Alpha-2-Plasmin Inhibitor Deficiency

Mendelian MONDO:0009883 Pathograph 26 Show in embeddings browser Bleeding Disorder Fibrinolytic Disorder Rare Bleeding Disorder

Congenital alpha-2-plasmin inhibitor (alpha-2-antiplasmin) deficiency is a rare autosomal recessive bleeding disorder caused by pathogenic variants in SERPINF2, which encodes the main fast-acting physiological inhibitor of plasmin. Alpha-2-antiplasmin is a liver-derived serpin that restrains fibrinolysis by forming a covalent complex with plasmin, by blocking plasminogen binding to fibrin, and by being cross-linked into fibrin by activated factor XIII so that the clot itself resists local lysis. When it is missing, a haemostatic plug forms normally but is dissolved before the injured vessel has healed, so the characteristic pattern is delayed bleeding after trauma, surgery, dental extraction or circumcision rather than spontaneous bleeding. Homozygous patients present in childhood with haemophilia-like bleeding that can include umbilical bleeding, joint and muscle haematomas and, unusually, intramedullary haemorrhage into the diaphyses of long bones; heterozygotes are usually mildly affected or asymptomatic but can bleed heavily after surgery. Prothrombin time, activated partial thromboplastin time, platelet count and platelet function are normal, so the diagnosis is missed unless alpha-2-antiplasmin activity, a global fibrinolysis assay or SERPINF2 sequencing is requested. Antifibrinolytic agents (tranexamic acid, epsilon-aminocaproic acid) are the mainstay of treatment, with fresh frozen plasma as a source of the missing inhibitor for severe bleeding or high-risk surgery.

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1
Inheritance
5
Pathophys.
12
Phenotypes
26
Pathograph
1
Genes
4
Variants
2
Medical Actions
2
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Severe disease requires two SERPINF2 pathogenic alleles. Heterozygous carriers have roughly half-normal alpha-2-antiplasmin and are usually asymptomatic or mildly affected, but they can bleed after surgery, dental procedures or trauma, so the carrier state is not clinically silent.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:31427261 SUPPORT REVIEW SYNTHESIS Human Clinical
"Both these disorders are rare and have an autosomal recessive pattern of inheritance."
Review of inherited fibrinolytic disorders stating that alpha-2-antiplasmin deficiency (one of the two disorders referred to) is autosomal recessive.
PMID:33337837 SUPPORT Human Clinical
"Homozygous patients develop symptomatology in early childhood, while heterozygous individuals may be asymptomatic or bleed profusely following invasive dental procedures, surgery or trauma late in life."
Literature survey of 123 reported cases contrasting the homozygous and heterozygous phenotypes that the recessive model rests on.
⚙

Pathophysiology

5
SERPINF2 Loss-of-Function Variants
Biallelic loss-of-function variants in SERPINF2 (chromosome 17p13) are the initiating lesion. The best-characterised alleles are in-frame deletions and frameshifts that produce a misfolded protein retained in the endoplasmic reticulum: alpha-2-PI Okinawa (deletion of Glu137) and alpha-2-PI Nara, together with a single-thymine deletion in exon 5 that truncates the protein after 83 native residues. Most variants therefore cause a quantitative (type I) deficiency with parallel loss of antigen and activity. Heterozygous carriers of a single pathogenic allele, such as the reactive-site-adjacent missense p.Val384Met or the intron 6 splice-donor allele Artas that skips exon 6, have intermediate activity and antigen and bleed after surgery or trauma. Variants are largely private to individual families.
SERPINF2 hgnc:9075 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SERPINF2 (hgnc:9075). hgnc:9075 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
serine-type endopeptidase inhibitor activity GO:0004867 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased serine-type endopeptidase inhibitor activity (GO:0004867). GO:0004867 is a molecular function from the Gene Ontology.
Downstream
Endoplasmic Reticulum Retention and Degradation of Mutant Alpha-2-Antiplasmin
Show evidence (6 references)
PMID:2572590 SUPPORT Human Clinical
"By sequencing all the coding exons and exon-intron boundaries of the gene, a trinucleotide deletion in exon VII that results in deletion of Glu137 was identified."
Identifies the Okinawa in-frame deletion in a patient homozygous for the deficiency.
PMID:12152655 SUPPORT Human Clinical
"We have carried out molecular analysis of American family members with congenital PI deficiency, and detected a single thymine deletion at nucleotide position 332 in exon 5."
A frameshift allele found in both alleles of affected homozygotes in an American family.
PMID:42257473 SUPPORT Human Clinical
"Her evaluation showed normal coagulation studies, platelet function, and von Willebrand factor assays, with persistently low α2AP activity and a homozygous SERPINF2 variant confirming the diagnosis."
A recent case confirming the diagnosis by a homozygous SERPINF2 variant.
+ 3 more references
Endoplasmic Reticulum Retention and Degradation of Mutant Alpha-2-Antiplasmin
Mutant alpha-2-antiplasmin made in hepatocytes is retained in the endoplasmic reticulum as an endoglycosidase H-sensitive form and then degraded by the proteasome after mannose trimming of its N-glycans, so little or none reaches plasma. Structural integrity of a short region spanning residues 127 to 137, rather than the identity of any single residue, is what secretion depends on.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Downstream
Reduced Plasma Alpha-2-Antiplasmin
Show evidence (4 references)
PMID:10671537 SUPPORT In Vitro
"The mutant alpha(2)PI-Nara and alpha(2)PI-Okinawa proteins were found to be retained and degraded in cells stably expressing these mutant forms of alpha(2)PI."
Shows both characterised deficiency alleles are retained and degraded intracellularly.
PMID:10671537 SUPPORT In Vitro
"Our findings show that modification of oligosaccharides of the mutant forms of alpha(2)PI determines their recognition by the degradation apparatus and that mannose trimming is important for targeting the mutant alpha(2)PI proteins for the degradation pathway."
Names the glycan-processing step that routes the mutant protein to proteasomal degradation.
PMID:7911462 SUPPORT In Vitro
"The results suggest that structural integrity of the region, rather than its component amino acids, is important for the intracellular transport and secretion of alpha 2PI."
Mutagenesis study defining the region whose integrity secretion depends on.
+ 1 more reference
Reduced Plasma Alpha-2-Antiplasmin
Plasma alpha-2-antiplasmin activity is low or undetectable in homozygotes and about half of normal in heterozygotes. Normal plasma carries 0.8 to 1.2 IU/mL. In the mouse knockout, antigen and activity are undetectable in homozygotes and about half of wild type in heterozygotes, the same gene dosage relationship seen in human families.
serine-type endopeptidase inhibitor activity GO:0004867 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased serine-type endopeptidase inhibitor activity (GO:0004867). GO:0004867 is a molecular function from the Gene Ontology.
Downstream
Unopposed Plasmin Activity on Fibrin
Reduced alpha-2-antiplasmin activity
Show evidence (2 references)
PMID:33957960 SUPPORT Human Clinical
"Nevertheless, the concentration of α2-AP in the patient's plasma was 0.2 IU/ml (reference range is 0.80-1.20 IU/ml)."
A measured plasma level well below the normal range in a congenitally affected child.
PMID:10090937 SUPPORT Model Organism
"Immunologic and functional alpha2-AP levels were undetectable in plasma of alpha2-AP-/- mice, and were about half of wild-type in heterozygous littermates (alpha2-AP+/-)."
Gene dosage of the plasma inhibitor in the knockout mouse.
Unopposed Plasmin Activity on Fibrin
Without alpha-2-antiplasmin, plasmin generated on the fibrin surface is neither neutralised in a covalent serpin complex nor prevented from binding fibrin, and no inhibitor is cross-linked into the clot by factor XIIIa. Fibrin-bound plasmin therefore degrades the clot freely. Plasma fibrinogen stays normal, consistent with alpha-2-macroglobulin still restraining free plasmin in the circulation.
fibrinolysis GO:0042730 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased fibrinolysis (GO:0042730). GO:0042730 is a biological process from the Gene Ontology. negative regulation of fibrinolysis GO:0051918 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of fibrinolysis (GO:0051918). GO:0051918 is a biological process from the Gene Ontology.
Animal models
Serpinf2 knockout mouse Mouse recapitulates Faster lysis of labelled plasma clots in knockout than in wild-type mice.
Downstream
Premature Dissolution of the Haemostatic Plug
Shortened euglobulin clot lysis time
Show evidence (4 references)
PMID:42257473 SUPPORT BACKGROUND Human Clinical
"Mechanistically, α2AP restrains fibrinolysis by (i) forming a covalent serpin complex with plasmin, (ii) blocking plasminogen binding to fibrin, and (iii) undergoing factor XIIIa-mediated cross-linking into fibrin to harden clots against local lysis."
Lists the three mechanisms of fibrinolysis restraint that are lost in the deficiency.
PMID:19141165 SUPPORT REVIEW SYNTHESIS Human Clinical
"Congenital deficiency of alpha(2)-antiplasmin causes a rare bleeding disorder because of increased fibrinolysis."
Review stating that the bleeding disorder arises through increased fibrinolysis.
PMID:10090937 SUPPORT Model Organism
"Spontaneous lysis after 4 hours of intravenously injected 125I-fibrin-labeled plasma clots was significantly higher in alpha2-AP-/- than in alpha2-AP+/+ mice"
In vivo demonstration that clots lyse faster in knockout mice.
+ 1 more reference
Premature Dissolution of the Haemostatic Plug
The haemostatic plug forms with normal platelet function and normal fibrin generation, but is lysed before the injured vessel has been repaired. Bleeding therefore restarts hours to days after an injury or procedure that initially stopped bleeding, which is the clinical signature of the disease.
Animal models
Serpinf2 knockout mouse Mouse fails to recapitulate Knockout mice stop bleeding normally after tail or toe amputation.
Scottish deerhound delayed postoperative hemorrhage (SERPINF2 p.A202V) Dog recapitulates Dogs carrying the variant bleed days after surgery that was initially haemostatic.
Downstream
Delayed bleeding after trauma or surgery
Prolonged bleeding after dental extraction
Epistaxis
Gingival bleeding
Joint hemorrhage
Intramedullary haemorrhage of long bones
Intramuscular hematoma
Menorrhagia
Umbilical cord bleeding
Intracranial hemorrhage
Show evidence (2 references)
PMID:40589561 SUPPORT BACKGROUND Human Clinical
"In congenital α2-PI deficiency, these plugs are dissolved prematurely, before injured vessel repair, resulting in a strong hemorrhagic tendency."
States the plug-dissolution mechanism directly.
PMID:42257473 SUPPORT BACKGROUND Human Clinical
"Alpha-2 antiplasmin (α2AP) deficiency is a rare fibrinolytic disorder characterized by unregulated plasmin activity and premature clot breakdown."
Characterises the disorder by premature clot breakdown.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Alpha-2-Plasmin Inhibitor Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Blood 11
Delayed bleeding after trauma or surgery Delayed onset bleeding HP:0040232 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed onset bleeding (HP:0040232). HP:0040232 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:40589561 SUPPORT BACKGROUND Human Clinical
"Congenital α2-PI deficiency is inherited in an autosomal recessive manner and is rare; delayed bleeding associated with this disease occurs in response to trauma, surgery, or dental procedures."
States the delayed, provoked bleeding pattern.
PMID:33957960 SUPPORT Human Clinical
"The patient had a history of delayed bleeding episodes since the day of circumcision, which took approximately 1 month to stop."
A case of delayed bleeding after circumcision.
PMID:42257473 SUPPORT Human Clinical
"We describe a woman with decades of delayed postoperative bleeding, transfusion dependence, and a presumed diagnosis of von Willebrand disease, ultimately found to have congenital α2AP deficiency."
Decades of delayed postoperative bleeding in an adult with confirmed homozygous SERPINF2 deficiency.
Prolonged bleeding after dental extraction HP:0006298 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prolonged bleeding after dental extraction (HP:0006298). HP:0006298 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33337837 SUPPORT Human Clinical
"Homozygous patients develop symptomatology in early childhood, while heterozygous individuals may be asymptomatic or bleed profusely following invasive dental procedures, surgery or trauma late in life."
Bleeding after dental procedures is part of the reported phenotype, including in heterozygotes.
PMID:15357795 SUPPORT INDIRECT Human Clinical
"For the treatment of continuous bleeding, such as post-extraction bleeding, 20 mg kg(-1) of tranexamic acid should be administered intravenously"
A clinical series on intraoral bleeding in congenital alpha-2-PI deficiency that addresses post-extraction bleeding.
Epistaxis HP:0000421 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epistaxis (HP:0000421). HP:0000421 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33957960 SUPPORT Human Clinical
"who had a lifelong intermittent hemorrhagic tendency (gum bleeding, epistaxis, and exaggerated bleeding after trauma)"
Epistaxis in a child with congenital deficiency.
Gingival bleeding HP:0000225 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gingival bleeding (HP:0000225). HP:0000225 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33957960 SUPPORT Human Clinical
"who had a lifelong intermittent hemorrhagic tendency (gum bleeding, epistaxis, and exaggerated bleeding after trauma)"
Gum bleeding in a child with congenital deficiency.
Joint hemorrhage HP:0005261 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hemorrhage (HP:0005261). HP:0005261 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40589561 SUPPORT BACKGROUND Human Clinical
"Other abnormal bleeding, such as prolonged bleeding after lacerations or contusions, gingival bleeding, hemarthroses, subarachnoid and epidural hemorrhage, muscle hematomas, hemothorax, hernia, and severe post adenoidectomy bleeding have been reported."
Lists haemarthroses among the reported bleeding manifestations.
PMID:33957960 SUPPORT Human Clinical
"Hemorrhage into joints also occurred after trauma. Spontaneous joint bleeding was not reported."
Trauma-provoked joint bleeding without spontaneous haemarthrosis.
Intramedullary haemorrhage of long bones Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intramedullary haemorrhage of long bones, annotated with Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Coarse binding: no hpo term
Show evidence (4 references)
PMID:40589561 SUPPORT BACKGROUND Human Clinical
"Furthermore, the unusual symptom of intramedullary hemorrhage into the diaphyses of long bones occurring spontaneously and in response to trauma has been described."
Describes intramedullary haemorrhage into long-bone diaphyses.
PMID:40589561 SUPPORT Human Clinical
"As a child, she had a surgical history of intramedullary hematoma associated with congenital α2-PI deficiency, and her two sisters, but not her two brothers, had also been diagnosed with the same disease."
A patient with an intramedullary haematoma in childhood.
PMID:9880645 SUPPORT Human Clinical
"The association of intramedullary haematoma of the left femoral diaphysis and congenital alpha2-plasmin inhibitor deficiency in a 6-year-old boy is reported."
A femoral intramedullary haematoma in a child with congenital deficiency.
+ 1 more reference
Menorrhagia HP:0000132 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Menorrhagia (HP:0000132). HP:0000132 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33957960 SUPPORT Human Clinical
"The mother had a history of severe interval bleeding diathesis (menorrhagia)."
Menorrhagia in the mother of an affected child, consistent with a symptomatic carrier.
Umbilical cord bleeding Abnormal bleeding HP:0001892 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical stump bleeding, annotated with Abnormal bleeding (HP:0001892). HP:0001892 is a phenotype from the Human Phenotype Ontology.
Coarse binding: no hpo term
Show evidence (1 reference)
PMID:40589561 SUPPORT BACKGROUND Human Clinical
"Umbilical bleeding may be the first event of this disease."
States that umbilical bleeding can be the presenting event.
Intracranial hemorrhage HP:0002170 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial hemorrhage (HP:0002170). HP:0002170 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40589561 SUPPORT BACKGROUND Human Clinical
"Other abnormal bleeding, such as prolonged bleeding after lacerations or contusions, gingival bleeding, hemarthroses, subarachnoid and epidural hemorrhage, muscle hematomas, hemothorax, hernia, and severe post adenoidectomy bleeding have been reported."
Lists subarachnoid and epidural haemorrhage among reported bleeds.
Reduced alpha-2-antiplasmin activity HP:0040245 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced alpha-2-antiplasmin activity (HP:0040245). HP:0040245 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42257473 SUPPORT Human Clinical
"Her evaluation showed normal coagulation studies, platelet function, and von Willebrand factor assays, with persistently low α2AP activity and a homozygous SERPINF2 variant confirming the diagnosis."
Low activity with normal routine coagulation and platelet studies.
Shortened euglobulin clot lysis time Reduced euglobulin clot lysis time HP:0040247 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced euglobulin clot lysis time (HP:0040247). HP:0040247 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33957960 SUPPORT Human Clinical
"The main interesting finding in this patient was that the whole blood clot lysis was extremely fast, completed within 5-8 hours. The second abnormal finding is that the euglobulin clot lysis time was short."
Accelerated whole-blood clot lysis and a short euglobulin lysis time.
Musculoskeletal 1
Intramuscular hematoma HP:0012233 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intramuscular hematoma (HP:0012233). HP:0012233 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40589561 SUPPORT BACKGROUND Human Clinical
"Other abnormal bleeding, such as prolonged bleeding after lacerations or contusions, gingival bleeding, hemarthroses, subarachnoid and epidural hemorrhage, muscle hematomas, hemothorax, hernia, and severe post adenoidectomy bleeding have been reported."
Lists muscle haematomas among the reported bleeding manifestations.
🧬

