Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis

INTRODUCTION — The hemostatic system mediates clot formation (hemostasis) and clot breakdown (fibrinolysis):

●Hemostasis – Most bleeding and clotting disorders are caused by abnormalities in hemostasis (dysfunction of platelets and/or clotting proteins). (See "Overview of hemostasis".)

●Fibrinolysis – Less commonly, excessive bleeding or clotting can be caused by abnormalities in the fibrinolytic system. These disorders are the subject of this topic review.

General discussions of causes of excess bleeding and excess clotting are presented separately. (See "Approach to the adult with a suspected bleeding disorder" and "Overview of the causes of venous thrombosis".)

OVERVIEW OF THE FIBRINOLYTIC SYSTEM

Fibrinolytic process — The fibrinolytic system is essential for restoring blood vessel patency following clot formation. It also plays important roles in wound healing and tissue remodeling. The fibrinolytic system consists of proteolytic and regulatory factors.

The key components are illustrated in (figure 1) and include the following [1,2]:

●Proteases

•Plasmin, which cleaves fibrin

•Plasminogen, the precursor molecule (proenzyme) to plasmin

•Tissue-type plasminogen activator (tPA), the protease that cleaves plasminogen to plasmin

•Urokinase (also referred to as urinary-type plasminogen activator [uPA]), which also cleaves plasminogen to form plasmin

●Inhibitors

•Plasminogen activator inhibitor 1 (PAI-1), the physiologic inhibitor of tPA and uPA

•Alpha-2-antiplasmin, the physiologic inhibitor of plasmin

•Thrombin-activatable fibrinolysis inhibitor (TAFI), a proenzyme that, upon activation, inhibits recruitment of plasminogen and tPA to the clot by removing C-terminal lysine residues from fibrin fragments, thereby slowing fibrinolysis

Disorders affecting the abundance or function of these proteins can cause excess bleeding or thrombosis, with the clinical phenotype depending on which component is altered and whether its activity is increased or decreased.

Changes that increase the activity of plasmin can result in bleeding disorders (see 'Disorders with excess bleeding' below), whereas those that decrease plasmin activity can result in thrombosis. (See 'Thrombotic disorders' below.)

Plasmin has broad substrate specificity. It cleaves the polymerized fibrin strand at arginine and lysine residues, thereby producing fibrin degradation products (FDPs). Plasmin also cleaves fibrinogen and several other plasma proteins and clotting factors.

One of the major FDPs is D-dimer, which consists of two D domains from adjacent fibrin monomers that have been crosslinked by activated factor XIII (FXIIIa). Since D-dimer is generated from cross-linked fibrin, but not from fibrinogen, an elevated plasma concentration of D-dimer indicates recent or ongoing intravascular blood coagulation [3]. (See "Clinical use of coagulation tests", section on 'Fibrin D-dimer'.)

Roles of specific proteins — Fibrinolytic proteins are summarized in the table (table 1) and discussed below.

Plasminogen — Plasminogen, the central zymogen of the fibrinolytic system, circulates in plasma at a concentration of approximately 2 microM. Plasminogen activators (see 'tPA and uPA' below) convert plasminogen to plasmin, a serine protease that degrades fibrin and other proteins.

Plasmin activity is tightly regulated by control of its formation and by the plasmin inhibitor alpha-2-antiplasmin. (See 'Alpha-2-antiplasmin' below.)

The plasminogen molecule contains specific lysine-binding sites, referred to as kringles, that mediate interactions with its targets (fibrin and plasminogen receptors) and major inhibitor (alpha-2-antiplasmin).

tPA and uPA — Tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA; urokinase) are the two main activators of plasminogen to plasmin.

●tPA – tPA is secreted by vascular endothelial cells and circulates in plasma in trace concentrations (typically below 10 ng/mL).

The primary role of tPA is to degrade intravascular fibrin by converting plasminogen to plasmin. Plasminogen binds to fibrin, which greatly accelerates its rate of activation by tPA. Therefore, tPA is a fibrin-specific plasminogen activator, which limits formation of plasmin in plasma and focuses its activity at sites of fibrin formation.

Recombinant forms of tPA are used clinically as thrombolytic therapy for arterial and large venous thrombi. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and "Acute ST-elevation myocardial infarction: The use of fibrinolytic therapy".)

●uPA – uPA (urokinase) is secreted by a variety of cell types, including nonvascular cells.

Like tPA, uPA is present in low concentrations in plasma (typically 5 to 10 ng/mL), where it catalyzes plasmin formation and fibrinolysis. In contrast to tPA, uPA is not fibrin-specific. A more important role for uPA appears to be within the extravascular compartment, where it regulates fibrin accumulation within parenchyma and controls cell migration and function by binding to the uPA receptor (uPAR), which is expressed by many cell types [4].

Congenital deficiency of tPA or uPA has not been described in the medical literature, suggesting that complete deficiency of either of these factors may be lethal in utero. tPA and uPA are metabolized by the liver. Thus, severe liver disease can lead to increased circulating levels and increased bleeding risk. (See 'Excess tPA or uPA' below and "Hemostatic abnormalities in patients with liver disease", section on 'Altered fibrinolytic system'.)

Alpha-2-antiplasmin — Alpha-2-antiplasmin (also referred to as alpha-2-plasmin inhibitor) is produced in the liver and is abundant in plasma (concentration, 1 microM), where it is the major physiologic inhibitor of plasmin [5].

