Inherited Disorders of the Fibrinolytic Pathway: Pathogenic Phenotypes and Diagnostic Considerations of Extremely Rare Disorders

Abstract

Fibrinolysis is initiated by the activation of plasminogen to plasmin via tissue-plasminogen activator (tPA) and urokinase-plasminogen activator (uPA); plasmin then converts fibrin to fibrin degradation products (FDPs). The antifibrinolytics counterbalancing this system include plasminogen activator inhibitor-1 (PAI-1), which inhibits tPA and uPA, α-2 antiplasmin (α₂AP), which inhibits plasmin, and thrombin activatable fibrinolysis inhibitor, which inhibits the conversion of fibrin to FDP. Inherited disorders of the fibrinolytic pathway are rare and primarily have hemorrhagic phenotypes in humans: PAI-1 deficiency, α₂AP deficiency, and Quebec platelet disorder. Patients with these disorders are usually treated for bleeds or receive prophylaxis to prevent bleeds in the surgical setting, with pharmacological antifibrinolytics such as aminocaproic acid and tranexamic acid. Disorders of the fibrinolytic pathway with fibrin deposition are extremely rare, mostly noted in patients with plasminogen deficiency, who have more recently benefited from advances in human plasma-derived plasminogen concentrates administered intravenously or locally. These disorders can be very difficult to diagnose using conventional or even specialized coagulation testing, as testing can be nonspecific or have low sensitivity. Testing of the corresponding protein's activity and antigen (where applicable) can be obtained in specialized centres, and routine laboratory measures are not diagnostic. Genetic testing of the pathogenic mutations is recommended in patients with a high suspicion of an inherited disorder of the fibrinolytic pathway.

 

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Keywords

fibrinolysis - plasminogen activators - PAI-1 - α-2 antiplasmin - plasminogen deficiency

Fibrinolysis is the regulatory pathway of the hemostatic system that serves to counterbalance the prothrombotic pathway.[1] Fibrinolysis facilitates the breakdown of the fibrin clot, a structure comprised of the platelet plug and fibrin that is crosslinked by factor XIII (FXIII). The primary fibrinolytic agent is plasmin, which is activated from circulating plasminogen by tissue-plasminogen activator (tPA) and urokinase-plasminogen activator (uPA). Plasmin has a direct fibrinolytic effect on the fibrin clot. Further regulation of the fibrinolytic pathway itself occurs via the antifibrinolytic system with multiple inhibitors, namely plasminogen activator inhibitor-1 (PAI-1), α-2 antiplasmin (α₂AP), and thrombin-activatable fibrinolysis inhibitor (TAFI). Disequilibrium of the profibrinolytic and antifibrinolytic system can lead to clinically significant manifestations in patients, as will be discussed in this review.

Pathophysiology

A summary of the involved profibrinolytics and antifibrinolytics is shown in [Tables 1] and [2], with the fibrinolytic pathway shown in [Fig. 1].

Table 1 Characteristics of profibrinolytics: plasminogen, plasmin, tPA, and uPA

	Plasmins		Plasminogen activators
	Plasminogen	Plasmin	tPA	uPA
Form	Proenzyme in two forms: Glu-plasminogen and Lys-plasminogen	Serine protease	Serine protease	Serine protease
Synthesis	Liver (primary)	From plasminogen, cleaved by tPA or uPA	Endothelial cells	Renal epithelial cells
Size	88.4 kDa	Two-chain structure: 54.4 kDa (heavy chain) + 25.2 kDa (light chain)	70 kDa	53 kDa
Biologic half-life	Glu-plasminogen: 2–2.5 d Lys-plasminogen: 0.8 d	100 ms	3 min	9–16 min
Activated/potentiated by	Fibrin	Plasminogen	tPA is converted to its active form by plasmin	uPA is converted to its active form by plasmin
Effect	Converted to plasmin by tPA and uPA	Cleaves fibrin into FDP	Converts plasminogen to plasmin	Converts plasminogen to plasmin
Inhibited by	No known direct inhibitor in the native state	Primary: α2AP. Secondary: α2M and C1-inh	PAI-1, PAI-2	PAI-1, PAI-2

Abbreviations: α₂AP, α-2 antiplasmin; α2M, α-2 macroglobulin; C1-inh, C1 esterase inhibitor; FDP, fibrin degradation products; PAI-1, plasminogen activator inhibitor 1; PAI-2, plasminogen activator inhibitor; tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator.

