategy for
αIIb defects
Losonczy, G., Rosenberg, N., Boda, Z. etal. (2007). Three novel muta-
tions in the glycoprotein IIb gene in a patient with type II Glanzmann
thrombasthenia. Haematologica 92: 698–701.
Vijapurkar, M., Ghosh, K., and Shetty, S. (2009). Novel mutations in GPIIb
gene in Glanzmann’s thrombasthenia from India. Platelets 20: 35–40.
本书版权归John Wiley & Sons Inc.所有
264 Molecular Hematology
https://t.me/med1917
β3 defects
Chen, P., Melchior, C., Brons, N.H. et al. (2001). Probing conforma-
tional changes in the Ihuman α3integrins following disulfide bond disruption by cysteine
mutations: identification of cysteine 598involved in αIIbβ3 activation. J. Biol. Chem. 276: 38628–38635.
D’Andrea, G., Bafunno, V., Del Vecchio, L. et al. (2008). A α3 Asp217αVa l
substitution in a patient with variant Glanzmann thrombasthenia
severely affects integrin αIIbβ3 functions. Blood Coagul. Fibrinolysis
19: 657–662.
Gonzalez- Manchon, C., Butta, N., Larrucea, S. etal. (2004). A variant
thrombasthenic phenotype associated with compound heterozygosity of integrin α3zation rendering a decreased number of constitutive active αIIbβ3
receptors. Thromb. Haemost. 92: 1377–1386.
Liu, J., Jackson, C.W., Gruppo, R.A. etal. (2005). The α3 subunit of the
integrin αIIbβ3 regulates αIIb105: 4345–4352.
Mor-
Cohen, R., Rosenberg, N., Peretz, H. etal. (2007). Disulfide bond
disruption by a α3- Cys549Arg mutation in six Jordanian families
with Glanzmann thrombasthenia causes diminished production of
constitutively active αIIbβ3. Thromb. Haemost. 98: 1257–1265.
Nurden, P., Poujol, C., Winckler, J. etal. (2002). A Ser752βPro substitu-
tion in the cytoplasmic domain of α3in a Glanzmann thrombasthenia variant fails to prevent interactions between the αIIbβ3integrin
and the platelet granule pool of fibrinogen. Br. J. Haematol. 118:
1143–1151.
Ruiz, C., Liu, C.Y., Sun, Q.H. et al. (2001). A point mutation in the
cysteine- rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb- IIIa (αIIbβ3) integrin receptor locked in a
high- affinity state and a Glanzmann thrombasthenia- like phenotype. Blood 98: 2432–2441.
Wang, R., Shattil, S.J., Ambruso, D.R., and Newman, P.J. (1997).
Truncation of the cytoplasmic domain of α3in a variant form of
Glanzmann thrombasthenia abrogates signaling through the integrin αIIbβ3 complex. J. Clin. Investig. 100: 2393–2403.
like domain and the cysteine- rich repeat of
subunit: (Met124Val)α3 alters the subunit dimeri-
mediated outside in signaling. Blood
Oury, C., Toth-
Does the P2X1del variant lacking 17 amino acids in its extracellular
domain represent a relevant functional ion channel in platelets?
Blood 99: 2275–2277.
Oury, C., Toth-
The platelet ATP and ADP receptors. Curr. Pharm. Des.
12:859–875.
Remijn, J.A., Ijsseldijk, M.J., Strunk, A.L. etal. (2007). Novel molecular
defect in the platelet ADP receptor P2Y12 of a patient with haemorrhagic diathesis. Clin. Chem. Lab. Med. 45: 187–189.
Zsamboki, E., Vermylen, J., and Hoylaerts, M.F. (2002).
Zsamboki, E., Vermylen, J., and Hoylaerts, M.F. (2006).
Other primary agonist receptor defects
Hirata, T., Kakizuka, A., Ushikubi, F. et al. (1994). Arg60 to Leu
mutation of the human thromboxane A2 receptor in a dominantly
inherited bleeding disorder. J. Clin. Investig. 94: 1662–1667.
Edelstein, L.C., Simon, L.M., Lindsay, C.R. etal. (2014). Common vari-
ants in the human platelet PAR4 thrombin receptor alter platelet
function and differ by race. Blood 124: 3450–3458.
Intracellular signaling pathway defects
Bellucci, S., Huisse, M.G., Boval, B. et al. (2005). Defective
collagen- induced platelet activation in two patients with malignant
haemopathies is related to a defect in the GPVIpathway. Thromb. Haemost. 93: 130–138.
Dunkley, S., Arthur, J.F., Evans, S. et al. (2007). A familial platelet
function disorder associated with abnormal signalling through the
glycoprotein VI pathway. Br. J. Haematol. 137: 569–577.
Mao, G.F., Vaidyula, V.R., Kunapuli, S.P., and Rao, A.K. (2002). Lineage-
specific defect in gene expression in human platelet phospholipase
C- α2 deficiency. Blood 99: 905–911.
Patel, Y.M., Patel, K., Rahman, S. etal. (2003). Evidence for a role for
Gαi1 in mediating weak agonisthuman platelets: reduced Gαi1 expression and defective Gi signaling
in the platelets of a patient with a chronic bleeding disorder. Blood
101: 4828–4835.
induced platelet aggregation in
coupled signalling
Kindlins andleukocyte adhesion defect
Pasvolsky, R., Feigelson, S.W., Kilic, S.S. etal. (2007). A LAD- III syn-
drome is associated with defective expression of the Rap- 1 activator
CalDAG- GEFI in lymphocytes, neutrophils, and platelets. J. Exp.
