1060:. While recurrence of amyloidosis in the transplanted kidney occurs and is to be expected, transplant survival rates for this form of amyloidosis are significantly better than those for transplants in other forms of systemic renal amyloidosis. Relatively healthy individuals with hereditary fibrinogen Aα-Chain-related renal amyloidosis may be considered for kidney and liver bi-transplantation with the expectation that survival of the transplanted kidney will be prolonged by replacing the fibrinogen Aα-Chain-producing liver with a non-diseased donor liver.
206:, i.e. only some family members with one of these mutant genes develop dysfibrinogenemia-related symptoms. While both of these congenital disorders as well as acquired dysfibrinogenemia are considered very rare, it is estimated that ~0.8% of individuals with venous thrombosis have either a congenital or acquired dysfibrinogenemia. Hence, the dysfibrinogenemia disorders may be highly under-diagnosed conditions due to isolated thrombotic events that are not appreciated as reflecting an underlying fibrinogen disorder.
77:
22:
966:. They do not evidence pathological bleeding or thrombosis and their amyloidosis is non-systemic in that it is restricted to the kidney. In a report on 474 patients with renal amyloidosis, hereditary fibrinogen Aα chain disease represented only 1.3% of all cases whereas aberrant immunoglobulin-induced renal amyloidosis (e.g.
213:. Both disorders involve the circulation of dysfunctional fibrinogen but in congenital hypodysfibrinogenemia plasma fibrinogen levels are low while in congenital dysfibrinogenemia they are normal. Furthermore, the two disorders involve different gene mutations and inheritance patterns as well as somewhat different symptoms.
920:
or fibrinogen concentrates are recommended for prophylactic treatment prior to minor surgery while fibrinogen concentrates are recommended prior to major surgery with fibrinogen concentrates usage seeking to maintain fibrinogen activity levels at >1 gram/liter. Women undergoing vaginal or
Cesarean
869:
In a study of 189 individuals diagnosed with congenital dysfibrinogenemia, ~33% were asymptomatic, ~47% experienced episodic bleeding, and ~20% experienced episodic thromboses. Due to the rareness of this disorder, treatment of individuals with these presentations are based primarily on case reports,
541:
of the γ chain that lead to defective assembly of fibrin in early clot formation and thereby a bleeding predisposition. Two particular missense mutations represent the majority (74% in one study of 101 individuals) of all mutations associated with dysfibrinogenemia and therefore represent prime sites
1039:
gene mutations, and the occurrence of these mutations in family members. The disorder exhibits a highly variable penetrance among family members. Hereditary fibrinogen Aα-Chain amyloidosis shows variable penetrance among family members, a distinctive histological appearance, proteinuria, progressive
852:
tests are usually prolonged regardless of history of bleeding or thrombosis. Where available, laboratory analyses of the fibrinogen genes and peptide chains solidify the diagnosis. Initial examination of these genes or protein chains should search specifically for "hot spot" mutations, i.e. the most
835:
The diagnosis of congenital dysfibrinogenmia is made by clinical laboratory studies that find normal levels of plasma fibrinogen but significant excess in the amount of immunologically detected compared to functionally detected (i.e. able to be clotted) fibrinogen. The ratio of functionally-detected
878:
Treatment of asymptomatic congenital dysfibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as estimated based on the history of family members with the disorder and, where available, determination of the exact mutation causing the disorder plus
860:
by the finding of normal immunologically-detected levels of fibrinogen in congenital dysfibrinogenemia and sub-normal levels of immunologically-detected fibrinogen in congenital hypodysfibrinogenemia. Both disorders exhibit mass ratios of functionally-detected to immunologically-detected fibrinogen
433:
Many cases of congenital dysfibrinogenemia are asymptomatic. Since manifestations of the disorder generally occur in early adulthood or middle-age, younger individuals with a gene mutation causing it may not have had time to develop symptoms while previously asymptomatic individuals of advanced age
1082:
Acquired dysfibrinogenemia occurs as a known or presumed consequence of an underlying disease which directly or indirectly interferes with the clotting function of fibrinogen. Individuals with acquired dysfibrinogenemias have a greater tendency for bleeding complications than those with congenital
995:
viz., c.1622delT: Thr525Leu, is also a cause of the disorder. The fibrinogen bearing these mutant Aα-chains is secreted into the circulation and gradually accumulates in, and causes significant injury to, the kidney. The mutant fibrinogen does not appear to accumulate in, or injure, extra-renal
1255:
Treatment of acquired dysfibrinogenemia follows the guidelines recommended for congenital dysfibrinogenemia. In addition, treatment of any disease thought to be responsible for the dysfibrinogenemia might be useful. For example, therapeutic plasma exchange and chemotherapy to reduce monoclonal
940:
for a period that depends on personal and family history of thrombosis events. Prophylactic treatment prior to minor surgery should avoid fibrinogen supplementation and use prophylactic anticoagulation measures; prior to major surgery, fibrinogen supplementation should be used only if serious
1073:
Acquired dysfibrinogenemia commonly present with signs, symptoms, and/or prior diagnoses of the underlying causative disease or drug intake in an individual with an otherwise unexplained bleeding tendency or episode. Bleeding appears to be more prominent in acquired compared to congenital
990:
of Aα chain mutations the most common of which is hemoglobin
Indianapolis, a heterozygous missense (c.1718G>T: Arg554Leu) mutation. Other missense mutations causing this disorder are unnamed; they include 1634A>T: Glu526Val; c.1670C>A: Thr538lys; c.1676A.T:Glu540Val; and
887:
and all individuals with fibrinogen activity in clotting tests below 0.5 grams/liter are prone to bleeding and spontaneous abortions. Women with multiple miscarriages and individuals with excessively low fibrinogen activity levels should be considered for
853:
common mutations (see
Pathophysiology section) that comprise the large bulk of mutations in the disorder. In cases of dysfibrinogenemia in which acquired disease is suspected, diagnosis requires a proper diagnosis of the presence of a causable disease.
879:
the propensity of the particular mutation type to develop these complications. In general, individuals with this disorder require regular follow-up and multidiscipline management prior to surgery, pregnancy, and giving
921:
child birth should be treated at a hemophilia center with fibrinogen concentrates to maintain fibrinogen activity levels at 1.5 gram/liter. The latter individuals require careful observation for bleeding during their
550:
at either the 35th position of FGA (termed Arg35; see fibrinogen Metz1 and fibrinogen
Bicetre in the Table below) and or the 301st position of FGG (termed Arg301; see fibrinogen Baltimore IV in the Table below).