Genetic Associations

1
SERPINF2
Gene: SERPINF2 hgnc:9075 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SERPINF2 (hgnc:9075). hgnc:9075 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
CGGV:assertion_a8fa2353-ff89-41f1-b030-bde64517edbb-2020-09-23T160000.000Z SUPPORT Other
"SERPINF2 | HGNC:9075 | alpha-2-plasmin inhibitor deficiency | MONDO:0009883 | AR | Definitive"
ClinGen Definitive gene-disease validity for this pair.
Variants (4)
Okinawa (p.Glu137del)
In-frame deletion of Glu137 found homozygous in an affected individual; the protein is retained in the endoplasmic reticulum.
Show evidence (1 reference)
PMID:2572590 SUPPORT Human Clinical
"By sequencing all the coding exons and exon-intron boundaries of the gene, a trinucleotide deletion in exon VII that results in deletion of Glu137 was identified."
Identifies the Okinawa allele.
Exon 5 single-thymine deletion (frameshift)
A frameshift found on both alleles of affected homozygotes in an American family, truncating the protein after 83 native residues.
Show evidence (1 reference)
PMID:12152655 SUPPORT Human Clinical
"The deletion was found in both alleles of the homozygotes and in one allele of the heterozygotes, and the patterns of restriction fragment length polymorphism created by the mutation in the family members were compatible with their phenotypes."
Segregation of the frameshift with deficiency.
p.Val384Met
Heterozygous missense eight residues C-terminal of the reactive-site P1 residue, segregating with bleeding and intermediate activity.
Show evidence (1 reference)
PMID:10583218 SUPPORT Human Clinical
"Heterozygosity for a G --> A mutation converting Val384(GTG) to Met(ATG) associated with plasmin inhibitor (alpha2-antiplasmin) deficiency was identified in three family members with bleeding tendency."
Identifies the missense allele.
Artas (intron 6 splice donor)
Heterozygous splice-donor variant causing exon 6 skipping, with intermediate activity and antigen and bleeding after surgery or trauma.
Show evidence (1 reference)
PMID:12544738 SUPPORT Human Clinical
"Gene sequencing makes it possible to find a splicing donor site mutation of intron 6, leading to exon 6 skipping."
Identifies the Artas splice allele.
💊

Medical Actions

2
Antifibrinolytic therapy (tranexamic acid or epsilon-aminocaproic acid)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tranexamic acid CHEBI:48669 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tranexamic acid (CHEBI:48669). CHEBI:48669 is a therapeutic agent from Chemical Entities of Biological Interest. epsilon-aminocaproic acid CHEBI:16586 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses epsilon-aminocaproic acid, annotated with 6-aminohexanoic acid (CHEBI:16586). CHEBI:16586 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Lysine-analogue antifibrinolytics block plasminogen binding to fibrin and so substitute for the missing inhibitor. They are used to treat bleeds and as prophylaxis before dental extraction or surgery; oral tranexamic acid is started before a procedure and continued for about a week.
Mechanism Target:
INHIBITS Unopposed Plasmin Activity on Fibrin — Prevents plasminogen and plasmin binding to fibrin, restraining fibrinolysis of the haemostatic plug.
Show evidence (2 references)
PMID:31427261 SUPPORT REVIEW SYNTHESIS Human Clinical
"Antifibrinolytic agents, such as tranexamic acid or ε-aminocaproic acid, are the mainstays of treatment which inhibit fibrinolysis by preventing the binding of plasminogen to fibrin and thereby stabilizing the fibrin clot."
Names antifibrinolytics as the mainstay of treatment and gives their mechanism.
PMID:15357795 SUPPORT Human Clinical
"When extracting teeth from patients with congenital alpha2-PI deficiency, we advocate that 7.5-10 mg kg(-1) of tranexamic acid be administered orally every 6 h, starting 3 h before surgery and continuing for about 7 days."
Peri-procedural tranexamic acid regimen for dental extraction.
Fresh frozen plasma
Action: Fresh Frozen Plasma TransfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Fresh Frozen Plasma Transfusion (NCIT:C116475). NCIT:C116475 is a clinical intervention from the NCI Thesaurus. NCIT:C116475
Platform: Protein replacement
Plasma supplies alpha-2-antiplasmin and is used for severe bleeding or combined with tranexamic acid as prophylaxis for major surgery; it was used this way for a lung transplant in a patient with congenital deficiency.
Mechanism Target:
RESTORES Reduced Plasma Alpha-2-Antiplasmin — Donor plasma temporarily replaces the missing inhibitor.
Show evidence (2 references)
PMID:33957960 SUPPORT Human Clinical
"Patients with congenital or acquired α2-AP deficiency who have extreme bleeding should receive fresh-frozen plasma (FFP) transfusion as a source of α2-AP."
Recommends plasma as a source of the inhibitor in severe bleeding.
PMID:40589561 SUPPORT Human Clinical
"Lung transplantation for a patient with α2-PI deficiency was safely performed with the use of planned FFP transfusion and tranexamic acid."
Planned plasma plus tranexamic acid for major surgery.
🔬

Diagnosis

1
Alpha-2-antiplasmin activity assay and SERPINF2 sequencing
Routine coagulation screening is normal, so the disease is found only when alpha-2-antiplasmin activity or a global fibrinolysis assay is requested, with SERPINF2 sequencing to confirm. Viscoelastic testing (thromboelastography or ROTEM) shows accelerated clot lysis and has been used to monitor fibrinolysis during surgery.
Show evidence (3 references)
PMID:42257473 SUPPORT Human Clinical
"Standard hemostatic panels may fail to detect α2AP deficiency, and testing with functional activity assays or genetic analysis is required."
States that routine panels miss the disease and names the tests needed.
PMID:39299257 SUPPORT Human Clinical
"Genetic testing of the pathogenic mutations is recommended in patients with a high suspicion of an inherited disorder of the fibrinolytic pathway."
Review recommending genetic testing for suspected inherited fibrinolytic disorders.
PMID:40589561 SUPPORT Human Clinical
"We used the point of care test (POC) rotational thromboelastometry (ROTEM) to diagnose intraoperative coagulopathy."
ROTEM used to monitor fibrinolysis during surgery in a patient with congenital deficiency.
📊

Prevalence

1
Worldwide (published case reports)
Cases In Literature Ultra Rare
A 2020 literature survey found 123 patients across 33 publications. No population-based prevalence estimate exists.
Show evidence (1 reference)
PMID:33337837 SUPPORT Human Clinical
"Thirty-three publications were identified encompassing one hundred twenty-three patients."
Counts every reported case in the literature up to 2020.
🐁

