Alpha-2-plasmin inhibitor deficiency

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Alpha-2-plasmin inhibitor deficiency, also known as alpha-2-antiplasmindeficiency or congenital alpha-2-antiplasmin deficiency, is a rare autosomal recessive coagulopathy characterized by impaired inhibition of plasmin, leading to increased fibrinolysis and a heightened risk of bleeding. [1] [2]

Contents

Genetics

Alpha-2-plasmin inhibitor deficiency is caused by mutations in the SERPINF2 gene, which encodes the alpha-2-plasmin inhibitor (Alpha 2-antiplasmin) protein. [3] The condition is inherited in an autosomal recessive manner, meaning that an individual must inherit two defective copies of the gene, one from each parent, to develop the disorder. [4]

Pathophysiology

The pathophysiology of alpha-2-plasmin inhibitor deficiency is intricately linked to the crucial role that alpha-2-plasmin inhibitor plays in regulating fibrinolysis. This serine protease inhibitor, also known as a serpin, is primarily responsible for inactivating plasmin, the key enzyme involved in breaking down fibrin clots. In normal physiological conditions, alpha 2-antiplasmin acts as a regulatory brake on the fibrinolytic system, ensuring that blood clots are not prematurely dissolved. [5] In individuals with alpha-2-plasmin inhibitor deficiency, the absence or significant reduction of functional α2-antiplasmin leads to a dysregulation of the fibrinolytic process. [6] Without this inhibitory protein, plasmin activity goes largely unchecked, resulting in an accelerated and excessive breakdown of fibrin clots. [7] This means that even as the body forms necessary blood clots in response to injury or during normal hemostasis, these clots are rapidly and precipitously dissolved. [8]

Despite the significant impact on fibrinolysis, alpha-2-plasmin inhibitor deficiency does not affect the initial stages of blood coagulation. Standard coagulation tests such as prothrombin time (PT) and activated partial prothrombin time (aPTT) typically remain within normal ranges. [6] Furthermore, the condition does not lead to a systemic lytic state or disseminated intravascular coagulation, distinguishing it from other disorders that might cause widespread clotting abnormalities. [6] [9]

Symptoms

One of the hallmark symptoms is a tendency for prolonged bleeding following minor trauma or injury. Patients often report experiencing delayed oozing from wound sites, which can persist long after the initial injury has occurred. This delayed bleeding is a result of the premature dissolution of blood clots due to uninhibited plasmin activity. [10] Spontaneous bleeding episodes are another significant concern. These episodes can manifest in various ways, including recurrent epistaxis and gum bleeding. Some patients may experience more severe spontaneous hemorrhages, which can occur in atypical locations such as the diaphysis of long bones. [11] Patients with congenital deficiency of alpha 2-antiplasmin may present with a severe hemorrhagic disorders. [12]

Diagnosis

Diagnosis of alpha-2-plasmin inhibitor deficiency involves clinical evaluation of bleeding symptoms and family history assessment. Laboratory tests include a functional α2-antiplasmin assay (levels below 10% in homozygous individuals), genetic testing for mutations in the SERPINF2 gene and normal results for standard coagulation tests (PT, aPTT). [1] [6] Clinical assays for Alpha 2-antiplasmin levels are not widely available, and many patients are identified during comprehensive hematologic evaluations for unexplained delayed bleeding episodes. [6]

Treatment

The treatment of alpha-2-plasmin inhibitor deficiency primarily focuses on managing bleeding episodes and preventing complications. Antifibrinolytic therapy is the cornerstone of treatment, with aminocaproic acid or tranexamic acid being the most commonly used medications. These drugs help stabilize blood clots by inhibiting plasmin formation and activity, thereby compensating for the lack of alpha-2-plasmin inhibitor. [12]

For patients experiencing severe bleeding episodes or those undergoing surgical procedures, fresh frozen plasma (FFP) transfusion is recommended as a source of exogenous alpha-2-plasmin inhibitor. This temporary supplementation can help restore normal fibrinolytic balance and reduce bleeding risk. [10]

In some cases, additional supportive measures may be necessary. For instance, vitamin K supplementation has been reported to improve the condition of some patients, although the mechanism of action in this context is not fully understood. [10]

Epidemiology

Alpha-2-plasmin inhibitor deficiency is extremely rare, with fewer than 20 cases of homozygous deficiency reported worldwide as of the most comprehensive review. The true prevalence may be underestimated due to diagnostic challenges and potential misdiagnosis. [6]

Related Research Articles

<span class="mw-page-title-main">Thrombus</span> Blood clot

A thrombus, colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through a healthy blood vessel in the circulatory system.

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Disseminated intravascular coagulation</span> Medical condition where blood clots block small blood vessels

Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts of the body. As clotting factors and platelets are used up, bleeding may occur. This may include blood in the urine, blood in the stool, or bleeding into the skin. Complications may include organ failure.

<span class="mw-page-title-main">Fibrinogen</span> Soluble protein complex in blood plasma and involved in clot formation

Fibrinogen is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.

