Disorders of fibrinogen and fibrinolysis

I. Background

Fibrinogen is a large (340 kDa) hexameric glycoprotein expressed by hepatocytes.¹ Fibrinogen is encoded by three different genes (FGA, FGB, and FGG) and assembled as a dimer of trimers, with each half consisting of 3 polypeptide chains known as Aα, Bβ, and γ (Figure 1). These chains are arranged with N-termini in the center of the molecule and C-termini extending outward, and are held together by disulfide bonds. Once secreted, fibrinogen circulates in plasma at a concentration of 200-400 mg/dL, with a half-life of 3-4 days.¹ As an acute phase protein, fibrinogen levels in circulation may increase 2-4-fold during an inflammatory response.

Figure 1. Conversion of fibrinogen to fibrin.

(A) Thrombin cleaves fibrinopeptides on the N-termini of the Aα and Bβ chains, resulting in fibrin monomers

(B) Polymerization of the fibrin monomers occurs between the newly-exposed knobs in the N-termini of the α and β chains (E-domain) of one fibrin monomer and the C-terminal regions of the γ and β chain (in the D-domain) of another fibrin monomer in a half-staggered pattern to form fibrin protofibrils

Fibrinogen plays an important role in both primary and secondary hemostasis. During primary hemostasis, the carboxy-terminal end of the γ chains bind to glycoprotein IIb–IIIa (integrin αIIbβ3) on the surface of activated platelets, leading to platelet aggregation and the formation of a platelet ‘plug’ at the site of tissue injury.² In secondary hemostasis, fibrinogen is converted into fibrin in a stepwise manner.^1,3 First, thrombin cleaves fibrinopeptides on the N-termini of the Aα and Bβ chains, producing fibrin monomers (Figure 1A). Next, polymerization of the fibrin monomers occurs via interactions between the newly exposed N-terminal knobs of the α and β chains (E-domain) of one fibrin monomer and pockets in the C-terminal domains of the γ and β chains (D-domain) of another fibrin monomer. This process results in a half-staggered conformation, forming fibrin protofibrils (Figure 1B). Protofibrils undergo lateral aggregation to produce fibers, which branch to form the fibrin network. The fibrin network becomes crosslinked by activated factor XIII (FXIIIa), which catalyzes the formation of intermolecular ε-N-(γ-glutamyl)-lysyl crosslinks that stabilize and strengthen the structural integrity of the fibrin clot.⁴

A physiologic variant of fibrinogen, fibrinogen γ’ (γA/γ’), occurs due to alternative splicing of the γ-chain mRNA and constitutes about 8% to 15% of overall fibrinogen in plasma.⁵ Fibrinogen γ’ has a complex modulatory effect on thrombin activity. Fibrinogen γ’ binds to thrombin with high affinity, and sequesters thrombin into the fibrin clot, thus reducing the availability of thrombin in plasma (an antithrombin-like activity of fibrinogen γ’). Conversely, the sequestration of thrombin into the fibrin clot protects thrombin against inhibition by antithrombin and heparin.^6,7 Fibrinogen γ’ can also influence fibrin clot architecture. Fibers produced with fibrinogen γ′ have reduced protofibril packing and less compact structures, and fibrin clots containing the γ′ isoform are resistant to lysis.^8–10

During the process leading to fibrin dissolution (fibrinolysis), plasminogen is activated to plasmin by one of the two serine proteases, tPA (tissue-type plasminogen activator) or uPA (urokinase-type plasminogen activator) (Figure 2).¹¹ The binding of tPA and plasminogen to lysine residues on fibrin facilitates plasmin generation.¹² Plasmin then cleaves the fibrin fibers, releasing fibrin degradation products (FDP), including D-dimer.

Figure 2. Overview of the coagulation and fibrinolytic pathways.

The formation of a fibrin clot is the end-point of the coagulation cascade. Subsequent degradation of the fibrin network into fibrin degradation products (FDPs, e.g., D-dimer) is mediated by the fibrinolytic system. Balance between these two pathways is essential in hemostasis, while abnormalities in these pathways may lead to bleeding and/or thrombosis.

FDPs, fibrin degradation products; PAI-1, plasminogen activator inhibitor type 1; TAFI, thrombin activated fibrinolysis inhibitor; TF, tissue factor; tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator

The fibrinolytic system is inhibited by serpins, including plasminogen activator inhibitor-1 (PAI-1) and α₂-antiplasmin (α_2-AP), and a non-serpin inhibitor, thrombin activated fibrinolysis inhibitor (TAFI) (Figure 2).¹¹ PAI-1 is released in high concentrations by endothelial cells, monocytes, hepatocytes, and adipocytes, and rapidly inhibits both tPA and uPA, resulting in their short half-lives in circulation (approximately 4-8 minutes).¹³ α_2-AP is synthesized by hepatocytes and binds to and inactivates plasmin. When plasmin is bound to fibrin, it is protected from inactivation by α_2-AP, thus highlighting complex contributions of fibrin to fibrinolysis. TAFI is activated (TAFIa) by thrombomodulin-associated thrombin, which then cleaves lysine residues on the fibrin clot.¹⁴ This results in a deceleration in plasmin generation, impairment in fibrinolysis and clot stabilization.