Med. 204: 1571–1582.
Rognoni, E., Ruppert, R., and Fässler, R. (2016). The kindlin family:
functions, signaling properties and implications for human disease.
J. Cell Sci. 129: 17–27.
ADP andATP receptor defects
Cattaneo, M. (2006). Disorders of platelet function. Abnormalities of
the platelet P2 receptors. Pathophysiol. Haemost. Thromb. 35: 10–14.
Daly, M.E., Dawood, B.B., Lester, W.A. etal. (2009). Identification and
characterization of a novel P2Y12 variant in a patient diagnosed with
type 1 von Willebrand disease in the European MCMDM- 1VWD
study. Blood 113: 4110–4113.
Leon, C., Hechler, B., Freund, M. etal. (1999). Defective platelet aggre-
gation and increased resistance to thrombosis in purinergic P2Y1
receptor- null mice. J. Clin. Investig. 104: 1731–1737.
本书版权归John Wiley & Sons Inc.所有
Platelet secretion defects (storage pool
disease) Gray platelet syndrome
Albers, C.A., Cvejic, A., Favier, R. etal. (2011). Exome sequencing iden-
tifies NBEAL2 as the causative gene for gray platelet syndrome. Nat.
Genet. 43: 735–737.
Deppermann, C., Cherpokova, D., Nurden, P. etal. (2013). Gray platelet
syndrome and defective thrombo- inflammation in Nbeal2- deficient
mice. J. Clin. Investig. 123: 3331–3342.
Drouin, A., Favier, R., Masse, J.M. et al. (2001). Newly recognized
cellular abnormalities in the gray platelet syndrome. Blood
98:1382–1391.
Gunay- Aygun, M., Falik- Zaccai, T.C., Vilboux, T. etal. (2011). NBEAL2
is mutated in gray platelet syndrome and is required for biogenesis of
platelet α- granules. Nat. Genet. 43: 732–734.
Kahr, W.H., Hinckley, J., Li, L. et al. (2011). Mutations in NBEAL2,
encoding a BEACH protein, cause gray platelet syndrome. Nat.
Genet. 43: 738–740.
Nurden, A.T. and Nurden, P. (2007). The gray platelet syndrome: clini-
cal spectrum of the disease. Blood Rev. 21: 21–36.
Platelet disorders 265
https://t.me/med1917
Nurden, P., Jandrot- Perrus, M., Combrie, R. et al. (2004). Severe
deficiency of glycoprotein VI in a patient with gray platelet syndrome.
Blood 104: 107–114.
Quebec platelet disorder
Diamandis, M., Veljkovic, D.K., Maurer- Spurej, E. etal. (2008). Quebec
platelet disorder: features, pathogenesis and treatment. Blood Coagul.
Fibrinolysis 19: 109–119.
Veljkovic, D.K., Rivard, G.E., Diamandis, M. et al. (2009). Increased
expression of urokinase plasminogen activator in Quebec platelet
disorder is linked to megakaryocyte differentiation. Blood 113:
1535–1542.
Hermansky–Pudlak syndrome
Gautam, R., Novak, E.K., Tan, J. etal . (2006). Interaction of Hermansky–
Pudlak syndrome genes in the regulation of lysosome organelles. Tra ffic 7: 779–792.
Huizing, M., Parkes, J.M., Helip- Wooley, A. et al. (2007). Platelet
α- granules in BLOC- 2 and BLOC- 3 subtypes of Hermansky–Pudlak
syndrome. Platelets 18: 150–157.
Spritz, R.A. (1998). Molecular genetics of the Hermansky–Pudlak and
Chediak–Higashi syndromes. Platelets 9: 21–29.
Walker, M., Payne, J., Wagner, B., and Vora, A. (2007). Hermansky–
Pudlak syndrome. Br. J. Haematol. 138: 671.
related
Chédiak–Higashi syndrome
Kaplan, J., De Domenico, I., and Ward, D.M. (2008). Chediak–Higashi
syndrome. Curr. Opin. Hematol. 15: 22–29.
Nagle, D.L., Karim, M.A., Woolf, E.A. etal. (1996). Identification and
mutation analysis of the complete gene for Chediak–Higashi syndrome. Nat. Genet. 14: 307–311.
Westbroek, W., Adams, D., Huizing, M. etal. (2007). Cellular defects in
Chediak–Higashi syndrome correlate with the molecular genotype
and clinical phenotype. J. Investig. Dermatol. 127: 2674–2677.
Griscelli syndrome
Barral, D.C., Ramalho, J.S., Anders, R. etal. (2002). Functional redun-
dancy of Rab27 proteins and the pathogenesis of Griscelli syndrome.
J. Clin. Investig. 110: 247–257.
Novak, E.K., Gautam, R., Reddington, M. etal. (2002). The regulation
of platelet- dense granules by Rab27a in the ashen mouse, a model of
Hermansky–Pudlak and Griscelli syndromes, is granule- specific and
dependent on genetic background. Blood 100: 128–135.
Wiskott–Aldrich syndrome
Imai, K., Nonoyama, S., and Ochs, H.D. (2003). WASP (Wiskott–
Aldrich syndrome protein) gene mutations and phenotype. Cu rr.