Animal Models

2
Serpinf2 knockout mouse
Homozygous knockout mice lack plasma alpha-2-antiplasmin and show enhanced clot lysis in vivo, but do not bleed after tail or toe amputation, so the model reproduces the fibrinolytic defect without the human bleeding phenotype.
Species
Mouse
Genotype
Serpinf2 -/- (targeted deletion of exon 2 through part of exon 10)
Publication
PMID:10090937
Pathograph links
Unopposed Plasmin Activity on Fibrin recapitulates fidelity: high Faster lysis of labelled plasma clots in knockout than in wild-type mice.
Show evidence (1 reference)
PMID:10090937 SUPPORT Model Organism
"Spontaneous lysis after 4 hours of intravenously injected 125I-fibrin-labeled plasma clots was significantly higher in alpha2-AP-/- than in alpha2-AP+/+ mice"
Direct in vivo measurement of enhanced fibrinolysis.
Premature Dissolution of the Haemostatic Plug fails to recapitulate fidelity: low Knockout mice stop bleeding normally after tail or toe amputation.
Limitations: Tail and toe amputation assays may not detect the delayed rebleeding that characterises the human disease.
Show evidence (1 reference)
PMID:10090937 SUPPORT Model Organism
"After amputation of tail or toe tips, bleeding stopped spontaneously in alpha2-AP+/+, as well as in alpha2-AP+/- and alpha2-AP-/- mice."
No overt bleeding in the knockout, in contrast to the human disease.
Scottish deerhound delayed postoperative hemorrhage (SERPINF2 p.A202V)
A naturally occurring canine bleeding disorder, delayed postoperative hemorrhage, mapped by whole-genome association to a SERPINF2 missense variant with a strong gene-dose effect. It reproduces the delayed, procedure-provoked bleeding that the mouse knockout does not.
Species
Dog
Genotype
SERPINF2 c.605C>T (p.A202V), homozygous or heterozygous
Publication
PMID:36780177
Pathograph links
Premature Dissolution of the Haemostatic Plug recapitulates fidelity: moderate Dogs carrying the variant bleed days after surgery that was initially haemostatic.
Limitations: The variant has not been shown to lower plasma alpha-2-antiplasmin, so the link from genotype to fibrinolytic defect is inferred from the gene rather than measured.
Show evidence (2 references)
PMID:36780177 SUPPORT Model Organism
"Genome-wide association analysis identified a single locus on chromosome 9 spanning 40 genes. One of these genes (SERPINF2 encoding alpha-2 antiplasmin) was directly linked to the pathophysiology of DEPOH."
Maps the canine delayed-bleeding disorder to SERPINF2.
+ 1 more reference
{ }