II. Clinical laboratory evaluation

a. Fibrinogen

Abnormalities in fibrinogen may be initially suspected with prolongation of common coagulation assays including prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time. However, significant fibrinogen abnormalities are required to affect these assays, so dedicated studies of fibrinogen function and/or concentration are warranted when a fibrinogen disorder is suspected.

The Clauss assay is most commonly used to measure fibrinogen function. It requires mixing of dilute patient platelet-poor plasma with high concentrations of exogenous thrombin (to overcome any abnormalities in endogenous thrombin generation in the plasma), and measures the time to clot formation using a photo-optical system. Using a standard curve, the time is converted to a fibrinogen concentration and reported in grams per liter. Factors that reduce fibrin formation (e.g. heparin, direct thrombin inhibitors) or factors that decrease light transmission (e.g. hyperbilirubinemia, free hemoglobin, lipemia) can lead to inaccurate results.¹⁵

A PT-based assay (PT-Fg) can also be used to measure fibrinogen. In this assay, a PT assay is performed on patient platelet-poor plasma and compared to the PT from a series of plasma dilutions with known fibrinogen concentrations. Because of variability in reagents and instrument calibration, as well as the potential for overestimation of fibrinogen levels in qualitative disorders,¹⁶ routine clinical use of this method is not recommended.¹⁵

Immunological assays are available to measure fibrinogen concentration; this is most commonly performed via an enzyme-linked immunosorbent assay (ELISA). The clinical utility of an immunoassay is primarily in conjunction with the Clauss functional assay to identify discrepancies between fibrinogen concentration and activity, to differentiate between quantitative and qualitative fibrinogen disorders.^15,17

b. Fibrinolysis

Multiple laboratory assays attempt to quantify fibrinolytic function, but assay interpretation and ultimate diagnosis of abnormal fibrinolysis is challenging as no true “gold standard” diagnostic test exists.¹⁸ Here, we focus on the most widely used assays in clinical practice, and conclude with a discussion of other tests that can be considered in specific scenarios.

i. Fibrin(ogen) degradation products and D-dimer

Fibrin(ogen) degradation product (FDP) is a broad term for the protein fragments generated during fibrin or fibrinogen degradation. D-dimer is a specific FDP that contains cross-linked D fragments of the fibrin(ogen) molecule. Measurement of D-dimer is used clinically as an indicator of endogenous activation of the patient’s coagulation system and has been incorporated into diagnostic tools for venous thromboembolism, disseminated intravascular coagulation, and aortic aneurysm.¹⁹ Over 30 different assays are commercially available to measure D-dimer, and there is significant variability in the units reported (fibrinogen equivalent units [FEU], D-dimer units [DDU]) and unit magnitude (μg/mL, μg/L).²⁰ Therefore, clinicians need to be aware of the units reported and the normal range from a given laboratory when using D-dimer thresholds from published literature for clinical decision-making.

ii. Viscoelastic testing

Viscoelastic testing, including thromboelastography^® (TEG^®) and rotational thromboelastometry (ROTEM^®), provide dynamic measurements of clot formation, strength, and resistance to lysis. For both assays, whole blood is placed in a cup with a pin inserted and connected to a detection device (a torsion wire in TEG^®, an optical detector in ROTEM^®). As the pin moves relative to the cup (the cup moves in TEG^®, the pin moves in ROTEM^®), the detection device measures changes in resistance to that movement and creates tracings of those changes over time. Although attempts have been made to define reference ranges for viscoelastic testing,²¹ values reflecting hyperfibrinolysis are not standardized or well defined; published examples are outlined in Table 1. These assays provide point-of-care flexibility, but have significant limitations including operator dependence, lack of standardization, and frequent inter-sample inconsistency.^22,23

Table 1.

Published measures of fibrinolysis using viscoelastic testing

Measurement	Abbreviation	Patient population	Threshold to define accelerated fibrinolysis	Reference
ROTEM ®
Maximum lysis	ML	Post-partum hemorrhage, Trauma	>15%	82, 101
Clot lysis at 30 minutes	LI30	Trauma	≤71%	102
Maximum clot firmness	MCF-EXTEM		≤18mm
Change in maximum clot firmness with addition of fibrinolysis inhibitor	∆MCF-APTEM		>7%
Total clot breakdown	x	Trauma	Within 30 minutes: Fulminant hyperfibrinolysis	103
			Between 30-60 minutes: Intermediate hyperfibrinolysis
TEG ®
Clot lysis at 30 minutes after maximum clot strength	LY30	x	>7.5%	104
		Trauma	≥3%	105
Estimated percent lysis	EPL	Trauma	≥15%	106

ROTEM^®, rotational thromboelastometry; TEG^®, thromboelastography; EXTEM, assay on ROTEM^® that initiates clotting via extrinsic pathway with tissue factor; APTEM, assay on ROTEM^® that initiates clotting via extrinsic pathway with addition of aprotinin

iii. Other laboratory assays to assess fibrinolysis

Assays quantifying individual components of the fibrinolytic pathway are useful in specific clinical scenarios, particularly in diagnosing congenital disorders. These include assays to quantify the concentration and function of PAI-1, t-PA, u-PA, TAFI, and α_2-AP.

