Fibrinogen: Difference between revisions

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{{DrugProjectFormSinglePage
{{infobox protein
|authorTag={{KS}}
| Name = [[fibrinogen alpha chain]]
|genericName=fibrinogen
| caption = Crystallographic structure of a fragment of human [[fibrin]].<ref name="pmid9628725">{{PDB|1FZC}}; {{cite journal |vauthors=Everse SJ, Spraggon G, Veerapandian L, Riley M, Doolittle RF | title = Crystal structure of fragment double-D from human fibrin with two different bound ligands | journal = Biochemistry | volume = 37 | issue = 24 | pages = 8637–42 |date=June 1998 | pmid = 9628725 | doi = 10.1021/bi9804129 | url = }}</ref>
|aOrAn=a
| image =Fibrinandligand.png
|drugClass=blood modifier agent
| width =
|indicationType=treatment
| HGNCid = 3661
|indication=acute bleeding episodes in patients with congenital fibrinogen deficiency, including [[afibrinogenemia]] and [[hypofibrinogenemia]]
| Symbol = [[fibrinogen alpha chain|FGA]]
|adverseReactions=[[fever]], [[headache]], [[pulmonary embolism]], [[myocardial infarction]], [[deep vein thrombosis]], [[anaphylaxis|anaphylactic reactions]]
| AltSymbols =
|blackBoxWarningTitle=<span style="color:#FF0000;">ConditionName: </span>
| EntrezGene = 2243
|blackBoxWarningBody=<i><span style="color:#FF0000;">ConditionName: </span></i>
| OMIM = 134820
 
| RefSeq = NM_000508
* Content
| UniProt = P02671
 
| PDB =
<!--Adult Indications and Dosage-->
| ECnumber =
 
| Chromosome = 4
<!--FDA-Labeled Indications and Dosage (Adult)-->
| Arm = q
|fdaLIADAdult===Indications==
| Band = 28
* RiaSTAP®, Fibrinogen Concentrate (Human) is indicated for the treatment of acute bleeding episodes in patients with congenital [[fibrinogen deficiency]], including [[afibrinogenemia]] and [[hypofibrinogenemia]].
| LocusSupplementaryData =
 
}}
* The effectiveness of RiaSTAP is based on maximum clot firmness, which measures the structural integrity of a clot, reflecting the underlying effectiveness of the fibrinogen present to form a fibrin clot.
{{infobox protein
 
| Name = [[fibrinogen beta chain]]
* There are no controlled trials demonstrating a direct benefit on treatment of bleeding episodes with RiaSTAP.
| caption =
 
| image =
* RiaSTAP is not indicated for dysfibrinogenemia.
| width =
 
| HGNCid = 3662
==Dosage For Congenital Fibrinogen Deficiency==
| Symbol = [[fibrinogen beta chain|FGB]]
 
| AltSymbols =
* RiaSTAP dosing, duration of dosing and frequency of administration should be individualized based on the extent of bleeding, laboratory values, and the clinical condition of the patient.
| EntrezGene = 2244
 
| OMIM = 134830
'''RiaSTAP dose when baseline fibrinogen level is known'''
| RefSeq = NM_005141
 
| UniProt = P02675
* Dose should be individually calculated for each patient based on the target plasma fibrinogen level based on the type of bleeding, actual measured plasma fibrinogen level and body weight, using the following formula
| PDB =
 
| ECnumber =
[[File:Riastap dose.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
| Chromosome = 4
 
| Arm = q
'''RiaSTAP dose when baseline fibrinogen level is not known'''
| Band = 28
 
| LocusSupplementaryData =
* If the patient's fibrinogen level is not known, the recommended dose is 70 mg per kg of body weight administered intravenously.
}}
 
{{infobox protein
* Monitoring of patient's fibrinogen level is recommended during treatment with RiaSTAP. A target fibrinogen level of 100 mg/dL should be maintained until hemostasis is obtained.
| Name = [[Fibrinogen gamma chain]]
 
| caption =
==DOSAGE FORMS AND STRENGTHS==
| image =
 
| width =
* RiaSTAP is available as a single-use vial containing 900 mg to 1300 mg lyophilized fibrinogen concentrate powder for reconstitution with 50 mL of Sterile Water for Injection.
| HGNCid = 3694
 
| Symbol = [[Fibrinogen gamma chain|FGG]]
* The actual fibrinogen potency for each lot is printed on the vial label and carton.
| AltSymbols =
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
| EntrezGene = 2266
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in adult patients.
| OMIM = 134850
 
| RefSeq = NM_021870
 
| UniProt = P02679
 
| PDB =
<!--FDA-Labeled Indications and Dosage (Pediatric)-->
| ECnumber =
|fdaLIADPed=There is limited information regarding <i>FDA-Labeled Use</i> of {{PAGENAME}} in pediatric patients.
| Chromosome = 4
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
| Arm = q
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of {{PAGENAME}} in pediatric patients.
| Band = 28
|contraindications=* RiaSTAP is contraindicated in individuals who have manifested severe immediate [[hypersensitivity]] reactions, including [[anaphylaxis]] to RiaSTAP or its components.
| LocusSupplementaryData =
|warnings='''Allergic Reactions'''
}}
 
{{Infobox protein family
* Allergic reactions may occur. If symptoms of allergic or early signs of hypersensitivity reactions (including [[hives]], generalized [[urticaria]], [[tightness of the chest]], [[wheezing]], [[hypotension]], and [[anaphylaxis]]) occur, immediately discontinue administration. The treatment required depends on the nature and severity of the reaction.
| Symbol = Fib_alpha
 
| Name = Fibrinogen alpha/beta chain family
'''Thrombosis'''
| image = PDB 1m1j EBI.jpg
 
| width =
* [[Thrombosis]] may occur spontaneously in patients with congenital fibrinogen deficiency with or without the use of fibrinogen replacement therapy.1 Thromboembolic events have been reported in patients treated with RiaSTAP. Weigh the benefits of RiaSTAP administration versus the risk of thrombosis. Patients receiving RiaSTAP should be monitored for signs and symptoms of thrombosis.
| caption = crystal structure of native chicken fibrinogen with two different bound ligands
 
| Pfam = PF08702
'''Transmissible Infectious Agents'''
| Pfam_clan =
 
| InterPro = IPR012290
* RiaSTAP is made from human plasma. Products made from human plasma may contain infectious agents (e.g., viruses and theoretically the [[Creutzfeldt-Jakob disease]] agent [CJD]) that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing.Despite these measures, such products may still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL.
| SMART =
|clinicalTrials=* The most serious adverse reactions that have been reported in clinical studies or through postmarketing surveillance following RiaSTAP treatment are allergic-[[anaphylactic reactions]] and thromboembolic episodes, including [[myocardial infarction]], [[pulmonary embolism]], [[deep vein thrombosis]], and [[arterial thrombosis]].
| PROSITE =
 
| MEROPS =
* The most common adverse reactions that have been reported in clinical studies or through postmarketing surveillance following RiaSTAP treatment are [[allergy|allergic reactions]] and generalized reactions such as [[chills]], [[fever]], [[nausea]], and [[vomiting]].
| SCOP = 1m1j
 
| TCDB =
'''Clinical Studies Experience'''
| OPM family =
 
| OPM protein =
* Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in practice.
| CAZy =
 
| CDD =
* The most common adverse reactions observed in more than one subject in clinical studies (frequency >1%) were [[fever]] and [[headache]].
}}
|postmarketing=* Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
{{Infobox protein family
 
| Symbol = Fibrinogen_aC
* Adverse reactions reported in patients receiving RiaSTAP for treatment of fibrinogen deficiency include allergic-[[anaphylactic reactions]] (including [[rash]], [[dyspnea]], etc.), general reactions such as [[chills]], [[fever]], [[nausea]], [[vomiting]] and thromboembolic complications such as [[myocardial infarction]], [[pulmonary embolism]], and [[deep vein thrombosis]].
| Name = Fibrinogen alpha C domain
 
| image =
* The following adverse reactions, identified by system organ class, have shown a possible causal relationship with RiaSTAP.
| width =
 
| caption = nmr solution structure, stability, and interaction of the recombinant bovine fibrinogen alphac-domain fragment
:*''Allergic-anaphylactic reactions'': [[anaphylaxis]], [[dyspnea]], [[rash]]
| Pfam = PF12160
:*''Cardiovascular'': [[thromboembolism]], [[pulmonary embolism]]
| Pfam_clan =
:*''General/Body as a Whole'': [[chills]], [[fever]], [[nausea]], [[vomiting]]
| InterPro = IPR021996
|useInPregnancyFDA=* Pregnancy Category C. Animal reproduction studies have not been conducted with RiaSTAP. It is not known whether RiaSTAP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RiaSTAP should be used during pregnancy only if clearly needed.
| SMART =
|useInLaborDelivery=* RiaSTAP has not been studied for use during labor and delivery.
| PROSITE =
|useInNursing=* RiaSTAP has not been studied in nursing mothers with congenital fibrinogen deficiency.
| MEROPS =
|useInPed=* RiaSTAP studies have included subjects below the age of 16 years. In the pharmacokinetic study, 2 children (8 and 11 years), 3 adolescents (12, 14 and 16 years), were studied. Subjects less than 16 years of age (n = 4) had shorter half-life (69.9 ± 8.5h) and faster clearance (0.7 ± 0.1 mg/L) compared to adults (half-life: 82.3 ± 20.0h, clearance: 0.53 ± 0.1 mg/L). The number of subjects less than 16 years of age in this study limits statistical interpretation.
| SCOP =
|useInGeri=* The safety and efficacy of RiaSTAP in the geriatric population has not been studied. There were an insufficient number of subjects in this age group to determine whether they respond differently from younger subjects.
| TCDB =
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
| OPM family =
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
| OPM protein =
|useInRenalImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with renal impairment.
| CAZy =
|useInHepaticImpair=There is no FDA guidance on the use of {{PAGENAME}} in patients with hepatic impairment.
| CDD =
|useInReproPotential=There is no FDA guidance on the use of {{PAGENAME}} in women of reproductive potentials and males.
}}
|useInImmunocomp=There is no FDA guidance one the use of {{PAGENAME}} in patients who are immunocompromised.
{{Infobox protein family
|administration=* Intravenous
| Symbol = Fibrinogen_C
* Reconstitute prior to use.
| Name = Fibrinogen beta and gamma chains, C-terminal globular domain
* Do not mix RiaSTAP with other medicinal products or intravenous solutions, and should be administered through a separate injection site.
| image = PDB 1m1j EBI.jpg
 