Although alpha-2-antiplasmin rapidly inactivates plasmin, it circulates at lower concentrations than plasminogen (2 microM). Therefore, intense plasminogen activation (eg, as occurs after administration of streptokinase, a non-fibrin-specific plasminogen activator purified from streptococci and used as a drug to lyse thrombi) can generate a concentration of plasmin exceeding that of alpha-2-antiplasmin, resulting in circulating free plasmin and a systemic fibrinolytic state.

PAI-1 — Plasminogen activator inhibitor-1 (PAI-1), encoded by the SERPINE1 gene, is present in plasma in concentrations that usually range from 17 to 300 ng/mL [6]. It is secreted by multiple cell types, including vascular endothelium, smooth muscle cells, hepatocytes, and adipocytes. Blood platelets contain PAI-1 and secrete it at sites of platelet activation.

PAI-1 suppresses fibrinolysis by inhibiting tPA and uPA and in turn suppressing plasmin formation [7-9].

TAFI — Thrombin activatable fibrinolysis inhibitor (TAFI) is a circulating procarboxypeptidase that is activated by thrombin, plasmin, or the thrombin-thrombomodulin complex. Activated TAFI cleaves C-terminal lysine and arginine residues from fibrin fragments (to which plasminogen and tPA bind with high affinity via their kringle domains), thereby disrupting recruitment of plasminogen and tPA to the partially digested fibrin clot, inhibiting fibrinolysis.

EPIDEMIOLOGY

●Congenital – Congenital disorders of fibrinolysis are very rare. The prevalence has not been defined, as publications of these abnormalities generally involve reports of isolated cases or extended pedigrees.

●Acquired – Acquired abnormalities of fibrinolysis are also rare and of undefined prevalence. However, these disorders are recognized to occur in specific clinical settings that are discussed below.

DISORDERS WITH EXCESS BLEEDING — Abnormal bleeding can result from fibrinogen deficiency/dysfunction or conditions that enhance fibrinolysis, either due to excessive plasminogen activation or deficiencies of fibrinolysis inhibitors.

Evaluation and laboratory testing for these disorders is discussed below. (See 'Evaluation for abnormal fibrinolysis' below.)

Fibrinogen deficiency and dysfunction are discussed separately. (See "Disorders of fibrinogen".)

Excess tPA or uPA — Congenital overexpression of tissue-type or urinary-type plasminogen activator (tPA or uPA), causing hyperfibrinolysis via excess activation of plasminogen to plasmin, is extremely rare, described only in case reports [10-13].

Acquired excesses in tPA or uPA can occur with chronic liver disease or the anhepatic period during orthotopic liver transplantation. The liver is responsible for metabolizing tPA and uPA, so decreased hepatic function can lead to a hyperfibrinolytic state due to decreased clearance of tPA from the circulation. (See "Hemostatic abnormalities in patients with liver disease", section on 'Altered fibrinolytic system' and "Hemostatic abnormalities in patients with liver disease", section on 'Bleeding'.)

Quebec platelet disorder — Quebec platelet disorder (QPD), also called Quebec platelet syndrome (QPS), is a congenital platelet disorder in which excessive production of uPA within platelet alpha granules is responsible for increased bleeding risk [14-18]. The condition is extremely rare, with an estimated prevalence of 1:220,000 in Quebec, Canada and 1:655,000 in Canada overall [16]. Its prevalence worldwide is less. Inheritance is autosomal dominant with high penetrance. QPD is due to a tandem duplication of PLAU, the gene that encodes uPA [19]. The duplicated copy of the PLAU gene is placed in a region of DNA controlled by a strong megakaryocyte-specific transcriptional enhancer, markedly increasing its expression [20,21].

The resulting platelets have high levels of uPA overexpression, which appears to inhibit normal hemostasis by several mechanisms:

●Premature clot lysis – Overexpression of uPA and its release upon platelet activation contributes to premature lysis of thrombi. Studies of transgenic mice with platelet-specific overexpression of uPA suggest that premature clot lysis due to localized release of uPA from platelets is the predominant cause of bleeding [22].

●Low platelet factor V – In individuals without QPD, approximately 20 percent of factor V in blood is carried within the alpha granules of platelets, with the balance in the plasma. During platelet activation, factor V and other active compounds carried in alpha granules are released, generating high local concentrations of these procoagulant factors within the forming clot.

•Individuals with QPD have overexpression of uPA within platelet alpha granules.

•The uPA activates plasminogen (which is also present within alpha granules) to plasmin, degrading intra-platelet stores of factor V and other hemostasis-related proteins, such as fibrinogen, producing a hemostatic abnormality [23].

Clinically, QPD is characterized by moderately severe bleeding that typically occurs 12 to 24 hours after surgery or trauma [24]. In a questionnaire sent to members of a large extended kindred with QPD, bleeding into joints, bleeding longer than 24 hours after dental extraction or deep cuts, poor wound healing, heavy menstrual bleeding, spontaneous hematuria, and large bruises were commonly reported by affected relatives [25].

On laboratory evaluation, mild thrombocytopenia is common. Platelet aggregation studies can be abnormal [13]. Specialized laboratory testing, including analysis of platelet factor V, fibrinogen, and uPA, can be useful in establishing the diagnosis [16]. Genetic testing can be used for diagnostic confirmation [19].

Management may include administration of antifibrinolytic agents (tranexamic acid or aminocaproic acid) at the time of bleeding or perioperatively [26-28]. (See 'Management' below.)