Another class of assays measure functional characteristics. These assays rely on changes in the absorbance of plasma (turbidity) over time after initiation of coagulation.^24–25 The euglobulin clot lysis time (ECLT) developed in the 1950s is one of the original assays for global fibrinolysis assessment. A “euglobulin fraction” is created from patient platelet-poor plasma by removing fibrinolysis inhibitors (PAI-1, α_2-AP), while leaving pro-fibrinolytic factors (fibrin[ogen], plasminogen, tPA), so that fibrinolytic activity can be measured.¹⁸ Because this assay is complex and requires multiple processing steps, the ECLT has been largely replaced in clinical practice by TEG and ROTEM. Other plasma-based assays to assess fibrinolytic capacity use tissue factor or thrombin to trigger fibrin formation and t-PA to stimulate clot lysis and measure clot formation and lysis as an increase and subsequent decrease in turbidity.^26,27

III. Disorders of fibrinogen

a. Congenital disorders

i. Diagnosis and clinical manifestations:

Congenital fibrinogen disorders (CFD) are rare and thought to represent about 8% of the rare bleeding disorders.²⁸ CFD occur due to mutations in FGA, FGB or FGB that result in a qualitative and/or quantitative defect in fibrinogen.²⁹ These defects can be diagnosed using the Clauss assay and an antigenic fibrinogen level (as described in Section II.a). Traditionally, CFD were classified according to functional and antigenic fibrinogen levels (italicized in Table 2).³⁰ Recently, the Scientific Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) proposed a reclassification of CFD based on both the fibrinogen levels and clinical presentation.¹⁷ Table 2 shows the reclassification of CFD and its clinical description along with references for more detailed information.

Table 2. ISTH classification of congenital fibrinogen disorders.

Adapted from Casini et al; with permission

Types and subtypes	Clinical presentation and description	Reference
1. Afibrinogenemia (quantitative)	Complete absence of fibrinogen - Bleeding can occur in all tissues, including umbilical stump and muscles - Can uniquely present with spontaneous splenic rupture, poor wound healing, and painful bone cysts - Can present with thrombosis in large arterial and venous vessels	59,107–109
1A. Afibrinogenemia	Afibrinogenemic patients either with a bleeding phenotype or asymptomatic individuals	37
1B. Afibrinogenemia with a thrombotic phenotype	Afibrinogenemic patients with a thrombotic phenotype	36
2. Hypofibrinogenemia (quantitative)	Proportional decrease of functional and antigenic fibrinogen levels - Less symptomatic but can have major bleeding with severe hypofibrinogenemia (i.e., fibrinogen levels <0.5 g/L) - Less thrombotic events than in afibrinogenemia	38,59
2A. Severe hypofibrinogenemia	Functional fibrinogen level <0.5 g/L
2B. Moderate hypofibrinogenemia	Functional fibrinogen level between 0.5 and 0.9 g/L
2C. Mild hypofibrinogenemia	Functional fibrinogen level between 1 g/L and lower limit of normal value
2D. Hypofibrinogenemia with fibrinogen storage disease	Familial hypofibrinogenemia with histologically proven accumulation of fibrin in hepatocytes	110,111
3. Dysfibrinogenemia (qualitative)	Decreased functional and normal antigenic fibrinogen levels - Typically mild mucocutaneous bleed, associated with surgery, trauma or delivery	59
3A. Dysfibrinogenemia	Dysfibrinogenemic patients either with bleeding phenotype or with thrombotic phenotype not fulfilling criteria for dysfibrinogenemia 3B or asymptomatic individuals	31
3B. Thrombotic-related dysfibrinogenemia	Dysfibrinogenemic patients carriers of a thrombotic fibrinogen mutation* or suffering from thrombotic events with a first-degree familial thrombotic history (relatives with the same genotype) without any other thrombophilia	33,35
4. Hypodysfibrinogenemia (qualitative)	Discrepant decrease of functional and antigenic fibrinogen levels - Typically more symptomatic with severe bleeding and thrombosis compared with dysfibrinogenemia	32
4A. Severe hypodysfibrinogenemia	Antigenic fibrinogen level <0.5 g/L
4B. Moderate hypodysfibrinogenemia	Antigenic fibrinogen level between 0.5 and 0.9 g/L
4C. Mild hypodysfibrinogenemia	Antigenic fibrinogen level between 1 g/L and lower limit of normal value

^*Fibrinogen Dusart, Fibrinogen Caracas V, Fibrinogen Ijmuiden, Fibrinogen New York I, Fibrinogen Nijmegen, Fibrinogen Naples at homozygous state, Fibrinogen Melun.