Source YAML

click to show 
name: Alpha-2-Plasmin Inhibitor Deficiency
creation_date: '2026-10-12T18:40:00Z'
category: Mendelian
parents:
- Bleeding Disorder
- Fibrinolytic Disorder
- Rare Bleeding Disorder
disease_term:
  preferred_term: alpha-2-plasmin inhibitor deficiency
  term:
    id: MONDO:0009883
    label: alpha-2-plasmin inhibitor deficiency
synonyms:
- alpha-2-antiplasmin deficiency
- congenital alpha-2-antiplasmin deficiency
- congenital alpha-2-plasmin inhibitor deficiency
- plasmin inhibitor deficiency
- SERPINF2 deficiency
description: >-
  Congenital alpha-2-plasmin inhibitor (alpha-2-antiplasmin) deficiency is a
  rare autosomal recessive bleeding disorder caused by pathogenic variants in
  SERPINF2, which encodes the main fast-acting physiological inhibitor of
  plasmin. Alpha-2-antiplasmin is a liver-derived serpin that restrains
  fibrinolysis by forming a covalent complex with plasmin, by blocking
  plasminogen binding to fibrin, and by being cross-linked into fibrin by
  activated factor XIII so that the clot itself resists local lysis. When it
  is missing, a haemostatic plug forms normally but is dissolved before the
  injured vessel has healed, so the characteristic pattern is delayed bleeding
  after trauma, surgery, dental extraction or circumcision rather than
  spontaneous bleeding. Homozygous patients present in childhood with
  haemophilia-like bleeding that can include umbilical bleeding, joint and
  muscle haematomas and, unusually, intramedullary haemorrhage into the
  diaphyses of long bones; heterozygotes are usually mildly affected or
  asymptomatic but can bleed heavily after surgery. Prothrombin time,
  activated partial thromboplastin time, platelet count and platelet function
  are normal, so the diagnosis is missed unless alpha-2-antiplasmin activity,
  a global fibrinolysis assay or SERPINF2 sequencing is requested.
  Antifibrinolytic agents (tranexamic acid, epsilon-aminocaproic acid) are the
  mainstay of treatment, with fresh frozen plasma as a source of the missing
  inhibitor for severe bleeding or high-risk surgery.
prevalence:
- population: Worldwide (published case reports)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2020 literature survey found 123 patients across 33 publications. No
    population-based prevalence estimate exists.
  evidence:
  - reference: PMID:33337837
    reference_title: "Congenital Alpha-2 Antiplasmin Deficiency: a Literature Survey and Analysis of 123 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-three publications were identified encompassing one hundred twenty-three patients."
    explanation: >-
      Counts every reported case in the literature up to 2020.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Severe disease requires two SERPINF2 pathogenic alleles. Heterozygous
    carriers have roughly half-normal alpha-2-antiplasmin and are usually
    asymptomatic or mildly affected, but they can bleed after surgery, dental
    procedures or trauma, so the carrier state is not clinically silent.
  evidence:
  - reference: PMID:31427261
    reference_title: "Inherited disorders of the fibrinolytic pathway."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Both these disorders are rare and have an autosomal recessive pattern of inheritance."
    explanation: >-
      Review of inherited fibrinolytic disorders stating that alpha-2-antiplasmin
      deficiency (one of the two disorders referred to) is autosomal recessive.
  - reference: PMID:33337837
    reference_title: "Congenital Alpha-2 Antiplasmin Deficiency: a Literature Survey and Analysis of 123 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous patients develop symptomatology in early childhood, while heterozygous individuals may be asymptomatic or bleed profusely following invasive dental procedures, surgery or trauma late in life."
    explanation: >-
      Literature survey of 123 reported cases contrasting the homozygous and
      heterozygous phenotypes that the recessive model rests on.
genetic:
- name: SERPINF2
  gene_term:
    preferred_term: SERPINF2
    term:
      id: hgnc:9075
      label: SERPINF2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_a8fa2353-ff89-41f1-b030-bde64517edbb-2020-09-23T160000.000Z
    evidence:
    - reference: CGGV:assertion_a8fa2353-ff89-41f1-b030-bde64517edbb-2020-09-23T160000.000Z
      reference_title: "SERPINF2 / alpha-2-plasmin inhibitor deficiency (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SERPINF2 | HGNC:9075 | alpha-2-plasmin inhibitor deficiency | MONDO:0009883 | AR | Definitive"
      explanation: >-
        ClinGen classifies the SERPINF2-alpha-2-plasmin inhibitor deficiency
        relationship as Definitive with autosomal recessive inheritance.
  notes: >-
    Biallelic loss-of-function variants cause severe deficiency; single
    alleles cause intermediate levels and provoked bleeding. Variants are
    largely private to individual families.
  evidence:
  - reference: CGGV:assertion_a8fa2353-ff89-41f1-b030-bde64517edbb-2020-09-23T160000.000Z
    reference_title: "SERPINF2 / alpha-2-plasmin inhibitor deficiency (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SERPINF2 | HGNC:9075 | alpha-2-plasmin inhibitor deficiency | MONDO:0009883 | AR | Definitive"
    explanation: >-
      ClinGen Definitive gene-disease validity for this pair.
  variants:
  - name: Okinawa (p.Glu137del)
    description: >-
      In-frame deletion of Glu137 found homozygous in an affected
      individual; the protein is retained in the endoplasmic reticulum.
    evidence:
    - reference: PMID:2572590
      reference_title: "Hereditary alpha 2-plasmin inhibitor deficiency caused by a transport-deficient mutation (alpha 2-PI-Okinawa). Deletion of Glu137 by a trinucleotide deletion blocks intracellular transport."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "By sequencing all the coding exons and exon-intron boundaries of the gene, a trinucleotide deletion in exon VII that results in deletion of Glu137 was identified."
      explanation: >-
        Identifies the Okinawa allele.
  - name: Exon 5 single-thymine deletion (frameshift)
    description: >-
      A frameshift found on both alleles of affected homozygotes in an
      American family, truncating the protein after 83 native residues.
    evidence:
    - reference: PMID:12152655
      reference_title: "A single thymine nucleotide deletion responsible for congenital deficiency of plasmin inhibitor."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The deletion was found in both alleles of the homozygotes and in one allele of the heterozygotes, and the patterns of restriction fragment length polymorphism created by the mutation in the family members were compatible with their phenotypes."
      explanation: >-
        Segregation of the frameshift with deficiency.
  - name: p.Val384Met
    description: >-
      Heterozygous missense eight residues C-terminal of the reactive-site
      P1 residue, segregating with bleeding and intermediate activity.
    evidence:
    - reference: PMID:10583218
      reference_title: "A novel missense mutation in the human plasmin inhibitor (alpha2-antiplasmin) gene associated with a bleeding tendency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Heterozygosity for a G --> A mutation converting Val384(GTG) to Met(ATG) associated with plasmin inhibitor (alpha2-antiplasmin) deficiency was identified in three family members with bleeding tendency."
      explanation: >-
        Identifies the missense allele.
  - name: Artas (intron 6 splice donor)
    description: >-
      Heterozygous splice-donor variant causing exon 6 skipping, with
      intermediate activity and antigen and bleeding after surgery or trauma.
    evidence:
    - reference: PMID:12544738
      reference_title: "A splicing donor site point mutation in intron 6 of the plasmin inhibitor (alpha2 antiplasmin) gene with heterozygous deficiency and a bleeding tendency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Gene sequencing makes it possible to find a splicing donor site mutation of intron 6, leading to exon 6 skipping."
      explanation: >-
        Identifies the Artas splice allele.
pathophysiology:
- name: SERPINF2 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function variants in SERPINF2 (chromosome 17p13) are the
    initiating lesion. The best-characterised alleles are in-frame deletions
    and frameshifts that produce a misfolded protein retained in the
    endoplasmic reticulum: alpha-2-PI Okinawa (deletion of Glu137) and
    alpha-2-PI Nara, together with a single-thymine deletion in exon 5 that
    truncates the protein after 83 native residues. Most variants therefore
    cause a quantitative (type I) deficiency with parallel loss of antigen and
    activity. Heterozygous carriers of a single pathogenic allele, such as the
    reactive-site-adjacent missense p.Val384Met or the intron 6 splice-donor
    allele Artas that skips exon 6, have intermediate activity and antigen
    and bleed after surgery or trauma. Variants are largely private to
    individual families.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: SERPINF2
    term:
      id: hgnc:9075
      label: SERPINF2
  molecular_functions:
  - preferred_term: serine-type endopeptidase inhibitor activity
    modifier: DECREASED
    term:
      id: GO:0004867
      label: serine-type endopeptidase inhibitor activity
  evidence:
  - reference: PMID:2572590
    reference_title: "Hereditary alpha 2-plasmin inhibitor deficiency caused by a transport-deficient mutation (alpha 2-PI-Okinawa). Deletion of Glu137 by a trinucleotide deletion blocks intracellular transport."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By sequencing all the coding exons and exon-intron boundaries of the gene, a trinucleotide deletion in exon VII that results in deletion of Glu137 was identified."
    explanation: >-
      Identifies the Okinawa in-frame deletion in a patient homozygous for the
      deficiency.
  - reference: PMID:12152655
    reference_title: "A single thymine nucleotide deletion responsible for congenital deficiency of plasmin inhibitor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have carried out molecular analysis of American family members with congenital PI deficiency, and detected a single thymine deletion at nucleotide position 332 in exon 5."
    explanation: >-
      A frameshift allele found in both alleles of affected homozygotes in an
      American family.
  - reference: PMID:42257473
    reference_title: "Alpha-2 antiplasmin deficiency: a rare fibrinolytic disorder identified after decades of diagnostic delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her evaluation showed normal coagulation studies, platelet function, and von Willebrand factor assays, with persistently low α2AP activity and a homozygous SERPINF2 variant confirming the diagnosis."
    explanation: >-
      A recent case confirming the diagnosis by a homozygous SERPINF2 variant.
  - reference: PMID:10583218
    reference_title: "A novel missense mutation in the human plasmin inhibitor (alpha2-antiplasmin) gene associated with a bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygosity for a G --> A mutation converting Val384(GTG) to Met(ATG) associated with plasmin inhibitor (alpha2-antiplasmin) deficiency was identified in three family members with bleeding tendency."
    explanation: >-
      A heterozygous missense allele segregating with bleeding in one family.
  - reference: PMID:10583218
    reference_title: "A novel missense mutation in the human plasmin inhibitor (alpha2-antiplasmin) gene associated with a bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The plasma plasmin inhibitor activities of the affected family members were reduced to 49-66% of normal."
    explanation: >-
      Intermediate activity in symptomatic heterozygotes.
  - reference: PMID:12544738
    reference_title: "A splicing donor site point mutation in intron 6 of the plasmin inhibitor (alpha2 antiplasmin) gene with heterozygous deficiency and a bleeding tendency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gene sequencing makes it possible to find a splicing donor site mutation of intron 6, leading to exon 6 skipping."
    explanation: >-
      A splice-site allele (Artas) causing heterozygous deficiency with
      bleeding after surgery or trauma.
  downstream:
  - target: Endoplasmic Reticulum Retention and Degradation of Mutant Alpha-2-Antiplasmin
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:2572590
      reference_title: "Hereditary alpha 2-plasmin inhibitor deficiency caused by a transport-deficient mutation (alpha 2-PI-Okinawa). Deletion of Glu137 by a trinucleotide deletion blocks intracellular transport."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These results suggest that the Glu137 deletion leads to the alpha 2-plasmin inhibitor deficiency by causing a block in its intracellular transport from the endoplasmic reticulum to the Golgi complex."
      explanation: >-
        Transfection of the Okinawa allele into COS-7 cells shows the variant
        acts by blocking secretion of the protein.
- name: Endoplasmic Reticulum Retention and Degradation of Mutant Alpha-2-Antiplasmin
  biological_scale: CELLULAR
  description: >-
    Mutant alpha-2-antiplasmin made in hepatocytes is retained in the
    endoplasmic reticulum as an endoglycosidase H-sensitive form and then
    degraded by the proteasome after mannose trimming of its N-glycans, so
    little or none reaches plasma. Structural integrity of a short region
    spanning residues 127 to 137, rather than the identity of any single
    residue, is what secretion depends on.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:10671537
    reference_title: "Mannose trimming targets mutant alpha(2)-plasmin inhibitor for degradation by the proteasome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutant alpha(2)PI-Nara and alpha(2)PI-Okinawa proteins were found to be retained and degraded in cells stably expressing these mutant forms of alpha(2)PI."
    explanation: >-
      Shows both characterised deficiency alleles are retained and degraded
      intracellularly.
  - reference: PMID:10671537
    reference_title: "Mannose trimming targets mutant alpha(2)-plasmin inhibitor for degradation by the proteasome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings show that modification of oligosaccharides of the mutant forms of alpha(2)PI determines their recognition by the degradation apparatus and that mannose trimming is important for targeting the mutant alpha(2)PI proteins for the degradation pathway."
    explanation: >-
      Names the glycan-processing step that routes the mutant protein to
      proteasomal degradation.
  - reference: PMID:7911462
    reference_title: "Secretion of alpha 2-plasmin inhibitor is impaired by amino acid deletion in a small region of the molecule."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results suggest that structural integrity of the region, rather than its component amino acids, is important for the intracellular transport and secretion of alpha 2PI."
    explanation: >-
      Mutagenesis study defining the region whose integrity secretion depends
      on.
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "α2-AP is synthesized in the liver."
    explanation: >-
      Background statement locating synthesis of the protein in the liver,
      which is why the hepatocyte is the cell type of this node.
  downstream:
  - target: Reduced Plasma Alpha-2-Antiplasmin
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12152655
      reference_title: "A single thymine nucleotide deletion responsible for congenital deficiency of plasmin inhibitor."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The mutant PI was retained and underwent progressive degradation within the cells, and was minimally excreted into the media."
      explanation: >-
        Retention and degradation mean little mutant inhibitor is secreted,
        which is the step from the cellular defect to the plasma deficiency.
- name: Reduced Plasma Alpha-2-Antiplasmin
  biological_scale: ORGANISM
  description: >-
    Plasma alpha-2-antiplasmin activity is low or undetectable in homozygotes
    and about half of normal in heterozygotes. Normal plasma carries 0.8 to
    1.2 IU/mL. In the mouse knockout, antigen and activity are undetectable in
    homozygotes and about half of wild type in heterozygotes, the same gene
    dosage relationship seen in human families.
  molecular_functions:
  - preferred_term: serine-type endopeptidase inhibitor activity
    modifier: DECREASED
    term:
      id: GO:0004867
      label: serine-type endopeptidase inhibitor activity
  evidence:
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nevertheless, the concentration of α2-AP in the patient's plasma was 0.2 IU/ml (reference range is 0.80-1.20 IU/ml)."
    explanation: >-
      A measured plasma level well below the normal range in a congenitally
      affected child.
  - reference: PMID:10090937
    reference_title: "Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunologic and functional alpha2-AP levels were undetectable in plasma of alpha2-AP-/- mice, and were about half of wild-type in heterozygous littermates (alpha2-AP+/-)."
    explanation: >-
      Gene dosage of the plasma inhibitor in the knockout mouse.
  downstream:
  - target: Unopposed Plasmin Activity on Fibrin
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31427261
      reference_title: "Inherited disorders of the fibrinolytic pathway."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "The most severe clinical phenotype is caused by α2-Antiplasmin (α2-AP) deficiency which results in excess fibrinolysis due to the inability to inhibit plasmin."
      explanation: >-
        States that the deficiency causes excess fibrinolysis because plasmin
        is no longer inhibited.
  - target: Reduced alpha-2-antiplasmin activity
- name: Unopposed Plasmin Activity on Fibrin
  biological_scale: MOLECULAR
  description: >-
    Without alpha-2-antiplasmin, plasmin generated on the fibrin surface is
    neither neutralised in a covalent serpin complex nor prevented from
    binding fibrin, and no inhibitor is cross-linked into the clot by factor
    XIIIa. Fibrin-bound plasmin therefore degrades the clot freely. Plasma
    fibrinogen stays normal, consistent with alpha-2-macroglobulin still
    restraining free plasmin in the circulation.
  biological_processes:
  - preferred_term: fibrinolysis
    modifier: INCREASED
    term:
      id: GO:0042730
      label: fibrinolysis
  - preferred_term: negative regulation of fibrinolysis
    modifier: DECREASED
    term:
      id: GO:0051918
      label: negative regulation of fibrinolysis
  evidence:
  - reference: PMID:42257473
    reference_title: "Alpha-2 antiplasmin deficiency: a rare fibrinolytic disorder identified after decades of diagnostic delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Mechanistically, α2AP restrains fibrinolysis by (i) forming a covalent serpin complex with plasmin, (ii) blocking plasminogen binding to fibrin, and (iii) undergoing factor XIIIa-mediated cross-linking into fibrin to harden clots against local lysis."
    explanation: >-
      Lists the three mechanisms of fibrinolysis restraint that are lost in
      the deficiency.
  - reference: PMID:19141165
    reference_title: "Alpha2-antiplasmin and its deficiency: fibrinolysis out of balance."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Congenital deficiency of alpha(2)-antiplasmin causes a rare bleeding disorder because of increased fibrinolysis."
    explanation: >-
      Review stating that the bleeding disorder arises through increased
      fibrinolysis.
  - reference: PMID:10090937
    reference_title: "Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Spontaneous lysis after 4 hours of intravenously injected 125I-fibrin-labeled plasma clots was significantly higher in alpha2-AP-/- than in alpha2-AP+/+ mice"
    explanation: >-
      In vivo demonstration that clots lyse faster in knockout mice.
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite the hyperfibrinolysis activity in this patient, the fibrinogen concentration was within the normal range."
    explanation: >-
      Normal fibrinogen despite hyperfibrinolysis; the same report proposes
      that alpha-2-macroglobulin limits fibrinogenolysis.
  downstream:
  - target: Premature Dissolution of the Haemostatic Plug
    causal_link_type: DIRECT
  - target: Shortened euglobulin clot lysis time
- name: Premature Dissolution of the Haemostatic Plug
  biological_scale: TISSUE
  description: >-
    The haemostatic plug forms with normal platelet function and normal fibrin
    generation, but is lysed before the injured vessel has been repaired.
    Bleeding therefore restarts hours to days after an injury or procedure that
