612:
fibrinogen levels are >1 gram/liter for major surgery, >0.5 gram/liter for minor surgery, >0.5 to 1-2 gram/liter for spontaneous bleeding (depending on its severity), >0.5 to > 1 gram/liter for the first two trimesters of pregnancy, and >1 to <2 gram/liter for the last trimester of pregnancy and postpartum period. Functional fibrinogen below these levels should be treated preferably with fibrinogen concentrate or if not available, fibrinogen-rich
103:
Hypodysfibrinogenemia causes episodes of pathological bleeding and thrombosis due not only to low levels of circulating fibrinogen but also to the dysfunction of a portion of the circulating fibrinogen. The disorder can lead to very significant bleeding during even minor surgical procedures and women
124:
In a study of 32 individuals diagnosed with hypodysfibrinogenemia, 41% presented with episodic bleeding, 43% presented with episodic thrombosis, and 16% were asymptomatic, being detected by abnormal blood tests. Bleeding and thrombosis generally begin in adulthood with the average age at the time of
624:
or (ε-aminocaproic acid) may be considered as an alternative preventative or therapeutic treatments in cases of minor surgery, dental extractions, mucosal bleeding, or other episodes of mild bleeding. In individuals with a personal or family history of thrombosis, should be considered for long-term
594:
plus a reduction in inducible blood clot formation so that the ratio of functionally-detected fibrinogen mass (i.e. detected in induced clots) to immunoassay-detected fibrinogen mass is abnormally low, i.e. <0.7. This contrast with individuals with congenital dysfibrinogenemia who exhibit normal
133:
period. Excessive bleeding following major or minor surgery, including dental extractions, occurs in both females and males with the disorder. Thrombotic complications of the disorder are often (≈50%) recurrent and can involve central and peripheral arteries, deep and superficial veins. Thrombotic
99:
termed congenital dysfibrinogenemia. However, congenital dysfibrinogenemia differs form hypodysfibrinogenemia in four ways. Congenital dysfibrinogenemia involves: the circulation at normal levels of fibrinogen at least some of which is dysfunctional; a different set of causative gene mutations; a
607:
case should be evaluated for the presence of hypodysfibrinogenemia. Individuals with the disorder need to be advised on its inheritance, complications, and preventative measures that can be taken to avoid bleeding and/or thrombosis. Since >80% of individuals may develop bleeding or thrombosis
611:
Measures to prevent and/or treat complications of hypodysfibrinogenemia should be tailored to the personal and family history of the individual by a specialized center. Individuals with a personal or family history of bleeding are considered to be of low risk of bleeding when their functional
595:
levels of fibrinogen as measured by immunoassay but low functionally-detected to immunoassay-detected fibrinogen mass ratios, i.e. <0.7. Where available, specialized laboratories can conduct studies to define the exact gene mutation(s) and fibrinogen abnormalities underlying the disorder.
281:) occur in each of the two copies of one of the cited genes, with one mutation coding for reduced formation of a functionally normal circulating fibrinogen and the second mutation coding for the circulation of a dysfunctional fibrinogen, e.g. fibrinogen Leipzig.
249:
each occurring in 12.5% of cases. The causes of two fibrinogen abnormalities that characterize hypodysfibrinogenemia, i.e. circulation at reduced levels of fibrinogen at least some of which is dysfunctional, reflect different molecular mechanisms:
973:
273:
mutation in both copies of one of the cited genes leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Otago, fibrinogen
Marburg, and fibrinogen
194:
4q31.3, 4q31.3, and 4q32.1, respectively) and are the sites where mutations occur that code for a dysfunctional fibrinogen and/or reduced fibrinogen levels which are the cause of congenital hypodysfibrinogenemia.
284:
Two different mutations occur in one copy of the cited genes, with one mutation causing hypofibrinogenemia and the other mutation coding for a dysfunctional fibrinogen, e.g. fibrinogen Keokuk.