The clinical presentations of patients with CFD are heterogenous, ranging from asymptomatic to bleeding symptoms of varying severity (easy bruising, menorrhagia, epistaxis, post-partum hemorrhage, post-surgical bleed, gastrointestinal bleeding and rarely, intracranial hemorrhage).^31–38 Patients with CFD can also present with thrombotic events, with both arterial and venous thrombosis reported in up to 20% of patients.^39,40 Several factors are thought to contribute to the pathophysiology of thrombosis in patients with CFD, which include the absence/decrease of antithrombin-like properties of fibrinogen γ′ (see Section I) and production of clots with abnormal fibrin structure.

Due to incomplete penetrance, it is not uncommon for individuals with CFD to be diagnosed incidentally during routine coagulation assay testing or to present for evaluation due to a positive family history.³¹ Even so, individuals with CFD who are asymptomatic at the time of diagnosis, especially when diagnosed at a young age, may be at increased risk of future bleeding and/or thrombosis based on the type of CFD.

Women with CFD are also at increased risk of obstetrical complications.⁴¹ A systematic review of 188 pregnancies in 70 women with CFD between 1985 and 2018 found that 43% of pregnancies resulted in miscarriages, with the majority (76%) occurring during the first trimester.⁴¹ Compared to the general population, these women also had higher rates of placental abruption (8% vs 0.5%) and post-partum hemorrhage (19.4% vs 2-3%).⁴¹

ii. Approach to management

1. Acute bleeding event

Due to the rarity of CFD, recommendations for management are largely derived from expert opinion, and are dependent on the patient’s clinical presentation and family history (Table 3).^42–44 Patients presenting with a major bleeding event, regardless of the type of CFD, should receive replacement therapy with fibrinogen derived from human plasma in the form of fresh-frozen plasma (FFP), cryoprecipitate, or virally-inactivated fibrinogen concentrates.^42,43 Expert consensus recommends a target peak fibrinogen level of >150 mg/dL for cerebral bleeding, >100 mg/dL for hemarthrosis and >50 mg/dL for muscular bleeding without compartment syndrome for patients with afibrinogenemia.^43,44 For all other bleeds, a target trough fibrinogen level of >50 mg/dL is recommended until bleeding stops.⁴⁵

Table 3.

Summary of consensus recommendations for target fibrinogen levels depending on type of CFD and clinical situation^{42–44,51,53}

Clinical situation	Consensus recommendation
Acute major bleed	- Cerebral bleeding: >150 mg/dL (peak) - Hemarthrosis: >100 mg/dL (peak) - Muscular bleeding without compartment syndrome: >50 mg/dL (peak) - For all other bleeds: >50 mg/dL (trough) until bleeding stops
Acute minor bleed	Consider anti-fibrinolytic agents*
Surgery, high bleeding risk #	- Pre-operatively: >150 mg/dL (peak) for major procedure or >100 mg/dL (peak) for minor procedure - Post-operatively: >100 mg/dL (trough) until hemostasis is achieved - >50 mg/dL(trough) until wound healing is complete
Surgery, low bleeding risk $	Consider anti-fibrinolytic agents*
Routine prophylaxis	>50 mg/dL(trough)
Pregnancy	- >50-100 mg/dL (trough) once confirmed& - >150-200 mg/dL (trough) at time of delivery

^#Personal bleeding history or has afibrinogenemia

^*Antifibrinolytic agents include tranexamic acid and aminocaproic acid

^$If no personal bleeding history

^&If fibrinogen activity <50 mg/dL or with prior adverse pregnancy outcomes

As both FFP and cryoprecipitate require large volumes to ensure adequate replacement until hemostasis is achieved, fibrinogen concentrates may be a safer option, if available. The FORMA-02 and FORMA-04 studies demonstrated the efficacy and safety of fibrinogen concentrates for on-demand treatment of bleeding and as surgical prophylaxis in patients with congenital afibrinogenemia.^46,47 Currently in the United States, there are 2 concentrated forms of human fibrinogen, RiaSTAP (CSL Behring, Marburg, Germany) and Fibryga (Octapharma US, Inc., Hoboken, N.J.). Both are approved by the Food and Drug Administration for the treatment of bleeding in patients with afibrinogenemia and hypofibrinogenemia, but not dysfibrinogenemia.^48,49 The lack of approval for dysfibrinogenemia is due to the risk that fibrinogen concentrates could potentiate the thrombotic phenotype more commonly seen in dysfibrinogenemia. In a multicenter observational cohort study of 22 patients with CFD who were treated with RiaSTAP, thrombosis of the right cephalic vein was reported in a pregnant patient with dysfibrinogenemia (aged 35 years), who was receiving prophylaxis.⁵⁰ For patients with CFD presenting with mild bleeding events, the use of anti-fibrinolytic agents, such as tranexamic acid, may be sufficient for bleeding cessation.^42,43