Table 2 Characteristics of antifibrinolytics: PAI-1, α₂AP, and TAFI

	PAI-1	α2AP	TAFI
Form	Serine protease inhibitor	Serine protease inhibitor	Proenzyme
Synthesis	Megakaryocytes, endothelial cells, and other cells	Liver	Liver
Size	45–50 kDa	51 kDa	56 kDa
Biologic half-life	2 h	2–6 d	10 min
Activated/potentiated by	Normal clotting process	Formation of plasmin	Activated by the thrombin-thrombomodulin complex to the active form, TAFIa
Effect	Inhibits tPA and uPA	Inhibits plasmin	Inhibits fibrin
Inhibited by	uPA	No known direct inhibitor in the native state	No known direct inhibitor in the native state

Abbreviations: α₂AP, α-2 antiplasmin; PAI-1, plasminogen activator inhibitor 1; TAFI, thrombin-activatable fibrinolysis inhibitor; tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator.

Fig. 1 Profibrinolytics and antifibrinolytics of the hemostatic system. α₂AP, α-2 antiplasmin; FDP, fibrin degradation products; PAI-1, plasminogen activator inhibitor 1; TAFI, thrombin-activatable fibrinolysis inhibitor; TAFIa, activated TAFI; tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator (Created in BioRender. Abou-ismail, Y. (2025) https://BioRender.com/z06b055).

 

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Profibrinolytics

Plasminogen and Plasmin

Plasminogen is a proenzyme (inactive precursor enzyme) that is primarily synthesized by the liver.[2] This 88.4 kDa protein[3] is present in two forms: Glu-plasminogen and Lys-plasminogen,[4] which have a half-life of 2 to 2.5 and 0.8 days, respectively.[5] Plasminogen itself is activated by fibrin: when fibrin is formed, it exposes lysine binding sites, which binds to plasminogen and leads to its unfolding.[6] This unfolding allows for plasminogen's cleavage by tPA and uPA into the activated two-chain serine protease plasmin.[7]

Plasmin consists of a 54.4 kDa heavy chain and 25.2 kDa light chain[3] and its main effect is the cleavage of fibrin into fibrin degradation products (FDPs). Plasmin is primarily inhibited by α₂AP, and secondarily by α-2 macroglobulin (α2M)[8] and C1 esterase inhibitor.[9] The half-life is 100 ms[10] due to α₂AP's potent effect.

 

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Tissue-Plasminogen Activator and Urokinase-Plasminogen Activator

The plasminogen activators (PA), tPA and uPA, are serine proteases synthesized primarily in vascular endothelial cells[11] and renal epithelial cells,[12] respectively. tPA is 70 kDa[13] with a half-life of 3 minutes[14] and uPA is 53 kDa[15] with a half-life of 9 to 16 minutes.[4] They activate plasminogen into plasmin, potentiating the fibrinolytic pathway, with plasmin further converting the inactive form of these PAs into their active form. They are inhibited by PAI-1 and plasminogen activator inhibitor-2 (PAI-2).

 

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Antifibrinolytics

Plasminogen Activator Inhibitor-1

PAI-1 is more potent in inhibiting the PAs than PAI-2.[16] This 45 to 50 kD single-chain serine protease inhibitor[17] has a half-life of 2 hours.[18] PAI-1 binds to tPA or uPA forming an inactive complex that halts fibrinolysis.[19] PAI-1 also has additional effects related to tissue fibrosis, atherosclerosis, and tumorigenic function with evolving understanding.[20]

 

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Alpha-2 Antiplasmin

This serine protease inhibitor,[21] α₂AP, is primarily synthesized in the liver, weighing 51 kDa with a half-life of 2 to 6 days.[22] Its antifibrinolytic effects occur via two main mechanisms: formation of the plasmin–antiplasmin (PAP) complex and binding within a thrombus. In the first, α₂AP binds to lysine binding sites on plasmin[23] (that fibrin would bind to leading to propagation of fibrinolysis), leading to an inactive PAP complex that directly halts plasmin's fibrinolytic activity.[22] [24] In the second mechanism, it is bound by FXIII to fibrin within a thrombus, thereby halting plasmin's ability to exert its effect on fibrin.[22] [24]