| width =
* Use aseptic technique when administering RiaSTAP.
| caption = crystal structure of native chicken fibrinogen with two different bound ligands
 
| Pfam = PF00147
* Administer RiaSTAP at room temperature by slow intravenous injection at a rate not exceeding 5 mL per minute.
| Pfam_clan = CL0422
 
| InterPro = IPR002181
'''Preparation and Reconstitution'''
| SMART =
 
| PROSITE = PDOC00445
* The procedures below are provided as general guidelines for preparation and reconstitution of RiaSTAP.
| MEROPS =
| SCOP = 1fza
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}


* Do not use RiaSTAP beyond the expiration date. RiaSTAP contains no preservative. Use aseptic technique when preparing and reconstituting RiaSTAP.
'''Fibrinogen''' ('''''factor I''''') is a [[glycoprotein]] that circulates in the blood of [[vertebrates]]. During tissue and vascular injury it is converted [[Enzyme|enzymatically]] by [[thrombin]] to [[fibrin]] and subsequently to a fibrin-based [[blood clot]]. Fibrinogen functions primarily to occlude blood vessels and thereby stop excessive [[bleeding]]. However, fibrinogen's product, fibrin, binds and reduces the activity of thrombin. This activity, sometimes referred to as '''antithrombin I''', serves to limit blood clotting. Loss or reduction in this antithrombin 1 activity due to mutations in fibrinogen genes or hypo-fibrinogen conditions can lead to excessive blood clotting and [[thrombosis]].<ref name="pmid23852822">{{cite journal | vauthors = de Moerloose P, Casini A, Neerman-Arbez M | title = Congenital fibrinogen disorders: an update | journal = Seminars in Thrombosis and Hemostasis | volume = 39 | issue = 6 | pages = 585–95 | year = 2013 | pmid = 23852822 | doi = 10.1055/s-0033-1349222 | url = }}</ref> Fibrin also mediates blood [[platelet]] and [[endothelial cell]] spreading, tissue [[fibroblast]] proliferation, [[Capillary action|capillary tube formation]], and [[angiogenesis]] and thereby functions to  promote tissue revascularization, wound healing, and [[tissue repair]].<ref name="pmid16102057">{{cite journal | vauthors = Mosesson MW | title = Fibrinogen and fibrin structure and functions | journal = Journal of Thrombosis and Haemostasis | volume = 3 | issue = 8 | pages = 1894–904 | year = 2005 | pmid = 16102057 | doi = 10.1111/j.1538-7836.2005.01365.x | url = }}</ref>


* Reconstitute RiaSTAP at room temperature as follows:
Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired human [[List of fibrinogen disorders|fibrinogen-related disorders]]. These disorders represent a clinically important group of rare conditions in which individuals may present with severe episodes of pathological bleeding and thrombosis; these conditions are treated by supplementing blood fibrinogen levels and inhibiting blood clotting, respectively.<ref name="pmid27019462">{{cite journal | vauthors = Casini A, de Moerloose P, Neerman-Arbez M | title = Clinical Features and Management of Congenital Fibrinogen Deficiencies | journal = Seminars in Thrombosis and Hemostasis | volume = 42 | issue = 4 | pages = 366–74 | year = 2016 | pmid = 27019462 | doi = 10.1055/s-0036-1571339 | url = }}</ref><ref name="pmid21952526">{{cite journal | vauthors = Undas A | title = Acquired dysfibrinogenemia in atherosclerotic vascular disease | journal = Polskie Archiwum Medycyny Wewnetrznej | volume = 121 | issue = 9 | pages = 310–9 | year = 2011 | pmid = 21952526 | doi = | url = }}</ref> Certain of these disorders may also be the cause of liver and kidney diseases.<ref name="pmid23852822"/>


* Remove the cap from the product vial to expose the central portion of the rubber stopper.
Fibrinogen is a "positive" [[acute-phase protein]], i.e. its blood levels rise in response to systemic inflammation, tissue injury, and certain other events. It is also elevated in various cancers. Elevated levels of fibrinogen in [[inflammation]] as well as cancer and other conditions have been suggested to be the cause of thrombosis and vascular injury that accompanies these conditions.<ref name="pmid22037947">{{cite journal | vauthors = Davalos D, Akassoglou K | title = Fibrinogen as a key regulator of inflammation in disease | journal = Seminars in Immunopathology | volume = 34 | issue = 1 | pages = 43–62 | year = 2012 | pmid = 22037947 | doi = 10.1007/s00281-011-0290-8 | url = }}</ref><ref name="pmid28833193">{{cite journal | vauthors = Repetto O, De Re V | title = Coagulation and fibrinolysis in gastric cancer | journal = Annals of the New York Academy of Sciences | volume = 1404| issue = | pages = 27–48| year = 2017 | pmid = 28833193 | doi = 10.1111/nyas.13454 | url = }}</ref>


* Clean the surface of the rubber stopper with an antiseptic solution and allow it to dry.
== Genes ==
Fibrinogen is made and secreted into the blood primarily by liver [[hepatocyte]] cells. [[Endothelium]] cells are also reported to make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood [[platelet]]s and their precursors, bone marrow [[megakaryocytes]], while once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein.<ref name="pmid27019462"/><ref name="pmid28833193"/> The final secreted, hepatocyte-derived glycoprotein is composed of two [[Protein trimer|trimers]] with each trimer composed of three different [[polypeptide chains]], the [[fibrinogen alpha chain]] (also termed the Aα or α chain) encoded by the ''FGA'' gene, the [[fibrinogen beta chain]] (also termed the Bβ or β chain) encoded by the ''FGB'' gene, and the [[fibrinogen gamma chain]] (also termed the γ chain) encoded by the ''FGG'' gene. All three genes are located on the long or "p" arm of human chromosome 4 (at [[Locus (genetics)#Nomenclature|positions]] 4q31.3, 4q31.3, and 4q32.1, respectively).<ref name="pmid23852822"/> [[Alternate splicing]] of the ''FGA'' gene produces a minor expanded [[isoform]] of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen; alternate splicing of ''FGG'' produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen; FGA is not alternatively spliced. Hence, the final fibrinogen product is composed principally of Aα, Bβ, and  γ chains with a small percentage of it containing AαE and/or γ' chains in place of Aα and/or γ chains, respectively. The three genes are [[Transcription (biology)|transcribed]] and [[Translation (biology)|translated]] in co-ordination by a mechanism(s) which remains incompletely understood.<ref name="pmid27019463">{{cite journal | vauthors = Neerman-Arbez M, de Moerloose P, Casini A | title = Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders | journal = Seminars in Thrombosis and Hemostasis | volume = 42 | issue = 4 | pages = 356–65 | year = 2016 | pmid = 27019463 | doi = 10.1055/s-0036-1571340 | url = }}</ref><ref name="pmid27784620">{{cite journal | vauthors = Duval C, Ariëns RA | title = Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ' as thrombomobulin II | journal = Matrix Biology | volume = 60–61 | issue = | pages = 8–15 | year = 2017 | pmid = 27784620 | doi = 10.1016/j.matbio.2016.09.010 | url = }}</ref><ref name="pmid17635718">{{cite journal | vauthors = Vu D, Neerman-Arbez M | title = Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins | journal = Journal of Thrombosis and Haemostasis | volume = 5 Suppl 1 | issue = | pages = 125–31 | year = 2007 | pmid = 17635718 | doi = 10.1111/j.1538-7836.2007.02465.x | url = }}</ref><ref name="pmid22836683">{{cite journal | vauthors = Fish RJ, Neerman-Arbez M | title = Fibrinogen gene regulation | journal = Thrombosis and Haemostasis | volume = 108 | issue = 3 | pages = 419–26 | year = 2012 | pmid = 22836683 | doi = 10.1160/TH12-04-0273 | url = }}</ref><ref name="pmid16999847">{{cite journal | vauthors = Asselta R, Duga S, Tenchini ML | title = The molecular basis of quantitative fibrinogen disorders | journal = Journal of Thrombosis and Haemostasis | volume = 4 | issue = 10 | pages = 2115–29 | year = 2006 | pmid = 16999847 | doi = 10.1111/j.1538-7836.2006.02094.x | url = }}</ref> The coordinated transcription of these three fibrinogen genes is rapidly and greatly increased by systemic conditions such as inflammation and tissue injury. Cytokines produced during these systemic conditions, such as [[interleukin 6]] and [[interleukin 1β]], appear responsible for up-regulating this transcription.<ref name="pmid22836683"/>