2. Surgery

For any surgical procedures, patients with a known history of prior bleeding or those with afibrinogenemia (regardless of personal history of bleeding) should receive prophylactic therapy to achieve a pre-operative peak fibrinogen level of >150 mg/dL for major procedures and >100 mg/dL for minor procedures.^42,43,45,51 Post-operatively, a target fibrinogen level of >100 mg/dL is recommended until hemostasis is achieved and >50 mg/dL until wound healing is complete.⁵¹ For surgical procedures associated with low bleeding risk, persons with CFD without a bleeding history (other than those with afibrinogenemia) may be managed conservatively without prophylactic therapy or consider the use of anti-fibrinolytic agents post-procedure.⁴³

3. Routine prophylaxis

The majority of persons with CFD do not require routine prophylaxis. Expert opinions recommend initiating secondary prophylaxis in patients with afibrinogenemia or hypofibrinogenemia with activity levels <10 mg/dL who suffered a first life-threatening bleed, to maintain a trough fibrinogen level of >50 mg/dL.⁴³ For recurrent non-life-threatening bleeds, initiation of secondary prophylaxis could be considered.^42,43

4. Pregnancy

Due to the high rates of obstetrical complications, it is recommended that women with fibrinogen activity <50 mg/dL or with prior adverse pregnancy outcomes receive prophylaxis with fibrinogen concentrate once pregnancy is confirmed with a target goal of >50-100 mg/dL.^42,43,52 It is generally agreed that the target fibrinogen level should increase throughout the pregnancy, but there is no consensus on the optimal target level. For women with hypofibrinogenemia (fibrinogen levels >50 mg/dL) or dysfibrinogenemia, and no prior adverse pregnancy outcomes, a rationale for using prophylactic fibrinogen concentrates throughout pregnancy is unclear. Generally, in the absence of prior bleeding or clotting history, expectant management is recommended.⁵³ However, it is worth restating that the risk of bleeding, thrombosis, and/or adverse pregnancy outcomes can be unpredictable in patients with CFD, even in the absence of prior complications.⁵⁴

As the pregnancy progresses, trough fibrinogen levels should be monitored at least monthly in afibrinogenemic women, and ultrasound for monitoring fetal and placenta development is recommended.⁴³ For all women with CFD, expert opinions suggest a target fibrinogen level of >150 mg/dL at the time of delivery for vaginal delivery and >200 mg/dL for cesarean sections, and maintained for at least 3 days post-partum.^42,43,53 The efficacy and safety of such a strategy was demonstrated in a single-center case series of 12 full-term pregnancies in 11 women with hypofibrinogenemia (mean pre-pregnancy fibrinogen level 72 mg/dL). All 11 women received fibrinogen concentrates during labor and delivery, and reported no obstetrical complications peri and postpartum.⁵⁵

Additionally, depending on the patient’s thrombotic history and other risk factors for VTE (e.g. obesity, family history, cesarean section), postpartum thromboprophylaxis should be considered in patients with CFD.

5. Thrombotic events

Patients with afibrinogenemia can present with thrombosis, as these patients lack the protective antithrombin-like activity of fibrinogen γ′. As such, it is recommended that fibrinogen concentrates be started concomitantly with the introduction of anticoagulation therapy in these patients. For arterial thrombotic events that require anti-platelet agents, concomitant fibrinogen concentrates are typically not indicated in patients with afibrinogenemia but can be considered if bleeding occurs.⁴³ For patients with hypofibrinogenemia or dysfibrinogenemia who present with VTE, anticoagulation alone is typically sufficient.

In terms of choice of anticoagulation, the use of low-molecular-weight-heparin is favored over the use of vitamin K antagonist due to the difficulty in monitoring the International Normalized Ratio (INR) when the baseline PT is prolonged.⁴³ Data on the use of direct oral anticoagulants in CFD are sparse, although some experts are open to this possibility.^43,56,57 Duration of anticoagulation therapy should be similar to guidelines for management of VTE in the general population.⁵⁸

Regardless of the type of CFD, thromboprophylaxis with low-molecular-weight heparin should be considered in high-risk clinical situations, such as surgery, or when fibrinogen concentrate is given, taking into consideration the patient’s personal and family history of bleeding and thrombosis.^33,59

b. Acquired disorders

i. Diagnosis and clinical manifestations:

Acquired fibrinogen disorders (typically hypofibrinogenemia) can present due to a consumptive coagulopathy (e.g. disseminated intravascular coagulopathy [DIC]) or trauma-induced coagulopathy (e.g. hemodilution after blood loss with volume replacement).^60–62 Liver disease can also result in hypofibrinogenemia due to reduced liver synthetic function or dysfibrinogenemia. Other causes of acquired fibrinogen disorders include medications (e.g. L-asparaginase), malignancy (e.g. multiple myeloma), the use of plasma exchange using albumin as a replacement fluid and auto-immune conditions resulting in anti-fibrinogen antibodies (e.g. rheumatoid arthritis and systemic lupus erythematosus).^63–66 Similar to CFD, patients with acquired fibrinogen disorders can be asymptomatic or present with either bleeding and/or thrombotic events. The heterogeneity in clinical manifestation is dependent on the etiology of the acquired fibrinogen disorder and whether other coagulation factors (both procoagulant and anticoagulant) are affected.