2212:
98:
194:
is a sub-category of congenital dysfibrinogenemia in which the dysfunctional fibrinogen does not cause bleeding or thrombosis but rather gradually accumulates in, and disrupts the function of, the kidney.
1601:
1074:
dysfibrinogenemia; pathological thrombosis, while potentially occurring in these individuals as a complication of their underlying disease, is an uncommon feature of the acquired disorder.
908:
that interfere with normal platelet function. During bleeding episodes, treatment with fibrinogen concentrates or in emergencies or when these concentrates are unavailable, infusions of
936:
agents. They should be instructed on antithrombotic behavioral methods fur use in high risk situations such as long car rides and air flights. Venous thrombosis should be treated with
458:. In one study of 37 individuals >50 years old afflicted with this disorder, 19% had a history of thrombosis. Thrombotic complications occur in both arteries and veins and include
2101:
247:, although once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein. The final secreted, hepatocyte-derived glycoprotein is made of two
2158:
Post GR, James L, Alapat D, Guillory V, Cottler-Fox M, Nakagawa M (2013). "A case of acquired dysfibrinogenemia in multiple myeloma treated with therapeutic plasma exchange".
202:
occurring in more than 400 families have been found to cause it. All of these mutations as well as those causing hereditary fibrinogen Aα-Chain amyloidosis exhibit partial
1247:
Diagnosis of acquired dysfibrinogenemia uses the same laboratory tests that are used for congenital dysfibrinogenemia plus evidence for an underlying causative disease.
1083:
fibrinogenemia. The following Table gives some abnormalities, causes, and apparent pathophysiology along with some comments on examples of acquired dysfibrinogenemia.
416:
Based on these fibrinogen functions, a fibrinogen mutation may act either to inhibit or promote blood clot formation and/or lysis to thereby produce in individuals a
2290:
2115:
Kotlín R, Sobotková A, Riedel T, Salaj P, Suttnar J, Reicheltová Z, Májek P, Khaznadar T, Dyr JE (2008). "Acquired dysfibrinogenemia secondary to multiple myeloma".
275:
4q31.3, 4q31.3, and 4q32.1, respectively) and may contain mutations that are the cause of congenital dysfibrinogenemia. The heximer is assembled as a protein in the
1032:
1575:
McDonagh, J (2001). "Dysfibrinogenemia and other disorders of fibrinogen structure or function". In Colman R, Hirsh J, Marder V, Clowes A, George J (eds.).
1961:
Blombäck M, Blombäck B, Mammen EF, Prasad AS (1968). "Fibrinogen
Detroit--a molecular defect in the N-terminal disulphide knot of human fibrinogen?".
1750:
Neerman-Arbez M, de
Moerloose P, Casini A (2016). "Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders".
1468:
Casini A, Neerman-Arbez M, Ariëns RA, de
Moerloose P (2015). "Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management".
378:
pathways act to limit clot formation and dissolve clots no longer needed. Fibrinogen and its Aα fibrin chain have several functions in this process:
928:
Individuals experiencing episodic thrombosis as a result of congenital dysfibrinogenemia should also be treated at a center specialized in treating
1256:
antibody levels has been used successfully to reverse otherwise uncontrollable bleeding in cases of multiple myeloma-associated dysfibrinogenemia.
442:. Less common manifestations of bleeding may be severe or even life-threatening; these include excessive bleeding after tooth extraction, surgery,
334:
The normal process of blood clot formation involves the coordinated operation of two separate pathways that feed into a final common pathway: 1)
295:
enzyme pathways thereby converting the heximer to a functional fibrinogen glycoprotein. The final circulating glycoprotein (notated as (AαBβγ)
2283:
900:
Individuals experiencing episodic bleeding as a result of congenital dysfibrinogenemia should be treated at a center specialized in treating
482:
probably stemming form deep vein thrombosis. About 26% of individuals with the disorder suffer both bleeding and thrombosis complications.
610:
comments. Unless noted as a deletion (del), frame shift (fs), or homozygous mutation, all mutations are heterozygous, missense mutations.
2017:
Said SM, Sethi S, Valeri AM, Leung N, Cornell LD, Fidler ME, Herrera
Hernandez L, Vrana JA, Theis JD, Quint PS, Dogan A, Nasr SH (2013).
434:
with such a mutation are unlikely to develop symptoms. Bleeding episodes in most cases of this disorder are mild and commonly involve
1795:"Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ' as thrombomobulin II"
2276:
542:
to examine in the initial testing of individuals having a congenital dysfibrinogenmia bleeding disorder. These mutations alter the
1008:
a dysfunctional plasma fibrinogen, i.e. significantly less functionally-detected compared to immunologically-detected fibrinogen;
595:
1035:. Specialized centers use immunological and genetic studies to define the nature of the renal amyloid deposits, the presence of
2407:
2910:
1584:
154:
is an inherited disorder in which one of the parental genes produces an abnormal fibrinogen. This fibrinogen interferes with
1648:
Casini A, de
Moerloose P, Neerman-Arbez M (2016). "Clinical Features and Management of Congenital Fibrinogen Deficiencies".
474:. In one series of 33 individuals with a history of thrombosis due to congenital dysfibrinogenemia, five developed chronic
239:
cells also make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood
2582:
2565:
2227:
335:
58:
2644:
2596:
1926:
Tengborn L, Blombäck M, Berntorp E (2015). "Tranexamic acid--an old drug still going strong and making a revival".
1013:
382:
Blood clotting: fibrinogen concentration is the rate-limiting factor in blood clot formation and along with blood
1104:
970:) represented 86% of the cases). Hereditary fibrinogen Aα-Chain amyloidosis is, however, the most common form of
2363:
1526:
Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA, Zeng CH, Liu ZH, Li LS, Wechalekar A, Hawkins PN (2009).
987:
2650:
2636:
1794:
2624:
2587:
2457:
1156:
937:
405:
2256:
2777:
2353:
841:
837:
2732:
2577:
2400:
983:
971:
861:
that are below <0.7. Genetic and protein analyses can definitively differentiate the two disorders.
1528:"Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis"
2848:
2419:
459:
32:
370:
formed from this cleavage. In the final common pathway fibrin is cross-linked by activated clotting
2818:
2808:
2561:
2390:
963:
889:
870:
guidelines set by the United
Kingdom, and expert opinions rather than controlled clinical studies.