* Using an appropriate transfer device or syringe, transfer 50 mL of Sterile Water for Injection into the product vial.
== Structure ==
The Aα, Bβ, and γ chains are [[Transcription (genetics)|transcribed]] and [[translated]] coordinately on the [[endoplasmic reticulum]] (ER) with their peptide chains being passed into the ER while their [[signal peptide]] portions are removed. Inside the ER, the three chains are assembled initially into Aαγ and Bβγ dimers, then to AαBβγ trimers, and finally to (AαBβγ)<sub>2</sub> heximers, i.e. two AαBβγ trimers joined together by numerous [[disulfide bonds]]. The heximer is transferred to the [[Golgi apparatus|Golgi]] where it is [[N-linked glycosylation|glycosylated]], [[hydroxylated]], [[sulfated]], and [[Phosphorylation|phosphorylated]] to form the mature fibrinogen glycoprotein that is secreted into the blood.<ref name="pmid17635718"/><ref name="pmid16999847"/> Mature fibrinogen is arranged as a long flexible protein array of three nodules held together by a very thin thread which is estimated to have a diameter between 8 and 15&nbsp;[[Angstrom]] (Å). The two end nodules (termed D regions or domains) are alike in consisting of Bβ and γ chains while the center slightly smaller nodule (termed the E region or domain) consists of two intertwined Aα alpha chains. Measurements of shadow lengths indicate that nodule diameters are in the range 50 to 70&nbsp;Å. The length of the dried molecule is 475 ± 25&nbsp;Å.<ref>{{cite journal|last=Hall, Ph.D.|first=Cecil E.|author2=HENRY S. SLAYTER |title=The Fibrinogen Molecule: Its Size, Shape, and Mode  of Polymerization|journal=The Journal of Biophysical and Biochemical Cytology|date=18 August 1958|volume= 5|series=Plate 1|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2224630/pdf/11.pdf|accessdate=24 May 2014|publisher=e Department of Biology, Massachusetts Institute of Technology|location=Cambridge, M|pmc=2224630|pmid=13630928|issue=1|pages=11–6|doi=10.1083/jcb.5.1.11}}</ref>


* Gently swirl the product vial to ensure the product is fully dissolved. Do not shake the vial.
The fibrinogen molecule circulates as a soluble [[blood plasma|plasma]] [[glycoprotein]] with a typical [[molecular weight]] (depending on its content of Aα verses AαE and γ versus γ' chains) of ~340&nbsp;[[kDa]]. It has a rod-like shape with dimensions of 9 × 47.5 × 6&nbsp;nm and has a negative net charge at physiological pH ( its [[isoelectric point]] is pH 5.8).<ref name="journalofphysics">{{cite journal|last=Marucco|first=Arianna|title=Interaction of fibrinogen and albumin with titanium dioxide nanoparticles of different crystalline phases|journal=Journal of Physics|date=2013|volume=429|series=Conference Series|issue= 1|url=http://iopscience.iop.org/1742-6596/429/1/012014/pdf/1742-6596_429_1_012014.pdf|accessdate=24 May 2014|display-authors=etal}}</ref><ref name="pmid23621148">{{cite journal | vauthors = Cieśla M, Adamczyk Z, Barbasz J, Wasilewska M | title = Mechanisms of fibrinogen adsorption at solid substrates at lower pH | journal = Langmuir : the ACS Journal of Surfaces and Colloids | volume = 29 | issue = 23 | pages = 7005–16 | year = 2013 | pmid = 23621148 | doi = 10.1021/la4012789 | url = }}</ref> The normal concentration of fibrinogen in blood [[Blood plasma|plasma]] is 150–400&nbsp;mg/dL with levels appreciably below or above this range associated with pathological bleeding and/or thrombosis. Fibrinogen has a circulating half-life of ~4 days.<ref name="pmid16999847"/>


* After reconstitution, the RiaSTAP solution should be colorless and clear to slightly opalescent. Inspect visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates. Do not freeze RiaSTAP solution. Discard partially used vials.
== Blood clot formation ==
{{main|Coagulation}}
{{main|fibrinolysis}}


* RiaSTAP is stable for 8 hours after reconstitution when stored at 20-25ºC and should be administered within this time period.
During blood clotting, [[thrombin]] attacks the [[N-terminus]] of the Aα and Bβ chains in fibrinogen to form individual fibrin strands plus two small [[polypeptide]]s, fibrinopeptides a and b derived from these respective chains. The individual fibrin strands then polymerize and are cross-linked with other fibrin stands by blood factor XIIIa to form an extensive interconnected fibrin network that is the basis for the formation of a mature fibrin clot.<ref name="pmid16102057"/><ref name="pmid28833193"/><ref name="pmid27713652">{{cite journal | vauthors = Besser MW, MacDonald SG | title = Acquired hypofibrinogenemia: current perspectives | journal = Journal of Blood Medicine | volume = 7 | issue = | pages = 217–225 | year = 2016 | pmid = 27713652 | pmc = 5045218 | doi = 10.2147/JBM.S90693 | url = }}</ref> In addition to forming fibrin, fibrinogen also promotes blood clotting by forming bridges between, and activating, blood [[platelet]]s through binding to their [[glycoprotein IIb/IIIa|GpIIb/IIIa]] surface membrane fibrinogen receptor.<ref name="pmid27713652"/>
|monitoring=There is limited information regarding <i>Monitoring</i> of {{PAGENAME}} in the drug label.


Fibrin participates in limiting blood clot formation and lysing formed blood clots by at least two important mechanisms. First, it possesses three low affinity binding sites (two in fibrin's E domain; one in its D domain) for thrombin; this binding sequesters thrombin from attacking fibrinogen.<ref name="pmid27713652"/> Second, fibrin's Aα chain accelerates by at least 100-fold the mount of plasmin activated by [[tissue plasminogen activator]]; plasmin breaks-down blood clots.<ref name="pmid21952526"/><ref name="pmid27713652"/><ref name="pmid16102057"/><ref name="pmid28833193"/> Plasmin's attack on fibrin releases D-dimers (also termed DD dimers). The detection of these dimers in blood is used as a clinical test for fibrinolysis.<ref name="pmid21952526"/>


== Fibrinogen disorders ==
Several [[List of fibrinogen disorders|disorders]] in the quantity and/or quality of fibrinogen cause pathological bleeding, pathological blood clotting, and/or the deposition of fibrinogen in the liver, kidneys, and other tissues. The following list of these disorders briefly describes and compares them and gives linkages to main article Wikipedia pages that offer more complete descriptions.


<!--IV Compatibility-->
=== Congenital afibrinogenemia ===
|IVCompat=There is limited information regarding <i>IV Compatibility</i> of {{PAGENAME}} in the drug label.
{{main|Congenital afibrinogenemia}}
|overdose=There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
Congenital afibrinogenemia is a rare and generally [[autosomal recessive]] inherited disorder in which blood does not clot due to a lack of fibrinogen (plasma fibrinogen levels typically 0 but sometimes detected at extremely low levels, e.g. <10&nbsp;mg/dL. This severe disorder is usually caused by mutations in both the maternal and paternal copies of either the ''FGA, FGB,'' or ''FBG'' gene. The mutations have virtually complete genetic [[penetrance]] with essentially all [[homozygous]] bearers experiencing frequent and sometimes life-threatening episodes of bleeding and/or thrombosis. Pathological bleeding occurs early in life, for example often being seen at birth with excessive hemorrhage from the [[Navel|umbilicus]].<ref name="pmid27019462"/>


=== Congenital hypofibrinogenemia ===
{{main|Congenital hypofibrinogenemia}}


Congenital hypofibrinogenemia is a rare inherited disorder in which blood may not clot normally due to reduced levels of fibrinogen (plasma fibrinogen typically <150 but >50&nbsp;mg/dL). The disorder reflects a disruptive mutation in only one of the two parental ''FGA, FGB,'' or ''FBG'' genes and has a low degree of genetic penetrance, i.e. only some family members with the defective gene ever exhibit symptoms. Symptoms of the disorder, which more often occurs in individuals with lower plasma fibrinogen levels include episodic bleeding and thrombosis that typically begin in late childhood or adulthood.<ref name="pmid27019462"/>


<!--Drug box 2-->
=== Fibrinogen storage disease ===
|mechAction=* Fibrinogen (factor I) is a soluble plasma glycoprotein with a molecular weight of about 340 kDa. The native molecule is a dimer and consists of three pairs of polypeptide chains (Aα, Bβ and γ). Fibrinogen is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin.
{{main|Congenital hypofibrinogenemia#Fibringogen storage disease}}


* During the coagulation process, thrombin cleaves the Aα and Bβ chains releasing fibrinopeptides A and B (FPA and FPB, respectively).2 FPA is separated rapidly and the remaining molecule is a soluble fibrin monomer (fibrin I). The slower removal of FPB results in formation of fibrin II that is capable of polymerization that occurs by aggregation of fibrin monomers.2 The resulting fibrin is stabilized in the presence of calcium ions and by activated factor XIII, which acts as a transglutaminase. Factor XIIIa-induced cross-linking of fibrin polymers renders the fibrin clot more elastic and more resistant to fibrinolysis.3 Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic platelet plug and structure to the vessel wall.
Fibringogen storage disease is a extremely rare disorder. It is a form of congenital hypofibrinogenemia in which certain specific hereditary mutations in one copy of the ''FGG'' gene causes its fibrinogen product to accumulate in, and damage, liver cells. The disorder has not reported with ''FGA'' or ''FGB'' mutations. Symptoms of these ''FGG'' mutations have a low level of penetrance. The plasma fibrinogen levels (generally <150 but >50&nbsp;mg/dL) detected in this disorder reflect the fibrinogen made by the normal gene. Fibrinogen storage disease may lead to abnormal bleeding and thrombosis but is distinguished by also sometimes leading to liver [[cirrhosis]].<ref name="pmid25990487">{{cite journal | vauthors = Casini A, Sokollik C, Lukowski SW, Lurz E, Rieubland C, de Moerloose P, Neerman-Arbez M | title = Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature | journal = Haemophilia | volume = 21 | issue = 6 | pages = 820–7 | year = 2015 | pmid = 25990487 | doi = 10.1111/hae.12719 | url = }}</ref>
|PD=* Administration of RiaSTAP to patients with congenital fibrinogen deficiency replaces the missing, or low coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.4
|PK=* A prospective, open label, uncontrolled, multicenter pharmacokinetic study was conducted in 5 females and 9 males with congenital fibrinogen deficiency (afibrinogenemia), ranging in age from 8 to 61 years (2 children, 3 adolescents, 9 adults). Each subject received a single intravenous dose of 70 mg/kg RiaSTAP. Blood samples were drawn from the patients to determine the fibrinogen activity at baseline and up to 14 days after the infusion. The pharmacokinetic parameters of RiaSTAP are summarized in Table 2.