Platelet transfusion is not recommended, as it does not provide benefit.

Alpha-2-antiplasmin deficiency — Congenital deficiency of alpha-2-antiplasmin is a very rare bleeding disorder of undefined prevalence that results in enhanced plasmin activity and fibrinolysis [29-31].

Since the blood coagulation system and platelets function normally in individuals with alpha-2-antiplasmin deficiency, initial blood clotting after trauma is usually normal, with affected individuals typically presenting with delayed bleeding. Prolonged bleeding, mimicking hemophilia, can also occur.

Bleeding after dental extraction and surgery are the most reported presentations. Multiple sites of bleeding have been observed, including epistaxis, gastrointestinal, and heavy menstrual bleeding, as well as intramedullary hematoma, an unusual form of bleeding.

Homozygous (complete) deficiency of alpha-2-antiplasmin produces a more severe bleeding phenotype than heterozygous deficiency. A systematic literature review found 104 individuals with heterozygous deficiency, of which 63 percent were asymptomatic; however, severe bleeding with heterozygous deficiency of alpha-2-antiplasmin has been reported [13].

Acquired alpha-2-antiplasmin deficiency has been reported with several disorders, including:

●Amyloidosis [32]

●Severe liver disease, which causes impaired synthesis

●Nephrotic syndrome, which causes increased renal excretion

●Disseminated intravascular coagulation (DIC), which causes increased consumption

●Acute promyelocytic leukemia [33,34]

●Malignancy [34]

●Abdominal aortic aneurism [34]

●Head injury [35]

●Following thrombolytic therapy, which causes depletion [36]

Laboratory testing usually shows a shortened euglobulin clot lysis time. (See 'Euglobulin clot lysis time (ECLT)' below.)

The diagnosis is established by measuring plasma levels of alpha-2-antiplasmin with either immunological or functional assays.

Management of bleeding episodes and surgery may include plasma transfusion and/or oral antifibrinolytic agents (tranexamic acid or aminocaproic acid).

PAI-1 deficiency — Plasminogen activator inhibitor-1 (PAI-1) deficiency produces a hyperfibrinolytic state (deficiency of an inhibitor). Its prevalence is not defined, but it is very rare [37-40].

Only congenital forms have been described. Two studies reported a kindred with complete PAI-1 deficiency due to a small insertion within the PAI1 gene that resulted in the production of a non-functional protein [41,42].

●Heterozygous individuals carrying only a single copy of the defective gene did not exhibit abnormal bleeding, even after surgery.

●Homozygous deficient individuals exhibited delayed bleeding after surgery or trauma only, suggesting that their initial hemostatic response was normal, but their clots were lysed prematurely due to excessive fibrinolysis.

A second study reported that complete PAI-1 deficiency due to a different mutation in the PAI-1 gene resulted in a severe bleeding disorder [43].

Postoperative and post-traumatic bleeding are the most reported manifestations of PAI-1 deficiency. In women, heavy menstrual bleeding is common. Other reported findings include:

●Obstetric complications, including preterm labor and miscarriage, are prevalent, a distinguishing feature from other fibrinolysis-inhibitor deficiency states [13].

●Delayed wound healing [43].

●Cardiac fibrosis [44].

Diagnosis of PAI-1 deficiency is challenging, as approximately 10 to 20 percent of healthy individuals with no history of abnormal bleeding have PAI-1 levels below the lower limit of detectability of commonly used commercial assays [45,46].

The euglobulin clot lysis time can be shortened but is sometimes normal. Qualitative deficiency of PAI-1 has been described [39]. Therefore, measurement of both plasma PAI-1 antigen and activity is recommended if the diagnosis is suspected.

Management includes antifibrinolytic agents (tranexamic acid or aminocaproic acid), especially perioperatively or in patients undergoing dental procedures, as well as for women with heavy menstrual bleeding or other forms of gynecologic and obstetric bleeding [42,47,48].

TAFI deficiency — Thrombin activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase that circulates in an inactive form [49]. TAFI is activated (TAFIa) by thrombin cleavage, which is greatly accelerated when thrombin is bound to its cofactor, thrombomodulin, on the endothelial cell surface. Plasmin can also activate TAFI [50]. (See "Overview of hemostasis", section on 'CPB2/TAFI'.)

TAFIa is a basic carboxypeptidase that cleaves C-terminal lysine residues from fibrin fragments generated during the initial stages of plasmin-mediated fibrinolysis. Since plasminogen and tPA bind to C-terminal lysines with high affinity, TAFIa disrupts recruitment of plasminogen and tPA to the partially digested fibrin clot, thereby inhibiting fibrinolysis (figure 1).

TAFI deficiency could in theory produce a hemorrhagic defect.

●Congenital TAFI deficiency has not been reported

●Acquired TAFI deficiency with hyperfibrinolysis has been reported in patients with cirrhosis [51]

Enhanced fibrinolysis can also be a complication of coagulation factor deficiencies, such as in deficiencies of factor VIII, IX, or XI, due to decreased production of thrombin, and consequently a decreased activation of TAFI to TAFIa [49,52-54].

Therefore, decreased TAFI activation could contribute to the bleeding phenotype associated with coagulation factor deficiencies.

Plasma TAFI concentration can be measured by immunoassays. However, such testing is generally not recommended in patients with undiagnosed bleeding disorders. Functional assays of TAFIa exist but are not commercially available and are generally not performed for clinical indications [6].