198:
Congenital dysfibrinogenemia is the commonest of these three disorders. Some 100 different genetic
1324:
2905:
2601:
554:
The following Table lists examples of mutations causing congenital dysfibrinogenemias. It gives:
272:
2915:
2722:
2697:
2655:
2066:
Ashby MA, Lazarchick J (1986). "Acquired dysfibrinogenemia secondary to mithramycin toxicity".
1057:
475:
252:
103:
2717:
2707:
2525:
1129:
916:(a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter.
857:
467:
398:
355:
276:
260:
210:
183:
209:
Congenital dysfibrinogenemia is distinguished from a similar inherited disorder, congenital
2473:
2368:
2358:
1970:
1703:
1184:
1160:
530:
526:
471:
401:
receptors and thereby promotes blood clot formation through the primary hemostasis pathway.
394:
40:
1052:
Treatment of hereditary fibrinogen Aα-Chain amyloidosis has relied on chronic maintenance
146:
consist of three types of fibrinogen disorders in which a critical blood clotting factor,
8:
2838:
2712:
2702:
2498:
2378:
1299:
1152:
1147:
1124:
1024:
909:
522:
518:
455:
417:
174:
is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of
86:
1974:
1707:
1273:
1040:
renal impairment, and markedly better survival rates than other forms of systemic renal
2520:
2478:
2452:
2325:
2140:
2043:
2018:
1994:
1908:
1862:
1775:
1727:
1673:
1552:
1527:
1493:
1422:
1395:
1164:
491:
479:
271:
gene. All three genes are located on the long (i.e. "p") arm of human chromosome 4 (at
179:
2503:
2412:
2268:
2175:
2132:
2083:
2079:
2048:
1986:
1943:
1900:
1854:
1849:
1832:
1813:
1767:
1719:
1665:
1621:
1580:
1557:
1485:
1427:
1357:
905:
494:
2144:
1866:
1779:
1731:
1677:
1497:
2833:
2553:
2493:
2488:
2348:
2167:
2124:
2075:
2038:
2030:
1998:
1978:
1939:
1935:
1912:
1892:
1844:
1805:
1759:
1711:
1657:
1613:
1547:
1539:
1477:
1417:
1407:
1347:
1339:
1133:
941:
bleeding occurs; otherwise, prophylactic anticoagulation measures are recommended.
701:
675:
367:
363:
2171:
2019:"Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases"
1579:(4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 855–92.
1325:"Clinical conditions responsible for hyperviscosity and skin ulcers complications"
514:
510:
2858:
2667:
2508:
2373:
1809:
1180:
917:
913:
892:
therapy with fibrinogen replacement during pregnancy, delivery, and/or surgery.
533:
in one of these genes. The most frequent sites for these mutations code for the
2868:
2570:
2513:
2395:
1190:
967:
933:
849:
649:
347:
328:
280:
248:
244:
2221:
1617:
343:
2899:
2878:
2690:
2685:
2680:
2437:
1694:
Repetto O, De Re V (2017). "Coagulation and fibrinolysis in gastric cancer".
845:
443:
288:
175:
2611:
408:, an agent that breaks down blood clots to participate thereby in promoting
339:
2320:
2179:
2136:
2052:
1947:
1904:
1896:
1883:
Ruiz-Saez A (2013). "Occurrence of thrombosis in rare bleeding disorders".
1858:
1817:
1771:
1763:
1723:
1669:
1661:
1625:
1561:
1543:
1489:
1431:
1361:
1234:
1053:
884:
451:
409:
375:
228:
159:
2087:
1990:
986:
termed hereditary fibrinogen Aα-Chain amyloidosis. The disorder is due to
2863:
2828:
2803:
2675:
2483:
2315:
2304:
2034:
1220:
1204:
1114:
1041:
959:
955:
922:
836:
to immunologically detected fibrinogen masses in these cases is <0.7.
594:
the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using
447:
439:
387:
371:
292:
284:
236:
155:
2204:
1352:
2853:
2447:
2429:
1715:
1412:
1224:
1216:
992:
929:
901:
880:
856:
Congenital dysfibrinogenmia is initially distinguished form congenital
801:
relatively rare; nucleotides 1033-1038 and amino acids 319-320 deleted
538:
534:
374:(termed factor XIIIa) to form mature gel-like fibrin clots. Subsequent
232:
222:
203:
167:
147:
2128:
1481:
1343:
327:) is arranged as a long flexible rod with nodules at both ends termed
2798:
2762:
2385:
1982:
1467:
1304:
1208:
1028:
1020:
383:
351:
199:
2813:
2767:
2752:
2442:
2300:
2251:
1525:
575:
547:
404:
Blood clot lysis: The Aα fibrin chain formed from fibrinogen binds
359:
240:
163:
982:
Certain mutations in the fibrinogen Aα-chain gene cause a form of
657:
relatively rare; first description of congenital dysfibrinogenmia
420:
to develop pathological bleeding, thrombosis, or both conditions.
2772:
1212:
587:
583:
579:
2232:
2757:
2216:
1749:
1647:
726:
thin clot, increased clot strength, impaired plasmin generation
571:
470:, retinal artery thrombosis, peripheral artery thrombosis, and
463:
435:
187:
162:
of blood clots. The condition therefore may cause pathological
883:. Women with the disorder appear to have an increased rate of
490:
Congenital dysfibrinogenemia is most often caused by a single
944:
543:
1960:
2114:
1004:
The diagnosis of this disorder depends on demonstrating:
358:, i.e. cleavage of the Aα and Bβ chains of fibrinogen by
190:. It is associated primarily with pathological bleeding.
1925:
1323:
Caimi G, Canino B, Lo Presti R, Urso C, Hopps E (2017).
1322:
2157:
279:
of hepatocytes and then transferred to the Golgi where
251:
each of which is composed of three polypeptide chains,
2298:
2023:
Clinical Journal of the American Society of Nephrology
602:
the cause of the mutated fibrinogen's misfunction(s);
598:) found in the normal-mutated circulating fibrinogen;
570:), its mutation site (i.e. numbered nucleotide in the
362:
to form individual fibrin strands plus the respective
991:
c1712C>A:Pro552His. A deletion mutation causing a
37:
In particular, it has problems with not using MEDMOS.
2194:
2016:
231:
made and secreted into the blood primarily by liver
150:, circulates at normal levels but is dysfunctional.