 

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Thrombin-Activatable Fibrinolysis Inhibitor

Unlike the serine protease inhibitors PAI-1 and α₂AP, TAFI is a proenzyme, which is activated by the thrombin-thrombomodulin complex to the active form, TAFIa.[25] TAFIa removes lysine binding sites on fibrin that plasminogen would bind to,[26] thereby halting fibrinolysis. TAFI is synthesized in the liver, weighing 56 kDa.[27]

 

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Inherited Disorders of the Fibrinolytic Pathway

[Table 3] reviews the inherited disorders of the fibrinolytic pathway with clinical implications. Interestingly, the most clinically significant manifestations of these inherited disorders primarily lead to increased fibrinolysis and thus bleeding. Additional phenotypes have been observed in mice models, particularly with increased thrombotic risk, fibrin deposition, and/or clot lysis related to congenital deficiencies in tPA, uPA, and TAFI[17] [28]—these have not been observed in humans, although genetic polymorphisms have been noted with thrombotic phenotypes in humans.[28]

Table 3 Inherited disorders of the fibrinolytic pathway

Phenotype	Hemorrhagic phenotype			Thrombotic/fibrin deposition phenotype
Disorder	PAI-1 deficiency	α2-AP deficiency	Quebec platelet disorder	Plasminogen deficiency
Defect	Deficiency	Deficiency	Gain of function	Deficiency
Genetic defect	SERPINE1 gene	SERPINF2 gene	PLAU gene	PLG gene
Inheritance	AR	AR	AD	AR
Pathophysiology	tPA and uPA abundance	Plasmin abundance	uPA abundance in platelets leading to increased plasminogen activation	Plasminogen deficiency
Prevalence	Unknown	Unknown	Estimated: Canada: 1 in 655,000. Quebec: 1 in 220,000	1.6 per million
Clinical presentation	Hemorrhagic: Menorrhagia Postsurgery Posttrauma Postdental extraction Epistaxis/ecchymoses Hemorrhagic ovarian apoplexy Hemarthrosis CNS bleeding Gingival bleeding GI bleeding Subhyaloidal hemorrhage Hematuria Umbilical bleeding Obstetric complications (including prematurity and miscarriage)	Hemorrhagic: Menorrhagia Posttrauma Postdental extraction Postsurgery Epistaxis/ecchymoses Intramedullary hematoma Hematoma Hemarthrosis Umbilical bleeding Hematuria Renal bleeding CNS bleeding Tongue bleed Hemothorax Obstetric complications	Hemorrhagic: Postdental extraction Posttrauma Epistaxis/ecchymoses Prolonged wound healing Postsurgery Hematuria Menorrhagia Hemarthrosis	Ligneous conjunctivitis Ligneous gingivitis Congenital occlusive hydrocephalus Juvenile colloid milium Impaired wound healing Infertility Involvement of: • Respiratory tract (e.g., ligneous laryngitis) • Middle ear • Female genital tract (e.g., ligneous vaginitis) • GI tract • Renal
Homozygous state	Severe bleeding	Severe bleeding	Incompatible with life	Homozygous and compound heterozygous exhibit similar manifestations
Heterozygous state	Asymptomatic	Asymptomatic or mild bleeding	Variable
Recommended diagnostic tests	• PAI-1 activity and antigen • SERPINE1 pathogenic mutation	• α2-AP activity and antigen • SERPINF2 pathogenic mutation	• Platelet function testing • PLAU pathogenic mutation	• Plasminogen activity and antigen • PLG pathogenic mutation
Treatment	Antifibrinolytics	Antifibrinolytics Desmopressin is contraindicated	Antifibrinolytics. No role for platelet transfusion	• Local or IV FFP • Local or IV plasminogen concentrate • Hormonal therapy • Steroids
Surgical precautions	Antifibrinolytic prophylaxis	Antifibrinolytic prophylaxis	Antifibrinolytic prophylaxis	Plasminogen concentrate/FFP

Abbreviations: α₂AP, α-2 antiplasmin; AR, autosomal recessive; AD, autosomal dominant; CNS, central nervous system; FFP, fresh frozen plasma; GI, gastrointestinal; IV, intravenous; PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen activator; uPA, urokinase-type plasminogen activator.