General hyperfibrinolytic states — While single factor defects described above are rare, multifactorial hyperfibrinolysis and associated bleeding accompanied by activation of blood coagulation may be seen more commonly, especially in ill or hospitalized patients.

As examples:

●DIC – In disseminated intravascular coagulation (DIC), excessive fibrinolysis can be triggered by:

•Release of tPA (from endothelial cells) or uPA (from cancer cells) [55,56]

•Depletion of alpha-2-antiplasmin

These and other mechanisms are discussed separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Pathogenesis'.)

●Thrombolytic therapy – Administration of a fibrin-specific plasminogen activator such as recombinantly produced tPA, or, more commonly, non-fibrin-specific plasminogen activator such as streptokinase or urokinase, can induce depletion of alpha-2-antiplasmin, plasminogen, and fibrinogen [36].

●Cardiopulmonary bypass – Bleeding is not uncommon after cardiopulmonary bypass. While multifactorial in etiology, activation of fibrinolysis can contribute to the bleeding diathesis. Use of antifibrinolytic agents in this setting can reduce perioperative blood loss. (See "Postoperative complications among patients undergoing cardiac surgery", section on 'Bleeding'.)

●Heat stroke – Increased fibrinolysis with bleeding can occur in heat stroke and is typically accompanied by multiple coagulation abnormalities [57,58]. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults" and "Heat stroke in children".)

●Postpartum hemorrhage – Most patients with postpartum hemorrhage (PPH) do not have hemostatic or fibrinolytic impairment. (See "Overview of postpartum hemorrhage", section on 'Causes of postpartum hemorrhage'.)

However, a rare subgroup of patients with PPH exhibit a severe hyperfibrinolytic state, likely multifactorial in etiology, which has been termed acute obstetric coagulopathy and is characterized by massively elevated plasma concentrations of plasmin-antiplasmin complex (as much as 30-fold increased), increased D-dimer, hypofibrinogenemia/dysfibrinogenemia, decreases in factor V and factor VIII, and increased activated protein C [59]. A similar hyperfibrinolytic coagulopathy can be seen rarely in patients with amniotic fluid embolism [60].

THROMBOTIC DISORDERS — Reduced fibrinolytic activity, due to a deficiency of plasminogen or its activators, or excessive expression of fibrinolysis inhibitors, can predispose to thrombosis.

Plasminogen deficiency — Congenital plasminogen deficiency is an autosomal recessive disorder caused by pathogenic variants in the PLG gene. The phenotype involves poor wound healing and formation of fibrin-rich pseudomembranes on the eyes (ligneous conjunctivitis) and other tissues. The bulk of the evidence suggests that plasminogen deficiency is not a risk factor for thrombosis. Details are presented separately. (See "Plasminogen deficiency".)

tPA or uPA deficiency — Documentation of a true deficiency of either tissue-type plasminogen activator (tPA) or urinary-type plasminogen activator (uPA; urokinase) is difficult, as these factors are normally present at very low concentration in the circulation. In addition, plasma levels of tPA or uPA may be affected by other factors, such as elevated levels of PAI-1.

●Congenital tPA or uPA deficiency due to genetic causes (pathogenic variants in the PLAT or PLAUR genes, respectively) has not been described in the literature, suggesting that complete deficiency of these factors may be lethal in utero.

●tPA is released by vascular endothelial cells after transient venous occlusion or other provocations. There are rare case reports of defective tPA synthesis and/or release in patients with venous thrombosis. However, studies involving large series of patients with venous thrombosis failed to find an abnormality in provocable tPA release [61,62]. There is no conclusive evidence that isolated tPA or uPA deficiency produces a thrombotic disorder in humans [61].

●Antibodies to tPA have been described in some patients with thrombosis secondary to the antiphospholipid syndrome (APS) [63,64]. (See "Clinical manifestations of antiphospholipid syndrome".)

Plasma tPA antigen and activity can be measured by immunologic (enzyme-linked immunosorbent assay [ELISA]-type) and functional assays, respectively. However, testing for tPA deficiency is rarely indicated for patients with undiagnosed thrombotic disorders.

PAI-1 overexpression — Numerous studies have associated elevated plasma PAI-1 levels with thrombosis, both venous and arterial [65]. Elevated PAI-1 has also been associated with septic shock and multiple organ system failure [66-68].

Selected examples of the association between PAI-1 overexpression and human diseases include:

●Ischemic heart disease – Particular interest has been paid to the potential role of PAI-1 in the pathogenesis of coronary heart disease and myocardial infarction [69]. As examples:

•The European Concerted Action on Thrombosis and Disabilities Study prospectively followed 3043 patients with angina pectoris for two years and found that elevated baseline plasma levels of PAI-1 were associated with an increased incidence of myocardial infarction or sudden cardiac death [70]. However, this association disappeared after correction for factors reflecting insulin resistance, such as obesity, body mass index, and serum triglyceride concentration.

•An analysis of the Framingham Heart Study offspring cohort, which included 3203 individuals without prior cardiovascular disease, revealed that elevated plasma PAI-1, assessed at baseline and after four years, was independently associated with development of cardiovascular disease (eg, myocardial infarction, prolonged angina pectoris, heart failure, and stroke) during an average follow-up period of 10 years [71].

•A study using a Mendelian randomization approach and summary statistics from large genome-wide association studies (GWAS) suggested that enhanced PAI-1 expression has a causal effect on the development of coronary artery disease, possibly mediated by effects on glucose metabolism [72].