1396:"Acquired hypofibrinogenemia: current perspectives"
84:It has been suggested that this article should be
606:the clinical consequence(s) of the mutation; and
2897:
1119:most common cause of acquired dysfibrinogenemia
1023:evidence of often massive obliteration of renal
958:present with evidence ranging from asymptomatic
954:Individuals with hereditary fibrinogen Aα-chain
2065:
2012:
2010:
2008:
1878:
1876:
1833:"Fibrinogen and fibrin structure and functions"
1745:
1743:
1741:
1689:
1687:
1606:Archives of Pathology & Laboratory Medicine
1463:
1461:
1393:
1031:staining. There also should be no evidence for
590:) at these sites before>after the mutation;
423:
1643:
1641:
1639:
1637:
1635:
1521:
1519:
1517:
1515:
1513:
1511:
1509:
1507:
1459:
1457:
1455:
1453:
1451:
1449:
1447:
1445:
1443:
1441:
1389:
1387:
1385:
1383:
1381:
1379:
1377:
1375:
1373:
1371:
1318:
1316:
1314:
1312:
574:gene), and the names of the nucleotides (i.e.
2284:
1532:Journal of the American Society of Nephrology
1063:
2151:
2108:
2068:The American Journal of the Medical Sciences
2005:
1919:
1873:
1824:
1786:
1738:
1693:
1684:
1169:polyclonal antibody interferes with clotting
1139:monoclonal antibody interferes with clotting
2059:
1954:
1792:
1632:
1574:
1504:
1438:
1368:
1309:
1177:production of abnormal fibrinogen by cancer
873:
2291:
2277:
1696:Annals of the New York Academy of Sciences
1332:Clinical Hemorheology and Microcirculation
945:Hereditary fibrinogen Aα-Chain amyloidosis
895:
393:Platelet aggregation: fibrinogen promotes
192:Hereditary fibrinogen Aα-Chain amyloidosis
99:Hereditary fibrinogen Aα-Chain amyloidosis
2042:
1882:
1848:
1551:
1421:
1411:
1351:
59:Learn how and when to remove this message
1830:
331:and central nodule termed the E domain.
2545:
450:. Rarely, these individuals may suffer
2898:
2272:
1885:Seminars in Thrombosis and Hemostasis
1837:Journal of Thrombosis and Haemostasis
1752:Seminars in Thrombosis and Hemostasis
1650:Seminars in Thrombosis and Hemostasis
1599:
1470:Journal of Thrombosis and Haemostasis
842:activated partial thromboplastin time
1077:
977:
962:to progressive renal impairment and
558:the mutated protein's trivial name;
70:
15:
1211:, direct thrombin inhibitors (e.g.
386:is critical to this formation (see
354:at sites of vascular injury and 2)
13:
1602:"Dysfibrinogenemia and thrombosis"
485:
243:and their precursors, bone marrow
14:
2927:
2190:
2160:Transfusion and Apheresis Science
1068:
949:
2645:platelet storage pool deficiency
2597:Heparin-induced thrombocytopenia
2080:10.1097/00000441-198607000-00011
1850:10.1111/j.1538-7836.2005.01365.x
1394:Besser MW, MacDonald SG (2016).
1278:Genetic and Rare Diseases (GARD)
509:gene; rarely, it is caused by a
75:
20:
2094:
1105:post-translational modification
428:
263:(also termed β) encoded by the
255:(also termed α) encoded by the
2364:Activated protein C resistance
1940:10.1016/j.thromres.2014.11.012
1593:
1568:
1292:
1266:
1250:
1242:
1047:
999:
988:autosomal dominant inheritance
29:This article needs editing to
1:
2172:10.1016/j.transci.2012.06.021
1259:
216:
2911:Autosomal dominant disorders
2458:Trousseau sign of malignancy
1810:10.1016/j.matbio.2016.09.010
1157:systemic lupus erythematosus
938:low molecular weight heparin
864:
830:
755:relatively rare; homozygous
622:Protein chain: site mutation
424:Congenital dysfibrinogenemia
406:tissue plasminogen activator
152:Congenital dysfibrinogenemia
7:
2778:Nonthrombocytopenic purpura
2354:Antithrombin III deficiency
1793:Duval C, Ariëns RA (2017).
838:Partial thromboplastin time
818:impaired fiber interactions
795:impaired fiber interactions
772:impaired fiber interactions
267:gene, and γ encoded by the
136:Dysfibrinogenemia, familial
10:
2932:
2733:Congenital afibrinogenemia
2637:Glanzmann's thrombasthenia
2401:Essential thrombocythaemia
1064:Acquired dysfibrinogenemia
1027:by amyloid as detected by
984:familial renal amyloidosis
972:familial renal amyloidosis
749:defective thrombin binding
397:by cross-linking platelet
283:(i.e. complex sugars) and
220:
172:Acquired dysfibrinogenemia
2849:Gastrointestinal bleeding
2788:
2745:
2666:
2651:Hermansky–Pudlak syndrome
2610:
2552:
2538:
2466:
2428:
2420:Antiphospholipid syndrome
2341:
2334:
2311:
2242:
2198:
1618:10.5858/2002-126-1387-DAT
1577:Hemostasis and Thrombosis
1400:Journal of Blood Medicine
546:coded for the amino acid
460:transient ischemic attack
132:
127:
2819:Subconjunctival bleeding
2809:Intracranial haemorrhage
2625:Bernard–Soulier syndrome
2588:Upshaw–Schulman syndrome
2562:Thrombocytopenic purpura
2391:Sticky platelet syndrome
964:end-stage kidney disease
904:. They should avoid all
874:Asymptomatic individuals
287:are added by respective
31:comply with Knowledge's
1016:of kidney disease; and
896:Symptomatic individuals
806:fibrinogen BarccelonaIV
729:bleeding and thrombosis
562:the gene mutated (i.e.
537:of the Aα chain or the
2723:Factor XIII deficiency
2703:Hypoprothrombinemia/II
2698:von Willebrand disease
2656:Gray platelet syndrome
1897:10.1055/s-0033-1353391
1764:10.1055/s-0036-1571340
1662:10.1055/s-0036-1571339
1544:10.1681/ASN.2008060614
1130:plasma cell dyscrasias
1058:kidney transplantation
760:fibrinogen BaltimoreIV
619:Gene: site of mutation
596:standard abbreviations
476:pulmonary hypertension
184:plasma cell dyscrasias
2718:Factor XII deficiency
2708:Factor VII deficiency
2526:Renal vein thrombosis
1056:and, where possible,
1014:signs and/or symptoms
858:hypodysfibrinogenemia
783:fibrinogen Vlissingen
517:missense mutation, a
515:compound heterozygous
468:myocardial infarction
399:Glycoprotein IIb/IIIa
350:of circulating blood
277:endoplasmic reticulum
211:hypodysfibrinogenemia
156:normal blood clotting
90:into articles titled
2474:Deep vein thrombosis
2369:Protein S deficiency
2359:Protein C deficiency
2035:10.2215/CJN.10491012
1831:Mosesson MW (2005).