Opin. Allergy Clin. Immunol. 3: 427–436.
Lutskiy, M.I., Shcherbina, A., Bachli, E.T. etal. (2007). WASP localizes
to the membrane skeleton of platelets. Br. J. Haematol. 139:
98–105.
Ochs, H.D., Filipovich, A.H., Veys, P. et al. (2008). Wiskott–Aldrich
syndrome: diagnosis, clinical and laboratory manifestations, and
treatment. Biol. Blood Marrow Transplant. 15 (1 Suppl): 84–90.
Sabri, S., Foudi, A., Boukour, S. etal. (2006). Deficiency in the Wiskott–
Aldrich protein induces premature proplatelet formation and platelet
production in the bone marrow compartment. Blood 108: 134–140.
Procoagulant regulation defects
Solum, N.O. (1999). Procoagulant expression in platelets and defects
leading to clinical disorders. Arterioscler. Thromb. Vasc. Biol.
19:2841–2846.
Weiss, H.J. (2009). Impaired platelet procoagulant mechanisms in
patients with bleeding disorders. Semin. Thromb. Hemost.
35:233–241.
Scott syndrome
Bettache, N., Gaffet, P., Allegre, N. etal. (1998). Impaired redistribution
of aminophospholipids with distinctive cell shape change during
2+
Ca
- induced activation of platelets from a patient with Scott syn-
drome. Br. J. Haematol. 101: 50–58.
Castoldi, E., Collins, P.W., Williamson, P.L., and Bevers, E.M. (2011).
Compound heterozygosity for 2 novel TMEM16F mutations in a
patient with Scott syndrome. Blood 117: 4399–4400.
van Geffen, J.P., Swieringa, F., and Heemskerk, J.W. (2016). Platelets and
coagulation in thrombus formation: aberrations in the Scott syndrome. Thromb. Res. 141 (Suppl 2): S12–S16.
Kunzelmann, K., Nilius, B., Owsianik, G. etal. (2014). Molecular func-
tions of anoctamin 6 (TMEM16F): a chloride channel, cation channel, or phospholipid scramblase? Pflugers Arch. 466: 407–414.
Suzuki, J., Umeda, M., Sims, P.J., and Nagata, S. (2010). Calcium-
dependent phospholipid scrambling by TMEM16F. Nature 468:
834–838.
Stormorken syndrome
Stormorken, H., Holmsen, H., Sund, R. etal. (1995). Studies on the hae-
mostatic defect in a complicated syndrome. An inverse Scott syndrome platelet membrane abnormality? Thromb. Haemost. 74:
1244–1251.
Misceo, D., Holmgren, A., Louch, W.E. et al. (2014). A dominant
STIM1 mutation causes Stormorken syndrome. Hum. Mutat. 35:
556–564.
Giant platelet syndromes andcytoskeletal
defects
Althaus, K. and Greinacher, A. (2009). MYH9- related platelet disor-
ders. Semin. Thromb. Hemost. 35: 189–203.
Chen, Z. and Shivdasani, R.A. (2009). Regulation of platelet biogenesis:
insights from the Maydisorders. J. Thromb. Haemost. 7: 272–276.
Leon, C., Eckly, A., Hechler, B. etal. (2007). Megakaryocyte- restricted
MYH9inactivation dramatically affects hemostasis while preserving
platelet aggregation and secretion. Blood 110: 3183–3191.
Massey, G., Tyrrell, L., Diab, Y., and Gunning, W.T. 3rd (2022). Medich
giant platelet syndrome: an evolving qualitative and quantitative
platelet disorder. Hematol. Rep. 14: 349–357.
Nurden, A.T., Federici, A.B., and Nurden, P. (2009). Altered megakary-
ocytopoiesis in von Willebrand type 2B disease. J. Thromb. Haemost.
7: 277–281.
Hegglin anomaly and other MYH9- related
本书版权归John Wiley & Sons Inc.所有
266 Molecular Hematology
https://t.me/med1917
Provaznikova, D., Geierova, V., Kumstyrova, T. et al. (2009). Clinical
manifestation and molecular genetic characterization of MYH9
disorders. Platelets 26: 1–8.
Saito, H., Matsushita, T., Yamamoto, K. et al. (2005). Giant platelet
syndrome. Hematology 10: 41–46.
Stächele, J., Bakchoul, T., Najm, J. et al. (2015). Congenital
macrothrombocytopenia associated with a combination of functional
polymorphisms in the TUBB1 gene. Hamostaseologie 35 (Suppl 1):
S18–S21.
Toren, A., Rozenfeld-
of autosomaltion with fibulin-
White, J.G. (2007). Platelet pathology in carriers of the X-
GATA-
1macrothrombocytopenia. Platelets 18: 620–627.
Granot, G., Heath, K.E. etal. (2003). MYH9 spectrum
dominant giant platelet syndromes: unexpected associa-
1 variant- D inactivation. Am. J. Hematol. 74: 254–262.
linked
Glycosylation defects
Kauskot, A., Mallebranche, C., Bruneel, A. et al. (2023). MAGT1
deficiency in XMEN disease is associated with severe platelet dysfunction and impaired platelet glycoprotein NJ.Thromb. Haemost. 21: 3268–3278.
glycosylation.