●Hemolytic uremic syndrome – Increased levels of PAI-1 have been described in children with post-diarrheal hemolytic uremic syndrome (HUS); more severely affected patients had a higher plasma PAI-1 concentration, and normalization of plasma levels was correlated with an improvement in kidney function [73]. However, a smaller study did not find that plasma PAI-1 levels were predictive of clinical outcome [72]. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children".)

●Venous thromboembolic disease – A polymorphism in the PAI-1 promoter (designated 4G/5G) may affect the risk of venous thromboembolic (VTE) disease when combined with other thrombophilic gene variants.

•A 2014 meta-analysis found a slightly increased risk of unprovoked VTE in individuals with the 4G allele, which is associated with higher PAI-1 expression (odds ratio [OR] 1.3, 95% CI 1.1-1.5); this was further increased in individuals who also carried the factor V Leiden (FVL) mutation (OR 1.7, 95% CI 1.2-2.5) [74].

•In a 2015 analysis of a cohort of individuals from the Malmö Thrombophilia Study who had a prior VTE event, the factor V Leiden (FVL) variant plus the PAI-1 4G allele conferred a slightly increased risk of VTE recurrence compared with isolated FVL or 4G allele (hazard ratio [HR] 2.3, 95% CI 1.5-3.3) [75].

•In prospective analyses of healthy general populations, one study found that elevated PAI-1 antigen was positively associated with future incident VTE [76]. However, another study did not find this association [77].

•In patients with pancreatic cancer, plasma concentration of active PAI-1 was positively associated with future risk of VTE [78].

Further studies are necessary to define the consequences of enhanced PAI-1 expression more precisely in humans.

TAFI overexpression — Enhanced thrombin activatable fibrinolysis inhibitor (TAFI) expression is a potential risk factor for thrombosis, which is supported by the following clinical studies:

●A report from the Leiden Thrombophilia Study found that elevated plasma levels of TAFI (>90^th percentile) were more common in patients with deep venous thrombosis (DVT) than in an age- and sex-matched control group, suggesting that elevated plasma TAFI was a risk factor for DVT (relative risk 1.7, 95% CI 1.1-2.5) [79].

●In a study of 600 patients with spontaneous (unprovoked) DVT who had completed at least three months of treatment with oral vitamin K antagonists (eg, warfarin), the relative risk of VTE recurrence was 1.7 (95% CI 1.1-2.7) among those with plasma TAFI levels ≥75^th percentile compared with those having lower levels [80].

●A study of 770 venous thrombosis patients and 743 healthy controls found that elevated plasma TAFI concentration was associated with increased risk of first venous thromboembolic event, even after unconditional logistic regression analysis was performed to adjust for potential confounding effects of age, sex, body mass index, and plasma levels of acute phase proteins such as fibrinogen and factor VIII [81].

●A case-control study found that functional plasma TAFI levels >120 percent of normal were associated with an approximately sixfold increased risk of ischemic stroke [82].

●However, another study found that increased plasma TAFI was not associated with increased risk of either venous or arterial thrombosis in thrombophilic families [83].

Alpha-2-antiplasmin — One study found that elevated alpha-2-antiplasmin levels were independently associated with increased risk of myocardial infarction [84]. The Atherosclerosis Risk in Communities (ARIC) study found a modest, statistically significant association between alpha-2-antiplasmin plasma level and risk of ischemic stroke [85]. However, after multivariate adjustment for other clinical variables, the hazard ratio no longer retained statistical significance.

Lipoprotein(a) increases — Lipoprotein(a) [Lp(a)] is a modified form of low-density lipoprotein (LDL) cholesterol that might be prothrombotic, mediated through effects on fibrinolytic proteins. Indications for Lp(a) testing and management implications are discussed separately. (See "Lipoprotein(a)".)

Lp(a) is composed of apoprotein(a) covalently linked by a single interchain disulfide bridge to apolipoprotein B-100. Apoprotein(a) contains a series of kringle domains, each of which contains a lysine-binding site. Kringles are also present in plasminogen and are responsible for its binding to fibrin and plasminogen receptors. Thus, Lp(a) can competitively inhibit binding of plasminogen to the fibrin clot and cell surfaces, inhibiting fibrinolysis and cell-associated plasmin formation.

Evidence of a potential link between increased Lp(a) levels and arterial thrombosis includes the following:

●A meta-analysis of prospective studies of plasma Lp(a) levels and the subsequent risk of acute coronary artery disease or death from coronary heart disease, stroke, or myocardial infarction found a positive correlation between Lp(a) and coronary heart disease [86].

●The Bruneck Study was a prospective, community-based investigation of atherosclerosis involving 826 adults in whom incident cardiovascular events were assessed prospectively over 15 years [87]. There was a direct correlation between baseline Lp(a) levels and subsequent major adverse cardiovascular events, suggesting that plasma Lp(a) levels might be useful in risk stratification of individuals at intermediate cardiovascular risk based on standard clinical variables.

●Two LPA variants have been identified that are strongly associated with an increased level of Lp(a) and an increased risk of coronary heart disease [88].

Some organizations have advocated that measurement of plasma Lp(a) be considered in individuals with a 10-year risk of atherosclerotic cardiovascular events in the borderline range (5 to 7.4 percent) or intermediate (7.5 to 19.9 percent), with results being used to influence initiation of pharmacologic interventions, such as statins [89].