1185:renal cell carcinoma
1161:rheumatoid arthritis
1113:abnormal fibrinogen
1110:severe liver disease
1033:systemic amyloidosis
792:λ: del Asn319-Asp320
531:splice site mutation
472:deep vein thrombosis
395:platelet aggregation
356:secondary hemostasis
2839:Pulmonary haematoma
2713:Factor X deficiency
2602:May–Hegglin anomaly
2379:Prothrombin G20210A
1975:1968Natur.218..134B
1928:Thrombosis Research
1708:2017NYASA1404...27R
1274:"Dysfibrinogenemia"
1153:autoimmune diseases
1148:polyclonal antibody
1125:monoclonal antibody
910:fresh frozen plasma
700:delayed release of
688:fibrinogen Bicetrel
674:delayed release of
523:frameshift mutation
456:cerebral hemorrhage
41:improve the content
2746:Signs and symptoms
2521:Pulmonary embolism
2326:Bleeding diathesis
2243:External resources
2117:Acta Haematologica
1716:10.1111/nyas.13454
1413:10.2147/JBM.S90693
1165:ulcerative colitis
824:relatively common
778:relatively common
709:relatively common
683:relatively common
636:fibrinogen Detroit
492:autosomal dominant
480:pulmonary embolism
336:primary hemostasis
180:autoimmune disease
144:dysfibrinogenemias
2893:
2892:
2889:
2888:
2741:
2740:
2728:Dysfibrinogenemia
2612:Platelet function
2534:
2533:
2413:Purpura fulminans
2266:
2265:
2129:10.1159/000160182
1600:Hayes, T (2002).
1586:978-0-7817-1455-6
1482:10.1111/jth.12916
1344:10.3233/CH-160218
1300:Dysfibrinogenemia
1240:
1239:
828:
827:
737:fibrinogen Naples
628:Clinical disorder
495:missense mutation
364:fibrinopeptides A
140:
139:
128:Dysfibrinogenemia
122:Medical condition
120:
119:
93:Dysfibrinogenemia
69:
68:
61:
2923:
2834:Haemopericardium
2554:Thrombocytopenia
2550:
2549:
2543:
2542:
2499:Lowenberg's sign
2349:Clotting factors
2339:
2338:
2293:
2286:
2279:
2270:
2269:
2196:
2195:
2184:
2183:
2155:
2149:
2148:
2112:
2106:
2105:
2098:
2092:
2091:
2063:
2057:
2056:
2046:
2014:
2003:
2002:
1983:10.1038/218134a0
1958:
1952:
1951:
1923:
1917:
1916:
1880:
1871:
1870:
1852:
1828:
1822:
1821:
1799:
1790:
1784:
1783:
1747:
1736:
1735:
1691:
1682:
1681:
1645:
1630:
1629:
1597:
1591:
1590:
1572:
1566:
1565:
1555:
1523:
1502:
1501:
1465:
1436:
1435:
1425:
1415:
1391:
1366:
1365:
1355:
1329:
1320:
1307:
1296:
1290:
1289:
1287:
1285:
1270:
1193:effect of cancer
1134:multiple myeloma
1086:
1085:
789:: c.1033_1038del
732:relatively rare
714:fibrinogen Perth
702:fibrinopeptide A
676:fibrinopeptide A
662:fibrinogen Metz1
613:
612:
227:Fibrinogen is a
125:
124:
115:
112:
79:
78:
71:
64:
57:
53:
50:
44:
24:
23:
16:
2931:
2930:
2926:
2925:
2924:
2922:
2921:
2920:
2896:
2895:
2894:
2885:
2859:Haemoperitoneum
2784:
2737:
2668:Clotting factor
2662:
2606:
2530:
2479:Bancroft's sign
2462:
2453:Virchow's triad
2424:
2374:Factor V Leiden
2330:
2307:
2297:
2267:
2262:
2261:
2238:
2237:
2207:
2193:
2188:
2187:
2156:
2152:
2113:
2109:
2100:
2099:
2095:
2064:
2060:
2015:
2006:
1969:(5137): 134–7.
1959:
1955:
1924:
1920:
1881:
1874:
1843:(8): 1894–904.
1829:
1825:
1804:. 60–61: 8–15.
1797:
1791:
1787:
1748:
1739:
1692:
1685:
1646:
1633:
1612:(11): 1387–90.
1598:
1594:
1587:
1573:
1569:
1524:
1505:
1466:
1439:
1392:
1369:
1327:
1321:
1310:
1297:
1293:
1283:
1281:
1272:
1271:
1267:
1262:
1253:
1245:
1233:extremely rare
1196:extremely rare
1183:of epithelium,
1181:cervical cancer
1095:Pathophysiology
1080:
1078:Pathophysiology
1071:
1066:
1050:
1002:
980:
978:Pathophysiology
952:
947:
918:Tranexamic acid
914:cryoprecipitate
898:
876:
867:
833:
723:Aα: Pro495Leufs
642:: c.114G>C/T
625:Pathophysiology
527:insert mutation
488:
486:Pathophysiology
478:due to ongoing
431:
426:
326:
322:
318:
314:
310:
306:
302:
298:
281:Polysaccharides
225:
219:
123:
116:
110:
107:
80:
76:
65:
54:
48:
45:
38:
33:Manual of Style
25:
21:
12:
11:
5:
2929:
2919:
2918:
2913:
2908:
2906:Coagulopathies
2891:
2890:
2887:
2886:
2884:
2883:
2882:
2881:
2873:
2872:
2871:
2869:Haematosalpinx
2866:
2861:
2856:
2851:
2843:
2842:
2841:
2836:
2831:
2823:
2822:
2821:
2816:
2811:
2806:
2801:
2792:
2790:
2786:
2785:
2783:
2782:
2781:
2780:
2770:
2765:
2760:
2755:
2749:
2747:
2743:
2742:
2739:
2738:
2736:
2735:
2730:
2725:
2720:
2715:
2710:
2705:
2700:
2695:
2694:
2693:
2688:
2683:
2672:
2670:
2664:
2663:
2661:
2660:
2659:
2658:
2653:
2641:
2640:
2639:
2629:
2628:
2627:
2616:
2614:
2608:
2607:
2605:
2604:
2599:
2593:
2592:
2591:
2590:
2585:
2575:
2574:
2573:
2571:Evans syndrome
2558:
2556:
2547:
2540:
2536:
2535:
2532:
2531:
2529:
2528:
2523:
2518:
2517:
2516:
2511:
2506:
2504:Peabody's sign
2501:
2496:
2491:
2486:
2481:
2470:
2468:
2464:
2463:
2461:
2460:
2455:
2450:
2445:
2440:
2434:
2432:
2426:
2425:
2423:
2422:
2417:
2416:
2415:
2405:
2404:
2403:
2398:
2396:Thrombocytosis
2393:
2383:
2382:
2381:
2376:
2371:
2366:
2361:
2356:
2345:
2343:
2336:
2332:
2331:
2329:
2328:
2323:
2318:
2312:
2309:
2308:
2296:
2295:
2288:
2281:
2273:
2264:
2263:
2260:
2259:
2247:
2246:
2244:
2240:
2239:
2236:
2235:
2224:
2208:
2203:
2202:
2200:
2199:Classification
2192:
2191:External links
2189:
2186:
2185:
2150:
2107:
2093:
2058:
2029:(9): 1515–23.