    initially stopped bleeding, which is the clinical signature of the disease.
  evidence:
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In congenital α2-PI deficiency, these plugs are dissolved prematurely, before injured vessel repair, resulting in a strong hemorrhagic tendency."
    explanation: >-
      States the plug-dissolution mechanism directly.
  - reference: PMID:42257473
    reference_title: "Alpha-2 antiplasmin deficiency: a rare fibrinolytic disorder identified after decades of diagnostic delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Alpha-2 antiplasmin (α2AP) deficiency is a rare fibrinolytic disorder characterized by unregulated plasmin activity and premature clot breakdown."
    explanation: >-
      Characterises the disorder by premature clot breakdown.
  downstream:
  - target: Delayed bleeding after trauma or surgery
  - target: Prolonged bleeding after dental extraction
  - target: Epistaxis
  - target: Gingival bleeding
  - target: Joint hemorrhage
  - target: Intramedullary haemorrhage of long bones
  - target: Intramuscular hematoma
  - target: Menorrhagia
  - target: Umbilical cord bleeding
  - target: Intracranial hemorrhage
phenotypes:
- name: Delayed bleeding after trauma or surgery
  category: Hematologic
  description: >-
    Bleeding that starts or restarts after initial haemostasis following
    trauma, surgery or circumcision. In one child bleeding after circumcision
    took about a month to stop.
  phenotype_term:
    preferred_term: Delayed onset bleeding
    term:
      id: HP:0040232
      label: Delayed onset bleeding
  evidence:
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Congenital α2-PI deficiency is inherited in an autosomal recessive manner and is rare; delayed bleeding associated with this disease occurs in response to trauma, surgery, or dental procedures."
    explanation: >-
      States the delayed, provoked bleeding pattern.
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had a history of delayed bleeding episodes since the day of circumcision, which took approximately 1 month to stop."
    explanation: >-
      A case of delayed bleeding after circumcision.
  - reference: PMID:42257473
    reference_title: "Alpha-2 antiplasmin deficiency: a rare fibrinolytic disorder identified after decades of diagnostic delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a woman with decades of delayed postoperative bleeding, transfusion dependence, and a presumed diagnosis of von Willebrand disease, ultimately found to have congenital α2AP deficiency."
    explanation: >-
      Decades of delayed postoperative bleeding in an adult with confirmed
      homozygous SERPINF2 deficiency.
- name: Prolonged bleeding after dental extraction
  category: Hematologic
  phenotype_term:
    preferred_term: Prolonged bleeding after dental extraction
    term:
      id: HP:0006298
      label: Prolonged bleeding after dental extraction
  evidence:
  - reference: PMID:33337837
    reference_title: "Congenital Alpha-2 Antiplasmin Deficiency: a Literature Survey and Analysis of 123 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous patients develop symptomatology in early childhood, while heterozygous individuals may be asymptomatic or bleed profusely following invasive dental procedures, surgery or trauma late in life."
    explanation: >-
      Bleeding after dental procedures is part of the reported phenotype,
      including in heterozygotes.
  - reference: PMID:15357795
    reference_title: "Haemostatic management of intraoral bleeding in patients with congenital deficiency of alpha2-plasmin inhibitor or plasminogen activator inhibitor-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "For the treatment of continuous bleeding, such as post-extraction bleeding, 20 mg kg(-1) of tranexamic acid should be administered intravenously"
    explanation: >-
      A clinical series on intraoral bleeding in congenital alpha-2-PI
      deficiency that addresses post-extraction bleeding.
- name: Epistaxis
  category: Hematologic
  phenotype_term:
    preferred_term: Epistaxis
    term:
      id: HP:0000421
      label: Epistaxis
  evidence:
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who had a lifelong intermittent hemorrhagic tendency (gum bleeding, epistaxis, and exaggerated bleeding after trauma)"
    explanation: >-
      Epistaxis in a child with congenital deficiency.
- name: Gingival bleeding
  category: Hematologic
  phenotype_term:
    preferred_term: Gingival bleeding
    term:
      id: HP:0000225
      label: Gingival bleeding
  evidence:
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who had a lifelong intermittent hemorrhagic tendency (gum bleeding, epistaxis, and exaggerated bleeding after trauma)"
    explanation: >-
      Gum bleeding in a child with congenital deficiency.
- name: Joint hemorrhage
  category: Musculoskeletal
  description: >-
    Haemarthroses, usually after trauma rather than spontaneously, which is
    one way the disorder differs from haemophilia.
  phenotype_term:
    preferred_term: Joint hemorrhage
    term:
      id: HP:0005261
      label: Joint hemorrhage
  evidence:
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Other abnormal bleeding, such as prolonged bleeding after lacerations or contusions, gingival bleeding, hemarthroses, subarachnoid and epidural hemorrhage, muscle hematomas, hemothorax, hernia, and severe post adenoidectomy bleeding have been reported."
    explanation: >-
      Lists haemarthroses among the reported bleeding manifestations.
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemorrhage into joints also occurred after trauma. Spontaneous joint bleeding was not reported."
    explanation: >-
      Trauma-provoked joint bleeding without spontaneous haemarthrosis.
- name: Intramedullary haemorrhage of long bones
  category: Musculoskeletal
  description: >-
    Spontaneous or trauma-induced haemorrhage into the medullary cavity of the
    diaphyses of long bones, an unusual manifestation of homozygous
    deficiency. No HPO term names intramedullary bone haemorrhage, so the
    general bleeding term is bound.
  phenotype_term:
    preferred_term: Intramedullary haemorrhage of long bones
    coarse_binding_basis: NO_HPO_TERM
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Furthermore, the unusual symptom of intramedullary hemorrhage into the diaphyses of long bones occurring spontaneously and in response to trauma has been described."
    explanation: >-
      Describes intramedullary haemorrhage into long-bone diaphyses.
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As a child, she had a surgical history of intramedullary hematoma associated with congenital α2-PI deficiency, and her two sisters, but not her two brothers, had also been diagnosed with the same disease."
    explanation: >-
      A patient with an intramedullary haematoma in childhood.
  - reference: PMID:9880645
    reference_title: "A case of intramedullary haematoma associated with congenital alpha2-plasmin inhibitor deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The association of intramedullary haematoma of the left femoral diaphysis and congenital alpha2-plasmin inhibitor deficiency in a 6-year-old boy is reported."
    explanation: >-
      A femoral intramedullary haematoma in a child with congenital
      deficiency.
  - reference: PMID:21873355
    reference_title: "Rare and unusual bleeding manifestations in congenital bleeding disorders: an annotated review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intramedullary hematomas of long bones have been described in α2-plasmin inhibitor or fibrinogen deficiencies."
    explanation: >-
      Review of unusual bleeding sites naming this disorder as one of two in
      which intramedullary haematomas occur.
- name: Intramuscular hematoma
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Intramuscular hematoma
    term:
      id: HP:0012233
      label: Intramuscular hematoma
  evidence:
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Other abnormal bleeding, such as prolonged bleeding after lacerations or contusions, gingival bleeding, hemarthroses, subarachnoid and epidural hemorrhage, muscle hematomas, hemothorax, hernia, and severe post adenoidectomy bleeding have been reported."
    explanation: >-
      Lists muscle haematomas among the reported bleeding manifestations.
- name: Menorrhagia
  category: Hematologic
  phenotype_term:
    preferred_term: Menorrhagia
    term:
      id: HP:0000132
      label: Menorrhagia
  evidence:
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mother had a history of severe interval bleeding diathesis (menorrhagia)."
    explanation: >-
      Menorrhagia in the mother of an affected child, consistent with a
      symptomatic carrier.
- name: Umbilical cord bleeding
  category: Hematologic
  description: >-
    Bleeding from the umbilical stump can be the first event in homozygous
    deficiency. No HPO term names umbilical cord or stump bleeding, so the
    general bleeding term is bound.
  phenotype_term:
    preferred_term: Umbilical stump bleeding
    coarse_binding_basis: NO_HPO_TERM
    term:
      id: HP:0001892
      label: Abnormal bleeding
  evidence:
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Umbilical bleeding may be the first event of this disease."
    explanation: >-
      States that umbilical bleeding can be the presenting event.
- name: Intracranial hemorrhage
  category: Neurologic
  description: >-
    Subarachnoid and epidural haemorrhage are reported; the two sisters of one
    patient had subarachnoid haemorrhage.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  evidence:
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Other abnormal bleeding, such as prolonged bleeding after lacerations or contusions, gingival bleeding, hemarthroses, subarachnoid and epidural hemorrhage, muscle hematomas, hemothorax, hernia, and severe post adenoidectomy bleeding have been reported."
    explanation: >-
      Lists subarachnoid and epidural haemorrhage among reported bleeds.
- name: Reduced alpha-2-antiplasmin activity
  category: Laboratory
  description: >-
    Low or absent plasma alpha-2-antiplasmin activity is the diagnostic
    finding, with antigen reduced in parallel in quantitative deficiency.
    Prothrombin time, activated partial thromboplastin time and platelet tests
    are normal.
  phenotype_term:
    preferred_term: Reduced alpha-2-antiplasmin activity
    term:
      id: HP:0040245
      label: Reduced alpha-2-antiplasmin activity
  evidence:
  - reference: PMID:42257473
    reference_title: "Alpha-2 antiplasmin deficiency: a rare fibrinolytic disorder identified after decades of diagnostic delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her evaluation showed normal coagulation studies, platelet function, and von Willebrand factor assays, with persistently low α2AP activity and a homozygous SERPINF2 variant confirming the diagnosis."
    explanation: >-
      Low activity with normal routine coagulation and platelet studies.
- name: Shortened euglobulin clot lysis time
  category: Laboratory
  description: >-
    Global fibrinolysis assays show accelerated lysis: a short euglobulin
    clot lysis time and fast whole-blood clot lysis, both corrected by adding
    normal plasma.
  phenotype_term:
    preferred_term: Reduced euglobulin clot lysis time
    term:
      id: HP:0040247
      label: Reduced euglobulin clot lysis time
  evidence:
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main interesting finding in this patient was that the whole blood clot lysis was extremely fast, completed within 5-8 hours. The second abnormal finding is that the euglobulin clot lysis time was short."
    explanation: >-
      Accelerated whole-blood clot lysis and a short euglobulin lysis time.
diagnosis:
- name: Alpha-2-antiplasmin activity assay and SERPINF2 sequencing
  description: >-
    Routine coagulation screening is normal, so the disease is found only when
    alpha-2-antiplasmin activity or a global fibrinolysis assay is requested,
    with SERPINF2 sequencing to confirm. Viscoelastic testing
    (thromboelastography or ROTEM) shows accelerated clot lysis and has been
    used to monitor fibrinolysis during surgery.
  evidence:
  - reference: PMID:42257473
    reference_title: "Alpha-2 antiplasmin deficiency: a rare fibrinolytic disorder identified after decades of diagnostic delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard hemostatic panels may fail to detect α2AP deficiency, and testing with functional activity assays or genetic analysis is required."
    explanation: >-
      States that routine panels miss the disease and names the tests needed.
  - reference: PMID:39299257
    reference_title: "Inherited Disorders of the Fibrinolytic Pathway: Pathogenic Phenotypes and Diagnostic Considerations of Extremely Rare Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing of the pathogenic mutations is recommended in patients with a high suspicion of an inherited disorder of the fibrinolytic pathway."
    explanation: >-
      Review recommending genetic testing for suspected inherited fibrinolytic
      disorders.
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We used the point of care test (POC) rotational thromboelastometry (ROTEM) to diagnose intraoperative coagulopathy."
    explanation: >-
      ROTEM used to monitor fibrinolysis during surgery in a patient with
      congenital deficiency.
treatments:
- name: Antifibrinolytic therapy (tranexamic acid or epsilon-aminocaproic acid)
  description: >-
    Lysine-analogue antifibrinolytics block plasminogen binding to fibrin and
    so substitute for the missing inhibitor. They are used to treat bleeds and
    as prophylaxis before dental extraction or surgery; oral tranexamic acid
    is started before a procedure and continued for about a week.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tranexamic acid
      term:
        id: CHEBI:48669
        label: tranexamic acid
    - preferred_term: epsilon-aminocaproic acid
      term:
        id: CHEBI:16586
        label: 6-aminohexanoic acid
  target_mechanisms:
  - target: Unopposed Plasmin Activity on Fibrin
    treatment_effect: INHIBITS
    description: >-
      Prevents plasminogen and plasmin binding to fibrin, restraining
      fibrinolysis of the haemostatic plug.
  evidence:
  - reference: PMID:31427261
    reference_title: "Inherited disorders of the fibrinolytic pathway."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Antifibrinolytic agents, such as tranexamic acid or ε-aminocaproic acid, are the mainstays of treatment which inhibit fibrinolysis by preventing the binding of plasminogen to fibrin and thereby stabilizing the fibrin clot."
    explanation: >-
      Names antifibrinolytics as the mainstay of treatment and gives their
      mechanism.
  - reference: PMID:15357795
    reference_title: "Haemostatic management of intraoral bleeding in patients with congenital deficiency of alpha2-plasmin inhibitor or plasminogen activator inhibitor-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When extracting teeth from patients with congenital alpha2-PI deficiency, we advocate that 7.5-10 mg kg(-1) of tranexamic acid be administered orally every 6 h, starting 3 h before surgery and continuing for about 7 days."
    explanation: >-
      Peri-procedural tranexamic acid regimen for dental extraction.
- name: Fresh frozen plasma
  description: >-
    Plasma supplies alpha-2-antiplasmin and is used for severe bleeding or
    combined with tranexamic acid as prophylaxis for major surgery; it was
    used this way for a lung transplant in a patient with congenital
    deficiency.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Fresh Frozen Plasma Transfusion
    term:
      id: NCIT:C116475
      label: Fresh Frozen Plasma Transfusion
  target_mechanisms:
  - target: Reduced Plasma Alpha-2-Antiplasmin
    treatment_effect: RESTORES
    description: >-
      Donor plasma temporarily replaces the missing inhibitor.
  evidence:
  - reference: PMID:33957960
    reference_title: "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with congenital or acquired α2-AP deficiency who have extreme bleeding should receive fresh-frozen plasma (FFP) transfusion as a source of α2-AP."
    explanation: >-
      Recommends plasma as a source of the inhibitor in severe bleeding.
  - reference: PMID:40589561
    reference_title: "Perioperative Management of Single Lung Transplantation for a Chronic Obstructive Lung Disease Patient with Congenital Alpha(2)-Plasmin Inhibitor Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lung transplantation for a patient with α2-PI deficiency was safely performed with the use of planned FFP transfusion and tranexamic acid."
    explanation: >-
      Planned plasma plus tranexamic acid for major surgery.
animal_models:
- name: Serpinf2 knockout mouse
  species: Mouse
  genotype: Serpinf2 -/- (targeted deletion of exon 2 through part of exon 10)
  publication: PMID:10090937
  description: >-
    Homozygous knockout mice lack plasma alpha-2-antiplasmin and show enhanced
    clot lysis in vivo, but do not bleed after tail or toe amputation, so the
    model reproduces the fibrinolytic defect without the human bleeding
    phenotype.
  modeled_mechanisms:
  - target: Unopposed Plasmin Activity on Fibrin
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Faster lysis of labelled plasma clots in knockout than in wild-type
      mice.
    evidence:
    - reference: PMID:10090937
      reference_title: "Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Spontaneous lysis after 4 hours of intravenously injected 125I-fibrin-labeled plasma clots was significantly higher in alpha2-AP-/- than in alpha2-AP+/+ mice"
      explanation: >-
        Direct in vivo measurement of enhanced fibrinolysis.
  - target: Premature Dissolution of the Haemostatic Plug
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Knockout mice stop bleeding normally after tail or toe amputation.
    limitations: >-
      Tail and toe amputation assays may not detect the delayed rebleeding
      that characterises the human disease.
    evidence:
    - reference: PMID:10090937
      reference_title: "Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "After amputation of tail or toe tips, bleeding stopped spontaneously in alpha2-AP+/+, as well as in alpha2-AP+/- and alpha2-AP-/- mice."
      explanation: >-
        No overt bleeding in the knockout, in contrast to the human disease.
- name: Scottish deerhound delayed postoperative hemorrhage (SERPINF2 p.A202V)
  species: Dog
  genotype: SERPINF2 c.605C>T (p.A202V), homozygous or heterozygous
  publication: PMID:36780177
  description: >-
    A naturally occurring canine bleeding disorder, delayed postoperative
    hemorrhage, mapped by whole-genome association to a SERPINF2 missense
    variant with a strong gene-dose effect. It reproduces the delayed,
    procedure-provoked bleeding that the mouse knockout does not.
  modeled_mechanisms:
  - target: Premature Dissolution of the Haemostatic Plug
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Dogs carrying the variant bleed days after surgery that was initially
      haemostatic.
    limitations: >-
      The variant has not been shown to lower plasma alpha-2-antiplasmin, so
      the link from genotype to fibrinolytic defect is inferred from the gene
      rather than measured.
    evidence:
    - reference: PMID:36780177
      reference_title: "Identification by whole genome sequencing of genes associated with delayed postoperative hemorrhage in Scottish deerhounds."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Genome-wide association analysis identified a single locus on chromosome 9 spanning 40 genes. One of these genes (SERPINF2 encoding alpha-2 antiplasmin) was directly linked to the pathophysiology of DEPOH."
      explanation: >-
        Maps the canine delayed-bleeding disorder to SERPINF2.
    - reference: PMID:36780177
      reference_title: "Identification by whole genome sequencing of genes associated with delayed postoperative hemorrhage in Scottish deerhounds."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Compared to dogs with the reference C/C genotype, the likelihood of DEPOH was significantly higher for dogs with the T/T genotype"
      explanation: >-
        Homozygous variant dogs are at much higher risk, the same gene-dose
        pattern seen in humans.
notes: >-
  No GeneReviews chapter covers this disorder (`just check-genereviews` reports
  NO_CHAPTER against the 2026-09-10 Bookshelf index). A dysfunctional
  (type II) allele, Enschede, which is secreted but does not inhibit plasmin,
  is named in the deep-research report without a resolvable primary citation,
  so no qualitative-deficiency subtype is recorded here.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