* No statistically relevant difference was observed between males and females for fibrinogen activity. Subjects less than 16 years of age (n=4) had shorter half-life (69.9 ± 8.5) and faster clearance (0.73 ± 0.14) compared to subjects >16 years of age. The number of subjects less than 16 years of age in this study limits statistical interpretations.
=== Congenital dysfibrinogenemia ===
{{main|Dysfibrinogenemia}}
Congenital dysfibrinogenemia is a rare [[autosomal dominant]] inherited disorder in which plasma fibrinogen is composed of a dysfunctional fibrinogen made by a mutated ''FGA, FGB,'' or ''FBG'' gene inherited from one parent plus a normal fibrinogen made by a normal gene inherited from the other parent. As a reflection of this duality, plasma fibrinogen levels measured by immunological methods are normal (>150&nbsp;mg/dL) but are c. 50% lower when measured by clot formation methods. The disorder exhibits [[Penetrance#Degrees of penetrance|reduced penetrance]] with only some individuals with the abnormal gene showing symptoms of abnormal bleeding and thrombosis.<ref name="pmid25816717">{{cite journal | vauthors = Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P | title = Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management | journal = Journal of Thrombosis and Haemostasis | volume = 13 | issue = 6 | pages = 909–19 | year = 2015 | pmid = 25816717 | doi = 10.1111/jth.12916 | url = }}</ref>


* The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.7 mg/dL (range 1.30 – 2.73 mg/dL) increase per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will increase patients' fibrinogen plasma concentration by approximately 120 mg/dL.
=== Hereditary fibrinogen Aα-Chain amyloidosis ===
{{main|Dysfibrinogenemia#Hereditary fibrinogen Aα-Chain amyloidosis}}


* The pharmacokinetic analysis using fibrinogen antigen data (ELISA) was concordant with the fibrinogen activity (Clauss assay).
Hereditary fibrinogen Aα-Chain amyloidosis is an autosomal dominant extremely rare inherited disorder caused by a mutation in one of the two copies of the ''FGA'' gene. It is a form of congenital dysfibrinogenemia in which certain mutations lead to the production of an abnormal fibrinogen that circulates in the blood while gradually accumulating in the kidney. This accumulation leads over time to one form of [[familial renal amyloidosis]]. Plasma fibrinogen levels are similar to that seen in other forms of congenital dysfibrinogenemia. Fibrinogen Aα-Chain amyloidosis has not associated with abnormal bleeding or thrombosis.<ref name="pmid19073821">{{cite journal | vauthors = Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA, Zeng CH, Liu ZH, Li LS, Wechalekar A, Hawkins PN | title = Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis | journal = Journal of the American Society of Nephrology : JASN | volume = 20 | issue = 2 | pages = 444–51 | year = 2009 | pmid = 19073821 | pmc = 2637055 | doi = 10.1681/ASN.2008060614 | url = }}</ref>


[[ File:Pharmacokinetics table2.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
=== Acquired dysfibrinogenemia ===
|nonClinToxic=There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label.
{{main|Dysfibrinogenemia}}
|clinicalStudies=* The pharmacokinetic study evaluated the single-dose PK (see PHARMACOKINETICS [12.3]) and maximum clot firmness (MCF) in subjects with afibrinogenemia. MCF was determined by thromboelastometry (ROTEM) testing. MCF was measured to demonstrate functional activity of replacement fibrinogen when a fixed dose of RiaSTAP was administered. Clot firmness is a functional parameter that depends on: activation of coagulation, fibrinogen content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for the assessment of fibrinogen content and for the effects of fibrinogen supplementation on clinical efficacy.5


* For each subject, the MCF was determined before (baseline) and one hour after the single dose administration of RiaSTAP. RiaSTAP was found to be effective in increasing clot firmness in patients with congenital fibrinogen deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that the MCF values were significantly higher after administration of RiaSTAP than at baseline (see TABLE 3). The mean change from pre-infusion to 1 hour post-infusion was 8.9 mm in the primary analysis (9.9 mm for subjects < 16 years old and 8.5 mm for subjects ≥ 16 to < 65 years old). The mean change in MCF values closely approximated the levels expected from adding known amounts of fibrinogen to plasma in vitro.6 Hemostatic efficacy in acute bleeding episodes, and its correlation with MCF, are being verified in a postmarketing study.
Acquired dysfibrinogenemia is a rare disorder in which circulating fibrinogen is composed at least in part of a dysfunctional fibrinogen due to various acquired diseases. One well-studied cause of the disorder is severe [[liver disease]] including [[hepatoma]], chronic active [[hepatitis]], [[cirrhosis]], and [[jaundice]] due to [[biliary tract obstruction]]. The diseased liver synthesizes a fibrinogen which has a normally functional [[amino acid]] sequence but is incorrectly [[glycosylation|glycosylated]] (i.e. has a wrong amount of sugar residues) added to it during its passage through the Golgi. The incorrectly glycosalated fibrinogen is dysfunctional and may cause pathological episodes of bleeding and/or blood clotting. Other, less well understood, causes are [[plasma cell dyscrasia]]s and [[autoimmune disorders]] in which a circulating abnormal immunoglobulin or other protein interferes with fibrinogen function, and rare cases of cancer and medication ([[isotretinoin]], [[glucocorticoids]], and [[antileukemic drug]]s) toxicities.<ref name="pmid27713652"/>


[[File:Fibrinogen table3.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
=== Congenital hypodysfibrinogenemia ===
|howSupplied=* RiaSTAP is supplied in a single-use vial. Each carton contains one vial of RiaSTAP. The components used in the packaging for RiaSTAP are latex-free.
{{main|Hypodysfibrinogenemia}}


* The actual potency of fibrinogen concentrate in milligram (mg) is stated on each RiaSTAP vial label and carton.
Congenital hypodysfibrinogenemia is a rare inherited disorder in which low levels (i.e. <150&nbsp;mg/d) of immunologically detected plasma fibrinogen are and composed at least in part of a dysfunctional fibrinogen. The disorder reflects mutations typically in both inherited fibrinogen genes one of which produces a dysfunctional fibrinogen while the other produces low amounts of fibrinogen. The disorder, while having [[Penetrance#Degrees of penetrance|reduced penetrance]] is usually more severe that congenital dysfibrinogenemia but like the latter disorder causes pathological episodes of bleeding and/or blood clotting.<ref name="pmid28211264">{{cite journal | vauthors = Casini A, Brungs T, Lavenu-Bombled C, Vilar R, Neerman-Arbez M, de Moerloose P | title = Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation | journal = Journal of Thrombosis and Haemostasis | volume = 15 | issue = 5 | pages = 876–888 | year = 2017 | pmid = 28211264 | doi = 10.1111/jth.13655 | url = }}</ref>


* The following dosage form is available:
=== Cryofibrinogenemia ===
 
{{main|Cryofibrinogenemia}}
[[File:Fibrinogen supply.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|storage=* When stored at temperatures of 2-25°C (36-77°F), RiaSTAP is stable for the period indicated by the expiration date on the carton and vial label (up to 30 months). Keep RiaSTAP in its original carton until ready to use. Do not freeze. Protect from light.
|packLabel=[[File:Fibrinogen image.jpg|thumb|none|600px|This image is provided by the National Library of Medicine.]]
 
[[File:Fibrinogen ingredients and appearance.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo='''Allergic Reactions'''
 
* Inform patients of the early signs of allergic or hypersensitivity reactions to RiaSTAP, including hives, chest tightness, wheezing, hypotension, and anaphylaxis. Advise them to notify their physician immediately if they experience any of these symptoms.
 
'''Thrombosis'''
 
* Inform patients that thrombosis with or without embolization may be due to the underlying fibrinogen deficiency and has been reported with the use of RiaSTAP. Any symptoms of thrombotic events such as unexplained pleuritic, chest and/or leg pain or edema, hemoptysis, dyspnea, tachypnea or unexplained neurologic symptoms should be reported to their physician immediately.
 