2004:
1953:
1918:
1872:
1823:
1802:Matrix Biology
1785:
1737:
1683:
1631:
1592:
1585:
1567:
1503:
1437:
1367:
1308:
1291:
1264:
1263:
1261:
1258:
1252:
1249:
1244:
1241:
1238:
1237:
1231:
1228:
1202:
1198:
1197:
1194:
1191:paraneoplastic
1188:
1178:
1174:
1173:
1170:
1167:
1150:
1144:
1143:
1140:
1137:
1127:
1121:
1120:
1117:
1111:
1108:
1100:
1099:
1096:
1093:
1090:
1079:
1076:
1070:
1067:
1065:
1062:
1049:
1046:
1001:
998:
979:
976:
968:AL amyloidosis
951:
948:
946:
943:
934:antithrombotic
897:
894:
875:
872:
866:
863:
850:reptilase time
832:
829:
826:
825:
822:
819:
816:
813:
807:
803:
802:
799:
796:
793:
790:
784:
780:
779:
776:
773:
770:
767:
761:
757:
756:
753:
750:
747:
744:
738:
734:
733:
730:
727:
724:
721:
715:
711:
710:
707:
704:
698:
695:
689:
685:
684:
681:
678:
672:
669:
663:
659:
658:
655:
652:
650:Polymerization
646:
643:
637:
633:
632:
629:
626:
623:
620:
617:
487:
484:
430:
427:
425:
422:
414:
413:
402:
391:
324:
320:
316:
312:
308:
304:
300:
296:
245:megakaryocytes
221:Main article:
218:
215:
138:
137:
134:
130:
129:
121:
118:
117:
83:
81:
74:
67:
66:
28:
26:
19:
9:
6:
4:
3:
2:
2928:
2917:
2916:Rare diseases
2914:
2912:
2909:
2907:
2904:
2903:
2901:
2880:
2879:Haemarthrosis
2877:
2876:
2874:
2870:
2867:
2865:
2862:
2860:
2857:
2855:
2852:
2850:
2847:
2846:
2844:
2840:
2837:
2835:
2832:
2830:
2827:
2826:
2824:
2820:
2817:
2815:
2812:
2810:
2807:
2805:
2802:
2800:
2797:
2796:
2794:
2793:
2791:
2787:
2779:
2776:
2775:
2774:
2771:
2769:
2766:
2764:
2761:
2759:
2756:
2754:
2751:
2750:
2748:
2744:
2734:
2731:
2729:
2726:
2724:
2721:
2719:
2716:
2714:
2711:
2709:
2706:
2704:
2701:
2699:
2696:
2692:
2689:
2687:
2684:
2682:
2679:
2678:
2677:
2674:
2673:
2671:
2669:
2665:
2657:
2654:
2652:
2649:
2648:
2647:
2646:
2642:
2638:
2635:
2634:
2633:
2630:
2626:
2623:
2622:
2621:
2618:
2617:
2615:
2613:
2609:
2603:
2600:
2598:
2595:
2594:
2589:
2586:
2584:
2581:
2580:
2579:
2576:
2572:
2569:
2568:
2567:
2563:
2560:
2559:
2557:
2555:
2551:
2548:
2544:
2541:
2537:
2527:
2524:
2522:
2519:
2515:
2512:
2510:
2507:
2505:
2502:
2500:
2497:
2495:
2494:Louvel's sign
2492:
2490:
2489:Lisker's sign
2487:
2485:
2482:
2480:
2477:
2476:
2475:
2472:
2471:
2469:
2465:
2459:
2456:
2454:
2451:
2449:
2446:
2444:
2441:
2439:
2438:Thrombophilia
2436:
2435:
2433:
2431:
2427:
2421:
2418:
2414:
2411:
2410:
2409:
2406:
2402:
2399:
2397:
2394:
2392:
2389:
2388:
2387:
2384:
2380:
2377:
2375:
2372:
2370:
2367:
2365:
2362:
2360:
2357:
2355:
2352:
2351:
2350:
2347:
2346:
2344:
2340:
2337:
2333:
2327:
2324:
2322:
2319:
2317:
2314:
2313:
2310:
2306:
2302:
2299:Disorders of
2294:
2289:
2287:
2282:
2280:
2275:
2274:
2271:
2258:
2254:
2253:
2249:
2248:
2245:
2241:
2234:
2230:
2229:
2225:
2223:
2219:
2218:
2214:
2210:
2209:
2206:
2201:
2197:
2181:
2177:
2173:
2169:
2165:
2161:
2154:
2146:
2142:
2138:
2134:
2130:
2126:
2122:
2118:
2111:
2103:
2097:
2089:
2085:
2081:
2077:
2073:
2069:
2062:
2054:
2050:
2045:
2040:
2036:
2032:
2028:
2024:
2020:
2013:
2011:
2009:
2000:
1996:
1992:
1988:
1984:
1980:
1976:
1972:
1968:
1964:
1957:
1949:
1945:
1941:
1937:
1934:(2): 231–42.
1933:
1929:
1922:
1914:
1910:
1906:
1902:
1898:
1894:
1891:(6): 684–92.
1890:
1886:
1879:
1877:
1868:
1864:
1860:
1856:
1851:
1846:
1842:
1838:
1834:
1827:
1819:
1815:
1811:
1807:
1803:
1796:
1789:
1781:
1777:
1773:
1769:
1765:
1761:
1758:(4): 356–65.