Acquired fibrinogen disorders may be suspected with a prolonged PT and PTT, and subsequently confirmed with an assay documenting a low fibrinogen level. However, since fibrinogen is an acute phase protein, the fibrinogen level may be within the normal range in acquired fibrinogen disorders. The term ‘relative fibrinogen deficiency’ maybe a more accurate description for hypofibrinogenemia in clinical situations where a normal range fibrinogen level actually represents a clinically relevant acquired fibrinogen disorder.⁶⁷

ii. Approach to management

In acquired fibrinogen disorders, management typically depends on the etiology. For patients in DIC with hypofibrinogenemia, adequate treatment of the underlying cause usually leads to resolution of the acquired fibrinogen disorder. Routine prophylactic use of fibrinogen replacement therapy based on low fibrinogen levels alone is not recommended. However, if there is active bleeding or a need for an invasive procedure, fibrinogen replacement therapy can be given to maintain fibrinogen levels >150 mg/dL.⁶¹

In patients with trauma-induced coagulopathy with major bleeding and hypofibrinogenemia, the guidelines recommend treatment with fibrinogen concentrate or cryoprecipitate to keep levels >150 mg/dL, with repeated doses as needed.⁶⁸ The use of FFP for the treatment of hypofibrinogenemia is not recommended due to the unpredictable amount of fibrinogen in FFP.⁶⁸

As the liver is the site of production of the majority of coagulation factors, patients with liver disease typically present with impaired hemostasis from multiple coagulation factor deficiencies, in addition to hypofibrinogenemia and/or dysfibrinogenemia. Depending on the hemostatic defect, various procoagulant therapies can be used, including FFP, cryoprecipitate, platelets, recombinant factor VIIa, and prothrombin complex concentrates. The clinical rationale for each procoagulant is outside the scope of this review. In the setting of an acquired fibrinogen disorder from liver disease, routine correction of fibrinogen is not typically recommended.⁶⁹ However, in the presence of active bleeding or an invasive procedure, cryoprecipitate (favored over FFP to avoid the large volume load and adverse effect on portal pressure) is recommended to maintain a fibrinogen level >100 mg/dL.⁶⁹

IV. Disorders of enhanced fibrinolysis or clot instability

a. Diagnosis and clinical manifestations:

Patients with enhanced fibrinolysis characteristically present with “delayed bleeding,” meaning initial hemostasis is obtained after trauma or an invasive procedure (surgery, dental extraction), but bleeding develops hours later due to enhanced dissolution of the fibrin clot. Patients may also present with bleeding at sites with inherent increased fibrinolytic activity including the uterus (heavy menstrual bleeding), nares (epistaxis), and genitourinary tract (hematuria). Diagnosis is challenging and may be frequently missed, as standard laboratory measurements of hemostasis appear normal and dedicated testing (as outlined in II. Laboratory Evaluation) is required.

i. Congenital disorders

Congenital disorders due to an inherited absence or dysfunction of components of the fibrinolytic pathway can result in enhanced fibrinolysis (Figure 2). An overview of the diagnosis and clinical manifestations of these rare disorders is presented in Table 4 along with references that provide more detailed information.

Table 4.

Congenital disorders of fibrinolysis

Disorder	Inheritance pattern	Subtypes	Diagnostic testing	Clinical presentation	Management	Reference
α2-AP deficiency	Autosomal recessive	-Type I: Quantitative -Type II: Qualitative	- Antigen and activity levels	- Heterozygous: Asymptomatic, rare bleeding with procedures/trauma - Homozygous: Severe bleeding, intramedullary hematomas	- Antifibrinolytic agents - Fresh-frozen plasma	70
PAI-1 deficiency	Autosomal recessive	- Quantitative - Qualitative	- Antigen and activity levels - Free tPA antigen	Mild-to-moderate bleeding, heavy menstrual bleeding, miscarriage, delayed bleeding after injury/surgery	Antifibrinolytic agents	76
uPA excess, QPD	Autosomal dominant		- Platelet count (low in 50%) - PLAU duplication mutation testing	Variable phenotypes within families but severe bleeding and spontaneous hematomas possible	Antifibrinolytic agents	78

α_2-AP, α₂-antiplasmin; PAI-1, plasminogen activator inhibitor type 1, tPA, tissue plasminogen activator; uPA, urokinase plasminogen activator; QPD, Quebec Platelet Disorder