608:
complications of the disorder, asymptomatic individuals diagnosed with hydposyfibrinogenemia are best handled at a specialized center in order to benefit from multidisciplinary management.
266:
gene leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen
Vlissingen, fibrinogen Philadelphia, and fibrinogen Freiburg.
88:. These mutations result in the production and circulation at reduced levels of fibrinogen at least some of which is dysfunctional. Hypodysfibrinogenemia exhibits
911:
Casini A, Neerman-Arbez M, Ariëns RA, de
Moerloose P (2015). "Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management".
830:
Neerman-Arbez M, de
Moerloose P, Casini A (2016). "Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders".
125:
presentation and diagnosis being 32 years. Bleeding is more frequent and severe in women of child-bearing age; these women may suffer miscarriages,
1054:
671:"Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation"
1044:
988:
875:"Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ' as thrombomobulin II"
104:
afflicted with the disorderoften suffer significant bleeding during and after giving child birth, higher rates of miscarriages, and
725:
Casini A, de
Moerloose P, Neerman-Arbez M (2016). "Clinical Features and Management of Congenital Fibrinogen Deficiencies".
586:
Hypodysfibrinogenemia is usually diagnosed in individuals who: have a history of abnormal bleeding or thrombosis or are a
630:
77:
590:
of such an individual. Initial laboratory findings include a decrease in serum fibrinogen mass levels as measured by
344:
the clinical consequence(s) of the mutation. Unless noted as a deletion (del) or frame shift (fs), all mutations are
288:
The following Table adds further information on the just cited examples of hypodysfibrinogenemias. The Table gives:
332:) occurring before-after the mutation at the numbered amino acid(s) sites in the circulating mutated fibrinogen;
109:
1039:
874:
278:
1017:
1049:
229:
209:
171:
143:
60:
52:
219:
179:
56:
207:
disorder caused by at least 32 different types of single mutations. Ten of these mutations are in the
454:
360:
and thereby a shorten polypeptide chain is notated by an X (PSC) after the altered amino acid codon.
151:
147:
246:
772:
936:
855:
750:
238:
204:
928:
893:
847:
805:
742:
692:
353:
349:
345:
242:
96:
35:
920:
885:
839:
795:
787:
734:
682:
617:
191:
126:
621:
613:
337:
135:
982:
669:
Casini A, Brungs T, Lavenu-Bombled C, Vilar R, Neerman-Arbez M, de
Moerloose P (2017).
426:
396:
167:
81:
1033:
626:
587:
328:
the name of the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using
940:
859:
754:
488:
255:
190:
gene. All three genes are located on the long or "q" arm of human chromosome 4 (at
163:
113:
773:"Clinical conditions responsible for hyperviscosity and skin ulcers complications"
100:
somewhat different mix of clinical symptoms; and a much lower rate of penetrance.
889:
80:
cause by mutations in one or more of the genes that encode a factor critical for
638:
591:
406:
105:
484:
460:
impaired fibrinogen assembly, poor fibrin clot lysis, defective polymerization
357:
329:
270:
130:
89:
85:
977:
48:
932:
897:
851:
843:
809:
746:
738:
696:
965:
1012:
634:
309:
800:
92:, i.e. only some family members with the mutated gene develop symptoms.
604:
508:
impaired secretion, defective calcium binding, defective polymerization
321:
317:
313:
924:
791:
687:
670:
572:
impaired assembly of intracelllar fibrinogen, defective polymerization
548:
impaired assembly of intracelllar fibrinogen, defective polymerization
528:
impaired assembly of intracelllar fibrinogen, defective polymerization
432:
402:
305:
139:
993:
616:
or plasma to attain low risk levels of functional fibrinogen.
771:
Caimi G, Canino B, Lo Presti R, Urso C, Hopps E (2017).
