REVIEW ARTICLE

Congenital structural and functional disorders: a primer for internists

Anetta Undas1, Alessandro Casini2 1 Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland 2 Division of Angiology and Haemostasis, Faculty of Medicine, University Hospitals of Geneva, Geneva, Switzerland

KEY WORDS ABSTRACT afibrinogenemia, Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities , caused by mutations in one of the 3 genes encoding individual fibrinogen polypeptide chains, located on fibrinogen, genetic chromosome 4q28. It is estimated that congenital fibrinogen disorder accounts for 8% of rare mutation factor deficiencies. Most of congenital fibrinogen disorders are suspected in individuals with bleeding tendency or coincidentally discovered, for instance prior to surgery. Fibrinogen disorders could be also found in patients with thrombotic events, impaired wound healing, and recurrent spontaneous abortions. Afibrinogenemia manifests as mild to severe bleeding, while hypofibrinogenemia is often asymptomatic. Dysfibrinogenemia, a qualitative fibrinogen disorder, is associated with bleeding, thrombosis, or with no symptoms. Recent recommendations issued by the International Society on Thrombosis and Haemostasis in 2018 do not encourage routine evaluation of thrombin time or other coagulation tests in patients with suspected congenital fibrinogen disorders, highlighting the value of fibrinogen antigen measurement and genetic analysis, added to the key finding, that is, reduced fibrinogen concentration determined with a coagulometric assay. The current review summarizes practical issues in diagnostic workup­ and clinical management of patients with afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia from a perspective of internists who may encounter patients with reduced fibrinogen concentration in everyday practice. Despite the fact that hematologists are in front line for the management of patients with bleeding tendency, internists should be aware of the clinical and labora- tory findings in patients with inherited fibrinogen disorders including the risk of thromboembolism and management prior to invasive procedures.

Fibrinogen structure Fibrinogen is a 340 kDa pro­ their lateral aggregation, thick fibers are tein synthesized in the liver.1 Its normal con­ crosslinked in a reaction catalyzed by thrombin­ centration in blood plasma is in the range of ‑activated factor XIII.1 Fibrin, together with plate­ 1.5 to 4.0 g/l. The half­‑life of circulating fibrin­ lets and red blood cells, provide structural in­ ogen is about 3 to 4 days. The fibrinogen mole­ tegrity to the hemostatic plug under physiolog­ cule is a hexamer, made up of 3 pairs of homolo­ ical conditions and to the growing thrombus in Correspondence to: Anetta Undas, MD, PhD, gous Aα, Bβ, and γ polypeptide chains connect­ thrombotic disorders. Institute of Cardiology, Jagiellonian ed by disulfide bridges that form a central E re­ The final fibrin clot has a highly heterogeneous University Medical College, gion composed by the N­‑terminal portions of structure, determined by genetic and, to a much ul. Prądnicka 80, 31-202 Kraków, all 6 chains and 2 terminal D regions containing larger extent, environmental factors, which re­ Poland, phone: +48 12 614 30 04, email: mmundas@cyf­‑kr.edu.pl the C­‑terminal fragments of the Bβ and γ chains.1 sults in a large interindividual variability of clot Received: December 3, 2019. The C­‑terminal fragments of the Aα chains form architecture, thickness of fibers, and their branch­ Accepted: December 4, 2019. 2 Published online: globular structures located near the central E re­ ing. Lower fibrinogen concentrations are known 1 December 23, 2019. gion. After cleavage of fibrinopeptides A and to result in the formation of thicker fibrin fibers Pol Arch Intern Med. 2019; B mediated by thrombin, fibrin monomers are creating looser meshwork which is more suscep­ 129 (12): 913-920 formed, which polymerize through the interac­ tible to fibrinolysis and mechanical fragmenta­ doi:10.20452/pamw.15082 Copyright by Medycyna Praktyczna, tion of the D region with the E regions of subse­ tion, eventually leading to an increased risk of Kraków 2019 quent monomers to form protofibrils and through bleeding. On the other hand, irregular abnormal