α_2-AP deficiencies are autosomal recessive and can be quantitative (type I) or qualitative (type II), permitting unregulated plasmin activity.^70,71 Patients with homozygous deficiency have severe bleeding phenotypes post-procedure or trauma, heavy menstrual bleeding, and intramedullary hematomas. Individuals with heterozygous deficiency are predominantly asymptomatic, although cases of bleeding complications have been reported with invasive procedures or trauma.⁷² Testing for abnormalities requires both determination of antigen concentration to identify type I deficiencies, as well as functional assays that measure the inhibitory activity of plasmin to identify type II abnormalities; activity levels <60% predict accelerated fibrinolysis with clinical bleeding in patients with acquired deficiencies.⁷³

Similarly, PAI-1 deficiency is autosomal recessive and can be quantitative or qualitative, leading to excess fibrinolysis due to lack of inhibition of tPA and uPA. In addition to bleeding post-procedures, heavy menstrual bleeding, and post-partum hemorrhage, PAI-1 deficiency is associated with a significant risk of miscarriage and preterm birth.⁷² Diagnosis requires measurement of PAI-1 antigen and activity, but both assays have important limitations.^72,74 PAI-1 antigen exhibits diurnal variation and therefore should be drawn in the morning.⁷⁵ PAI-1 activity assays are calibrated to detect increased rather than decreased activity and therefore cannot reliably identify pathologically low activity;⁷⁶ low PAI-1 activity levels (<1.0 IU/mL) have been reported in 10% of healthy volunteers.⁷⁷ Measurement of increased tPA activity can be helpful to confirm PAI-1 deficiency, although normal tPA activity does not exclude the diagnosis.⁷²

Quebec Platelet Disorder is a rare autosomal dominant condition that results in gain of function of uPA and thrombocytopenia. Severity of bleeding manifestations vary, with some patients developing spontaneous hemarthrosis in addition to other characteristic bleeding symptoms of enhanced fibrinolysis.⁷⁸ Standard coagulation testing and serum uPA assays may be normal because in some cases, uPA concentration is increased in platelet granules but not in serum. Therefore, diagnosis requires dedicated genetic testing for PLAU duplication mutations in patients with strong family history.⁷⁹

ii. Acquired disorders

Acquired disorders such as DIC and trauma can result in decreased clot stability and/or enhanced fibrinolytic activity and lead to severe bleeding phenotypes.

DIC can manifest with thrombosis, bleeding, or a combination of the two;⁸⁰ a bleeding-predominant phenotype due to accelerated fibrinolysis is characteristically seen in acute promyelocytic leukemia (APL)⁸¹ and post-partum hemorrhage.^82,83 Trauma induces variable degrees of fibrinolysis, with increased fibrinolytic activity associated with worse clinical outcomes.⁸⁴ Iatrogenic interventions such as the extracorporeal circuit in cardio-pulmonary bypass increase fibrinolysis and can result in bleeding,⁸⁵ while enhanced fibrinolysis is leveraged with the use of exogenous tPA for thrombolysis in pulmonary embolism, stroke, and other thrombotic disorders.

b. Approach to management

In patients with congenital or acquired enhanced fibrinolysis or clot instability, management of the contributing disorder is essential and often most effective to resolve the abnormality. In congenital disorders or when an acquired cause cannot be resolved, management hinges on the use of anti-fibrinolytic agents, which can decrease bleeding, reduce need for blood products, and improve clinical outcomes. The unique management of individual congenital disorders is presented in Table 4.

The two most widely used anti-fibrinolytic agents are tranexamic acid (TXA) and ε-aminocaproic acid (EACA). Both TXA and EACA are synthetic lysine analogs that inhibit fibrinolysis by displacing plasminogen from fibrin at the lysine binding site of plasminogen. TXA and EACA can both be given orally or via continuous intravenous infusion, but TXA can also be given as a single intravenous bolus or used topically.

Anti-fibrinolytic agents have shown significant benefit in multiple clinical scenarios in which accelerated fibrinolysis or decreased clot stability contributes to increased bleeding, including trauma⁸⁶ and post-partum hemorrhage.⁸⁷ Guidelines recommend early administration (within 3 hours) of TXA for all trauma patients regardless of laboratory measures of fibrinolysis.⁶⁸ In post-partum hemorrhage, TXA is recommended for all patients with refractory atonic bleeding or persistent trauma-related bleeding.⁸⁸ Although 1g TXA is used most commonly, lower dose TXA meets pharmacokinetic and pharmacodynamic metrics and may be effective for prophylaxis.⁸⁹ Empiric use of anti-fibrinolytics has also been recommended in specific surgical scenarios to decrease transfusion requirements including cardiac⁹⁰ and orthopedic surgery.⁹¹ Dosing varies significantly in published trials and for each indication, with dominant examples outlined in Table 5.