170:
each of which is composed of three polypeptide chains,
129:, and excessive bleeding during child birth and/or the
304:), its mutation site (i.e. numbered nucleotide in the
955:
531:
post-surgical, postpartum, and post-trauma bleeding
203:
Congenital hypodysfibrinogenemia is inherited as an
1003:
959:
44:
34:
26:
21:
340:for the mutated fibrinogen's misfunction(s); and
134:events may be serious and involve occlusion of a
258:mutation in one of the two copies of either the
324:) at these sites before>after the mutation;
825:
823:
821:
819:
766:
764:
720:
718:
716:
714:
712:
710:
708:
706:
664:
662:
660:
658:
656:
654:
8:
956:
780:Clinical Hemorheology and Microcirculation
18:
799:
686:
575:recurrent venous and arterial thromboses
551:recurrent venous and arterial thromboses
463:recurrent venous and arterial thromboses
308:gene), and name of the nucleotides (i.e.
362:
650:
435:bleeding, recurrent venous thrombosis
913:Journal of Thrombosis and Haemostasis
832:Seminars in Thrombosis and Hemostasis
727:Seminars in Thrombosis and Hemostasis
675:Journal of Thrombosis and Haemostasis
292:each mutated protein's trivial name;
95:The disorder is similar to a form of
7:
14:
74:congenital hypodysfibrinogenemia
30:Congenital hypodysfibrinogenemia
480:defective aggregation of fibrin
182:(also termed β) encoded by the
174:(also termed α) encoded by the
1055:Genetic diseases and disorders
395:impaired secretion; defective
1:
569:γ: Ala108Gly and λ: Gly377Ser
277:Two different mutations (see
1045:Autosomal dominant disorders
890:10.1016/j.matbio.2016.09.010
631:low molecular weight heparin
392:Aα: Arg268Gln followed by fs
237:). The mutations are mainly
162:Circulating fibrinogen is a
144:splanchnic venous thrombosis
873:Duval C, Ariëns RA (2017).
372:Polypeptide chain: mutation
186:gene, and γ encoded by the
150:presumptively secondary to
1071:
110:abnormally heavy bleeding
603:Blood relatives of the
516:fibrinogen Philadelphia
401:post-surgical and post-
296:the gene mutated (i.e.
279:Compound heterozygosity
76:, is a rare hereditary
844:10.1055/s-0036-1571340
739:10.1055/s-0036-1571339
330:standard abbreviations
233:gene (also termed the
230:fibrinogen gamma chain
223:gene (also termed the
213:gene (also termed the
210:fibrinogen alpha chain
61:fibrinogen gamma chain
53:fibrinogen alpha chain
627:anticoagulation drugs
556:fibrinogen Leipzig II
496:fibrinogen Vlissingen
227:gene), and 17 in the
220:fibrinogen beta chain
70:Hypodysfibrinogenemia
57:fibrinogen beta chain
22:Hypodysfibrinogenemia
588:close blood relative
505:γ: delAsn319-Asp-320
405:bleeding, recurrent
356:causing a premature
247:Frameshift mutations
152:deep vein thrombosis
148:pulmonary thrombosis
51:in the gene for the
536:fibrinogen Freiburg
457:; Aα: Gln321X (PSC)
446:: c.510 +1 G>T;
78:fibrinogen disorder
1004:External resources
562:: c.323C>G and
511:venous thrombosis
483:post-surgical and
450:c.1039C>T (PSC)
413:fibrinogen Marburg
378:Clinical disorder
350:nonsense mutations
239:missense mutations
205:autosomal dominant
90:reduced penetrance
1027:
1026:
925:10.1111/jth.12916
792:10.3233/CH-160218
688:10.1111/jth.13655
579:
578:
491:during pregnancy
440:fibrinogen Keokuk
422:Aα: Lys461X (PSC)
354:nonsense mutation
97:dysfibrinogenemia
67:
66:
16:Medical condition
1062:
957:
945:
944:
908:
902:
901:
879:
870:
864:
863:
827:
814:
813:
803:
777:
768:
759:
758:
722:
701:
700:
690:
666:
618:Antifibrinolytic
502:: c.1033_1038del
383:fibrinogen Otago
363:
127:menometrorrhagia
114:menstrual period
19:
1070:
1069:
1065:
1064:
1063:
1061:
1060:
1059:
1030:
1029:
1028:
1023:
1022:
999:
998:
968:
954:
949:
948:
910:
909:
905:
884:. 60–61: 8–15.