REVIEW ARTICLE Fibrinogen disorders 913 structure of fibrin, even at lower fibrinogen con­ FGA and other affecting Arg301 in exon 8 ofFGG . centrations, could paradoxically increase throm­ The mechanisms underlying clinical manifesta­ botic risk by impairing fibrin degradation by plas­ tions observed in qualitative congenital fibrin­ min or facilitating clot fragmentation.2,3 ogen disorders involve abnormal formation of a fibrin clot associated with disturbed release Congenital fibrinogen disorders Genetic background of fibrinopeptides, delayed fibrin polymeriza­ Congenital disorders of fibrinogen is a hetero­ tion or defective cross­‑linking.4,8,9 A single muta­ geneous group of rare abnormalities most of­ tion altering a fibrinogen chain may result in sig­ ten caused by mutations in one of the 3 separate nificant changes in the tertiary and quaternary genes encoding individual polypeptide chains, structure of the protein causing all of the above located on chromosome 4q28 in a cluster of disorders.4,8,9 To date, about 30 different muta­ about 50 kbp (FGA, FGB, and FGG, respectively, tions causing hypodysfibrinogenemia have been for chains Aα, Bβ, and γ, but the order of genes identified (10 in the FGA gene, 5 in the FGB gene, from centromere to telomer is as follows: FGB, and 15 in the FGG gene). Most of these fibrinogen FGA, and FGG).4 So far, over 450 mutations in mutations were inherited in an autosomal dom­ FGA, FGB, and FGG genes have been registered, of inant manner.10 Combined heterozygosity was which over 250 are symptomatic (www.geht.org). found in additional 7 patients with hypodysfi­ The most common mutations (50%–80%) are brinogenemia.10 In patients with hypodysfibrin­ single­‑amino acid missense mutations. Other ogenemia, the hypofibrinogenemic phenotype re­ defects responsible for fibrinogen abnormalities sults from mutation affecting synthesis, assembly, include nonsense mutations, read frame changes and secretion or leading to an increased fibrino­ through small deletions or insertions in the cod­ gen clearance, while the dysfibrinogenemic phe­ ing part of the gene (frameshift), splicing­‑site notype results from impaired fibrin polymeriza­ mutations, and large deletions.4 Less than 5% of tion and abnormal binding of calcium ions or tis­ cases are genetic variants located in the 3’ and sue plasminogen activator.10 5’ untranslated regions of the genes.5 Still, a few The first Polish case of dysfibrinogenemia,­ Fi patients with severe fibrinogen deficiency have brinogen Kraków associated with the Asn325Ile no identified genetic cause, and the use of next­ mutation in the fibrinogen γ chain and causing ‑generation sequencing can help clarify genetic hypodysfibrinogenemia with thrombotic man­ background of these disorders. ifestation, was described in 2009.11 Genetically The causative mutations described so far re­ characterized described for the first sult in either qualitative or quantitative fibrino­ time in Polish patients are shown in TABLE 1 (for gen disorders.4 Quantitative disorders are tradi­ the whole report, see Wypasek et al12). tionally divided into afibrinogenemia (complete absence of fibrinogen) and hypofibrinogenemia Clinical manifestations In patients with afibrino­ (proportionally reduced functional fibrinogen genemia, umbilical stump bleeding in newborns and its antigen levels).4,6 Afibrinogenemia is in­ is the typical first manifestation of the disease, herited in an autosomal recessive manner, while observed in 85% of cases.13 Bleeding in afibrino­ hypofibrinogenemia, dysfibrinogemia, and hy­ genemia may also commonly occur as nosebleeds podysfibrinogenemia are autosomal dominant.4 and less frequently cutaneous bleeding, gastro­ Afibrinogenemia is due to homozygosity or com­ intestinal hemorrhage, and genitourinary bleed­ pound heterozygosity of a null mutation.4 It is es­ ing. Intracranial bleeding, often spontaneous, is timated that quantitative congenital fibrinogen the most common cause of death in patients with disorder accounts for 8% of rare coagulation fac­ afibrinogenemia.13 Intramuscular and hemarthro­ tor deficiencies.5 The prevalence of afibrinogen­ sis also occur in afibrinogenemia, usually less re­ emia is estimated to be 1/1 000 000 or more in currently and less damaging than in severe he­ some countries where marriage of close relatives mophilia, even though severe arthropathies have is common, for example, in Iran.4 As hypofibri­ also been reported in afibrinogenemia.5 Three ad­ nogenemias are mainly caused by heterozygosi­ ditional manifestations are considered specific ty for fibrinogen gene mutation, they are much for afibrinogenemia, namely spontaneous spleen more frequent than afibrinogenemia. rupture, impaired wound healing, and the forma­ Qualitative fibrinogen disorders include dys­ tion of painful bone cysts.14 Afibrinogenemia in fibrinogenemia (normal amount of dysfunction­ women is typically associated with spontaneous al fibrinogen) and hypodysfibrinogenemia (de­ miscarriages in the first trimester