<span class="mw-page-title-main">Thrombin</span> Enzyme involved in blood coagulation in humans

Prothrombin is encoded in the human by the F2-gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin.

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.

alpha-2-Macroglobulin Large plasma protein found in the blood

α2-Macroglobulin (α2M) or alpha-2-macroglobulin is a large plasma protein found in the blood. It is mainly produced by the liver, and also locally synthesized by macrophages, fibroblasts, and adrenocortical cells. In humans it is encoded by the A2M gene.

<span class="mw-page-title-main">Plasmin</span> Enzyme in human blood that degrades clots and other proteins

Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, including fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.

Mixing studies are tests performed on blood plasma of patients or test subjects to distinguish factor deficiencies from factor inhibitors, such as lupus anticoagulant, or specific factor inhibitors, such as antibodies directed against factor VIII. Mixing studies are screening tests widely performed in coagulation laboratories. The basic purpose of these tests is to determine the cause of prolongation of Prothrombin Time (PT), Partial Thromboplastin Time, or sometimes of thrombin time (TT). Mixing studies take advantage of the fact that factor levels that are 50 percent of normal should give a normal Prothrombin time (PT) or Partial thromboplastin time (PTT) result.

<span class="mw-page-title-main">Alpha 2-antiplasmin</span> Protein-coding gene in the species Homo sapiens

Alpha 2-antiplasmin is a serine protease inhibitor (serpin) responsible for inactivating plasmin. Plasmin is an important enzyme that participates in fibrinolysis and degradation of various other proteins. This protein is encoded by the SERPINF2 gene.

<span class="mw-page-title-main">Plasminogen activator</span> Type of protein

Plasminogen activators are serine proteases that catalyze the activation of plasmin via proteolytic cleavage of its zymogen form plasminogen. Plasmin is an important factor in fibrinolysis, the breakdown of fibrin polymers formed during blood clotting. There are two main plasminogen activators: urokinase (uPA) and tissue plasminogen activator (tPA). Tissue plasminogen activators are used to treat medical conditions related to blood clotting including embolic or thrombotic stroke, myocardial infarction, and pulmonary embolism.

<span class="mw-page-title-main">Aminocaproic acid</span> Chemical compound

Aminocaproic acid is a derivative and analogue of the amino acid lysine, which makes it an effective inhibitor for enzymes that bind that particular residue. Such enzymes include proteolytic enzymes like plasmin, the enzyme responsible for fibrinolysis. For this reason it is effective in treatment of certain bleeding disorders, and it is sold under the brand name Amicar. Aminocaproic acid is also an intermediate in the polymerization of Nylon-6, where it is formed by ring-opening hydrolysis of caprolactam. The crystal structure determination showed that the 6-aminohexanoic acid is present as a salt, at least in the solid state.

<span class="mw-page-title-main">Hypoprothrombinemia</span> Medical condition

Hypoprothrombinemia is a rare blood disorder in which a deficiency in immunoreactive prothrombin, produced in the liver, results in an impaired blood clotting reaction, leading to an increased physiological risk for spontaneous bleeding. This condition can be observed in the gastrointestinal system, cranial vault, and superficial integumentary system, affecting both the male and female population. Prothrombin is a critical protein that is involved in the process of hemostasis, as well as illustrating procoagulant activities. This condition is characterized as an autosomal recessive inheritance congenital coagulation disorder affecting 1 per 2,000,000 of the population, worldwide, but is also attributed as acquired.

<span class="mw-page-title-main">Factor VII deficiency</span> Medical condition

Factor VII deficiency is a bleeding disorder characterized by a lack in the production of Factor VII (FVII) (proconvertin), a protein that causes blood to clot in the coagulation cascade. After a trauma factor VII initiates the process of coagulation in conjunction with tissue factor in the extrinsic pathway.

<span class="mw-page-title-main">Thrombin time</span> Medical diagnostic test

The thrombin time (TT), also known as the thrombin clotting time (TCT), is a blood test that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added. It is used to diagnose blood coagulation disorders and to assess the effectiveness of fibrinolytic therapy. This test is repeated with pooled plasma from normal patients. The difference in time between the test and the 'normal' indicates an abnormality in the conversion of fibrinogen to fibrin, an insoluble protein.

The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor, fibrinogen, circulates at normal levels but is dysfunctional. Congenital dysfibrinogenemia is an inherited disorder in which one of the parental genes produces an abnormal fibrinogen. This fibrinogen interferes with normal blood clotting and/or lysis of blood clots. The condition therefore may cause pathological bleeding and/or thrombosis. Acquired dysfibrinogenemia is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of liver disease, autoimmune disease, a plasma cell dyscrasias, or certain cancers. It is associated primarily with pathological bleeding. Hereditary fibrinogen Aα-Chain amyloidosis is a sub-category of congenital dysfibrinogenemia in which the dysfunctional fibrinogen does not cause bleeding or thrombosis but rather gradually accumulates in, and disrupts the function of, the kidney.