Transcription factor defects
Breton- Gorius, J., Favier, R., Guichard, J. etal. (1995). A new congenital
dysmegakaryopoietic thrombocytopenia (Paris–Trousseau) associated with giant platelet α11q23. Blood 85: 1805–1814.
Escher, R., Wilson, P., Carmichael, C. et al. (2007). A pedigree with
autosomal dominant thrombocytopenia, red cell macrocytosis, and
an occurrence of t(12 : 21) positive pre- B acute lymphoblastic
leukemia. Blood Cell Mol. Dis. 39: 107–114.
granules and chromosome 11 deletion at
Freson, K., Devriendt, K., Matthijs, G. et al. (2001). Platelet
characteristics in patients with X- linked macrothrombocytopenia
because of a novel GATA1mutation. Blood 98: 85–92.
Sun, L., Gorospe, J.R., Hoffman, E.P., and Rao, A.K. (2007). Decreased
platelet expression of myosin regulatory light chain polypeptide
(MYL9) and other genes with platelet dysfunction and CBFA2/
RUNX1 mutation: insights from platelet expression profiling.
J.Thromb. Haemost. 5: 146–154.
White, J.G. (2007). Platelet pathology in carriers of the X-
1macrothrombocytopenia. Platelets 18: 620–627.
GATA-
linked
Platelet protein polymorphisms
andtendency tothrombosis
Jones, C.I., Bray, S., Garner, S.F. et al. (2009). A functional genomics
approach reveals novel quantitative trait loci associated with platelet
signalling pathways. Blood 114: 1405–1416.
Martini, C.H., Doggen, C.J., Cavallini, C. et al. (2005). No effect of
polymorphisms in prothrombotic genes on the risk of myocardial
infarction in young adults without cardiovascular risk factors.
J.Thromb. Haemost. 3: 177–179.
Mega, J.L., Close, S.L., Wiviott, S.D. etal. (2009). Cytochrome P-
polymorphisms and response to clopidogrel. N. Engl. J. Med. 360:
354–362.
Meisel, C., Lopez, J.A., and Stangl, K. (2004). Role of platelet glycopro-
tein polymorphisms in cardiovascular diseases. Naunyn- Schmiedeb.
Arch. Pharmacol. 369: 38–54.
Ouwehand, W.H. (2007). Platelet genomics and the risk of
atherothrombosis. J. Thromb. Haemost. 5: 188–195.
Ouwehand, W.H. (2009). The discovery of genes implicated in myocar-
dial infarction. J. Thromb. Haemost. 7: 305–307.
450
本书版权归John Wiley & Sons Inc.所有
Chapter19
https://t.me/med1917
alloantigens
The molecular basis ofblood cell
Winnie Chong1, Louise Tilley2 and Colin Brown
1
Histocompatibility and Immunogenetics Service Development Laboratory, NHS Blood and Transplant, London, United Kingdom
2
International Blood Group Reference Laboratory, NHS Blood and Transplant, Bristol, United Kingdom
3
Histocompatibility and Immunogenetics Laboratory NHS Blood and Transplant, Colindale, London, United Kingdom
4
King’s College London, Faculty of Life Sciences & Medicine, London, United Kingdom
Introduction, 267
The major histocompatibility complex, 268
Post- transfusion purpura, 275
Platelet refractoriness, 275
Neonatal alloimmune thrombocytopenia, 276
Neonatal alloimmune neutropenia,
280
Introduction
TransfusionRed blood cell antigens and molecular typing, 280
Hemolytic disease of the fetus and newborn, 280
Conclusions, 283
Further reading, 283
by maternal blood cell alloantibodies may lead to the devel-
3,4
related acute lung injury, 280
opment of immune- mediated anemia, thrombocytopenia, or
Advances in molecular techniques have been pivotal in
improving our knowledge of the structure and function of
blood cell antigens that were originally defined using serological techniques when studying the immune responses following transfusion, transplantation, and pregnancy. Many blood
cell membrane determinants show allelic variation, which can
elicit the formation of alloantibodies. In nearly all transfusion
situations and pregnancies, the recipient’s immune system is
challenged by blood cells mismatched for multiple alloantigen
systems, but alloantibodies are only formed by a subset of
recipients. Red cell alloantibodies are detected in 1–1.5% of
pregnant women and in 2–3% of transfused individuals and
can increase significantly in multi- transfused patients. The
HLA alloantigens are more immunogenic than those of the
red cells, and 15–25% of multiparous women and 30–40% of
patients on long- term prophylactic platelet transfusions are
positive for HLA class I antibodies.
Alloantigens were initially defined as polymorphic membrane determinants identified by polyclonal alloantibodies
in serum samples from alloimmunized patients or pregnant
women, but the molecular basis of most alloantigens have
now been resolved and DNA-
based techniques are more
commonly used to characterize alloantigen polymorphisms.
Alloantigens can be categorized as those shared by all blood
cells, for example HLA class I, and those unique to one blood
cell type such as Rh on red cells and human platelet antigen
(HPA) on platelets (Table19.1). When expression is limited
to one type of blood cell, destruction of cells in the newborn
neutropenia of the newborn. In contrast, HLA class I alloantibodies do not cause cytopenias in the newborn but may
compromise the effectiveness of platelet transfusions, complicate organ transplantation, cause febrile non- hemolytic
transfusion reactions, or play a key role in the initiation of
transfusion- related acute lung injury and occasionally delay
engraftment in hemopoietic stem cell transplantation.