Venous thromboembolism (VTE) also has been associated with elevated plasma Lp(a) levels. One study of nearly 700 consecutive patients with VTE found that serum Lp(a) concentrations >30 mg/dL were found in 20 percent of thrombosis patients, but in only 7 percent of healthy controls [90]. This study, and a meta-analysis [91], concluded that a plasma Lp(a) level >30 mg/dL is an independent risk factor for VTE. Another meta-analysis of 14 published studies involving over 14,000 patients suggested that elevated plasma Lp(a) is significantly associated with VTE, though the difference in Lp(a) levels between VTE patients and controls was slight [92]. In addition, an elevated Lp(a) level may promote the penetrance of other prothrombotic defects, such as the factor V Leiden mutation [90].

EVALUATION FOR ABNORMAL FIBRINOLYSIS — As noted above, congenital fibrinolytic abnormalities are rare, and acquired disorders of fibrinolysis are often multifactorial.

Thus, for individuals with a negative family history of a fibrinolytic disorder, other evaluations for more common abnormalities are typically performed first, before proceeding to an evaluation for abnormal fibrinolysis.

Individuals with bleeding phenotypes — Bleeding phenotypes may be caused by hyperfibrinolysis.

●Primary hyperfibrinolytic states are rare and are due to excessive production of plasminogen activators or to decreased production of fibrinolysis inhibitors.

●A secondary hyperfibrinolytic state with abnormal bleeding can develop in multiple clinical settings, including trauma, malignancy, liver transplantation or failure, and cardiopulmonary bypass [93,94].

In an individual with abnormal bleeding, initial laboratory testing should assess for defects within the coagulation system or platelets. (See "Approach to the adult with a suspected bleeding disorder", section on 'Laboratory evaluation' and "Approach to the child with bleeding symptoms", section on 'Diagnostic approach'.)

If a disorder of coagulation or platelets is not found and bleeding consistent with a fibrinolytic disorder is seen, a congenital or acquired defect of fibrinolysis should be considered. (See 'Disorders with excess bleeding' above and "Approach to the adult with a suspected bleeding disorder", section on 'Positive bleeding history and normal initial testing'.)

●Clinical presentation – Clinical history is essential in guiding whether and how to test for a fibrinolytic system disorder. The typical type of bleeding seen with fibrinolytic disorders includes the following [13]:

•Delayed bleeding after trauma, surgery, or dental procedures

•Characteristic bleeding sites

-Mucocutaneous (epistaxis, dental)

-Heavy menstrual bleeding

-Spinal cord

-Peri-umbilical

•Pregnancy loss (miscarriage) and preterm birth, which are associated with PAI-1 deficiency [95].

●Laboratory findings – Laboratory testing should be undertaken only after careful consideration, typically involving consultation with a hematologist or other expert in bleeding disorders. Specialized fibrinolytic system testing may be helpful in diagnosing hyperfibrinolysis. However, these tests can be expensive and are generally more technically challenging and less well standardized than coagulation assays. (See 'Laboratory assays' below.)

Typical laboratory findings in hyperfibrinolytic states include (table 2):

•Complete blood count (CBC) and platelet count – Normal, unless there has been significant blood loss

•Prothrombin time (PT) and activated partial thromboplastin time (aPTT) – Normal or prolonged

•Fibrinogen – Low

•D-dimer – Increased

•Euglobulin clot lysis time (ECLT) – Shortened

•Thromboelastography (TEG) – Increased clot lysis at 30 minutes (LY30)

•Urea clot solubility (test for lack of fibrin cross-linking, as in factor XIII deficiency) – Normal

The PT and aPTT are often prolonged in hyperfibrinolytic states; however, the sensitivity is low, and normal values do not exclude the diagnosis. The mechanism of prolongation involves degradation of fibrinogen and/or upstream coagulation factors.

Tests such as the euglobulin clot lysis time (ECLT) and thromboelastography (TEG) may be helpful in the evaluation, but they have not been demonstrated to be of value in predicting risk of recurrent bleeding [96]. (See 'Euglobulin clot lysis time (ECLT)' below and 'Thromboelastography (TEG) and ROTEM' below.)

The diagnosis of a hyperfibrinolytic state depends on laboratory testing, medical history, and other clinical data; it cannot be made on laboratory testing alone. The observation of a beneficial clinical response to initiation of an antifibrinolytic drug can also help to establish a clinical diagnosis of hyperfibrinolysis.

Importantly, the possibility of DIC must be eliminated before an antifibrinolytic agent can be safely initiated, as the use of antifibrinolytic agents in DIC can result in massive thromboses. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Role of systemic therapies' and 'Therapies for hyperfibrinolytic states' below.)

●Differential diagnosis – The differential diagnosis of fibrinolytic disorders associated with excess bleeding includes:

•von Willebrand disease (VWD) – An inherited disorder of von Willebrand factor, which forms an adhesive bridge between platelets and sites of vascular injury; severe cases also have low factor VIII levels.

•Factor XIII deficiency – A bleeding disorder mediated by loss of fibrin-fibrin crosslinking and fibrin-alpha-2-antiplasmin crosslinking.

•Disseminated intravascular coagulation (DIC) – A disorder of intravascular clotting and fibrinolysis.

•Liver disease – Various disorders in which multiple hemostatic and fibrinolytic regulators are altered due to reduced hepatic synthesis or metabolism.