1757:
1753:
1746:
1744:
1742:
1733:
1729:
1725:
1721:
1717:
1713:
1709:
1705:
1701:
1697:
1690:
1688:
1679:
1675:
1671:
1667:
1663:
1659:
1656:(4): 366–74.
1655:
1651:
1644:
1642:
1640:
1638:
1636:
1627:
1623:
1619:
1615:
1611:
1607:
1603:
1596:
1588:
1582:
1578:
1571:
1563:
1559:
1554:
1549:
1545:
1541:
1538:(2): 444–51.
1537:
1533:
1529:
1522:
1520:
1518:
1516:
1514:
1512:
1510:
1508:
1499:
1495:
1491:
1487:
1483:
1479:
1476:(6): 909–19.
1475:
1471:
1464:
1462:
1460:
1458:
1456:
1454:
1452:
1450:
1448:
1446:
1444:
1442:
1433:
1429:
1424:
1419:
1414:
1409:
1405:
1401:
1397:
1390:
1388:
1386:
1384:
1382:
1380:
1378:
1376:
1374:
1372:
1363:
1359:
1354:
1349:
1345:
1341:
1337:
1333:
1326:
1319:
1317:
1315:
1313:
1306:
1302:
1301:
1295:
1279:
1275:
1269:
1265:
1257:
1248:
1236:
1232:
1229:
1226:
1222:
1218:
1214:
1210:
1206:
1203:
1200:
1199:
1195:
1192:
1189:
1186:
1182:
1179:
1176:
1175:
1171:
1168:
1166:
1162:
1158:
1154:
1151:
1149:
1146:
1145:
1141:
1138:
1135:
1131:
1128:
1126:
1123:
1122:
1118:
1116:
1112:
1109:
1107:of fibrinogen
1106:
1102:
1101:
1097:
1094:
1091:
1088:
1087:
1084:
1075:
1061:
1059:
1055:
1045:
1043:
1038:
1034:
1030:
1026:
1022:
1019:
1015:
1011:
1007:
997:
994:
989:
985:
975:
973:
969:
965:
961:
957:
942:
939:
935:
931:
926:
924:
919:
915:
911:
907:
903:
893:
891:
886:
882:
871:
862:
859:
854:
851:
847:
846:thrombin time
843:
839:
823:
820:
817:
814:
812:: c.902G>A
811:
808:
805:
804:
800:
797:
794:
791:
788:
785:
782:
781:
777:
774:
771:
768:
766:: c.901C>T
765:
762:
759:
758:
754:
751:
748:
745:
743:: c.292G>A
742:
739:
736:
735:
731:
728:
725:
722:
719:
716:
713:
712:
708:
705:
703:
699:
696:
694:: c.104C>G
693:
690:
687:
686:
682:
679:
677:
673:
670:
668:: c.103C>T
667:
664:
661:
660:
656:
653:
651:
647:
644:
641:
638:
635:
634:
630:
627:
624:
621:
618:
615:
614:
611:
609:
605:
601:
597:
593:
589:
585:
581:
577:
573:
569:
565:
561:
557:
552:
549:
545:
540:
536:
532:
528:
524:
520:
516:
512:
508:
504:
500:
496:
493:
483:
481:
477:
473:
469:
465:
461:
457:
453:
449:
445:
444:vaginal birth
441:
437:
436:easy bruising
421:
419:
411:
407:
403:
400:
396:
392:
389:
385:
381:
380:
379:
377:
373:
369:
365:
361:
357:
353:
349:
345:
341:
337:
332:
330:
294:
290:
289:glycosylation
286:
282:
278:
274:
270:
266:
262:
258:
254:
250:
246:
242:
238:
234:
230:
224:
214:
212:
207:
205:
201:
196:
193:
189:
186:, or certain
185:
181:
177:
176:liver disease
173:
169:
165:
161:
157:
153:
149:
145:
135:
131:
126:
114:
105:
101:
100:
95:
94:
89:
88:
82:
73:
72:
63:
60:
52:
49:February 2018
42:
36:
34:
27:
18:
17:
2727:
2643:
2631:
2619:
2509:Pratt's sign
2321:coagulopathy
2250:
2226:
2211:
2163:
2159:
2153:
2123:(2): 75–81.
2120:
2116:
2110:
2096:
2071:
2067:
2061:
2026:
2022:
1966:
1962:
1956:
1931:
1927:
1921:
1888:
1884:
1840:
1836:
1826:
1801:
1788:
1755:
1751:
1702:(1): 27–48.
1699:
1695:
1653:
1649:
1609:
1605:
1595:
1576:
1570:
1535:
1531:
1473:
1469:
1403:
1399:
1353:10447/238851
1338:(1): 25–34.
1335:
1331:
1298:
1294:
1282:. Retrieved
1277:
1268:
1254:
1246:
1235:case reports
1081:
1072:
1069:Presentation
1054:hemodialysis
1051:
1036:
1021:histological
1017:
1012:presence of
1009:
1005:
1003:
981:
953:
950:Presentation
927:
899:
885:miscarriages
877:
868:
855:
834:
815:λ: Arg301His
809:
786:
769:λ: Arg301Cys
763:
746:Bβ: Ala68thr
740:
720:: c.1541delC
717:
697:Aα: Arg35His
691:
671:Aα: Arg35Cys
665:
645:Aα: Arg19Ser
639:
616:Trivial name
607:
603:
599:
591:
567:
563:
559:
555:
553:
506:
502:
498:
489:
452:hemarthrosis
432:
429:Presentation
415:
410:fibrinolysis
376:fibrinolysis
333:
268:
264:
256:
229:glycoprotein
226:
208:
197:
191:
171:
151:
143:
141:
108:
97:
92:
91:
85:
55:
46:
39:Please help
30:
2864:Haematocele
2829:Haemothorax
2804:Haemoptysis
2676:Haemophilia
2632:aggregation
2514:Rose's sign
2484:Homans sign
2316:Coagulation
2166:(1): 35–8.
2074:(1): 53–5.
1406:: 217–225.