The formation of alloantibodies after an incompatible challenge in the form of blood transfusion is more the exception
than the rule. In contrast to our detailed understanding of the
molecular basis of blood cell alloantigens, we remain relatively
ignorant about the mechanism of non- responsiveness. We
have learned from animal experiments that restriction in the
ability to mount an immune response is largely controlled by
genes of the major histocompatibility complex (MHC) or
HLA. However, the reason why, for example, some 25% of
RhD- negative individuals fail to mount an anti- D response on
repeated challenges with RhD- positive red cells remains elusive. An exception to this is our detailed understanding of the
immune response against the HPA- 1a alloantigen on platelets.
There is a near- complete restriction on the ability to form
HPA- 1a antibodies by the HLA class II allele DRB3*01 : 01.
However, except for this example, our ability to identify the
genes controlling the risk of alloimmunization remains limited and further research is needed to identify the genetic basis
of this variability in responsiveness.
This chapter reviews the recent developments in the molecular aspects of blood cell alloantigens and highlights their
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
本书版权归John Wiley & Sons Inc.所有
267
268 Molecular Hematology
https://t.me/med1917
Table19.1 Antigen expression onperipheral blood cells
Antigens Erythrocytes Platelets Neutrophils B lymphocytes T lymphocytes Monocytes
A, B, H +
I + + + + + + + − − −
*
Rh
K + + + − − − − −
HLA class I −/(+) + + + + + + + + + + + + + + +
HLA class II − − −/+ + +† + + + −/+ + +† + + +
GPIIb/IIIa − + + + (+)‡ − − −
GPIa/IIa − + + + − − + + −
GPIb/IX/V − + + + − − − −
CD109 (+)/+ +† − − (−)/+ +† (+)
FcγRIIIB (CD16b) − − + + + − − −/+ + +§*%
CD177 − − + + +# − − −
CTL2 − ? + + + + +$ + +$ ?
CD11b − − +
CD11a − − + + − − + +
+, + +, + + + Level of antigen expression in increasing order. (+) Weak expression. ? Not known. * Non‡GPIIIa in association with an alternative α chain αv. § When differentiated to macrophages expressing FcγRIIIA. # Expressed on subpopulation
of neutrophils. & Also expressed on natural killer cells. $ B and T lymphocytes not separated. % Expressed on subpopulation of monocytes.
+ + + +/(+)
+ + + − − − − −
impact on clinical management. Recognizing the wide variety
of clinical conditions in which the HLA alloantigens play a role,
− − −
+ − − + +&
glycosylated. † On activated cells.
or gene conversion events can create novel combinations of
mutations.
−
we have placed the main emphasis on complications of HLA
class I alloimmunization in patients receiving prophylactic
platelet transfusions. We also describe conditions where maternal antibodies with a specificity for the mismatched paternal
antigens cross the placenta and cause the destruction of platelets (NAITP), neutrophils (NAIN), or erythrocytes (HDFN).
HLA antigens
The HLA antigens are a group of highly polymorphic cell
surface molecules that play a central role in the induction
and regulation of immune responses, and as such they are
involved in self/non- self- recognition, tolerance, rejection of
allografts and graft- versus- host disease. The genes coding
The major histocompatibility complex
for these molecules form part of a complex genetic system
called the MHC, located on the short arm of chromosome 6
The MHC is one of the most polymorphic genetic systems in
humans. Mutations such as single- nucleotide polymorphisms
(SNP) can give rise to variant molecules and recombination,
(Figure19.1). The HLA region spans a distance of approxi-
mately 4000 kb and is divided into HLA class I, class II, and
class III genes. Class III includes a group of non- MHC genes
DP
B2 A2 B1A1
Figure19.1 Human Major Histocompatibility Complex (MHC) highlighting the HLA genes. The human MHC is located on the short arm
of chromosome 6, spanning a region of approximately 8 Mb and can be subdivided into three main regions. The MHC class III subregion does not
contain HLA genes.
本书版权归John Wiley & Sons Inc.所有
MHC-class II
DQ
B2 A2 B3 B1 A1
HLA class II genes
HLA class II genes pseudogenes
DR
B1 B2 B5 B3 B4 A
MHC-class III
HLA class I genes
HFE
MHC-class I
BC A Hfe
The molecular basis ofblood cell alloantigens 269
https://t.me/med1917
coding for proteins with various immunological functions,
such as the complement factor 4 and tumor necrosis factor
(TNF)- α.
The development of recombinant DNA technology has
led to an increased understanding of the genetic complexity,
structure, and function of the HLA genes and molecules.
HLA class I genes
The HLA class I genes have been classified according to their
structure and function as classical and non- classical, or class
Ib genes. The classic HLA class I genes, HLA- A, HLA- B,
andHLA- Cw, code for heterodimers formed by a heavy (α)
chain of approximately 43 kDa, non- covalently linked to the
β2- microglobulin light chain of 12 kDa. The latter is coded for
by a gene located outside the HLA region on chromosome 15.
The extracellular portion of the α chain has three domains
(α1, α2, and α3) encoded by exons 2, 3, and 4, respectively. Each
domain is approximately 90 amino acids in length. The transmembrane and cytoplasmic domains are encoded by exons 5,
6, and 7, respectively. The β2- microglobulin, which confers
stability on the molecule, is non- covalently linked to the α3
domain (see Figure19.2(a)).