Individuals with VWD and factor XIII deficiency are otherwise well except for the bleeding disorder. VWD is common and is typically tested for early in the evaluation. Factor XIII deficiency is rare and associated with decreased plasma factor XIII activity and/or an abnormal urea clot solubility test. Evaluation for these disorders is discussed separately. (See "Clinical presentation and diagnosis of von Willebrand disease" and "Rare inherited coagulation disorders", section on 'Diagnostic evaluation'.)

Individuals with DIC or severe liver disease generally are ill from their underlying condition. (See "Disseminated intravascular coagulation in infants and children" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

The table summarizes differences in laboratory testing in fibrinolytic disorders and DIC (table 3).

Individuals with thrombotic phenotypes — Thrombotic phenotypes may be caused by hypofibrinolysis. This may be due to underexpression of a plasminogen activator (tissue-type plasminogen activator [tPA] or urinary-type plasminogen activator [uPA]), or overexpression of a fibrinolysis inhibitor, including plasminogen activator inhibitor 1 (PAI-1), alpha-2-antiplasmin, or thrombin activatable fibrinolysis inhibitor (TAFI). (See 'Thrombotic disorders' above.)

If laboratory evaluation is pursued to determine if a prothrombotic state is present, initial testing usually focuses on disorders associated with excessive thrombin activity, such as a hereditary thrombophilia or more common acquired conditions associated with increased thrombotic risk. (See "Overview of the causes of venous thrombosis".)

Evaluation for hypofibrinolysis typically is pursued only if there is a strong thrombotic phenotype (recurrent or highly atypical thrombosis) and other evaluations were unrevealing, there is a strong, unexplained familial thrombophilia, or an individual presents with ligneous conjunctivitis, suggestive of plasminogen deficiency. (See 'Plasminogen deficiency' above.)

Laboratory-based diagnosis of a hypofibrinolytic state can be difficult:

●Levels of plasminogen activators in plasma are very low under normal conditions, making definitive diagnosis of abnormally low levels difficult. Measurement of plasma tPA and uPA is generally not indicated in patients with unexplained thrombosis.

●The range for plasma levels of fibrinolysis inhibitors such as PAI-1 can vary widely among healthy individuals. This variability complicates establishing elevated plasma levels of a fibrinolysis inhibitor as the definitive cause of thrombosis in an individual patient.

Laboratory testing may reveal a prolonged ECLT (see 'Euglobulin clot lysis time (ECLT)' below) or other global assays, such as the plasma clot lysis time or the global thrombosis test (GTT), which have some clinical value in predicting recurrent thrombosis, but their specificity is not high [97-99].

Laboratory assays — Laboratory tests for fibrinolysis are discussed below and summarized in the table (table 2).

Thromboelastography (TEG) and ROTEM — TEG assesses the viscoelastic properties of whole blood, including clot formation and breakdown. TEG measures the torque on a pin dipped into a rotating plastic cup filled with non-anticoagulated whole blood. As a clot begins to form, the torque increases, and with clot breakdown from fibrinolysis, the torque decreases. TEG can be performed at the point of care, such as the operating room or emergency medicine department. Rotational thromboelastometry (ROTEM) is a related assay that also measures clot viscoelastic properties. TEG and ROTEM are considered especially useful in trauma patients and during orthotopic liver transplantation, which are associated with clinically significant excessive fibrinolysis [93].

Sample tracings and interpretation are presented separately. (See "Etiology and diagnosis of coagulopathy in trauma patients", section on 'Viscoelastic hemostatic assays'.)

●Advantages – This testing is useful for measuring the magnitude and timing of the fibrinolytic process. Other advantages include the ability to perform the test at the point of care and to repeat it frequently (eg, to monitor the patient's status over time or to determine if interventions have improved various parameters of clot formation and breakdown). TEG also can be used to guide optimal administration of blood products or other therapies [100].

●Disadvantages – In contrast to clotting assays such as the prothrombin time (PT), there is a lack of standardization of TEG results. Considerable expertise is required for interpretation of results, and there are limited data from clinical studies demonstrating the effectiveness of results in guiding clinical management. Additionally, these tests require fresh blood samples, and they are not available in many clinical laboratories.

Global thrombosis test (GTT) — The GTT is a point-of-care assay that measures shear-induced clot formation in non-anticoagulated whole blood. The assay also measures the time required for clot lysis to occur. Hence, it is a global assay of platelet function, the blood coagulation system, and the fibrinolytic system, rather than an isolated assay of the fibrinolytic system.

Clot lysis time assessed by the GTT is shortened in patients with hyperfibrinolysis and prolonged in patients with impaired fibrinolytic activity [99,101,102]. This test is not available in most clinical laboratories.

Euglobulin clot lysis time (ECLT) — The ECLT assesses the global function of the fibrinolytic system.

Dilution of citrated plasma at low ionic strength and low pH precipitates the euglobulin fraction, a population of proteins that includes fibrinogen, plasminogen, and tPA but lacks fibrinolysis inhibitors. The proteins in the euglobulin fraction are dissolved in buffer, clotted by addition of thrombin, and the time for clot lysis measured.

A shortened ECLT is characteristic of a hyperfibrinolytic state. The presence of a shortened ECLT in the absence of thrombocytopenia and schistocytosis is characteristic of primary hyperfibrinolysis and can be used to help differentiate primary hyperfibrinolysis from DIC and thrombotic thrombocytopenic purpura (TTP) (table 3).

The ECLT was developed in the 1950s. While still used, it has tended to be replaced by more rapidly performed assays that assess the global function of the fibrinolytic system under more physiologic conditions, such TEG and the GTT. (See 'Thromboelastography (TEG) and ROTEM' above and 'Global thrombosis test (GTT)' above.)