<span class="mw-page-title-main">Quebec platelet disorder</span> Medical condition

Quebec platelet disorder (QPD) is a rare autosomal dominant bleeding disorder first described in a family from the province of Quebec, Canada. The disorder is characterized by large amounts of the fibrinolytic enzyme urokinase-type plasminogen activator (uPA) in platelets. This causes accelerated fibrinolysis which can result in bleeding.

The fibrinolysis system is responsible for removing blood clots. Hyperfibrinolysis describes a situation with markedly enhanced fibrinolytic activity, resulting in increased, sometimes catastrophic bleeding. Hyperfibrinolysis can be caused by acquired or congenital reasons. Among the congenital conditions for hyperfibrinolysis, alpha-2-plasmin inhibitor deficiency or plasminogen activator inhibitor type 1 (PAI-1) are very rare. The affected individuals show a hemophilia-like bleeding phenotype. Acquired hyperfibrinolysis is found in liver disease, in patients with severe trauma, during major surgical procedures, and other conditions. A special situation with temporarily enhanced fibrinolysis is thrombolytic therapy with drugs which activate plasminogen, e.g. for use in acute ischemic events or in patients with stroke. In patients with severe trauma, hyperfibrinolysis is associated with poor outcome. Moreover, hyperfibrinolysis may be associated with blood brain barrier impairment, a plasmin-dependent effect due to an increased generation of bradykinin.

Thromboelastometry (TEM), previously named rotational thromboelastography (ROTEG) or rotational thromboelastometry (ROTEM), is an established viscoelastic method for hemostasis testing in whole blood. It is a modification of traditional thromboelastography (TEG).

Plasmin-α2-antiplasmin complex (PAP) is a 1:1 irreversibly formed inactive complex of the enzyme plasmin and its inhibitor α2-antiplasmin. It is a marker of the activity of the fibrinolytic system and a marker of net activation of fibrinolysis.

References

  1. 1 2 "A2PI - Overview: Alpha-2 Plasmin Inhibitor, Plasma". Archived from the original on 2023-03-23. Retrieved 2024-12-12.
  2. ↑ Carpenter, S. L.; Mathew, P. (2008). "Alpha2-antiplasmin and its deficiency: fibrinolysis out of balance". Haemophilia: The Official Journal of the World Federation of Hemophilia. 14 (6): 1250–1254. doi:10.1111/j.1365-2516.2008.01766.x. ISSN   1365-2516. PMID   19141165 . Retrieved 12 December 2024.
  3. ↑ "Orphanet: SERPINF2-serpin family F member 2". www.orpha.net. Retrieved 2024-12-12.
  4. ↑ "alpha-2-plasmin inhibitor deficiency - National Organization for Rare Disorders". rarediseases.org. Retrieved 2024-12-12.
  5. ↑ "Alpha2-Plasmin Inhibitor Assays". practical-haemostasis.com. Retrieved 2024-12-12.
  6. 1 2 3 4 5 6 Reed, Guy L; Houng, Aiilyan K; Singh, Satish; Wang, Dong (29 July 2016). "α2-Antiplasmin: New Insights and Opportunities for Ischemic Stroke". Seminars in Thrombosis and Hemostasis. 43 (2): 191–199. doi:10.1055/s-0036-1585077. PMC   5592111 . PMID   27472428.
  7. ↑ Singh, Satish; Saleem, Sofiyan; Reed, Guy L (2020). "Alpha2-Antiplasmin: The Devil You Don't Know in Cerebrovascular and Cardiovascular Disease". Frontiers in Cardiovascular Medicine. 7. doi: 10.3389/fcvm.2020.608899 . PMC   7785519 . PMID   33426005.
  8. ↑ Hou, YongZhong; Okada, Kiyotaka; Okamoto, Chikako; Ueshima, Shigeru; Matsuo, Osamu (2008). "Alpha2-Antiplasmin Is a Critical Regulator of Angiotensin II–Mediated Vascular Remodeling". Ahajournals. 28 (7): 1257–1262. doi:10.1161/ATVBAHA.108.165688. PMID   18436805 . Retrieved 12 December 2024.
  9. ↑ Meyer, K.; Williams, E. C. (September 1985). "Fibrinolysis and acquired alpha-2 plasmin inhibitor deficiency in amyloidosis". The American Journal of Medicine. 79 (3): 394–396. doi:10.1016/0002-9343(85)90321-3. ISSN   0002-9343. PMID   4036990.
  10. 1 2 3 Mohammed, Bashir Abdrhman Bashir (2021-05-07). "Alpha 2-antiplasmin deficiency in a Sudanese child: a case report". Journal of Medical Case Reports. 15 (1): 238. doi: 10.1186/s13256-021-02813-6 . ISSN   1752-1947. PMC   8103643 . PMID   33957960.
  11. ↑ "Orphanet: Congenital alpha2-antiplasmin deficiency". www.orpha.net. Retrieved 2024-12-12.
  12. 1 2 "Alpha 2-Antiplasmin Deficiency – Rare Coagulation Disorders". rarecoagulationdisorders.org. Retrieved 2024-12-12.
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