of pregnancy.13 creased amount of dysfunctional fibrinogen). Other pregnancy­‑related manifestations include Almost all dysfibrinogenemias are caused by pre- or postpartum hemorrhages, as well as pla­ heterozygous missense mutations in FGA and cental abruption. Indeed, fibrinogen ensures pla­ FGG genes. Their prevalence is unknown as they cental integrity and is necessary for the devel­ are often asymptomatic.6 In a recent systemat­ opment of blood vessels in its villi.13 Over 50% ic analysis of exome / genome data from about of women with afibrinogenemia have prolonged 140 000 individuals of genome databases, it was that requires hormonal estimated that their prevalence is up to 0.3% to treatment.13 Paradoxically, patients with afibrin­ 1%.7 Two hotspot mutations are particularly fre­ ogenemia may have thromboembolic events as­ quent, one affecting residue Arg35 in exon 2 of sociated with or without fibrinogen substitution

914 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (12) TABLE 1 Congenital fibrinogen disorders genetically characterized for the first time in Polish patients

Fibrinogen ISTH Gene Mutation Sex; age at Functional TT, s Clinical symptoms Bleeding / classification diagnosis, y fibrinogen / thrombosis fibrinogen in family antigen, g/l Belchatow 2B, moderate FGG IVS1+5 Woman; 33 0.94/1.2 31.8 2 postpartum Yes hypofibrino- G>C, hemorrhages, genemia c.78+G>C 2 miscarriages Cracow 4C, mild FGG c.1052A>T, Woman; 21 0.62/1.16 21.5 Accidental diagnosis Yes hypodysfibrino- p.Asn325Ile during the first genemia pregnancy; at age of 16 years, appendectomy complicated by DVT Cracow III 3A, dysfibryno- FGG c.124G>A, Woman; 44 2.1/2.29 22.5 Bleeding after delivery No genemia p.Gly16Ser and tooth extraction Poznan 2C, mild FGG c.331 A>T, Man; 25 1.0/1.12 21.1 32­‑hour bleeding after Yes hypofibrino- p.Lys111X tooth extraction, genemia bleeding from minor wounds and nose, easy bruising Poznan II 3A, dysfibrino- FGG del 177bp Woman; 47 1.81/2.6 19.1 Spontaneous miscarriage Yes genemia at 33 years complicated by vaginal bleeding, prolonged menstrual bleeding, easy bruising Zakopane 2B, moderate FGG IVS2­–2 A>C, Male; 23 0.93/1.2 26.3 Detected accidentally Yes hypofibrino- c.124­– genemia 2A>C

Abbreviations: DVT, ; TT, thrombin time

treatment. Deep vein thrombosis and ischemic and thrombosis was 6 and 13.5 per 1000 adult are frequent, but thromboses at unusu­ patient­‑years, respectively.8 About 25% of pa­ al arterial and / or venous sites have also been tients with dysfibrinogenemia reported a mild reported.4,6,13,15 bleeding tendency.8,13 Pregnant women with dys­ Hypofibrinogenemia is often asymptomatic fibrinogenemia can experience recurrent spon­ and diagnosed accidentally, especially when fibrin­ taneous miscarriages in the first trimester of ogen levels are higher than 1 g/l.6 In the remain­ pregnancy, placenta abruption, and postpartum ing patients, the bleeding phenotype predomi­ thrombosis.13 In a large patient cohort, approx­ nates, depending on the fibrinogen level. Spon­ imately 20% of women experienced postpar­ taneous bleeding events, such as heavy periods, tum hemorrhage, and the risk was 6­‑fold higher muscle hematomas, or gastrointestinal bleeding, in women with previous bleeding phenotype.14 occur in approximately 20% of patients with hy­ In about 20% of cases, there is a tendency for pofibrinogenemia, especially when plasma fibrin­ venous and / or arterial thrombosis. The most ogen concentrations do not exceed 0.5 g/l.13 Hy­ classic example is the Dusart Fibrinogen, due pofibrinogenemias are also associated with an in­ to a single base change (C>T) in the Aα­‑chain creased risk of bleeding related to pregnancy, trau­ gene, resulting in the amino acid substitution ma, or surgery.6 It should be noted that in rare Aα 554 Arg>Cys and consequently to the for­ subtypes of hypofibrinogenemia, fibrinogen ­ag mation of very thin fibrin fibers with defective gregates may accumulate in the endoplasmic re­ plasminogen binding.15 Dysfibrinogemia is a rare ticulum of hepatocytes, leading to liver storage cause of inherited thrombophilia (about 0.8%)16 disease of varying severity.13 as compared with deficiencies of natural anti­ Qualitative fibrinogen abnormalities are re­ coagulants, but it cannot be ignored.17,18 There lated to the reduced activity of normal amount is evidence that dysfibrinogenemia can lead to of fibrinogen.8,10 Clinical manifestations are a rare severe complication of pulmonary embo­ heterogeneous. Approximately 55% of patients lism such as thromboembolic pulmonary hy­ are asymptomatic, and about 50% to 60% of pertension.19 Therefore, an extensive fibrino­ patients