No GeneReviews chapter covers this disorder (`just check-genereviews` reports NO_CHAPTER against the 2026-09-10 Bookshelf index). A dysfunctional (type II) allele, Enschede, which is secreted but does not inhibit plasmin, is named in the deep-research report without a resolvable primary citation, so no qualitative-deficiency subtype is recorded here.

Create: Alpha-2-Plasmin Inhibitor Deficiency · 2026-10-12T18:53:38Z · View source

New entry for congenital alpha-2-plasmin inhibitor (alpha-2-antiplasmin) deficiency, MONDO:0009883, SERPINF2. Pathograph: SERPINF2 loss-of-function variants -> ER retention and proteasomal degradation of mutant protein in hepatocytes -> reduced plasma alpha-2-antiplasmin -> unopposed plasmin activity on fibrin -> premature dissolution of the haemostatic plug -> delayed and provoked bleeding phenotypes (all 11 phenotypes causally connected). Treatments: antifibrinolytics (tranexamic acid) and fresh frozen plasma. Animal models: Serpinf2 knockout mouse (recapitulates fibrinolysis, fails to recapitulate bleeding) and Scottish deerhound SERPINF2 p.A202V delayed postoperative hemorrhage. One OpenScientist deep-research report (research/Alpha-2-Plasmin_Inhibitor_Deficiency-deep-research-openscientist.md): the run's built-in validation aborted on an OLS read timeout, so reference and term validation were added afterwards with just validate-research-reference and just validate-research-terms (19/19 references resolved, no unresolved terms); just preflight-dr PASS (SERPINF2 mentioned 24 times). Additional primary references were found by PubMed search. No GeneReviews chapter exists (check-genereviews NO_CHAPTER). Validated with just validate-disorders (all snippets verified) and the offline CI gates.

OpenScientist ▸
Alpha-2-Plasmin Inhibitor Deficiency (α2-Antiplasmin Deficiency): A Comprehensive Disease Characterization
openscientist-autonomous 19 citations 2026-10-12T18:40:22.282345

Alpha-2-Plasmin Inhibitor Deficiency (α2-Antiplasmin Deficiency): A Comprehensive Disease Characterization

Disease: Alpha-2-Plasmin Inhibitor Deficiency (α2-antiplasmin deficiency; plasmin inhibitor deficiency) MONDO ID: MONDO:0009883 · OMIM: 262850 (disease), 613168 (gene) · Orphanet: ORPHA:465 · Gene: SERPINF2 (17p13.3) Category: Mendelian (autosomal recessive)

Summary

Alpha-2-plasmin inhibitor (α2-antiplasmin, α2-AP) deficiency is a rare, autosomal-recessive bleeding disorder caused by biallelic loss-of-function variants in SERPINF2, the gene encoding the principal physiological inhibitor of the fibrinolytic protease plasmin. In the normal hemostatic system, α2-antiplasmin restrains clot breakdown by three complementary mechanisms: it forms a rapid, covalent serpin–plasmin complex that neutralizes circulating plasmin; it competitively blocks plasminogen binding to fibrin; and it is cross-linked into the forming fibrin network by activated coagulation factor XIII (FXIIIa), hardening clots against local lysis. When α2-antiplasmin is absent or non-functional, plasmin activity goes unopposed and fibrin clots—though formed normally—are dissolved prematurely. The clinical consequence is a hyperfibrinolytic bleeding diathesis characterized by delayed bleeding after trauma, surgery, or dental extraction, mucosal bleeding, and, in severely affected homozygotes, spontaneous and potentially life-threatening hemorrhage.

The disorder is strongly gene-dose dependent. Homozygous (or compound heterozygous) individuals typically present in early childhood with severe bleeding, while heterozygous individuals may be asymptomatic or bleed excessively only after invasive procedures or trauma later in life. A distinctive and diagnostically useful manifestation is the intramedullary hematoma of long bones, well visualized on MRI. A central diagnostic challenge is that routine coagulation screening tests—prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count/function, and von Willebrand factor—are all normal, so the disease is frequently misdiagnosed or recognized only after decades of diagnostic delay. Specific diagnosis requires an α2-antiplasmin functional activity assay or SERPINF2 sequencing; global viscoelastic tests (thromboelastography/ROTEM) showing accelerated clot lysis can prompt detection.

Prognosis is generally favorable once the diagnosis is made, because antifibrinolytic agents (tranexamic acid, ε-aminocaproic acid) that prevent plasminogen binding to fibrin effectively stabilize clots and permit even major surgery to be performed safely with planned prophylaxis. Beyond hemostasis, α2-antiplasmin has emerged as a pleiotropic regulator of tissue remodeling—promoting fibrosis and endothelial-to-mesenchymal transition and modulating ischemic brain injury—making it both a disease gene and a therapeutic target of growing interest. A naturally occurring SERPINF2 missense variant causes an analogous delayed postoperative hemorrhage syndrome in Scottish deerhounds, and α2-antiplasmin knockout mice recapitulate key aspects of the human biology, providing validated comparative and model systems.

Section 1 — Disease Information

Overview. Alpha-2-antiplasmin deficiency is the most severe inherited disorder of the fibrinolytic system. It results from the inability to inhibit plasmin, leading to excess (unregulated) fibrinolysis and premature clot breakdown (PMID: 31427261; PMID: 42257473). As stated in the literature, "The most severe clinical phenotype is caused by α2-Antiplasmin (α2-AP) deficiency which results in excess fibrinolysis due to the inability to inhibit plasmin" (PMID: 31427261).

Key identifiers.

Resource Identifier
MONDO MONDO:0009883
OMIM (disease) 262850
OMIM (gene) 613168
Orphanet ORPHA:465 (prevalence listed <1/1,000,000)
Gene / HGNC SERPINF2 (alias α2-AP, PLI, AAP, API)
Cytogenetic locus 17p13.3

Synonyms / alternative names. Alpha-2-antiplasmin deficiency; α2-plasmin inhibitor deficiency; plasmin inhibitor deficiency; congenital α2-AP deficiency; "Miyasato disease" (historical name for the first reported homozygous case). Named variant alleles include "α2AP Enschede" and "α2AP Artas."

Source of information. The characterization is derived predominantly from aggregated disease-level resources (OMIM, Orphanet) and from the primary literature consisting of individual case reports and small case series, consolidated by a 2020 literature survey of 123 cases across 33 publications (PMID: 33337837). There is no large EHR-derived cohort; the evidence base is necessarily patient-level and aggregated from scattered reports.

Section 2 — Etiology

Primary cause (genetic). The disease is monogenic and Mendelian: biallelic pathogenic variants in SERPINF2 cause the severe (homozygous) phenotype, while a single pathogenic allele produces a milder, often provoked bleeding tendency. "Both these disorders are rare and have an autosomal recessive pattern of inheritance" (PMID: 31427261). There is no infectious or environmental cause of the inherited disease; the molecular lesion is a loss of α2-antiplasmin function.

Genetic risk factors. The causal variants are the SERPINF2 pathogenic alleles themselves. Variants are largely private to individual families (see Section 4). No independent susceptibility loci or validated modifier genes have been established for the Mendelian disorder.

Environmental / lifestyle risk factors. These are better described as triggers of bleeding episodes rather than causes of disease: trauma, surgery, dental extraction, and other invasive procedures provoke the characteristic delayed bleeding (PMID: 33337837). Consanguinity increases the likelihood of homozygous severe disease.

Protective factors. The pharmacological "protective" factor against bleeding is antifibrinolytic therapy (functionally restoring the fibrinolytic brake). No naturally occurring genetic protective modifier alleles have been defined. Conversely—and notably for the inverse disease biology—reduced α2-antiplasmin is protective against fibrosis and may enhance thrombolysis (see Section 6).

Gene–environment interactions. The dominant interaction is genotype × hemostatic challenge: homozygotes bleed spontaneously and after minor insults; heterozygotes typically bleed only when a procedural or traumatic challenge is superimposed on their partial deficiency (PMID: 33337837).

Section 3 — Phenotypes

The core phenotype is a hemorrhagic diathesis. Severity is gene-dose dependent, and routine laboratory screens are characteristically normal, making the absence of standard laboratory abnormalities itself a clinical clue.

Phenotype Type Onset / severity / frequency Suggested HPO term
Delayed post-surgical / post-traumatic bleeding Clinical sign Hallmark; homozygotes from early childhood HP:0004846 / HP:0011889 (abnormal bleeding/diathesis)
Prolonged bleeding after dental extraction Clinical sign Common provoked manifestation HP:0006298 (prolonged bleeding following procedure)
Mucosal / gingival bleeding, epistaxis Clinical sign Variable HP:0000421 (epistaxis), HP:0000225 (gingival bleeding)
Intramedullary hematoma of long bones Physical/imaging manifestation Distinctive; reported in children HP:0001892 context (abnormal bleeding of bone)
Intracranial hemorrhage Clinical sign Rare, severe, homozygotes HP:0002170 (intracranial hemorrhage)
Hemarthrosis / soft-tissue hematoma Clinical sign Variable HP:0003261 relevant
Low α2-antiplasmin activity Laboratory abnormality Diagnostic; constant (diagnostic assay)

Age of onset / severity / progression. "Homozygous patients develop symptomatology in early childhood, while heterozygous individuals may be asymptomatic or bleed profusely following invasive dental procedures, surgery or trauma late in life" (PMID: 33337837). The disease is chronic and lifelong; bleeding is episodic and provoked rather than steadily progressive.

Distinctive manifestation — intramedullary hematoma. "Intramedullary hematomas of long bones have been described in α2-plasmin inhibitor or fibrinogen deficiencies" (PMID: 21873355). A detailed pediatric case described a 6-year-old boy with intramedullary hematoma of the left femoral diaphysis, presenting with pain without swelling and no trauma (PMID: 9880645).