Table 5:

Dosing of antifibrinolytic agents in specific clinical scenarios

Indication	EACA	TXA
Trauma	x	1g bolus within 8h of injury followed by 1g infusion over 8h86
Post-partum hemorrhage	x	1g bolus with second 1g bolus if continued bleeding after 30m or re-bleeding within 24h87
Cardiac surgery	100 mg/kg bolus to patient, 5 mg/kg to CPB prime, followed by continuous infusion of 30 mg/kg during surgery 94	High dose: 30 mg/kg bolus to patient, 2 mg/kg to CPB prime, followed by continuous infusion of 16mg/ kg during surgery94 Low dose: 10mg/kg bolus to patient, 1-2 mg to CPB prime, followed by continuous infusion of 1mg/kg during surgery 94
Orthopedic surgery	THA, TKA: 5 g bolus if <50 kg, 10 g bolus if >50 kg 112 113	THA: 10-30 mg/kg +/− repeat bolus or infusion 95; 1 g bolus112 TKA: 1g bolus113
Heavy menstrual bleeding	x	1g PO four times daily on days 1-4 114; 1.3 g PO three times daily for up to 5 days with adjustment for creatinine >/ 1.4 mg/dL115

EACA, ε-aminocaproic acid; TXA, tranexamic acid; CPB, cardio-pulmonary bypass; PO, oral administration; THA, total hip arthroplasty; TKA, total knee arthroplasty; x, no trials or recommendations identified

Importantly, there are also published examples that challenge the broad efficacy of anti-fibrinolytics in improving outcomes in patients with excessive bleeding. For example, in a randomized trial of TXA (1g intravenous loading dose followed by 3g infusion over 24 hours) versus placebo in patients with acute gastrointestinal bleeding, TXA did not improve bleeding-related mortality.⁹² As a result, widespread empirical use of anti-fibrinolytic agents in the absence of trial data is discouraged.

The majority of patients tolerate anti-fibrinolytic agents without complications. However, studies have raised concern about seizure risk with TXA in cardiac surgery,⁹³ potentially due to structural similarities with gamma-aminobutyric acid (GABA) and/or glycine neurotransmitters. It is unclear if seizure contributes to increased mortality, and the limited data available suggest no long term neurologic sequelae in patients after a seizure event.⁹⁴ There are also concerns about the potential for anti-fibrinolytics to increase risk of thrombosis. Clinical trials do not consistently demonstrate an increased incidence in venous thromboembolism.^86,87,95 although risk may be increased in some populations⁹⁶ and with specific dosing strategies.⁹² This has been a particular concern for VTE risk in women with refractory heavy menstrual bleeding who are also receiving combined hormonal contraceptives, but clinical experience continues to suggest the combination is safe and effective in women without an inherited thrombophilia or history of thrombosis.^97,98

Topical TXA can also be considered in certain clinical scenarios. A meta-analysis in primarily surgical patients suggests that topical TXA reduces bleeding and blood transfusions, but the analysis raised concern about potential thrombotic risks which could not be quantified.⁹⁹ Data on epistaxis is unclear, with some suggestion of benefit, but limited by a lack of recent robust randomized controlled trials since new techniques in nasal cauterization, packing, and others have been incorporated.¹⁰⁰

V. Conclusion

Congenital and acquired disorders in fibrinogen concentration and/or function can increase the risk of bleeding and/or thrombosis, reflecting the complex role of fibrin(ogen) in coagulation and the fibrinolytic system. Depending on the clinical situation, fibrinogen concentrates may be used to achieve hemostatic control in congenital and acquired fibrinogen disorders. Global fibrinolysis assays are increasingly being used in clinical practice, yet due to their significant limitations, disorders involving clot instability and enhanced fibrinolysis remain challenging to diagnose. Antifibrinolytics remain the mainstay of treatment for both congenital and acquired disorders of enhanced fibrinolysis.

Synopsis.

Fibrinogen plays a fundamental role in coagulation through its support for platelet aggregation and its conversion to fibrin. Fibrin stabilizes clots and serves as a scaffold and immune effector before being broken down by the fibrinolytic system. Given its importance, abnormalities in fibrin(ogen) and fibrinolysis result in a variety of disorders with hemorrhagic and thrombotic manifestations. This review summarizes (i) the basic elements of fibrin(ogen) and its role in coagulation and the fibrinolytic system, (ii) the laboratory evaluation for fibrin(ogen) disorders, including the use of global fibrinolysis assays, and (iii) the management of congenital and acquired disorders of fibrinogen and fibrinolysis.

Key points.

• Disorders in fibrinogen concentration and/or function can increase the risk of bleeding and/or thrombosis.

• Depending on the clinical situation, fibrinogen concentrates may be used to achieve hemostatic control in fibrinogen disorders.

• Disorders of fibrinolysis can be congenital or acquired secondary to various clinical situations including trauma, malignancy, or sepsis.

• Antifibrinolytics are a mainstay of treatment for hyperfibrinolysis.

Clinics Care Points.

• Disorders in fibrinogen concentration and/or function can increase the risk of bleeding and/or thrombosis.

• Depending on the clinical situation, fibrinogen concentrates may be used to achieve hemostatic control in fibrinogen disorders.

• Disorders of fibrinolysis can be congenital or acquired secondary to various clinical situations including trauma, malignancy, or sepsis.

• Antifibrinolytics are a mainstay of treatment for disorders of enhanced fibrinolysis.