877:
872:
871:
867:
829:
828:
817:
775:
770:
769:
762:
724:
723:
704:
668:
667:
652:
647:
622:tranexamic acid
614:cryoprecipitate
601:
584:
468:fibrinogen Sfax
455:splice mutation
389:: c.858_859incC
375:Pathophysiology
338:pathophysiology
201:
199:Pathophysiology
160:
136:cerebral artery
122:
17:
12:
11:
5:
1068:
1066:
1058:
1057:
1052:
1047:
1042:
1040:Coagulopathies
1032:
1031:
1025:
1024:
1021:
1020:
1008:
1007:
1005:
1001:
1000:
997:
996:
985:
969:
964:
963:
961:
960:Classification
953:
952:External links
950:
947:
946:
903:
882:Matrix Biology
865:
815:
760:
702:
681:(5): 876–888.
649:
648:
646:
643:
620:drugs such as
600:
597:
583:
580:
577:
576:
573:
570:
567:
557:
553:
552:
549:
546:
543:
537:
533:
532:
529:
526:
523:
522:: c.1210T>C
517:
513:
512:
509:
506:
503:
497:
493:
492:
481:
478:
475:
469:
465:
464:
461:
458:
451:
441:
437:
436:
429:
427:polymerization
423:
420:
419:: c.1438A>T
414:
410:
409:
399:
397:polymerization
393:
390:
384:
380:
379:
376:
373:
370:
369:Gene: mutation
367:
286:
285:
282:
275:
267:
200:
197:
159:
156:
121:
118:
82:blood clotting
72:, also termed
65:
64:
46:
42:
41:
38:
32:
31:
28:
24:
23:
15:
13:
10:
9:
6:
4:
3:
2:
1067:
1056:
1053:
1051:
1050:Rare diseases
1048:
1046:
1043:
1041:
1038:
1037:
1035:
1019:
1015:
1014:
1010:
1009:
1006:
1002:
995:
991:
990:
986:
984:
980:
979:
975:
971:
970:
967:
962:
958:
951:
942:
938:
934:
930:
926:
922:
919:(6): 909–19.
918:
914:
907:
904:
899:
895:
891:
887:
883:
876:
869:
866:
861:
857:
853:
849:
845:
841:
838:(4): 356–65.
837:
833:
826:
824:
822:
820:
816:
811:
807:
802:
797:
793:
789:
785:
781:
774:
767:
765:
761:
756:
752:
748:
744:
740:
736:
733:(4): 366–74.