are diagnosed as part of work­up due gen work­up is suggested by experts in patients to prolonged routine clotting times or reduced with this type of pulmonary hypertension.14,20 functional fibrinogen levels, for example, be­ Prothrombotic mechanisms in dysfibrinogen­ fore invasive procedures or during hospitaliza­ emia may include reduced binding of thrombin tion.6 Remaining patients can present a bleed­ to the abnormal fibrin network, abnormalities ing or / and a thrombotic phenotype. In a large in fibrin polymerization with the formation of cohort of patients with a median follow­‑up of abnormal clot with tendency to fiber fragmenta­ 6 years, the overall incidence of major bleeding tion and impaired fibrinolysis.13,21 A correlation

REVIEW ARTICLE Fibrinogen disorders 915 between genotype and phenotype is best docu­ disease), confirmed by histological examination mented for some dysfibrinogenemias, including (2D subtype) thrombotic­‑related variants (described below).5 Patients with dysfibrinogenemia (type 3 con­ Hypodysfibrinogenemia is the most rarely re­ genital disorder) are distinguished by: ported congenital disorder of fibrinogen. It is as­ 1 Asymptomatic dysfibrinogenemia or dysfi­ sociated with symptoms characteristic of both brinogenemia with bleeding tendencies or occa­ hypofibrinogenemia and dysfibrinogenemia.10 sional thrombosis (subtype 3A), for which there In case of a discrepancy between reduced activ­ is no clear association with the genotype ity and reduced antigen fibrinogen levels, hypo­ 2 Dysfibrinogenemia associated with throm­ dysfibrinogenemia should be suspected.8,10 Post­ bosis (subtype 3B) found in patients carrying partum hemorrhage and heavy menstrual bleed­ a known mutation increasing the risk of thrombo­ ings are particularly frequent, which is why this sis (Fibrinogen Dusart, Caracas V, Ijmuiden, New subtype of anomaly is most often described in York I, Nijmegen, Melun, and Naples in a homo­ symptomatic women.10,13 The largest literature re­ zygous form) or in patients with venous throm­ view published so far, reporting 51 patients diag­ bosis or at an early age with a positive family his­ nosed with hypodysfibrinogenemia, showed that tory of thrombosis in first­‑degree relatives (of the cutoff of 0.7 for the ratio of functional concen­ the same genotype) with no other known cause tration of fibrinogen to its antigen level has a di­ of thrombophilia. agnostic sensitivity of 86%.10 Interestingly, 22% The last group of congenital fibrinogen disor­ of patients with hypodysfibrinogenemia did not ders (type 4) includes patients with hypodysfi­ show clinical manifestations at diagnosis, while brinogenemia classified as: 45% experienced at least 1 benign hemorrhagic 1 Severe hypodysfibrinogenemia with fibrin­ event prior to diagnosis, 30% of of bleedings oc­ ogen antigen of less than 0.5 g/l (subtype 4A) curred during pregnancy, puerperium, and men­ 2 Moderate hypodysfibrinogenemia with fibrin­ strual disorders.10 Overall, 43% of patients in ogen antigen levels between 0.5 and 0.9 g/l (sub­ the studied cohort had at least 1 thromboembol­ type 4B) ic event with a predominance of venous throm­ 3 Mild hypodysfibrinogenemia with fibrino­ bosis over arterial thrombosis (3:1).10 Spontane­ gen antigen levels from 1.0 g/l to a lower limit of ous bleeding associated with fibrinogen abnor­ the reference range (subtype 4C) malities usually occurs at functional fibrinogen This recent classification22 did not include pa­ levels of less than 0.7 g/l.9 tients with an inherited fibrinogen Aα­‑chain mu­ tation that causes amyloidosis and fibrinogen Classification of congenital fibrinogen disorders chain deposition in the kidneys because this fi­ The latest recommendations of the Research Stan­ brinogen variant does not affect routine coagu­ dardization Committee at the International Soci­ lation screening tests.23 ety on Thrombosis and Haemostasis (ISTH) pub­ Regardless of the type of the fibrinogen muta­ lished in 2018 introduced a new classification tion found, it is important to note in all patients: of fibrinogen disorders and a modified diagnos­ age at diagnosis; the circumstances in which tic approach to patients with such a suspicion.22 the disease was diagnosed; similar abnormali­ It has been suggested to classify congenital dis­ ties or symptoms in the family; and the type of orders in fibrinogen based on the clinical and bi­ clinical manifestation (hemorrhagic, with major ological (fibrinogen activity, antigen, and geno­ life­‑threatening bleeding, with recurrent throm­ type) phenotype.22 boembolic events, or with the need for fibrino­ Afibrinogenemia (type 1 congenital