The α1 and α2 domains are the most polymorphic regions
of these molecules and form a groove consisting of two α
helices, with an antiparallel- running β- pleated sheet forming the floor of the groove. This groove, which is approximately 2.5 nm long and 1 nm wide, can accommodate a
variety of antigen- derived peptides of about 8–10 amino
acids to be presented to T cells. In addition to the classical
HLA class I genes, the non- classical HLA class I genes are
also located in this region. They include HLA- E, HLA- F,
and HLA- G, and their exon/intron organization is similar to
that of the classical class I genes, but they have a more
restricted polymorphism. The HLA class I genes are
expressed on most tissues and blood cells, including T and B
lymphocytes and platelets (Table 19.1). The non- classical
class I genes HLA-
E and HLA- F are expressed on most tissues tested so far, whereas HLA- G has so far only been
detected on trophoblasts and monocytes.
Two MHC class I chain- related genes (MIC- A and MICB), located centromeric to HLA- B, have been described.
Unlike the classical and non- classical HLA class I, MIC
genes do not require binding to the β2- microglobulin or
peptide in order to be expressed on the cell surface. So far,
MIC expression has been detected on freshly isolated
endothelial cells, fibroblasts, keratinocytes, and monocytes.
They have also been found to be expressed on intestinal epithelial cells as a result of stress, and on a variety of tumors of
epithelial origin.
HFE is another non- classical class I gene, located
4 Mbtelomeric of HLA- A. This gene has been found to
be associated with the development of hereditary
hemochromatosis (HH). A single- point mutation, 845A,
replacing cysteine with tyrosine at position 282 (C282Y)
is found in over 90% of HH patients in the UK. The other
two mutations, replacing histidine by aspartate at amino
acid position 63 (H63D) and serine by cysteine at amino
acid 65 (S65C), appear to be associated with milder forms
of HH. This gene does not have a direct immune function
as it has lost the ability to bind antigenic peptides due to
closure of the antigen- binding groove. However, since
HFE can bind to the transferrin receptor, and in this way,
regulate iron uptake and availability, it is possible that
HFE may indirectly be involved in the regulation of
immune responses.
HLA class II genes
The HLA class II genes DR, DQ, and DP are all located
within the HLA class II region. There is one nonpolymorphic DRA and nine highly polymorphic DRB
genes, of which DRB2, DRB6, and DRB9 are pseudogenes.
These genes code for heterodimers formed by an α and a β
chain both encoded by genes within the MHC. The extracellular portion of these molecules has two domains (α1 and α2
and β1 and β2) encoded by exons 2 and 3 of each gene,
respectively. The α1 and β1 domains form the peptidebinding groove (see Figure19.2(b)).
The number of DRB genes expressed in each haplotype
varies depending on the DRB1 allele expressed; for example,
HLA DRB1*01, DRB1*01 : 03, DRB1*08, and DRB1*10haplotypes only express the DRB1 gene. DRB1*15 and
DRB1*16 haplotypes additionally express the DRB5 gene,
which codes for the DR51 product. The HLA DRB1*03 : 01
(DR17), DRB1*03 : 02 (DR18), DRB1*11, DRB1*12,
DRB1*13, and DRB1*14haplotypes also express the DRB3
genes, which code for the DR52 specificity, while the HLA
DRB1*04, DRB1*07, and DRB1*09 alleles also express the
DRB4 gene, which encodes the DR53 product. There are a
few exceptions to this gene distribution; for example, a DRB5
gene has been found linked to a DRB1*01haplotype, and
null DRB5 and DRB4 genes have been identified.
In contrast, there are two DQA and three DQB genes of
which only A1 and B1 are expressed, and both are polymorphic. Similarly, there are two DPA and two DPB genes
of which only DPA1 and DPB1 are expressed and are polymorphic. More than 37,000 HLA alleles have been named
in April 2023 (http://hla.alleles.org/nomenclature/index.
html).
Other HLA-
related genes located within the MHC class II
region include LMP2, LMP7, TAP1, and TAP2, which are
involved in the transport and processing of peptides presented by class I molecules, and the HLA DMA, DMB, DOA,
and DOB genes, which participate in the loading of peptides
in HLA class II molecules.
本书版权归John Wiley & Sons Inc.所有
270 Molecular Hematology
Immunoglobulin-
Transmembrane
Exon 2 Exon 3
(B)
Immunoglobulin-
Transmembrane
sequences
sequence
cytoplasmic
2
4
(A)
https://t.me/med1917
Peptide-
binding
region
like region
region
Cytoplasmic
region
Class IA
Peptide-
binding
β2–m
Regulatory
α
1
Leader
α
1
α
2
S
S
N
S
S
C
Exon
NN
S
S
C
S
α
3
P
P
P
Exon3Exon
β
1
S
3'UT
Transmembrane and
tively expressed on B lymphocytes, monocytes, and dendritic
cells, and on activated T lymphocytes and granulocytes
(Table19.1). HLA class II expression can also be induced on
β
2
Papain cleavage
sites
Exon 3 Transmembrane and
like region
Papain cleavage
region
Cytoplasmic
region
Class IIA
Class IIB
α
2
sites
Regulatory
sequences
S
S
C
Leader
sequence
S
S
C
Exon 2
The HLA class II genes (DR, DQ, and DP) are constitu-
Figure19.2 (A) Schematic presentation of HLA
covalent association between the
3'UT
cytoplasmic
classI. The nonHLA class I protein (with three immunoglobulinlike domains, α1, α2, and α3) and β2- microglobulin
(β2- m) is shown. The three α domains are encoded
by three exons of the HLA class IA gene on
chromosome 6. (B) Schematic presentation of
HLA class II. The α and β chains of the HLA class II
protein (each with two distinct immunoglobulinlike domains, α1 and α2, and β1 and β2) are
non- covalently associated. Both domains of each
chain are encoded by their respective exons of the
α and β class II genes on chromosome 6.
non- hematopoietic cells such as fibroblasts and endothelial
cells, as the result of activation or by the effect of certain
inflammatory cytokines, such as interferon (IFN)- γ and
TNF- α.