'''Transmissible Infectious Agents'''
 
* Inform patients that RiaSTAP is made from human plasma (part of the blood) and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain the risk that RiaSTAP may transmit an infectious agent has been reduced by screening the plasma donors, by testing the donated plasma for certain virus infections, and by a process demonstrated to inactivate and/or remove certain viruses during manufacturing. Symptoms of a possible virus infection include headache, fever, nausea, vomiting, weakness, malaise, diarrhea, or, in the case of hepatitis, jaundice.
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* RIASTAP ®<ref>{{Cite web | title =RIASTAP- fibrinogen injection, powder, lyophilized, for solution| url =http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=903dc8d0-39da-462c-9dac-004e0c7a26cc }}</ref>
|drugShortage=
}}
{{LabelImage
|fileName={{PAGENAME}}11.png
}}
{{LabelImage
|fileName={{PAGENAME}}11.png
}}
<!--Pill Image-->


[[Cryofibrinogenemia]] is an acquired disorder in which fibrinogen precipitates at cold temperatures and may lead to the intravascular precipitation of fibrinogen, [[fibrin]], and other circulating proteins thereby causing the [[infarction]] of various tissues and bodily extremities. Cryoglobulonemia may occur without evidence of an underlying associated disorders, i.e. primary cryoglobulinemia (also termed essential cryoglobulinemia) or, far more commonly, with evidence of an underlying disease, i.e. secondary cryoglobulonemia. Secondary cryofibrinoenemia can develop in individuals suffering infection (c. 12% of cases), [[malignant]] or [[premalignant]] disorders (21%), [[vasculitis]] (25%), and [[autoimmune disease]]s (42%). In these cases, cryofibinogenema may or may not cause tissue injury and/or other symptoms and the actual cause-effect relationship between these diseases and the development of cryofibrinogenmia is unclear. Cryofibrinogenemia can also occur in association with the intake of certain drugs.<ref name="pmid27734332">{{cite journal | vauthors = Grada A, Falanga V | title = Cryofibrinogenemia-Induced Cutaneous Ulcers: A Review and Diagnostic Criteria | journal = American Journal of Clinical Dermatology | volume = 18 | issue = 1 | pages = 97–104 | year = 2017 | pmid = 27734332 | doi = 10.1007/s40257-016-0228-y | url = }}</ref><ref name="pmid24679054">{{cite journal | vauthors = Chen Y, Sreenivasan GM, Shojania K, Yoshida EM | title = Cryofibrinogenemia After a Liver Transplant: First Reported Case Posttransplant and a Case-Based Review of the Nontransplant Literature | journal = Experimental and Clinical Transplantation | volume = 13 | issue = 3 | pages = 290–4 | year = 2015 | pmid = 24679054 | doi = 10.6002/ect.2014.0013 | url = }}</ref><ref name="pmid28550239">{{cite journal | vauthors = Caimi G, Canino B, Lo Presti R, Urso C, Hopps E | title = Clinical conditions responsible for hyperviscosity and skin ulcers complications | journal = Clinical Hemorheology and Microcirculation | volume = 67| issue = | pages = 25–34| year = 2017 | pmid = 28550239 | doi = 10.3233/CH-160218 | url = }}</ref><ref name="pmid23519183">{{cite journal | vauthors = Michaud M, Pourrat J | title = Cryofibrinogenemia | journal = Journal of Clinical Rheumatology : Practical Reports on Rheumatic & Musculoskeletal Diseases | volume = 19 | issue = 3 | pages = 142–8 | year = 2013 | pmid = 23519183 | doi = 10.1097/RHU.0b013e318289e06e | url = }}</ref>


=== Acquired hypofibrinogenemia ===
Acquired hypofibrinogenemia is a deficiency in circulating fibrinogen due to excessive consumption that may occur as a result of [[Physical trauma|trauma]], certain phases of [[disseminated intravascular coagulation]], and [[sepsis]]. It may also occur as a result of hemodilution as a result of blood losses and/or transfusions with [[packed red blood cells]] or other fibrinogen-poor whole blood replacements.<ref name="pmid19390253">{{cite journal |vauthors=Fries D, Innerhofer P, Schobersberger W | title = Time for changing coagulation management in trauma-related massive bleeding | journal = Current Opinion in Anesthesiology | volume = 22 | issue = 2 | pages = 267–74 |date=April 2009 | pmid = 19390253 | doi = 10.1097/ACO.0b013e32832678d9 | url = | issn =  }}</ref>


<!--Label Display Image-->
== Laboratory Tests ==
Clinical analyses of the fibrinogen disorders typically measure blood clotting using the following successive steps:<ref name="Lang">{{cite journal |vauthors=Lang T, Johanning K, Metzler H, Piepenbrock S, Solomon C, Rahe-Meyer N, Tanaka KA | title = The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia | journal = Anesthesia and Analgesia | volume = 108 | issue = 3 | pages = 751–8 |date=March 2009 | pmid = 19224779 | doi = 10.1213/ane.0b013e3181966675 | url = | issn = }}</ref> Higher levels are, amongst others, associated with [[cardiovascular disease]] (>3.43 g/L). It may be elevated in any form of [[inflammation]], as it is an [[acute-phase protein]]; for example, it is especially apparent in human [[gingiva|gingival tissue]] during the [[Periodontal disease#Initial lesion|initial phase of periodontal disease]].<ref name="P&S">{{cite journal |vauthors=Page RC, Schroeder HE | title = Pathogenesis of inflammatory periodontal disease. A summary of current work | journal = Lab. Invest. | volume = 34 | issue = 3 | pages = 235–49 |date=March 1976 | pmid = 765622 | doi = | url = | issn = }}</ref><ref name="pmid27384135">{{cite journal | vauthors = Nagler M, Kremer Hovinga JA, Alberio L, Peter-Salonen K, von Tengg-Kobligk H, Lottaz D, Neerman-Arbez M, Lämmle B | title = Thromboembolism in patients with congenital afibrinogenaemia. Long-term observational data and systematic review | journal = Thrombosis and Haemostasis | volume = 116 | issue = 4 | pages = 722–32 | year = 2016 | pmid = 27384135 | doi = 10.1160/TH16-02-0082 | url = }}</ref>
*Blood clotting is measured using standard tests, e.g. [[prothrombin time]], [[partial thromboplastin time]], [[thrombin time]], and/or [[reptilase time]]; low fibrinogen levels and dysfunctional fibrinogens usually prolong these times whereas the lack of fibrinogen (i.e. afibrinogenemia) renders these times infinitely prolonged.
*Antigenic levels of fibrinogen levels are measured in the [[Blood plasma|plasma]] isolated from [[vein|venous]] blood by immunoassays with normal levels being about 1.5-3 gram/liter, depending on the method used. These levels are normal in dysfibrinogenmia (i.e. 1.5-3 gram/liter), decreased in hypofibrinogenemia and hypdysfibrinogenemia (i.e. <1.5 gram/liter), and absent (i.e. <0.02 gram/liter) in afibrinogenima.
*Functional levels of fibrinogen are measured on plasma induced to clot. The levels of clotted fibrinogen in this test should be decreased in hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia and undetectable in afibrinogenemia.
*Functional fibrinogen/antigenic fibrinogen levels are <0.7 in hypofibrinogenemia, hypodsyfibrinogenemia, and dysfibringognemia and not applicable in afibringenemia.
*Fibrinogen analysis can also be tested on whole-blood samples by thromboelastometry. This analysis investigates the interaction of coagulation factors, their inhibitors, anticoagulant drugs, blood cells, specifically platelets, during clotting and subsequent fibrinolysis as it occurs in whole blood. The test provides information on hemostatic efficacy and maximum clod firmness to give additional information on fibrin-platelet interactions and the rate of fibrinolysis (see [[Thromboelastometry]]).
*Scanning electron microscopy and confocal laser scanning microscopy of in vitro-formed clots can give information on fibrin clot density and architecture.
*The '''fibrinogen uptake test''' or '''fibrinogen scan''' was formerly used to detect [[deep vein thrombosis]].  In this method, radioactively labeled fibrinogen, typically with [[radioiodine]], is given to individuals, incorporated into a [[thrombus]], and detected by [[scintigraphy]].


== Hyperfibrinogenemia ==
Levels of functionally normal fibrinogen increase in [[pregnancy]] to an average of 4.5 gram/liter compared to an average of 3 g/l in non-pregnant people. They may also increase in various forms of cancer, particularly [[gastric cancer|gastric]], [[lung cancer|lung]], [[prostate cancer|prostate]], and [[ovarian cancer]]s. In these cases, the '''hyperfibrinogenemia''' may contribute to the development of pathological thrombosis. A particular pattern of migratory [[superficial vein]] thrombosis, termed [[trousseau's syndrome]], occurs in, and may precede all other signs and symptoms of, these cancers.<ref name="pmid28833193"/><ref>{{cite book| last = Salvi| first = Vinita| title = Medical and Surgical Diagnostic Disorders in Pregnancy| url = https://books.google.com/?id=NCOuIwhaWNUC&pg=PA5| year = 2003| publisher = Jaypee Brothers Publishers| isbn = 978-81-8061-090-5| page = 5 }}</ref> Hyperfibrinogenemia has also been linked as a cause of [[Persistent fetal circulation#Functional obstruction of pulmonary blood flow|persistent pulmonary hypertension of the newborn]]<ref>{{cite journal |vauthors=Graves ED, Redmond CR, Arensman RM |title=Persistent pulmonary hypertension in the neonate |journal=Chest |volume=93 |issue=3 |pages=638–41 |date=March 1988  |pmid=3277808 |url=http://journal.publications.chestnet.org/article.aspx?volume=93&page=638 |doi=10.1378/chest.93.3.638}}</ref> and post-operative thrombosis.<ref name="pmid3307545">{{cite journal | vauthors = Müller R, Musikić P | title = Hemorheology in surgery--a review | journal = Angiology | volume = 38 | issue = 8 | pages = 581–92 | year = 1987 | pmid = 3307545 | doi = 10.1177/000331978703800802 | url = }}</ref> High fibrinogen levels had been proposed as a predictor of hemorrhagic complications during catheter-directed trombolysis for acute or subacute peripheral native artery and arterial bypass occlusions.<ref>{{Cite journal|date=1994-09-01|title=Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial|journal=Annals of Surgery|volume=220|issue=3|pages=251–266; discussion 266–268|issn=0003-4932|pmc=1234376|pmid=8092895|doi=10.1097/00000658-199409000-00003}}</ref> However, a systematic review of the available literature until January 2016 found that the predictive value of plasma fibrinogen level for predicting hemorrhagic complications after catheter-directed thrombolysis is unproven.<ref>{{Cite journal|last=Poorthuis|first=Michiel H. F.|last2=Brand|first2=Eelco C.|last3=Hazenberg|first3=Constantijn E. V. B.|last4=Schutgens|first4=Roger E. G.|last5=Westerink|first5=Jan|last6=Moll|first6=Frans L.|last7=de Borst|first7=Gert J.|date=2017-03-05|title=Plasma fibrinogen level as a potential predictor of hemorrhagic complications after catheter-directed thrombolysis for peripheral arterial occlusions|journal=Journal of Vascular Surgery|doi=10.1016/j.jvs.2016.11.025|issn=1097-6809|pmid=28274749|volume=65|pages=1519–1527.e26}}</ref>