fibrino­ gen concentrates).18 gen disorder): 1 Asymptomatic or bleeding patients are clas­ Diagnostic work­up of congenital fibrinogen disor- sified as afibrinogenemia (subtype 1A). ders Diagnosis of congenital fibrinogen disor­ 2 Patients with concomitant thromboembol­ ders is difficult due to the availability of a vast ic events are classified as afibrinogenemia with range of analytical methods and reagents to as­ phenotypic thrombosis (subtype 1B), even if ac­ sess the function of blood coagulation and a large companied by hemorrhagic episodes. number of mutations in the 3 fibrinogen genes Type 2 includes patients with hypofibrinogen­ leading to different protein concentrations.4,16 emia classified as: Traditionally, fibrinogen is the only coagulation 1 Severe hypofibrinogenemia with a function­ factor whose potency is expressed in units of al fibrinogen concentration of less than 0.5 g/l concentration (most commonly in clinical prac­ (subtype 2A) tice as g/l), rather than in activity units like oth­ 2 Moderate hypofibrinogenemia with a func­ er coagulation factors. The measurements of fi­ tional fibrinogen concentration of 0.5 to 0.9 g/l brinogen concentrations are standardized. De­ (subtype 2B) creased fibrinogen concentrations should lead 3 Mild hypofibrinogenemia with a functional ­fi to a suspicion of congenital fibrinogen disorders brinogen concentration from 1.0 g/l to the lower and a further diagnostic evaluation should be per­ limit of the reference range (2C subtype) formed. Of note, a concentration of fibrinogen, 4 Familial hypofibrinogenemia with accumula­ as an acute phase protein, increases in response tion of fibrinogen in the liver (fibrinogen storage to inflammatory diseases, infections, nephrotic

916 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (12) syndrome, during pregnancy, during the use of TT and reptilase time in the presence of con­ oral hormonal contraceptives, or after surgi­ genital fibrinogen disorders are often prolonged, cal interventions, making diagnosis even more but according to the current ISTH guidelines22 challenging and sometimes requiring repeated they should be considered only as additional tests measurements.1,4 in patients due to the limited diagnostic value. Coagulation tests most commonly used in Indeed, even though TT is commonly used by the diagnostic work­up of congenital fibrinogen hematologists as a dysfibrinogenemia screen­ disorders include: 1) prothrombin time (PT), also ing test, results ​​in the reference range (with pro­ automatically expressed in most laboratories as longed reptilase time), as well as prolonged TT, international normalized ratio (INR); 2) activat­ still require measurement of functional fibrino­ ed partial thromboplastin time (APTT); 3) throm­ gen and its antigen level. bin time (TT); 4) assessment of fibrinogen con­ Regardless of the diagnostic algorithm, in or­ centration by the von Clauss method.24 der to establish the definitive diagnosis of in­ Even a single measurement indicating plas­ herited fibrinogen disorders, a detailed analy­ ma fibrinogen concentration of less than1.5 g/l sis of the genes encoding individual fibrinogen should lead to a more extensive diagnostic work­ chains is necessary. Screening for these abnor­ up and, if necessary, genetic testing. The TT assay, malities should be performed in relatives along which is poorly standardized, has the highest di­ with the assessment of the relationship between agnostic sensitivity, although, similarly to PT and the genotype and the clinical phenotype.22 It is APTT, the TT assay has low specificity.25 The mea­ recommended that in quantitative fibrinogen dis­ surement of PT, APTT, functional concentration orders, genetic analysis should start by sequenc­ of fibrinogen, and the level of its antigen should ing FGA gene (exon 4 and 5), because they often constitute the first stage of diagnostic work­up in contain mutations associated with protein func­ a patient suspected of congenital fibrinogen dis­ tion loss.29 The next step should be the analysis orders.22 Determination of the functional concen­ of less commonly mutated exons (FGA, exon 2; tration of fibrinogen by the von Clauss method FGB, exons 2 and 6; and FGG, exons 6 and 8) is based on the measurement of the coagulation and, if necessary, sequencing of the remaining time of poor platelet plasma (by mechanical or exons.29 In dysfibrinogenemia, the first stage of optical methods) after activation with high con­ the diagnostic work­up should be the screening centration thrombin.26 Antigen levels are usually of exon 2 of the FGA gene and exon 8 of the FGG measured using specific antibodies with detection