 

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Disorders with Hemorrhagic Phenotype

Although these disorders are extremely rare, they are likely underreported because their diagnosis requires expert recognition, necessitated by both a high degree of suspicion and specialized testing. Nonspecific testing modalities are discussed in the Additional Laboratory Evaluation section, with results that are nonspecific or have low sensitivity. Directed testing of antigen/activity and/or the known genetic mutation is most likely to assist with diagnosis. Nonetheless, more common diagnoses with bleeding diatheses such as von Willebrand disease, procoagulant factor deficiencies, and platelet function disorders should be ruled out prior to pursuing these diagnoses. The primary treatment is the use of antifibrinolytics such as tranexamic acid and aminocaproic acid, which blocks the binding of plasminogen to fibrin, thus stabilizing the formed thrombus.[29] For individuals with hematuria as a clinical manifestation, antifibrinolytics should be avoided due to the concern for thrombus stabilization leading to renal obstruction, although the available evidence is weak.[30]

Plasminogen Activator Inhibitor-1 Deficiency

PAI-1 deficiency is an autosomal recessive disorder with severe bleeding noted in the homozygous state that is primarily postprocedural, along with abnormal uterine bleeding in girls and women. Obstetric complications are also common, with a quarter of women reporting miscarriages and half with premature births.[31] Heterozygous individuals can have minor bleeding concerns but are generally asymptomatic. Antifibrinolytics are the primary treatment and prophylactic measures have been used to prevent obstetric complications.[32]

Testing for PAI-1 deficiency should include measurements of antigen and activity, to differentiate between those with quantitative or qualitative defects. Patients with quantitative defects have both low activity and low antigen, but those with qualitative defects have low activity with normal antigen—thus, obtaining a PAI-1 antigen alone may lead to a missed diagnosis in patients with qualitative defects.[33] In addition, PAI-1 antigen and activity have a diurnal pattern, with higher levels noted in the morning,[34] thus levels for testing should be drawn early in the day. Establishing the diagnosis can be difficult due to low PAI-1 activity being defined as <1.0 U/mL[35]; however, many laboratory assays report normal ranges that can start from 0 U/mL, as they are primarily used to report elevations in PAI-1.[36] Concurrent measurement of the PAP complex, which is a marker of in vivo plasminogen activation (and thus fibrinolysis), has shown to be negatively correlated with PAI-1 levels.[37] Thus, patients with low PAI-1 activity, in the setting of a bleeding phenotype, are more likely to have elevated PAP, noting the difficulty in counterbalancing ongoing fibrinolysis.

An alternate testing modality, which can also be used for confirmation purposes in the setting of biochemical testing, is identification of the SERPINE1 pathogenic variant.[36]

 

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α-2 Antiplasmin Deficiency

Previously known as Miyasato disease, α₂AP deficiency is the most commonly reported inherited disorder of the fibrinolytic pathway, with the literature reporting 14 patients that are homozygous and 104 that are heterozygous.[31] This autosomal recessive deficiency leads to decreased plasmin inhibition, thus potentiating the fibrinolytic pathway, leading to its known hemorrhagic phenotype. Manifestations are similar to PAI-1 deficiency, with homozygous individuals manifesting severe bleeding, but heterozygous individuals can have a mild bleeding phenotype. Bleeding after trauma or procedures is the most common presentation, with noted menorrhagia in girls and women. Umbilical bleeding may be the first manifestation noted in homozygous infants,[22] which is comparable to the presentation of FXIII deficiency, and likely due to the known mechanism of FXIII binding plasmin within a thrombus.[38]

Similar to PAI-1 deficiency, testing for α₂AP deficiency should include measurements of both the antigen and activity, as patients may have quantitative defects (with low antigen and low activity), or qualitative defects (normal antigen but low activity).[29] Levels above 60% are considered normal.[39] There is typically no detectable antigen in homozygous individuals and the heterozygous state can present with half of the normal levels, with activity reported around 3 to 10%.[38] Genetic testing includes deletion/duplication analysis of the SERPINF2 gene.[40]