==References==
{{reflist|2}}


==External links==
{{Commons category|Fibrinogen}}
* Jennifer McDowall/Interpro: [http://www.ebi.ac.uk/interpro/potm/2006_11/Page1.htm Protein of the Month: ''Fibrinogen''.]
* D'Eustachio/reactome: ''[http://www.reactome.org/cgi-bin/link?SOURCE=Reactome&ID=REACT_214 fibrinogen → fibrin monomer + 2 fibrinopeptide A + 2 fibrinopeptide B]''
* Khan Academy Medicine (on YouTube): ''[https://www.youtube.com/watch?v=RQpBj8ebbNY&index=3&list=WL Clotting 1 - How do we make blood clots?]''


{{Coagulation}}
{{Acute phase proteins}}


<!--Category-->
[[Category:Acute phase proteins]]
[[Category:Acute phase proteins]]
[[Category:Drug]]
[[Category:Blood proteins]]
[[Category:Coagulation system]]
[[Category:Precursor proteins]]

Latest revision as of 11:56, 10 January 2019

fibrinogen alpha chain
File:Fibrinandligand.png
Crystallographic structure of a fragment of human fibrin.[1]
Identifiers
SymbolFGA
Entrez2243
HUGO3661
OMIM134820
RefSeqNM_000508
UniProtP02671
Other data
LocusChr. 4 q28
fibrinogen beta chain
Identifiers
SymbolFGB
Entrez2244
HUGO3662
OMIM134830
RefSeqNM_005141
UniProtP02675
Other data
LocusChr. 4 q28
Fibrinogen gamma chain
Identifiers
SymbolFGG
Entrez2266
HUGO3694
OMIM134850
RefSeqNM_021870
UniProtP02679
Other data
LocusChr. 4 q28
Fibrinogen alpha/beta chain family
File:PDB 1m1j EBI.jpg
crystal structure of native chicken fibrinogen with two different bound ligands
Identifiers
SymbolFib_alpha
PfamPF08702
InterProIPR012290
SCOP1m1j
SUPERFAMILY1m1j
Fibrinogen alpha C domain
Identifiers
SymbolFibrinogen_aC
PfamPF12160
InterProIPR021996
Fibrinogen beta and gamma chains, C-terminal globular domain
File:PDB 1m1j EBI.jpg
crystal structure of native chicken fibrinogen with two different bound ligands
Identifiers
SymbolFibrinogen_C
PfamPF00147
Pfam clanCL0422
InterProIPR002181
PROSITEPDOC00445
SCOP1fza
SUPERFAMILY1fza

Fibrinogen (factor I) is a glycoprotein that circulates in the blood of vertebrates. During tissue and vascular injury it is converted enzymatically by thrombin to fibrin and subsequently to a fibrin-based blood clot. Fibrinogen functions primarily to occlude blood vessels and thereby stop excessive bleeding. However, fibrinogen's product, fibrin, binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, serves to limit blood clotting. Loss or reduction in this antithrombin 1 activity due to mutations in fibrinogen genes or hypo-fibrinogen conditions can lead to excessive blood clotting and thrombosis.[2] Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby functions to promote tissue revascularization, wound healing, and tissue repair.[3]

Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired human fibrinogen-related disorders. These disorders represent a clinically important group of rare conditions in which individuals may present with severe episodes of pathological bleeding and thrombosis; these conditions are treated by supplementing blood fibrinogen levels and inhibiting blood clotting, respectively.[4][5] Certain of these disorders may also be the cause of liver and kidney diseases.[2]

Fibrinogen is a "positive" acute-phase protein, i.e. its blood levels rise in response to systemic inflammation, tissue injury, and certain other events. It is also elevated in various cancers. Elevated levels of fibrinogen in inflammation as well as cancer and other conditions have been suggested to be the cause of thrombosis and vascular injury that accompanies these conditions.[6][7]

Genes

Fibrinogen is made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells are also reported to make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood platelets and their precursors, bone marrow megakaryocytes, while once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein.[4][7] The final secreted, hepatocyte-derived glycoprotein is composed of two trimers with each trimer composed of three different polypeptide chains, the fibrinogen alpha chain (also termed the Aα or α chain) encoded by the FGA gene, the fibrinogen beta chain (also termed the Bβ or β chain) encoded by the FGB gene, and the fibrinogen gamma chain (also termed the γ chain) encoded by the FGG gene. All three genes are located on the long or "p" arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively).[2] Alternate splicing of the FGA gene produces a minor expanded isoform of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen; alternate splicing of FGG produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen; FGA is not alternatively spliced. Hence, the final fibrinogen product is composed principally of Aα, Bβ, and γ chains with a small percentage of it containing AαE and/or γ' chains in place of Aα and/or γ chains, respectively. The three genes are transcribed and translated in co-ordination by a mechanism(s) which remains incompletely understood.[8][9][10][11][12] The coordinated transcription of these three fibrinogen genes is rapidly and greatly increased by systemic conditions such as inflammation and tissue injury. Cytokines produced during these systemic conditions, such as interleukin 6 and interleukin 1β, appear responsible for up-regulating this transcription.[11]

Structure

The Aα, Bβ, and γ chains are transcribed and translated coordinately on the endoplasmic reticulum (ER) with their peptide chains being passed into the ER while their signal peptide portions are removed. Inside the ER, the three chains are assembled initially into Aαγ and Bβγ dimers, then to AαBβγ trimers, and finally to (AαBβγ)2 heximers, i.e. two AαBβγ trimers joined together by numerous disulfide bonds. The heximer is transferred to the Golgi where it is glycosylated, hydroxylated, sulfated, and phosphorylated to form the mature fibrinogen glycoprotein that is secreted into the blood.[10][12] Mature fibrinogen is arranged as a long flexible protein array of three nodules held together by a very thin thread which is estimated to have a diameter between 8 and 15 Angstrom (Å). The two end nodules (termed D regions or domains) are alike in consisting of Bβ and γ chains while the center slightly smaller nodule (termed the E region or domain) consists of two intertwined Aα alpha chains. Measurements of shadow lengths indicate that nodule diameters are in the range 50 to 70 Å. The length of the dried molecule is 475 ± 25 Å.[13]

The fibrinogen molecule circulates as a soluble plasma glycoprotein with a typical molecular weight (depending on its content of Aα verses AαE and γ versus γ' chains) of ~340 kDa. It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and has a negative net charge at physiological pH ( its isoelectric point is pH 5.8).[14][15] The normal concentration of fibrinogen in blood plasma is 150–400 mg/dL with levels appreciably below or above this range associated with pathological bleeding and/or thrombosis. Fibrinogen has a circulating half-life of ~4 days.[12]

Blood clot formation

Main article: Coagulation
Main article: fibrinolysis

During blood clotting, thrombin attacks the N-terminus of the Aα and Bβ chains in fibrinogen to form individual fibrin strands plus two small polypeptides, fibrinopeptides a and b derived from these respective chains. The individual fibrin strands then polymerize and are cross-linked with other fibrin stands by blood factor XIIIa to form an extensive interconnected fibrin network that is the basis for the formation of a mature fibrin clot.[3][7][16] In addition to forming fibrin, fibrinogen also promotes blood clotting by forming bridges between, and activating, blood platelets through binding to their GpIIb/IIIa surface membrane fibrinogen receptor.[16]

Fibrin participates in limiting blood clot formation and lysing formed blood clots by at least two important mechanisms. First, it possesses three low affinity binding sites (two in fibrin's E domain; one in its D domain) for thrombin; this binding sequesters thrombin from attacking fibrinogen.[16] Second, fibrin's Aα chain accelerates by at least 100-fold the mount of plasmin activated by tissue plasminogen activator; plasmin breaks-down blood clots.[5][16][3][7] Plasmin's attack on fibrin releases D-dimers (also termed DD dimers). The detection of these dimers in blood is used as a clinical test for fibrinolysis.[5]

Fibrinogen disorders

Several disorders in the quantity and/or quality of fibrinogen cause pathological bleeding, pathological blood clotting, and/or the deposition of fibrinogen in the liver, kidneys, and other tissues. The following list of these disorders briefly describes and compares them and gives linkages to main article Wikipedia pages that offer more complete descriptions.