Quality-of-life impact. Disease-specific QoL instruments have not been reported for this ultra-rare disorder. QoL impact derives from unpredictable bleeding, transfusion dependence in unrecognized disease, and procedural risk; with antifibrinolytic prophylaxis, most patients function well.

Section 4 — Genetic / Molecular Information

Causal gene. SERPINF2 (serpin family F member 2), 17p13.3; OMIM gene 613168. It encodes α2-antiplasmin, a secreted serpin.

Pathogenic variants — heterogeneity and classes. Disease-causing variants are typically private to each family—no single recurrent founder allele dominates globally—and span the full spectrum of classes: missense, nonsense, frameshift (insertion/deletion), and splice-site mutations (PMID: 10583218; PMID: 12544738).

Variant (name) Class Functional consequence Evidence
p.Val384Met Missense (P8′, near reactive site) Activity 49–66% of normal; antigen 57–68%; bleeding PMID: 10583218
Intron 6 splice-donor ("α2AP Artas") Splice-site → exon 6 skipping Heterozygous deficiency, bleeding PMID: 12544738
"α2AP Enschede" Frameshift (insertion) Dysfunctional protein secreted but non-inhibitory historical classic variant
p.Arg6Trp Polymorphism (allele freq ~0.19) Affects N-terminal cleavage; benign PMID: 33992873

The P1 reactive-center residue is Arg376: "The amino acid Val384 is located eight residues C-terminal (P8′) of the P1 residue (Arg376) in the reactive site" (PMID: 10583218), and heterozygous carriers showed that "The plasma plasmin inhibitor activities of the affected family members were reduced to 49–66% of normal" (PMID: 10583218). A splice mechanism is documented as "a splicing donor site mutation of intron 6, leading to exon 6 skipping" (PMID: 12544738).

Functional consequences. Variants act by loss of function—either quantitative deficiency (reduced secretion/antigen) or qualitative dysfunction (normal secretion but loss of plasmin-inhibitory activity, as in Enschede). Origin is germline.

Benign polymorphisms. p.Arg6Trp, p.Ala-26Val, p.Arg407Lys are population polymorphisms; p.Arg6Trp modulates the rate of N-terminal proteolytic processing but is not disease-causing.

Modifier genes / epigenetics / chromosomal abnormalities. No validated disease-modifier genes, disease-specific epigenetic marks, or recurrent chromosomal abnormalities have been established for this Mendelian disorder (not applicable / not available).

Section 5 — Environmental Information

The inherited disease has no environmental, toxic, or infectious cause. Environmental factors are relevant only as bleeding triggers (trauma, surgery, dental procedures). Of note, an acquired, phenocopy state of low α2-antiplasmin/hyperfibrinolysis can arise from malignancy (e.g., disseminated adenocarcinoma with hyperfibrinogenolysis, PMID: 9663712) and from severe factor XIII deficiency (which impairs α2-AP cross-linking to fibrin), but these are distinct from the congenital SERPINF2 disorder. No infectious agents are implicated.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain

  1. Biallelic loss-of-function variant in SERPINF2 leads to absent or non-functional α2-antiplasmin protein (quantitative deficiency or dysfunctional secreted serpin). [demonstrated]
  2. Loss of α2-antiplasmin removes all three physiological brakes on plasmin — it can no longer (i) form a covalent serpin–plasmin complex, (ii) block plasminogen binding to fibrin, or (iii) be FXIIIa-cross-linked into fibrin (PMID: 42257473). → results in unopposed, unregulated plasmin activity. [demonstrated]
  3. Unopposed plasmin → clots form normally but are prematurely degraded (hyperfibrinolysis) (PMID: 42257473). [demonstrated]
  4. Premature clot breakdown → delayed bleeding after an initial hemostatic plug forms and then dissolves, and spontaneous hemorrhage in severe deficiency. [demonstrated clinically]
  5. Branch (gene dose): homozygotes → severe early-childhood/spontaneous bleeding; heterozygotes → provoked bleeding (PMID: 33337837). [demonstrated]
  6. Branch (pleiotropy, inferred from models): reduced α2-AP → altered VEGF/angiogenesis in wound healing; reduced fibrosis/EndoMT; enhanced thrombolysis and modulated reperfusion brain injury (PMID: 16839360; PMID: 34709571; PMID: 42589214). [model-based]

Molecular detail

The three-pronged inhibitory mechanism is the heart of the pathophysiology: "α2AP restrains fibrinolysis by (i) forming a covalent serpin complex with plasmin, (ii) blocking plasminogen binding to fibrin, and (iii) undergoing factor XIIIa-mediated cross-linking into fibrin to harden clots against local lysis" (PMID: 42257473). Deficiency produces "a rare fibrinolytic disorder characterized by unregulated plasmin activity and premature clot breakdown" (PMID: 42257473).

Protein structure–function. The 2.65 Å crystal structure shows α2-antiplasmin is an unusual serpin with long N- and C-terminal extensions flanking the central serpin domain: "The N-terminal sequence is crosslinked to fibrin by factor XIIIa, whereas the C-terminal region mediates the initial interaction with plasmin" (PMID: 18063751). The serpin reactive-center loop presents P1 Arg376 to plasmin's active site. Circulating α2-AP is heterogeneous: "C-terminal cleavage converts the plasminogen-binding form (PB-α2-PI) to a non-plasminogen-binding form (NPB-α2-PI)" (PMID: 33992873); N-terminal cleavage by fibroblast activation protein yields a shorter form cross-linked to fibrin faster.

Pathway / process / cell types. Core pathway: the plasminogen–plasmin fibrinolytic system intersecting with FXIIIa-mediated fibrin stabilization. Cell types: hepatocytes (synthesis of plasma α2-AP), platelets (FXIII-A pool contributing to cross-linking), endothelium and fibroblasts (pleiotropic remodeling roles). Suggested GO terms: GO:0042730 (fibrinolysis), GO:0051918 (negative regulation of fibrinolysis), GO:0010951 (negative regulation of endopeptidase activity), GO:0007596 (blood coagulation). Suggested CL terms: CL:0000182 (hepatocyte), CL:0000233 (platelet), CL:0000115 (endothelial cell), CL:0000057 (fibroblast). Chemical entities (CHEBI): tranexamic acid (CHEBI:48669), ε-aminocaproic acid (CHEBI:28483).

Pleiotropy beyond hemostasis (model evidence). α2-AP regulates cell differentiation, cytokine production, ECM metabolism, and endothelial homeostasis. "the blockade of α2-antiplasmin suppresses fibrosis progression and vascular dysfunction in systemic sclerosis model mice" (PMID: 35330147); "α2AP deficiency attenuated EndoMT and fibrosis progression in DN model mice" (PMID: 34709571); and in stroke, "inhibition of α2AP with a specific monoclonal antibody caused a synergistic increase in TNK-tPA-mediated clot dissolution" (PMID: 42589214). These establish that α2-AP loss is deleterious for hemostasis but beneficial in fibrotic/thrombotic contexts—a therapeutic double-edged sword.

Section 7 — Anatomical Structures Affected

  • Body system: hematologic / cardiovascular (blood and vasculature). Suggested UBERON: UBERON:0000178 (blood), UBERON:0001969 (blood plasma).
  • Primary sites of bleeding: mucosal surfaces (oral/gingival, nasal), skin and soft tissue (hematoma), joints (hemarthrosis), bone marrow cavity of long bones (intramedullary hematoma — a distinctive localization; UBERON:0002371 bone marrow, long bone diaphysis), and the central nervous system (intracranial hemorrhage, severe cases).
  • Secondary involvement: organs subject to post-procedural bleeding (e.g., prostate after prostatectomy, lung during transplantation).
  • Tissue/cell level: no fixed tissue lesion; the "target" is the fibrin clot wherever it forms. Relevant cells: hepatocyte (source), platelet/endothelium/fibroblast (modulators).
  • Subcellular / localization: α2-AP is a secreted, extracellular plasma protein (GO cellular component GO:0005615 extracellular space); it acts in plasma and within the fibrin matrix. Bleeding lateralization is not fixed—manifestations are determined by site of hemostatic challenge.

Section 8 — Temporal Development

  • Onset: congenital/genetic; clinical onset in early childhood for homozygotes, later and provoked for heterozygotes (PMID: 33337837).
  • Onset pattern of bleeds: characteristically delayed after the inciting event (clot forms, then lyses).
  • Course: chronic, lifelong; episodic/provoked bleeding rather than continuous progression. No disease "stages" in the oncologic sense.
  • Remission patterns: bleeding episodes resolve with antifibrinolytic treatment (treatment-induced control); the underlying deficiency does not remit.
  • Critical periods / windows for intervention: peri-procedural and peri-traumatic windows are the key opportunities—prophylaxis before surgery/dental work prevents the delayed bleed (PMID: 15357795).

Section 9 — Inheritance and Population

  • Inheritance: autosomal recessive; severe disease in homozygotes/compound heterozygotes, mild/variable in heterozygotes (PMID: 31427261).
  • Epidemiology: ultra-rare; Orphanet lists prevalence <1/1,000,000 (ORPHA:465). No formal incidence established. A 2020 survey found only 123 patients in 33 publications (PMID: 33337837): "Thirty-three publications were identified encompassing one hundred twenty-three patients."
  • History / geography: first discovered in Japan (Koie, Aoki and colleagues; first homozygous case "Miyasato disease," 1978–1979). Reported subsequently across multiple ethnicities (Japanese, Indian, Sudanese, European, UK), with consanguineous families enriched among severe homozygous cases (PMID: 19141165): "Congenital deficiency of alpha(2)-antiplasmin causes a rare bleeding disorder because of increased fibrinolysis."
  • Penetrance / expressivity: homozygous disease is highly penetrant for bleeding; expressivity is variable and strongly gene-dose dependent. Heterozygotes show reduced penetrance (often only provoked bleeding).
  • Founder effects / recurrent alleles: none dominant; variants are largely private (Section 4).
  • Sex ratio / age distribution: no strong sex predilection reported (autosomal); affected individuals span childhood (homozygotes) to adulthood (heterozygotes diagnosed after procedures).

Section 10 — Diagnostics

The central diagnostic pitfall: routine coagulation screening is normal. "Her evaluation showed normal coagulation studies, platelet function, and von Willebrand factor assays, with persistently low α2AP activity and a homozygous SERPINF2 variant confirming the diagnosis" (PMID: 42257473). This causes frequent misdiagnosis (e.g., as von Willebrand disease) and diagnostic delay often spanning decades.

Recommended diagnostic approach.

Test Role Expected result
PT, aPTT, platelet count/function, VWF Screening Normal (hence misleading)
α2-antiplasmin functional activity assay Confirmatory Low / absent
α2-AP antigen (ELISA) Distinguishes quantitative vs dysfunctional Low (type I) or normal (type II dysfunctional)
Thromboelastography / ROTEM Global screen that can flag the defect Accelerated clot lysis
SERPINF2 sequencing Definitive genetic diagnosis Biallelic (severe) or single pathogenic variant
MRI (for intramedullary hematoma) Imaging of distinctive lesion T1/T2 hyperintense medullary signal

Viscoelastic testing can be the entry point to diagnosis: a novel SERPINF2 variant was detected after "Abnormal fibrinolysis recognized by thromboelastography in a case of severe bleeding with normal coagulation and platelet function" (PMID: 31282989). For the intramedullary hematoma, "MRI is diagnostic with the haematoma generating a specific hyperintense signal on T1-weighted and T2-weighted spin-echo images" (PMID: 9880645).

Genetic testing utility. Single-gene SERPINF2 testing is the targeted approach once the functional assay points to α2-AP deficiency; WES/WGS or small bleeding-disorder gene panels are useful when the phenotype is undifferentiated. CMA, karyotyping, FISH, mtDNA, and repeat-expansion testing are not applicable.

Differential diagnosis. Plasminogen activator inhibitor-1 (PAI-1) deficiency (the other inherited hyperfibrinolytic bleeding disorder), factor XIII deficiency (impaired α2-AP cross-linking; also normal PT/aPTT), mild von Willebrand disease, and acquired hyperfibrinolysis (malignancy, liver disease, DIC "bleeding type").