Antifibrinolytics are again the mainstay of treatment and prophylaxis. Although fresh frozen plasma has historically been utilized,[29] variations in preparation and resulting variability in the activity of α₂AP has not demonstrated increased effectiveness compared with antifibrinolytics. Thus, routine use of fresh frozen plasma is no longer recommended. It has also been recommended to avoid the use of desmopressin, the vasopressin analogue that potentiates release of von Willebrand factor and factor VIII for hemostatic control, due to the concern of release of uPA from platelets, subsequently increasing fibrinolytic activity.[41]

 

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Quebec Platelet Disorder

Quebec platelet disorder (QPD) is a disorder of increased fibrinolysis due to increased uPA in platelets.[42] The high penetrance of this autosomal dominant disorder is due to a gain of function in the PLAU gene,[43] [44] with all affected individuals in one study traced to a single common ancestor from Quebec, Canada.[45] The original name of the disorder was factor V Quebec, which is because of the low factor V (FV) in platelets of affected individuals.[46] Hemorrhagic symptoms are, again, primarily postprocedural or posttrauma, and are generally delayed in onset and prolonged.[45] No increase in obstetric complications has been noted, and antifibrinolytic prophylaxis is not recommended during pregnancy or uncomplicated vaginal birth.[47]

As opposed to the other deficiencies discussed, individuals with QPD may have thrombocytopenia, low platelet FV, and abnormal platelet aggregation studies, including absent aggregation with epinephrine and reduced aggregation with ADP and collagen.[48] Due to the nonspecific testing abnormalities, it is recommended that individuals with high clinical suspicion (specifically a considerable family history) undergo testing of the PLAU gene to identify the pathogenic tandem duplication.[48]

 

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Disorders with Fibrin Deposition or Thrombotic Phenotype

Plasminogen Deficiency

Plasminogen deficiency can be defined as type I (hypoplasminogenemia), with low plasminogen antigen and activity levels, or type II (dysplasminogenemia), with normal plasminogen antigen but low activity levels. In type I, plasminogen antigen levels can range between <1 and 9 mg/dL and activity levels around <1 and 51%[49] (normal activity ranges between 75 and 120%[50]). Testing of plasminogen levels is based on high clinical suspicion due to signs and symptoms (as listed below) or known family history. Homozygous and compound heterozygous individuals primarily present with ligneous conjunctivitis (85–96% of patients), along with ligneous gingivitis (that can lead to loss of all teeth) and obstructive hydrocephalus, with a median age of 1 year for onset.[50] [51] Other mucosal manifestations include involvement of the respiratory tract (ligneous laryngitis) and female genital tract (ligneous vaginitis). There is no associated increase in the rate of thrombosis.[6] A high rate of consanguinity has been noted in some populations.[50] Of note, plasminogen deficiency type II is not associated with increased risk of thrombosis or ligneous conjunctivitis.[52]

Treatment modalities for ligneous conjunctivitis include the local and intravenous use of fresh frozen plasma,[53] plasma-derived Glu-plasminogen,[54] and additional uses of hormonal therapy (e.g., estrogen) and immunosuppressive medications (e.g., cyclosporine or azathioprine).[49] The use of human plasma-derived plasminogen has been particularly favorable in both the intravenous and ophthalmic forms.

Plasminogen, human-tvmh has been studied in adult and pediatric patients, administered at a dose of 6.6 mg/kg intravenously every 2 to 5 days, which resulted in a plasminogen increase of over 10% above baseline, with all lesions improved by at least 50% over the 48-week study period (patients followed for up to 124 weeks).[55] More than half of patients experienced adverse events of nasopharyngitis, oropharyngeal pain, and headaches.

Human plasma-derived eye drops have also been studied in patients with ligneous conjunctivitis (primarily in pediatric patients), with two drops in each eye 8 times daily; those that improved continued the drops 6 times daily, and those that didn't underwent surgical excision with adjusted eye drop regimen.[56] No patients had pseudomembrane recurrence after this initial treatment, and they continued the eye drops 4 to 6 times daily.