本书版权归John Wiley & Sons Inc.所有
The molecular basis ofblood cell alloantigens 271
https://t.me/med1917
Function
The HLA molecules play a key role in the induction and regulation
of the immune response. Both the phenomenon of MHC restriction and the development of tolerance, learnt as T cells pass
through the thymus, result in the selection of a T- cell repertoire
that will form the basis of an individual’s capacity to respond to
antigens. HLA class I molecules are primarily but not exclusively
involved in the presentation of endogenous antigens, such as viral
peptides, to CD8+ cytotoxic T cells, whereas HLA class II molecules present primarily, but not exclusively, exogenous, such as
bacterial, antigenic peptides to CD4+ helper T cells. These cells,
once activated, can initiate and regulate a variety of processes leading to the maturation and differentiation of cellular and humoral
effector cells, including the secretion of cytokines. The presentation of antigenic peptides is a highly regulated process and requires
fine interaction between the antigenic peptide, the antigen- binding
groove of the HLA molecules, and the T- cell receptor. Allelic variation of the HLA molecules can profoundly affect the ability to
present certain peptides because of the presence or absence of critical contact residues in the peptide- binding groove.
HLA molecules on donor cells loaded with donor- derived
peptides can also be recognized directly by T cells of the host
by a mechanism called allorecognition. Two pathways of
allorecognition, direct and indirect, have been identified,
both of which lead to the strong alloimmunization seen in
patients receiving blood transfusions or a solid organ or
bone marrow/stem cell transplantation.
More recently, it has been shown that both classical and
non- classical HLA class I molecules interact with two functionally distinct types of receptors, inhibitory and activating,
present in natural killer (NK) cells. These receptors belong to
two families, the immunoglobulin superfamily, also called
killer immunoglobulin receptors (KIRs), and the C- type lectin
superfamily CD94, which can covalently assemble with several members of the NKG2 family. The KIRs interact with
products of the HLA- A, - B, - Cw, and - G loci, whereas CD94NKG2 recognize the non- classical HLA- E molecule presenting peptides derived from several HLA class I, A, B, or C alleles
and from HLAognized by receptors present on both NK and γδ T cells.
Thus, HLA molecules have become increasingly relevant
in a variety of clinical situations, such as susceptibility to certain autoimmune and infectious diseases and in solid organ
and stem cell transplantation and blood cell alloimmunization. With regard to the latter, two examples will be discussed: refractoriness for prophylactic platelet transfusion by
HLA alloimmunization and HLA class II restriction of the
formation of anti- HPA- 1a antibodies.
G. MIC- A and MIC- B gene products are rec-
alloantigens of the HLA system has been both a technical and
clinical challenge. It is wellmolecular techniques, such as high- resolution typing by nextgeneration sequencing, is contributing to improved outcome
in transplant patients. The following sections review the current molecular techniques used to define alleles of the HLA
genes, which can be applied to other blood cell alloantigens.
established that the use of modern
Molecular typing techniques
Initially, the detection and characterization of the HLA molecules and polymorphisms was carried out using serological
and cellular techniques. The rapid development of DNA- based
molecular techniques has enabled detailed analyses of these
molecules at the nucleotide level. The result of these analyses
has shown the existence of shared nucleotide sequence motifs
between alleles of the same and/or different loci. Similarly, it
has been shown that there are certain locus- specific nucleotide
sequences in both the coding regions (exons) and the noncoding regions (introns) of the various genes.
DNA sequencing of many HLA alleles has demonstrated that
many of the important SNP that define each HLA allele are
located in exons 2 and 3 of HLA class I and exon 2 of HLA class
II molecules. These exons code for the distal membrane domains
of the HLA molecules, which form the peptide- binding groove
(Figure19.2(a) and (b)). Based on this information, several techniques have been developed to identify these polymorphisms
using polymerase chain reaction (PCR). These include HLA typing using reverse PCR- SSOP (sequence- specific oligonucleotide
probes), PCR- SSP (sequence- specific primers), sequencingbased typing (SBT), and next- generation sequencing (NGS).
PCR- SSP
This technique involves the use of sequence- specific primers
in the PCR. A single nucleotide mismatch at the 3′- end of the
allele- specific primer will prevent the polymerase from commencing DNA amplification. Therefore, amplification will
only occur when the matched allele- specific primer anneals
to the template DNA. The amplified DNA product is visualized by gel electrophoresis, and this allows the rapid identification of HLA alleles in individual samples, since the readof this method is the presence or absence of an amplicon for
which an allele- specific primer was used. Although this is a
rapid technique, many PCR reactions would have to be set up
for each sample to capture all the alleles of each gene. The
target sequence of the alleles must be known, and novel
unknown sequence variations may not always be detected.