Congenital afibrinogenemia

Main article: Congenital afibrinogenemia

Congenital afibrinogenemia is a rare and generally autosomal recessive inherited disorder in which blood does not clot due to a lack of fibrinogen (plasma fibrinogen levels typically 0 but sometimes detected at extremely low levels, e.g. <10 mg/dL. This severe disorder is usually caused by mutations in both the maternal and paternal copies of either the FGA, FGB, or FBG gene. The mutations have virtually complete genetic penetrance with essentially all homozygous bearers experiencing frequent and sometimes life-threatening episodes of bleeding and/or thrombosis. Pathological bleeding occurs early in life, for example often being seen at birth with excessive hemorrhage from the umbilicus.[4]

Congenital hypofibrinogenemia

Main article: Congenital hypofibrinogenemia

Congenital hypofibrinogenemia is a rare inherited disorder in which blood may not clot normally due to reduced levels of fibrinogen (plasma fibrinogen typically <150 but >50 mg/dL). The disorder reflects a disruptive mutation in only one of the two parental FGA, FGB, or FBG genes and has a low degree of genetic penetrance, i.e. only some family members with the defective gene ever exhibit symptoms. Symptoms of the disorder, which more often occurs in individuals with lower plasma fibrinogen levels include episodic bleeding and thrombosis that typically begin in late childhood or adulthood.[4]

Fibrinogen storage disease

Main article: Congenital hypofibrinogenemia § Fibringogen storage disease

Fibringogen storage disease is a extremely rare disorder. It is a form of congenital hypofibrinogenemia in which certain specific hereditary mutations in one copy of the FGG gene causes its fibrinogen product to accumulate in, and damage, liver cells. The disorder has not reported with FGA or FGB mutations. Symptoms of these FGG mutations have a low level of penetrance. The plasma fibrinogen levels (generally <150 but >50 mg/dL) detected in this disorder reflect the fibrinogen made by the normal gene. Fibrinogen storage disease may lead to abnormal bleeding and thrombosis but is distinguished by also sometimes leading to liver cirrhosis.[17]

Congenital dysfibrinogenemia

Main article: Dysfibrinogenemia

Congenital dysfibrinogenemia is a rare autosomal dominant inherited disorder in which plasma fibrinogen is composed of a dysfunctional fibrinogen made by a mutated FGA, FGB, or FBG gene inherited from one parent plus a normal fibrinogen made by a normal gene inherited from the other parent. As a reflection of this duality, plasma fibrinogen levels measured by immunological methods are normal (>150 mg/dL) but are c. 50% lower when measured by clot formation methods. The disorder exhibits reduced penetrance with only some individuals with the abnormal gene showing symptoms of abnormal bleeding and thrombosis.[18]

Hereditary fibrinogen Aα-Chain amyloidosis

Main article: Dysfibrinogenemia § Hereditary fibrinogen Aα-Chain amyloidosis

Hereditary fibrinogen Aα-Chain amyloidosis is an autosomal dominant extremely rare inherited disorder caused by a mutation in one of the two copies of the FGA gene. It is a form of congenital dysfibrinogenemia in which certain mutations lead to the production of an abnormal fibrinogen that circulates in the blood while gradually accumulating in the kidney. This accumulation leads over time to one form of familial renal amyloidosis. Plasma fibrinogen levels are similar to that seen in other forms of congenital dysfibrinogenemia. Fibrinogen Aα-Chain amyloidosis has not associated with abnormal bleeding or thrombosis.[19]

Acquired dysfibrinogenemia

Main article: Dysfibrinogenemia

Acquired dysfibrinogenemia is a rare disorder in which circulating fibrinogen is composed at least in part of a dysfunctional fibrinogen due to various acquired diseases. One well-studied cause of the disorder is severe liver disease including hepatoma, chronic active hepatitis, cirrhosis, and jaundice due to biliary tract obstruction. The diseased liver synthesizes a fibrinogen which has a normally functional amino acid sequence but is incorrectly glycosylated (i.e. has a wrong amount of sugar residues) added to it during its passage through the Golgi. The incorrectly glycosalated fibrinogen is dysfunctional and may cause pathological episodes of bleeding and/or blood clotting. Other, less well understood, causes are plasma cell dyscrasias and autoimmune disorders in which a circulating abnormal immunoglobulin or other protein interferes with fibrinogen function, and rare cases of cancer and medication (isotretinoin, glucocorticoids, and antileukemic drugs) toxicities.[16]

Congenital hypodysfibrinogenemia

Main article: Hypodysfibrinogenemia

Congenital hypodysfibrinogenemia is a rare inherited disorder in which low levels (i.e. <150 mg/d) of immunologically detected plasma fibrinogen are and composed at least in part of a dysfunctional fibrinogen. The disorder reflects mutations typically in both inherited fibrinogen genes one of which produces a dysfunctional fibrinogen while the other produces low amounts of fibrinogen. The disorder, while having reduced penetrance is usually more severe that congenital dysfibrinogenemia but like the latter disorder causes pathological episodes of bleeding and/or blood clotting.[20]

Cryofibrinogenemia

Main article: Cryofibrinogenemia

Cryofibrinogenemia is an acquired disorder in which fibrinogen precipitates at cold temperatures and may lead to the intravascular precipitation of fibrinogen, fibrin, and other circulating proteins thereby causing the infarction of various tissues and bodily extremities. Cryoglobulonemia may occur without evidence of an underlying associated disorders, i.e. primary cryoglobulinemia (also termed essential cryoglobulinemia) or, far more commonly, with evidence of an underlying disease, i.e. secondary cryoglobulonemia. Secondary cryofibrinoenemia can develop in individuals suffering infection (c. 12% of cases), malignant or premalignant disorders (21%), vasculitis (25%), and autoimmune diseases (42%). In these cases, cryofibinogenema may or may not cause tissue injury and/or other symptoms and the actual cause-effect relationship between these diseases and the development of cryofibrinogenmia is unclear. Cryofibrinogenemia can also occur in association with the intake of certain drugs.[21][22][23][24]

Acquired hypofibrinogenemia

Acquired hypofibrinogenemia is a deficiency in circulating fibrinogen due to excessive consumption that may occur as a result of trauma, certain phases of disseminated intravascular coagulation, and sepsis. It may also occur as a result of hemodilution as a result of blood losses and/or transfusions with packed red blood cells or other fibrinogen-poor whole blood replacements.[25]

Laboratory Tests

Clinical analyses of the fibrinogen disorders typically measure blood clotting using the following successive steps:[26] Higher levels are, amongst others, associated with cardiovascular disease (>3.43 g/L). It may be elevated in any form of inflammation, as it is an acute-phase protein; for example, it is especially apparent in human gingival tissue during the initial phase of periodontal disease.[27][28]

  • Blood clotting is measured using standard tests, e.g. prothrombin time, partial thromboplastin time, thrombin time, and/or reptilase time; low fibrinogen levels and dysfunctional fibrinogens usually prolong these times whereas the lack of fibrinogen (i.e. afibrinogenemia) renders these times infinitely prolonged.
  • Antigenic levels of fibrinogen levels are measured in the plasma isolated from venous blood by immunoassays with normal levels being about 1.5-3 gram/liter, depending on the method used. These levels are normal in dysfibrinogenmia (i.e. 1.5-3 gram/liter), decreased in hypofibrinogenemia and hypdysfibrinogenemia (i.e. <1.5 gram/liter), and absent (i.e. <0.02 gram/liter) in afibrinogenima.
  • Functional levels of fibrinogen are measured on plasma induced to clot. The levels of clotted fibrinogen in this test should be decreased in hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia and undetectable in afibrinogenemia.
  • Functional fibrinogen/antigenic fibrinogen levels are <0.7 in hypofibrinogenemia, hypodsyfibrinogenemia, and dysfibringognemia and not applicable in afibringenemia.
  • Fibrinogen analysis can also be tested on whole-blood samples by thromboelastometry. This analysis investigates the interaction of coagulation factors, their inhibitors, anticoagulant drugs, blood cells, specifically platelets, during clotting and subsequent fibrinolysis as it occurs in whole blood. The test provides information on hemostatic efficacy and maximum clod firmness to give additional information on fibrin-platelet interactions and the rate of fibrinolysis (see Thromboelastometry).
  • Scanning electron microscopy and confocal laser scanning microscopy of in vitro-formed clots can give information on fibrin clot density and architecture.
  • The fibrinogen uptake test or fibrinogen scan was formerly used to detect deep vein thrombosis. In this method, radioactively labeled fibrinogen, typically with radioiodine, is given to individuals, incorporated into a thrombus, and detected by scintigraphy.