Section 11 — Outcome / Prognosis

Prognosis is generally good when the diagnosis is known and antifibrinolytic prophylaxis is applied. The disorder is chronic and lifelong, but major surgery can be performed safely: a congenital α2-PI-deficient patient underwent single-lung transplantation with prophylactic fresh frozen plasma plus tranexamic acid and ROTEM monitoring, with an uneventful course—"Lung transplantation for a patient with α2-PI deficiency was safely performed with the use of planned FFP transfusion and tranexamic acid" (PMID: 40589561).

The principal danger is unrecognized disease: severe bleeding with normal screening tests leads to diagnostic delay, transfusion dependence, and risk of life-threatening hemorrhage (including intracranial and intramedullary bleeds) in homozygotes. "Management of such patients may be challenging especially when the diagnosis of alpha-2 antiplasmin deficiency is not known" (PMID: 33337837).

  • Mortality / survival: no formal survival statistics for this ultra-rare disease; mortality risk is driven by severe unrecognized hemorrhage, which is largely preventable with treatment.
  • Morbidity: bleeding-related disability, anemia, transfusion burden; well controlled once recognized.
  • Prognostic factors: genotype (homozygous vs heterozygous), residual α2-AP activity, and—critically—whether the diagnosis is established before a major hemostatic challenge.

Section 12 — Treatment

Mainstay — antifibrinolytics. Tranexamic acid and ε-aminocaproic acid are first-line and mechanistically rational, substituting pharmacologically for the missing fibrinolytic brake: "Antifibrinolytic agents, such as tranexamic acid or ε-aminocaproic acid, are the mainstays of treatment which inhibit fibrinolysis by preventing the binding of plasminogen to fibrin and thereby stabilizing the fibrin clot" (PMID: 31427261).

Evidence-based procedural dosing (dental extraction). "we advocate that 7.5–10 mg kg⁻¹ of tranexamic acid be administered orally every 6 h, starting 3 h before surgery and continuing for about 7 days" (PMID: 15357795); continuous post-extraction bleeding is managed with IV tranexamic acid ~20 mg/kg.

Major surgery. Perioperative management combines prophylactic FFP plus tranexamic acid with viscoelastic (ROTEM) monitoring (PMID: 40589561).

Suggested NCIT terms: tranexamic acid (NCIT:C47748), aminocaproic acid (NCIT:C28987), fresh frozen plasma transfusion.

Not applicable / none established: no gene therapy, cell therapy, RNA therapy, targeted biologic, or α2-AP replacement product is approved for this indication. (Interestingly, α2-AP inhibition is being explored as a therapy for other diseases—stroke, fibrosis—the therapeutic inverse of this deficiency.) Pharmacogenomics: none specific.

Section 13 — Prevention

  • Primary prevention: not possible for a congenital genetic disorder; genetic counseling and carrier assessment in consanguineous or affected families are the key tools. Prenatal/preimplantation testing is feasible when the familial SERPINF2 variant is known.
  • Secondary prevention (early detection): recognizing the phenotype (bleeding with normal screens) and confirming with α2-AP activity assay / sequencing prevents morbidity; cascade testing of relatives identifies at-risk individuals.
  • Tertiary prevention (preventing complications): peri-procedural antifibrinolytic prophylaxis is the central preventive intervention—administering tranexamic acid before dental work, surgery, or after trauma prevents the delayed bleed (PMID: 15357795).
  • Immunization / public health / environmental: not applicable.

Section 14 — Other Species / Natural Disease

A naturally occurring, closely analogous disorder exists in dogs. Whole-genome-sequencing GWAS in 269 Scottish deerhounds mapped delayed postoperative hemorrhage (DEPOH) to a chromosome-9 locus, with SERPINF2 as the causal gene: "One of these genes (SERPINF2 encoding alpha-2 antiplasmin) was directly linked to the pathophysiology of DEPOH" (PMID: 36780177). The missense variant c.605C>T (p.A202V) shows a strong gene-dose effect: "the likelihood of DEPOH was significantly higher for dogs with the T/T genotype (odds ratio [OR] = 1235; 95% confidence interval [CI] = 23–6752; P = 0.0005)" (PMID: 36780177); heterozygotes OR = 28 (95% CI 1.4–542, P = 0.03).

  • Taxonomy: Canis lupus familiaris (NCBI Taxon 9615); model mouse Mus musculus (NCBI Taxon 10090).
  • Breed: Scottish deerhound (VBO term applicable).
  • Orthologous gene: canine and murine Serpinf2.
  • Comparative biology: the canine disorder recapitulates the human delayed-bleeding, gene-dose-dependent phenotype, confirming evolutionary conservation of α2-AP's hemostatic role and offering a naturally occurring veterinary model. No zoonotic potential (genetic disease).

Section 15 — Model Organisms

α2-antiplasmin knockout mouse (α2AP⁻/⁻). This is the principal validated mammalian model. Beyond confirming the hemostatic phenotype, it revealed pleiotropic roles: "an accelerated wound closure was observed in alpha(2)AP-deficient (alpha(2)AP⁻/⁻) mice in comparison with wild type (WT) mice" and "The lack of alpha(2)AP markedly causes an over-release of VEGF from the fibroblasts in cutaneous wound lesions, thereby inducing angiogenesis around the area" (PMID: 16839360). The same genetic model has been used to show reduced fibrosis/EndoMT in diabetic nephropathy (PMID: 34709571) and attenuated fibrosis in systemic-sclerosis models (PMID: 35330147).

Model Type Recapitulation Use Resource
α2AP⁻/⁻ mouse Knockout, mammalian Hyperfibrinolytic tendency; +wound-healing/angiogenesis, −fibrosis phenotypes Mechanism, therapeutics MGI
Scottish deerhound (natural) Spontaneous, canine Delayed postoperative hemorrhage, gene-dose Natural disease, genetics OMIA/VetCompass
Murine crystal structure (protein) In vitro/structural Serpin domain architecture Structure–function PDB

Limitations of models: mouse and dog capture hemostatic and remodeling biology, but species differences in fibrinolytic kinetics and clinical bleeding thresholds mean human dosing/management cannot be read directly from models.

Mechanistic Model / Interpretation

  SERPINF2 biallelic LOF variant
    │ (demonstrated)
    ▼
  Absent / non-functional α2-antiplasmin
    │  removes 3 brakes on plasmin:
    │   (i) covalent plasmin inhibition
    │   (ii) block plasminogen→fibrin binding
    │   (iii) FXIIIa cross-link into fibrin
    ▼
  Unopposed, unregulated plasmin activity
    │
    ▼
  Fibrin clots form normally → prematurely LYSED (hyperfibrinolysis)
    │
   ┌────────┴─────────────┐
   ▼                      ▼
 HOMOZYGOTE             HETEROZYGOTE
 severe, early-childhood,   mild / provoked bleeding
 spontaneous bleeding       (surgery, dental, trauma)
 (incl. intracranial,
  intramedullary hematoma)
    │
    ▼
  DELAYED bleeding (plug forms, then dissolves)
  with NORMAL PT/aPTT/platelets/VWF  → diagnostic delay
    │
    ▼
  Treatment: antifibrinolytics (TXA / EACA)
  pharmacologically restore the fibrinolytic brake → good prognosis

  PLEIOTROPY (model-based): ↓α2-AP → ↑VEGF/angiogenesis (wound healing),
  ↓fibrosis/EndoMT, ↑thrombolysis — therapeutic inverse of the deficiency

The unifying concept is a quantitative imbalance in fibrinolysis: α2-AP is the dominant, fastest-acting plasmin inhibitor, and its loss shifts the clot formation↔dissolution equilibrium toward dissolution. Because coagulation itself is intact, standard tests are normal and the defect is "invisible" unless fibrinolysis is specifically interrogated. The same biology that makes α2-AP essential for clot stability makes it a liability in fibrotic and thrombotic disease—explaining the active interest in α2-AP inhibition as therapy elsewhere.

Evidence Base

PMID Role in this report
31427261 Defines α2-AP deficiency as most severe inherited fibrinolytic disorder; AR inheritance; antifibrinolytic mainstay
42257473 Three-mechanism model; premature clot breakdown; diagnostic delay case with normal screens + homozygous SERPINF2
33337837 Literature survey of 123 cases; gene-dose phenotype; management challenge when undiagnosed
15357795 Evidence-based tranexamic acid dosing for dental extractions
31282989 TEG/thromboelastography detection leading to novel SERPINF2 variant
16839360 α2AP⁻/⁻ mouse: accelerated wound healing via VEGF/angiogenesis
36780177 Natural canine disease (Scottish deerhound DEPOH); SERPINF2 p.A202V; OR quantification
18063751 Crystal structure; N-terminal FXIIIa cross-link vs C-terminal plasmin binding
33992873 PB→NPB heterogeneity; polymorphisms affecting processing
19141165 Rarity; increased fibrinolysis mechanism; historical context
9880645 Intramedullary hematoma case; MRI diagnostic
10583218 Missense p.Val384Met near reactive-site Arg376; 49–66% activity
12544738 Splice-site variant (Artas) → exon 6 skipping
21873355 Intramedullary hematoma as rare manifestation
35330147 α2-AP blockade antifibrotic in systemic sclerosis model
34709571 α2-AP deficiency attenuates EndoMT/fibrosis (diabetic nephropathy)
42589214 α2-AP limits thrombolysis; anti-α2AP synergizes with tenecteplase
40589561 Safe lung transplant with FFP + TXA (favorable prognosis)

Evidence source types span human clinical (case reports/series, surveys), model organism (knockout mouse, natural canine disease), in vitro/structural (crystal structure, cross-linking biochemistry), and computational/aggregated (GWAS, literature survey).

Limitations and Knowledge Gaps

  1. Ultra-rarity and evidence quality. The entire human evidence base rests on ~123 reported patients and scattered case reports; there are no randomized trials, no prospective natural-history cohorts, and no formal incidence/prevalence or survival statistics.
  2. Genotype–phenotype correlation is incomplete. Variants are largely private; residual-activity thresholds that predict spontaneous vs provoked bleeding are not precisely defined.
  3. No validated modifiers / epigenetics. Disease-modifier genes and epigenetic contributions are unexplored.
  4. QoL and long-term outcomes are undocumented with standardized instruments.
  5. Dosing evidence is extrapolated from small series; optimal long-term antifibrinolytic regimens and thrombotic risk of chronic prophylaxis are not rigorously established.
  6. Pleiotropy findings derive mainly from mouse models; their relevance to human α2-AP-deficient patients (e.g., altered wound healing or fibrosis) has not been systematically assessed in patients.

Proposed Follow-up Experiments / Actions

  1. Establish an international patient registry for SERPINF2 deficiency to capture genotype, residual α2-AP activity, bleeding phenotype, treatment, and outcomes—enabling genotype–phenotype and natural-history analyses.
  2. Standardize diagnostics: promote reflex α2-AP functional activity testing (and TEG/ROTEM screening) in patients with bleeding plus normal PT/aPTT/VWF to shorten the diagnostic delay; curate a SERPINF2 variant database with ACMG classifications.
  3. Characterize residual-activity thresholds correlating α2-AP activity with spontaneous-bleeding risk to guide prophylaxis intensity.
  4. Prospective evaluation of antifibrinolytic prophylaxis regimens (dose, duration, route) around surgery and dental procedures, including thrombotic safety.
  5. Leverage the Scottish deerhound natural model and α2AP⁻/⁻ mouse for preclinical testing of α2-AP repletion strategies and to study the pleiotropic wound-healing/fibrosis phenotypes relevant to human patients.
  6. Clinical awareness in human/veterinary cross-talk: apply the canine SERPINF2 p.A202V finding to screen at-risk deerhound lines, and use comparative data to refine human variant interpretation.

Report prepared from a 5-iteration autonomous investigation (13 confirmed findings, 54 papers reviewed). Evidence is drawn exclusively from the cited primary literature; claims are attributed only to papers whose abstracts/quotes were verified during the investigation.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 19
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 26
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 13
Terms named correctly 11
Terms named as a different term 1
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0009883 (3 mentions) - the report calls it "if available", "MONDO"; MONDO calls it alpha-2-plasmin inhibitor deficiency

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0006298 (1 mention) - the report calls it "prolonged bleeding following procedure"; HP calls it Prolonged bleeding after dental extraction

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MONDO:0009883 - called "if available", "MONDO"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.