gene.29 Next, exon 5 in FGA, exon 2 in FGB, and by immunodiffusion techniques, immunonephe­ exons 3 and 5 in FGG should be assessed.29 How­ lometry, or immunoturbidimetry.26 ever, nowadays, the next­‑generation sequenc­ If the measurement of fibrinogen antigen is ing (eg, whole-exome sequencing) is being more not available in a given laboratory, the method of cost­‑effective in identifying a causative muta­ choice should be the determination of fibrinogen tion in a rare disease. Standard polymerase chain concentration based on PT (PT­‑derived fibrino­ reaction and Sanger sequencing are still useful gen assay).26 PT­‑derived fibrinogen is an indirect to confirm the molecular anomaly or for famil­ measurement in which the concentration of func­ ial studies. tional fibrinogen can be estimated on the basis of changes in the optical density of plasma, where Management of bleeding in congenital fibrinogen the difference in optical density is proportion­ disorders Treatment of a- or hypofibrinogen­ al to the concentration of fibrinogen compared emia and sometimes dysfibrinogenemia is to pro­ with subsequent dilutions of the standard with vide adequate concentrations of functional fi­ known concentration of this protein.26 Compared brinogen for proper hemostasis by using freshly with the von Clauss assay, this method is sensi­ frozen plasma (FFP), cryoprecipitate, or plasma­ tive to changes in plasma optical density associ­ ‑derived fibrinogen concentrate, with the last be­ ated with slower fibrinopeptide release and for­ ing the best option.5,14 Cryoprecipitate and FFP mation of thicker fibrin fibers.26 Therefore, in pa­ are associated with infusion­‑related adverse re­ tients with dysfibrinogenemia, the PT­‑based mea­ actions, including the risk of fluid overload and surement of fibrinogen concentrations overesti­ transfusion­‑related acute lung injury as a poten­ mates its actual concentration 5­‑fold compared tially fatal adverse event.30 In addition, the use with the von Clauss assay and thus correlates with of FFP and cryoprecipitate is associated with protein levels measured by immunological meth­ the supply of large amounts of other proteins ods.26 It is a common practice to use a cutoff of such as fibronectin, von Willebrand factor, fac­ less than 0.7 for the ratio of fibrinogen measured tor VIII, factor XIII, and macroglobulin.30 Final­ by the von Clauss assay and the antigen or the PT­ ly, both require thawing, which delays the infu­ ‑based method in the diagnosis of dysfibrinogen­ sion of the first dose. Clinical studies have shown emia.19 It should be noted that some variants, for that the risk of transmitting a pathogen by ad­ example, fibrinogen Longmont FGB( Arg166Cys) ministering fibrinogen concentrate is negligible.30 or fibrinogen Bordeaux FGA( Arg439Cys), have Fibrinogen concentrate infusion can be compli­ an apparent decrease in fibrinogen concentration cated by allergic reactions. The formation of an­ measured using the PT­‑based method compared tibodies against this protein have been reported, with the von Clauss assay.22,27,28 but without inhibitory effects.31

REVIEW ARTICLE Fibrinogen disorders 917 The patients who require fibrinogen supple­ of fibrinogen concentrate with a close monitoring mentation should be treated by hematologists of peak and trough fibrinogen levels.34 In wom­ trained in the management of bleeding disor­ en with dysfibrinogenemia and history of recur­ ders. To summarize the key concepts for internal rent miscarriages, fibrinogen supplementation medicine specialists, who may encounter such pa­ could be considered to achieve a functional con­ tients occasionally, it should be highlighted that centration of fibrinogen of around 1 g/l.30 How­ the therapeutic goal based on expert opinions and ever, such a strategy does not guarantee favor­ observational studies is to achieve a functional fi­ able outcomes and the risk of miscarriage, espe­ brinogen concentration (coagulometric method) cially in the first trimester of pregnancy, remains of 1 to 1.5 g/l. The value of 1 g/l is currently con­ significant.30 There are no data showing that he­ sidered the minimal concentration of fibrinogen mostasis is still defective after normalization of to maintain the asymptomatic state in most pa­ fibrinogen concentration in dysfibrinogenemia. tients, based on publication from the European Postpartum hemorrhage is a frequent complica­ Network of Rare Hemorrhagic Diatheses32; how­ tion in women with congenital fibrinogen dis­ ever, some experts suggest a lower target concen­ orders and should be monitored closely. An in­ tration of fibrinogen, that is, 0.5 to 1 g/l. Fibrino­ creased postpartum thrombotic risk has been gen is administrated either on demand in case of reported. An appropriate thromboprophylaxis acute bleeding or surgery, or as prophylaxis in pa­ should be considered in selected women follow­ tients with afibrinogenemia or severe hypofibrin­ ing childbirth.30 ogenemia to prevent bleeding. Long­‑term prophy­ laxis is recommended in patients with afibrino­ Management of thrombosis Occurrence of throm­ genemia and major recurrent bleedings, but such bosis in afibrinogenemia is a clinical conundrum. strategy can also be considered in primary pro­ One hypothesis is that the generation of throm­ phylaxis (ie, before occurrence of first bleeding). bin in a hematoma or during surgery or during Usual infusion strategies, according to the type pregnancy, without the antithrombin action of fi­ of product, are indicated below: brin (ie, acting as a trap for circulating thrombin) 1 On demand: fibrinogen concentrate, 50 to can lead to strong platelet activation and aggrega­ 100 mg/kg; cryoprecipitate, 15 to 20 ml/kg; FFP, tion stimulated by thrombin and endothelial cell 15 to 30 ml/kg.5 injury, which in turn promotes thrombus forma­ 2 As prophylaxis: fibrinogen concentrate, 30 to tion and thromboembolic events in both the ve­ 100 mg/kg of bw every week; cryoprecipitate, 1 nous and arterial systems.35 Thrombosis in such unit 3 times a week or 3 units every 7 to 10 days.5 patients requires simultaneous supplementation The final dosage should be adjusted individually of fibrinogen and administration of anticoagu­ depending on the frequency of bleedings and their lants, most often heparins, with close clinical su­ severity. Isolated cases of unsatisfactory hemosta­ pervision and laboratory monitoring. Oral direct sis with recurrent bleeding at fibrinogen concen­ thrombin inhibitors and antiplatelet agents, in trations of more than 1 g/l have been reported.30 particular vorapaxar, a protease­‑activated recep­ Increased fibrinogen clearance is seen during ma­ tor 1 antagonist, might be considered in afibrino­ jor bleeding, which requires increased fibrinogen genemic patients with recurrent arterial throm­ concentrate dosage with close monitoring. In case boses; however, in most countries, these agents of acute bleeding, it is recommended to admin­ are unavailable and their safety remains contro­ ister fibrinogen based at least on daily monitor­ versial.36 Besides the few thrombotic­‑related dys­ ing.30 can also be administered fibrinogenemic variants, all dysfibrinogenemias in the event of minor bleeding or minor surgery can contribute to an increased thrombotic risk. planned in patients with hypofibrinogenemia or Heparins, precisely low­‑molecular­‑weight hepa­ dysfibrinogenemia with a bleeding phenotype.14 rins, for example, enoxaparin, are the drugs of In women with heavy menstrual bleeding, espe­ choice in treatment of thrombosis in such pa­ cially with hypofibrinogenemia, hormonal agents tients, as vitamin K antagonists cannot be reli­ should be considered in addition to oral tranexam­ ably monitored with INR. The chromogenic assay ic acid during menstrual bleeding. of factor X could be used to determine the correct INR value on in patients with dysfibrin­ Management of pregnant women Pregnancy is ogenemia, in whom the INR cannot be accurate­ a high­‑risk clinical situation in women with con­ ly determined due to interference with the fibrin genital fibrinogen disorders, especially in afibrin­ endpoint in the INR assays.37 The duration of an­ ogenemia. A multidisciplinary approach including ticoagulation depends on the type of thrombosis, an obstetrician, hematologist, and anesthetist, the familial history, and the overall phenotype of preferably in a hemophilia center, is of key im­ a patient. In view of this potential thrombotic portance, and such women should be referred to risk, thromboprophylaxis with heparins should a hemophilia center at the first contact with an in­ be administrated in all clinical settings with an in­ ternist. In women with afibrinogenemia or severe creased thrombotic risk,16 in particular during hypofibrinogenemia, fibrinogen infusion should pregnancy and postpartum.38 be started as soon as possible.33 Increased fibrin­ ogen clearance is observed in the third trimester Key points for internists Due to the rarity of con­ of pregnancy, requiring an increase in the dosage genital fibrinogen disorders, internists are often