Hyperfibrinogenemia

Levels of functionally normal fibrinogen increase in pregnancy to an average of 4.5 gram/liter compared to an average of 3 g/l in non-pregnant people. They may also increase in various forms of cancer, particularly gastric, lung, prostate, and ovarian cancers. In these cases, the hyperfibrinogenemia may contribute to the development of pathological thrombosis. A particular pattern of migratory superficial vein thrombosis, termed trousseau's syndrome, occurs in, and may precede all other signs and symptoms of, these cancers.[7][29] Hyperfibrinogenemia has also been linked as a cause of persistent pulmonary hypertension of the newborn[30] and post-operative thrombosis.[31] High fibrinogen levels had been proposed as a predictor of hemorrhagic complications during catheter-directed trombolysis for acute or subacute peripheral native artery and arterial bypass occlusions.[32] However, a systematic review of the available literature until January 2016 found that the predictive value of plasma fibrinogen level for predicting hemorrhagic complications after catheter-directed thrombolysis is unproven.[33]

References

  1. ↑ PDB: 1FZC​; Everse SJ, Spraggon G, Veerapandian L, Riley M, Doolittle RF (June 1998). "Crystal structure of fragment double-D from human fibrin with two different bound ligands". Biochemistry. 37 (24): 8637–42. doi:10.1021/bi9804129. PMID 9628725.
  2. ↑ 2.0 2.1 2.2 de Moerloose P, Casini A, Neerman-Arbez M (2013). "Congenital fibrinogen disorders: an update". Seminars in Thrombosis and Hemostasis. 39 (6): 585–95. doi:10.1055/s-0033-1349222. PMID 23852822.
  3. ↑ 3.0 3.1 3.2 Mosesson MW (2005). "Fibrinogen and fibrin structure and functions". Journal of Thrombosis and Haemostasis. 3 (8): 1894–904. doi:10.1111/j.1538-7836.2005.01365.x. PMID 16102057.
  4. ↑ 4.0 4.1 4.2 4.3 Casini A, de Moerloose P, Neerman-Arbez M (2016). "Clinical Features and Management of Congenital Fibrinogen Deficiencies". Seminars in Thrombosis and Hemostasis. 42 (4): 366–74. doi:10.1055/s-0036-1571339. PMID 27019462.
  5. ↑ 5.0 5.1 5.2 Undas A (2011). "Acquired dysfibrinogenemia in atherosclerotic vascular disease". Polskie Archiwum Medycyny Wewnetrznej. 121 (9): 310–9. PMID 21952526.
  6. ↑ Davalos D, Akassoglou K (2012). "Fibrinogen as a key regulator of inflammation in disease". Seminars in Immunopathology. 34 (1): 43–62. doi:10.1007/s00281-011-0290-8. PMID 22037947.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Repetto O, De Re V (2017). "Coagulation and fibrinolysis in gastric cancer". Annals of the New York Academy of Sciences. 1404: 27–48. doi:10.1111/nyas.13454. PMID 28833193.
  8. ↑ Neerman-Arbez M, de Moerloose P, Casini A (2016). "Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders". Seminars in Thrombosis and Hemostasis. 42 (4): 356–65. doi:10.1055/s-0036-1571340. PMID 27019463.
  9. ↑ Duval C, Ariëns RA (2017). "Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ' as thrombomobulin II". Matrix Biology. 60–61: 8–15. doi:10.1016/j.matbio.2016.09.010. PMID 27784620.
  10. ↑ 10.0 10.1 Vu D, Neerman-Arbez M (2007). "Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins". Journal of Thrombosis and Haemostasis. 5 Suppl 1: 125–31. doi:10.1111/j.1538-7836.2007.02465.x. PMID 17635718.
  11. ↑ 11.0 11.1 Fish RJ, Neerman-Arbez M (2012). "Fibrinogen gene regulation". Thrombosis and Haemostasis. 108 (3): 419–26. doi:10.1160/TH12-04-0273. PMID 22836683.
  12. ↑ 12.0 12.1 12.2 Asselta R, Duga S, Tenchini ML (2006). "The molecular basis of quantitative fibrinogen disorders". Journal of Thrombosis and Haemostasis. 4 (10): 2115–29. doi:10.1111/j.1538-7836.2006.02094.x. PMID 16999847.
  13. ↑ Hall, Ph.D., Cecil E.; HENRY S. SLAYTER (18 August 1958). "The Fibrinogen Molecule: Its Size, Shape, and Mode of Polymerization" (PDF). The Journal of Biophysical and Biochemical Cytology. Plate 1. Cambridge, M: e Department of Biology, Massachusetts Institute of Technology. 5 (1): 11–6. doi:10.1083/jcb.5.1.11. PMC 2224630. PMID 13630928. Retrieved 24 May 2014.
  14. ↑ Marucco, Arianna; et al. (2013). "Interaction of fibrinogen and albumin with titanium dioxide nanoparticles of different crystalline phases" (PDF). Journal of Physics. Conference Series. 429 (1). Retrieved 24 May 2014.
  15. ↑ Cieśla M, Adamczyk Z, Barbasz J, Wasilewska M (2013). "Mechanisms of fibrinogen adsorption at solid substrates at lower pH". Langmuir : the ACS Journal of Surfaces and Colloids. 29 (23): 7005–16. doi:10.1021/la4012789. PMID 23621148.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 Besser MW, MacDonald SG (2016). "Acquired hypofibrinogenemia: current perspectives". Journal of Blood Medicine. 7: 217–225. doi:10.2147/JBM.S90693. PMC 5045218. PMID 27713652.
  17. ↑ Casini A, Sokollik C, Lukowski SW, Lurz E, Rieubland C, de Moerloose P, Neerman-Arbez M (2015). "Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature". Haemophilia. 21 (6): 820–7. doi:10.1111/hae.12719. PMID 25990487.
  18. ↑ Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P (2015). "Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management". Journal of Thrombosis and Haemostasis. 13 (6): 909–19. doi:10.1111/jth.12916. PMID 25816717.
  19. ↑ Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA, Zeng CH, Liu ZH, Li LS, Wechalekar A, Hawkins PN (2009). "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis". Journal of the American Society of Nephrology : JASN. 20 (2): 444–51. doi:10.1681/ASN.2008060614. PMC 2637055. PMID 19073821.
  20. ↑ Casini A, Brungs T, Lavenu-Bombled C, Vilar R, Neerman-Arbez M, de Moerloose P (2017). "Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation". Journal of Thrombosis and Haemostasis. 15 (5): 876–888. doi:10.1111/jth.13655. PMID 28211264.
  21. ↑ Grada A, Falanga V (2017). "Cryofibrinogenemia-Induced Cutaneous Ulcers: A Review and Diagnostic Criteria". American Journal of Clinical Dermatology. 18 (1): 97–104. doi:10.1007/s40257-016-0228-y. PMID 27734332.
  22. ↑ Chen Y, Sreenivasan GM, Shojania K, Yoshida EM (2015). "Cryofibrinogenemia After a Liver Transplant: First Reported Case Posttransplant and a Case-Based Review of the Nontransplant Literature". Experimental and Clinical Transplantation. 13 (3): 290–4. doi:10.6002/ect.2014.0013. PMID 24679054.
  23. ↑ Caimi G, Canino B, Lo Presti R, Urso C, Hopps E (2017). "Clinical conditions responsible for hyperviscosity and skin ulcers complications". Clinical Hemorheology and Microcirculation. 67: 25–34. doi:10.3233/CH-160218. PMID 28550239.
  24. ↑ Michaud M, Pourrat J (2013). "Cryofibrinogenemia". Journal of Clinical Rheumatology : Practical Reports on Rheumatic & Musculoskeletal Diseases. 19 (3): 142–8. doi:10.1097/RHU.0b013e318289e06e. PMID 23519183.
  25. ↑ Fries D, Innerhofer P, Schobersberger W (April 2009). "Time for changing coagulation management in trauma-related massive bleeding". Current Opinion in Anesthesiology. 22 (2): 267–74. doi:10.1097/ACO.0b013e32832678d9. PMID 19390253.
  26. ↑ Lang T, Johanning K, Metzler H, Piepenbrock S, Solomon C, Rahe-Meyer N, Tanaka KA (March 2009). "The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia". Anesthesia and Analgesia. 108 (3): 751–8. doi:10.1213/ane.0b013e3181966675. PMID 19224779.
  27. ↑ Page RC, Schroeder HE (March 1976). "Pathogenesis of inflammatory periodontal disease. A summary of current work". Lab. Invest. 34 (3): 235–49. PMID 765622.
  28. ↑ Nagler M, Kremer Hovinga JA, Alberio L, Peter-Salonen K, von Tengg-Kobligk H, Lottaz D, Neerman-Arbez M, Lämmle B (2016). "Thromboembolism in patients with congenital afibrinogenaemia. Long-term observational data and systematic review". Thrombosis and Haemostasis. 116 (4): 722–32. doi:10.1160/TH16-02-0082. PMID 27384135.
  29. ↑ Salvi, Vinita (2003). Medical and Surgical Diagnostic Disorders in Pregnancy. Jaypee Brothers Publishers. p. 5. ISBN 978-81-8061-090-5.
  30. ↑ Graves ED, Redmond CR, Arensman RM (March 1988). "Persistent pulmonary hypertension in the neonate". Chest. 93 (3): 638–41. doi:10.1378/chest.93.3.638. PMID 3277808.
  31. ↑ Müller R, Musikić P (1987). "Hemorheology in surgery--a review". Angiology. 38 (8): 581–92. doi:10.1177/000331978703800802. PMID 3307545.
  32. ↑ "Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial". Annals of Surgery. 220 (3): 251–266, discussion 266–268. 1994-09-01. doi:10.1097/00000658-199409000-00003. ISSN 0003-4932. PMC 1234376. PMID 8092895.
  33. ↑ Poorthuis, Michiel H. F.; Brand, Eelco C.; Hazenberg, Constantijn E. V. B.; Schutgens, Roger E. G.; Westerink, Jan; Moll, Frans L.; de Borst, Gert J. (2017-03-05). "Plasma fibrinogen level as a potential predictor of hemorrhagic complications after catheter-directed thrombolysis for peripheral arterial occlusions". Journal of Vascular Surgery. 65: 1519–1527.e26. doi:10.1016/j.jvs.2016.11.025. ISSN 1097-6809. PMID 28274749.

External links

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