 

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Polymorphisms

The role of decreased fibrinolysis in the development of venous thromboembolism (VTE) has been of great interest, particularly its possible role in increasing the risk of cardiovascular and cerebrovascular disease.[28] Several polymorphisms related to PAI-1, tPA, and TAFI have been assessed. The PAI-1 4G/5G polymorphism has been of particular interest, with noted increases in PAI-1 levels[57] that have been associated with increased risk of myocardial infarction[58]; however, the evidence has been overall weak with regard to this increased risk of myocardial infarctions[59] or stroke.[60] There is also weak evidence to suggest increased VTE, but this is in the setting of other thrombophilia such as Factor V Leiden, prothrombin gene mutation, or deficiencies of protein C or S.[61] The tPA 7351 C/T enhancer has been similarly studied but has not been found to be associated with increased risk of cerebrovascular accidents.[60] Two polymorphisms in TAFI (Thr325Ile and Ala147Thr) that have traditionally been associated with increased risk of cardiovascular disease, have also thus far shown weak or no associations.[62] The potential for increased thrombosis risk of these polymorphisms in combination with other inherited thrombophilia has been suggested but remains speculative.

 

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Additional Laboratory Evaluations

In addition to the specialized and directed testing for each disorder per above, below are additional considerations in the laboratory evaluation of inherited disorders of fibrinolysis.

Conventional Coagulation Testing

Assessment of conventional coagulation testing should reveal normal platelet count, prothrombin time, activated partial thromboplastin time, coagulation factors, fibrinogen, von Willebrand factor levels, and platelet aggregation studies. This is with the exception of the previously noted QPD that may have thrombocytopenia, low platelet FV, and abnormal platelet aggregation studies.

 

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Euglobulin Lysis Time

One of the traditional tests to assess for fibrinolysis, a precipitate of plasma known as “euglobulin” is obtained via incubation of a platelet poor plasma sample with acid. The acidification causes precipitation of clotting factors in a complex called the euglobulin fraction, which represents the fibrinolytic activity of plasma, and includes plasminogen, PAs, and fibrinogen. It thus excludes any antifibrinolytics. This precipitate is then mixed with thrombin to form a clot, and the time to clot lysis is observed (by agitating the test tube every 10 minutes until complete clot dissolution).[63] [64] A value below normal (<60 minutes) denotes hyperfibrinolysis. The euglobulin lysis time (ELT) has largely fallen out of favor due to the manual and technical difficulties with this testing modality. A shortened or normal ELT has been reported in α₂AP deficiency.[38]

 

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Viscoelastic Testing

Viscoelastic testing (VET) methods such as rotational thromboelastometry (ROTEM) and thromboelastography (TEG) provide assessment of whole blood coagulation from clot initiation to clot formation and clot lysis.[65] [66] They have been largely employed in guiding blood product replacement therapy,[67] [68] with fibrinolysis noted by the percentage of lysis after 30 minutes (30 minutes from clot initiation in ROTEM and 30 minutes from maximal clot amplitude for TEG). It can also be noted by the maximum lysis noted (typically with a 60-minute run time). However, these assessment methods are not typically sensitive outside the context of hyperfibrinolysis, such as trauma.[69] Additional dedicated fibrinolysis assays include the ROTEM APTEM assay that uses a fibrinolysis inhibitor to note any decrease in fibrinolysis compared with the EXTEM assay. However, as inherited disorders of the fibrinolytic pathway typically note delayed hemorrhage after surgery or trauma, VET has not been generally successful in identifying increased fibrinolysis at baseline for patients with disorders of fibrinolysis.

 

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Conclusion

Despite the complex mechanism and multiple players in the fibrinolytic pathway that lead to an overall hemostatic balance, only a few disorders have been identified with clinically relevant significance in humans. α₂AP deficiency is the most common, presenting with bleeding that can be severe secondary to trauma or surgery in homozygous individuals and asymptomatic to mild bleeding noted in the heterozygous state. PAI-1 deficiency, which can present with menorrhagia and obstetric bleeding complications, is less common. QPD is a rare, autosomal dominant disorder first identified in Quebec, Canada. There are no known deficiencies in the fibrinolytic pathway that lead to overt thrombosis in humans, although rare polymorphisms do exist. Antifibrinolytics are the mainstay of treatment for bleeding and for procedural prophylaxis for hemorrhagic phenotypes. Routine coagulation testing is neither sensitive or specific, and directed specialized testing for the disorder of concern should be pursued after ruling out more common disorders. Genetic testing for the genes associated with these disorders may enhance diagnostic accuracy, particularly in light of the inaccuracies and lack of standardization found in biochemical testing.

 

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Conflict of Interest

None declared.

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Publication History

Article published online:
19 September 2024