1221:bivalirudin
1205:mithramycin
1201:Drug effect
1115:sialylation
1089:Abnormality
1042:amyloidosis
960:proteinuria
956:amyloidosis
923:post-partum
906:medications
890:prophylaxis
462:, ischemic
448:miscarriage
440:menorrhagia
388:Coagulation
372:factor XIII
348:aggregation
338:, i.e. the
293:sialylation
285:sialic acid
237:Endothelium
133:Other names
2900:Categories
2854:Haemobilia
2448:Thrombosis
2102:"UpToDate"
1260:References
1225:argatroban
1217:dabigatran
1103:incorrect
993:frameshift
930:hemophilia
902:hemophilia
881:childbirth
821:thrombosis
798:thrombosis
775:thrombosis
752:thrombosis
539:C-terminus
535:N-terminus
511:homozygous
344:activation
233:hepatocyte
223:Fibrinogen
217:Fibrinogen
204:penetrance
168:thrombosis
148:fibrinogen
111:March 2019
2799:Epistaxis
2763:Haematoma
2386:Platelets
1305:eMedicine
1251:Treatment
1243:Diagnosis
1209:isoniazid
1172:uncommon
1142:uncommon
1048:Treatment
1029:Congo red
1025:glomeruli
1000:Diagnosis
996:tissues.
925:periods.
865:Treatment
831:Diagnosis
648:abnormal
564:FGA, FGB,
418:diathesis
384:platelets
352:platelets
329:D domains
273:positions
241:platelets
200:mutations
2845:abdomen
2814:Hyphaema
2768:Petechia
2753:Bleeding
2620:adhesion
2546:By cause
2539:Bleeding
2443:Thrombus
2342:By cause
2335:Clotting
2305:clotting
2301:bleeding
2252:Orphanet
2180:22842111
2145:45965368
2137:18841003
2053:23704299
1948:25559460
1905:23929306
1867:22077267
1859:16102057
1818:27784620
1780:12693693
1772:27019463
1732:10878584
1724:28833193
1678:12038872
1670:27019462
1626:12421146
1562:19073821
1498:10955092
1490:25816717
1432:27713652
1362:28550239
1284:19 March
1187:, others
1155:such as
1136:and MGUS
1132:such as
1098:Comment
706:bleeding
680:bleeding
654:bleeding
631:Comment
548:arginine
519:deletion
360:thrombin
340:adhesion
164:bleeding
2789:By site
2773:Purpura
2467:By site
2088:2940861
2044:3805078
1999:4165737
1991:5645286
1971:Bibcode
1913:8840970
1704:Bibcode
1553:2637055
1423:5045218
1230:unclear
1213:heparin
912:and/or
497:in the
299:, (αβγ)
249:trimers
235:cells.
188:cancers
166:and/or
158:and/or
104:discuss
2875:joint
2825:torso
2758:Bruise
2681:A/VIII
2233:616004
2178:
2143:
2135:
2086:
2051:
2041:
1997:
1989:
1963:Nature
1946:
1911:
1903:
1865:
1857:
1816:
1778:
1770:
1730:
1722:
1676:
1668:
1624:
1583:
1560:
1550:
1496:
1488:
1430:
1420:
1360:
932:using
848:, and
572:cloned
464:stroke
446:, and
346:, and
315:, or α
259:gene,
2795:head
2430:Clots
2257:98881
2222:D68.2
2141:S2CID
1995:S2CID
1909:S2CID
1863:S2CID
1798:(PDF)
1776:S2CID
1728:S2CID
1674:S2CID
1494:S2CID
1328:(PDF)
1280:. NIH
1092:Cause
544:codon
529:, or
505:, or
160:lysis
87:split
2691:C/XI
2686:B/IX
2303:and
2228:OMIM
2176:PMID
2133:PMID
2084:PMID
2049:PMID
1987:PMID
1944:PMID
1901:PMID
1855:PMID
1814:PMID
1768:PMID
1720:PMID
1700:1404
1666:PMID
1622:PMID
1581:ISBN
1558:PMID
1486:PMID
1428:PMID
1358:PMID
1286:2019
438:and
366:and
303:, Aα
291:and
182:, a
142:The
96:and
2583:TTP
2566:ITP
2408:DIC
2213:ICD
2168:doi
2125:doi
2121:120
2076:doi
2072:292
2039:PMC
2031:doi
1979:doi
1967:218
1936:doi
1932:135
1893:doi
1845:doi
1806:doi
1760:doi
1712:doi
1658:doi
1614:doi
1610:126
1548:PMC
1540:doi
1478:doi
1418:PMC
1408:doi
1348:hdl
1340:doi
1303:at
1037:FGA
810:FGG
787:FGG
764:FGG
741:FGB
718:FGA
692:FGA
666:FGA
640:FGA
568:FGG
566:or
513:or
454:or
269:FGG
265:FGB
257:FGA
106:)
102:. (
2902::
2578:TM
2564::
2255::
2231::
2220::
2217:10
2174:.
2164:48
2162:.
2139:.
2131:.
2119:.
2082:.
2070:.
2047:.
2037:.
2025:.
2021:.
2007:^
1993:.
1985:.
1977:.
1965:.
1942:.
1930:.
1907:.
1899:.
1889:39
1887:.
1875:^
1861:.
1853:.
1839:.
1835:.
1812:.
1800:.
1774:.
1766:.
1756:42
1754:.
1740:^
1726:.
1718:.
1710:.
1698:.
1686:^
1672:.
1664:.
1654:42
1652:.
1634:^
1620:.
1608:.
1604:.
1556:.
1546:.
1536:20
1534:.
1530:.
1506:^
1492:.
1484:.
1474:13
1472:.
1440:^
1426:.
1416:.
1402:.
1398:.
1370:^
1356:.
1346:.
1336:67
1334:.
1330:.
1311:^
1276:.
1223:,
1219:,
1215:,
1207:,
1163:,
1159:,
1044:.
1018:c)
1010:b)
1006:1)
974:.
844:,
840:,
608:f)
604:e)
600:d)
592:c)
586:,
582:,
578:,
560:b)
556:a)
525:,
521:,
503:Bβ
501:,
499:Aα
466:,
390:).
342:,
307:Bβ
261:Bβ
253:Aα
178:,
170:.
2292:e
2285:t
2278:v
2215:-
2205:D
2182:.
2170::
2147:.
2127::
2104:.
2090:.
2078::
2055:.
2033::
2027:8
2001:.
1981::
1973::
1950:.
1938::
1915:.
1895::
1869:.
1847::
1841:3
1820:.
1808::
1782:.
1762::
1734:.
1714::
1706::
1680:.
1660::
1628:.
1616::
1589:.
1564:.
1542::
1500:.
1480::
1434:.
1410::
1404:7
1364:.
1350::
1342::
1288:.
1227:)
588:G
584:A
580:T
576:C
507:γ
412:.
368:B
325:2
323:γ
321:2
319:β
317:2
313:2
311:γ
309:2
305:2
301:2
297:2
113:)
109:(
62:)
56:(
51:)
47:(
43:.
35:.
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