732:
728:
721:
719:
717:
715:
713:
711:
709:
707:
703:
698:
694:
689:
684:
680:
676:
672:
665:
663:
661:
659:
657:
655:
651:
644:
642:
640:
636:
632:
628:
623:
619:
615:
609:
606:
598:
596:
593:
589:
581:
574:
571:
568:
565:
561:
558:
555:
554:
550:
547:
544:
542:: c.103C>T
541:
538:
535:
534:
530:
527:
524:
521:
518:
515:
514:
510:
507:
504:
501:
498:
495:
494:
490:
486:
482:
479:
477:Bβ: Cys197Arg
476:
474:: c.679T>C
473:
470:
467:
466:
462:
459:
456:
452:
449:
445:
442:
439:
438:
434:
430:
428:
424:
421:
418:
415:
412:
411:
408:
404:
400:
398:
394:
391:
388:
385:
382:
381:
377:
374:
371:
368:
365:
364:
361:
359:
355:
351:
347:
343:
339:
335:
331:
327:
323:
319:
315:
311:
307:
303:
299:
295:
291:
283:
280:
276:
272:
268:
265:
261:
257:
253:
252:
251:
248:
244:
240:
236:
232:
231:
226:
222:
221:
216:
212:
211:
206:
198:
196:
193:
189:
185:
181:
177:
173:
169:
165:
157:
155:
153:
149:
145:
141:
137:
132:
128:
119:
117:
115:
111:
107:
101:
98:
93:
91:
87:
83:
79:
75:
71:
62:
58:
54:
50:
47:
43:
39:
37:
33:
29:
25:
20:
1011:
987:
972:
916:
912:
906:
881:
868:
835:
831:
801:10447/238851
786:(1): 25–34.
783:
779:
730:
726:
678:
674:
610:
602:
585:
566:c.1129G>A
563:
559:
539:
525:γ: Ser378Pro
519:
499:
489:metrorrhagia
471:
447:
443:
416:
407:miscarriages
386:
366:Trivial name
341:
333:
325:
301:
297:
293:
289:
287:
263:
259:
256:heterozygous
234:
228:
224:
218:
217:), 5 in the
214:
208:
202:
187:
183:
175:
166:made of two
164:glycoprotein
161:
123:
120:Presentation
102:
94:
73:
69:
68:
639:rivaroxaban
592:immunoassay
545:γ: Arg16Cys
138:leading to
112:during the
106:menorrhagia
27:Other names
1034:Categories
645:References
487:bleeding,
485:postpartum
425:defective
358:stop codon
271:homozygous
158:Fibrinogen
131:postpartum
86:fibrinogen
40:Hematology
599:Treatment
582:Diagnosis
298:FGA, FGB,
192:positions
49:Mutations
36:Specialty
1013:Orphanet
941:10955092
933:25816717
898:27784620
860:12693693
852:27019463
810:28550239
755:12038872
747:27019462
697:28211264
635:coumadin
629:such as
346:missense
260:FGA, FGB
243:nonsense
215:FGA gene
605:proband
235:FGG gen
168:trimers
108:, i.e.
1018:248408
994:616004
939:
931:
896:
858:
850:
808:
753:
745:
695:
433:partum
403:partum
306:cloned
178:gene,
146:, and
140:stroke
45:Causes
983:D68.2
978:10-CM
937:S2CID
878:(PDF)
856:S2CID
776:(PDF)
751:S2CID
637:, or
431:post-
274:Sfax.
262:, or
241:with
59:, or
989:OMIM
929:PMID
894:PMID
848:PMID
806:PMID
743:PMID
693:PMID
453:Aα:
352:. A
336:the
245:and
63:gene
974:ICD
921:doi
886:doi
840:doi
796:hdl
788:doi
735:doi
683:doi
564:FGG
560:FGG
540:FGG
520:FGG
500:FGG
472:FGB
448:FGA
444:FGA
417:FGA
387:FGA
348:or
302:FGG
300:or
264:FGG
225:FGB
188:FGG
184:FGB
176:FGA
1036::
1016::
992::
981::
935:.
927:.
917:13
915:.
892:.
880:.
854:.
846:.
836:42
834:.
818:^
804:.
794:.
784:67
782:.
778:.
763:^
749:.
741:.
731:42
729:.
705:^
691:.
679:15
677:.
673:.
653:^
641:.
633:,
342:e)
334:d)
326:c)
320:,
316:,
312:,
294:b)
290:a)
269:A
254:A
180:Bβ
172:Aα
154:.
142:,
116:.
84:,
55:,
976:-
966:D
943:.
923::
900:.
888::
862:.
842::
812:.
798::
790::
757:.
737::
699:.
685::
322:G
318:A
314:T
310:C
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