Using the PCR- SSP technique, it is possible to determine
whether the detected sequences are in cis or in trans.
out
Identification of HLA gene polymorphism
The impact of molecular biological techniques on our ability
to identify allelic variation of human genes is best exemplified
by the HLA system. For decades, the enormous diversity of the
本书版权归John Wiley & Sons Inc.所有
Reverse PCR- SSOP
Reverse PCR- SSOP is a widely used technique, whereby the
gene of interest is firstly amplified using generic primers
complementary to highly conserved gene segments. The
272 Molecular Hematology
https://t.me/med1917
PCR product is labeled with biotin and, following denaturation and neutralization steps, the product is hybridized to
oligonucleotide probes coupled to color beads. These oligonucleotide probes are designed to anneal to polymorphic
sequences present in HLA alleles. Following the addition of
- phycoerythrin- conjugated streptavidin (SAPE) to the
reaction, the fluorescence signal is measured using a fluoroanalyzer. Reverse SSOP, is particularly amenable to batch
testing a large number of samples rather than single sample
testing.
Sequencing- based typing
Unlike PCR- SSP and reverse PCR- SSOP, which rely on utilizing known sequence polymorphisms for genotyping,
sequencing techniques allow unknown novel variants in the
gene sequences to be detected. This technology has enabled
the discovery of new HLA alleles. SBT by dye- terminator
Sanger DNA sequencing involves firstly denaturing the DNA
to provide a single- strand DNA template. A sequencing
primer is then added and the addition of a polymerase in the
presence of excess nucleotides and fluorescently- labeled dideoxy chain- terminating nucleotides (ddNTPs) enables
extension of the template. Upon incorporation of a ddNTP
chain terminator into the DNA strand, elongation is interrupted, leading to chain termination. Random incorporation
of the chain terminators generates products of varying
length. These products are then analyzed by capillary array
electrophoresis and the sequence is read by the fluorescent
signal generated by each product using an automated DNA
sequencer.
Next generation sequencing
NGS or massively parallel sequencing offers high throughput
scalability compared with SBT. Millions of fragments of
DNA can be sequenced in parallel and individual samples
can be ligated with identifiers to enable sequencing of hundreds of samples in a single sequencing run. The rapid
advancement in nexthas enabled an exponential increase in the rate of discovery
of new HLA alleles.
HLA NGS involves firstly enriching for the region, gene,
or exon of interest either by PCR amplification and pooling
of the resulting amplicons, or by PCR- free hybridization capture using specific probes. Two main approaches have been
used in the application of NGS for the definition of HLA
alleles. The first involves the amplification and sequencing of
the exons containing the polymorphic positions of the HLA
genes (exons 2 and 3 for HLA class I; A, B, and C and exon 2
for HLA class II; DRB1, DQB1, and DPB1). The second
approach involves the amplification and sequencing of the
whole gene of interest. The main advantage of this latter
approach is that it allows the detection of polymorphisms in
generation sequencing technologies
all exons and introns of the relevant gene, thus reducing the
number of HLA typing ambiguities obtained with the exonbased approach.
For short- read sequencing platforms, the amplification
step is followed by the fragmentation of these amplicons and
the ligation of adapters and unique indexes or identifiers, in
order to prepare a DNA library. The fragmented and adapterligated products are then clonally amplified and sequenced.
NGS generates hundreds of thousands of sequences, and
sorting and aligning them to the reference genome can be
extremely challenging. To achieve this, complex bioinformatic analysis algorithms have been developed.
Short- reading sequencing is currently the most used NGS
method, providing high accuracy and high throughput capability. However, sequencing read lengths are limited to
approximately 600 bases (depending on the sequencing platform) and this has an impact on phasing between distal SNPs
separated by large conserved intronic regions (Figure19.3).
The result is ambiguous HLA genotyping results, and this is
well- documented for HLA- DPB1 sequencing.
Long- read sequencing/third- generation
sequencing
For long- read sequencing, the adapters and unique identifiers can be ligated directly to the full- length amplicons
without the need for fragmentation. Long- read sequencing
platforms are able to sequence the entire amplicon, which
can be the length of an entire HLA gene. Two platform
developers that currently provide this capability include
Pacific Biosystems and Oxford Nanopore Technologies. The
latter allows for both short and long- read sequencing and
utilizes biological nanopores. These are embedded in a
membrane with an electric current flowing through them.
When a DNA molecule passes through the nanopore, the
current is disrupted and the signal generated is decoded to
determine a DNA sequence in real time. The large data outputs generated from these long- read sequencing technologies require significantly more computational power for
bioinformatic analyses.
Long-
read sequencing resolves the issue of HLA phasing
ambiguities seen with short- read sequencing and future
HLA sequencing strategies will rely on advances in this technology (Figure19.3).
DNA microarray genotyping
Sequencing is a process to investigate the whole sequence or
gene, whereas genotyping is a process to investigate the variation within a sequence, gene, or individual. Genotyping
studies require prior knowledge of the sequence and commonly targeted SNPs. Advancement in sequencing
techniques and the availability of sequences of the genes coding for blood cell surface molecules have facilitated the
本书版权归John Wiley & Sons Inc.所有
Соседние файлы в папке Библиотека им академика М.И. Перельмана