918 POLISH ARCHIVES OF INTERNAL MEDICINE 2019; 129 (12) TABLE 2 General considerations for internists managing patients with fibrinogen available and cheap determination of plasma fi­ disorders brinogen concentration using a coagulation assay In afibrinogenemia and severe hypofibrinogenemia, all new symptoms should be should be considered in patients with bleeding in­ considered as bleeding and treated accordingly until additional investigations are cluding persistent minor bleeds and heavy men­ performed. ses, in particular when there is a positive family In afibrinogenemia and severe bleeding, all invasive procedures (including history. Fibrinogen level measurement should be venipuncture) should be avoided and performed only upon approval of hematologist. also considered in pregnancy complications and Nonsteroidal anti­‑inflammatory drugs should be avoided in patients with a bleeding thrombosis without clear risk factors. A patient phenotype and paracetamol should be preferably used. suspected of having afibrinogenemia, hypofibri­ Hormonal contraception should be suggested in afibrinogenemic women and severe nogenemia, or dysfibrinogenemia, with lower ­fi hypofibrinogenemic women with heavy menses. brinogen concentrations (without obvious ac­ Annual visit to a hemophilia center should be organized for all patients with fibrinogen quired cause, for example, disseminated intra­ disorders. vascular coagulation or massive acute thrombo­ Thromboprophylaxis should be considered in patients with dysfibrinogenemia sis), should be referred to a specialist hematolo­ according to recommendations of a given hemophilia center. gy center for further diagnostic work­up including Surgical procedure and pregnancy management should be performed under genetic evaluation and family counselling. Prop­ the guidance of specialized centers dealing with bleeding disorders er management is effective in most patients who manifest bleeding related to fibrinogen disorders, therefore search for this abnormality should be not aware of such a condition. Patients in whom encouraged. In Poland, like in many lower­‑income reduced fibrinogen concentrations are measured countries, congenital fibrinogen disorders are un­ should be referred to hematologists for further derdiagnosed and sparsely reported. Efforts to work­up regardless of the presence or absence of change this situation should be started from in­ any clinical manifestations to establish a defi­ creased awareness of afibrinogenemia, hypofibri­ nite diagnosis. Even if patients with severe fi­ nogenemia, or dysfibrinogenemia among gener­ brinogen disorders are treated in hemophilia al practitioners and internists. centers, internists should recognize signs and symptoms that should require an emergency ARTICLE INFORMATION treatment as well as refer patients and their rel­ ACKNOWLEDGMENTS This work was supported by Jagiellonian Univer- atives suspected of this type of disorders to spe­ sity Medical College (no. N41/DBS/000184; to AU). cialized centers. Internists and general practitio­ CONFLICT OF INTEREST None declared. ners should endorse the management in coop­ OPEN ACCESS This is an Open Access article distributed under the terms eration with the hematologist and treat other of the Creative Commons AttributionNonCommercialShareAlike 4.0 Interna- tional License (CC BY­‑NC­‑SA 4.0), allowing third parties to copy and redis- diseases, for example, influenza or bacterial in­ tribute the material in any medium or format and to remix, transform, and fections, in patients with congenital fibrinogen build upon the material, provided the original work is properly cited, distrib- uted under the same license, and used for noncommercial purposes only. For disorders, being knowledgeable about thrombot­ commercial use, please contact the journal office at [email protected]. ic or bleeding risk. In terms of the management HOW TO CITE Undas A, Casini A. Congenital structural and functional fi- of pain, internists should be aware of the fact brinogen disorders: a primer for internists. Pol Arch Intern Med. 2019; 129: that nonsteroidal anti­‑inflammatory drugs in­ 913-920. doi:10.20452/pamw.15082 hibiting platelet aggregation, for example, aspi­ rin should be avoided in patients with congen­ REFERENCES ital fibrinogen disorders and a bleeding pheno­ 1 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost. 2005; 3: 1894-1904.  type.39 Thienopirydines should not be used in 2 Ząbczyk M, Undas A. Plasma fibrin clot structure and thromboembolism: such patients either. In asymptomatic fibrino­ clinical implications. Pol Arch Intern Med. 2017; 127: 873-881.  gen disorders, the use of antiplatelet agents fol­ 3 Undas A, Zabczyk M. Antithrombotic medications and their impact on fi- lowing acute myocardial infarction or stroke is brin clot structure and function. 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