Fibrinolytic factor levels — Plasma levels of specific components of the fibrinolytic system can be measured by immunologic and functional assays. Testing is available for:

●Alpha-2-antiplasmin

●PAI-1

●TAFI

●tPA

These tests are available in some clinical laboratories. If not available locally, they can be performed on frozen citrated plasma samples as a "send-out" test to a specialty laboratory.

MANAGEMENT

Treatment of the underlying disorder — Treatment of abnormal fibrinolysis is initially geared at correcting underlying cause(s).

Examples include:

●Cancer – If hyperfibrinolysis is secondary to prostate cancer or acute promyelocytic leukemia, successful treatment of the malignancy can restore normal fibrinolytic function. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'Control of coagulopathy' and 'General hyperfibrinolytic states' above.)

●Trauma – In coagulopathy of trauma, attention to body temperature, pH, and fluid status may reduce the severity of the coagulopathy. (See "Etiology and diagnosis of coagulopathy in trauma patients" and "Perioperative blood management: Strategies to minimize transfusions", section on 'Maintenance of normothermia'.)

●DIC – For disseminated intravascular coagulation (DIC), treatment of causative infections or other underlying causes removes the ongoing stimulus for consumption of clotting factors and generation of fibrin. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treat the underlying cause'.)

Therapies for hyperfibrinolytic states — Fibrinolysis inhibitors, also called antifibrinolytic agents, have been used to treat hyperfibrinolytic states and reduce perioperative blood losses in conditions associated with activation of the fibrinolytic system [103]. (See 'Tranexamic acid and aminocaproic acid' below and 'Aprotinin' below.)

The use of these agents in patients with liver disease and hyperfibrinolysis is discussed separately. (See "Hemostatic abnormalities in patients with liver disease", section on 'Bleeding'.)

Tranexamic acid and aminocaproic acid — Tranexamic acid (TXA) and aminocaproic acid (also called epsilon-aminocaproic acid [EACA]) are lysine analogues that bind to the kringle domains of plasminogen and disrupt binding interactions between plasminogen and lysine residues within fibrin. By inhibiting recruitment of plasminogen to the clot surface, these drugs inhibit fibrinolysis. (See 'Fibrinolytic process' above.)

TXA binds plasminogen and plasmin more avidly than aminocaproic acid does, and TXA may produce a more potent anti-hemorrhagic effect [104].

Antifibrinolytic agents have been recommended for use in settings where fibrinolysis is prominent, such as when tissues with high fibrinolytic activity are involved (eg, oropharynx, prostate, endometrium), in selected patients with hemorrhagic shock who have an elevated D-dimer and depleted fibrinogen, and in the coagulopathy of trauma. They are not particularly effective for other types of bleeding, such as from esophageal varices, and they are less effective when given late (more than three hours after bleeding has started) [105]. Viscoelastic testing may be used to assess the presence of hyperfibrinolysis and to guide administration of antifibrinolytic therapy and transfusions.

Importantly, disseminated intravascular coagulation (DIC) should be excluded before these agents are administered, since antifibrinolytic therapy can precipitate thrombosis in individuals with DIC. Consequently, DIC is considered a contraindication to the use of antifibrinolytic drugs. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Prevention/treatment of bleeding'.)

●Trauma – Major trauma is associated with activation of fibrinolytic pathways, mediated by tissue hypoperfusion and damage of the vascular endothelium, producing a hyperfibrinolytic, prohemorrhagic state [106]. However, a marked inhibition of fibrinolysis is also well recognized in trauma patients, with one study reporting that as many of 64 percent of severely injured patients have "fibrinolytic shutdown" [107].

•CRASH-2, a randomized trial involving over 10,000 patients, found that early administration of TXA to trauma patients with bleeding or at significant risk of bleeding resulted in a significant reduction in the risk of hemorrhagic death without significantly increasing thrombotic events [108].

•Based on subsequent analyses of the CRASH-2 trial, administration of TXA is recommended in patients with trauma and major hemorrhage if the drug can be administered within three hours of injury, including administration in the field prior to transfer to hospital.

Details of management, including use of antifibrinolytic agents and other therapies, are discussed separately. (See "Etiology and diagnosis of coagulopathy in trauma patients" and "Ongoing assessment, monitoring, and resuscitation of the severely injured patient", section on 'Management of acute traumatic coagulopathy'.)

●Liver disease – (See "Hemostatic abnormalities in patients with liver disease", section on 'General approach to managing bleeding'.)

●Gynecologic bleeding – (See "Managing an episode of acute uterine bleeding", section on 'Tranexamic acid' and "Abnormal uterine bleeding in adolescents: Management", section on 'Addition of hemostatic therapy' and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management", section on 'Nonhormonal therapies'.)

●Cardiac surgery – TXA has also been studied in patients undergoing cardiovascular surgery [109]. The use of antifibrinolytic agents in patients undergoing coronary artery bypass surgery is discussed separately. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Antifibrinolytic agents' and "Blood management and anticoagulation for cardiopulmonary bypass", section on 'Antifibrinolytic administration'.)

Aprotinin — Aprotinin is a 58-amino acid protein isolated from bovine lung that inhibits plasmin, kallikrein, and other proteases. Aprotinin inhibits fibrinolysis, thrombin generation, and inflammatory responses. Due to safety concerns discussed below, it was removed from the market by the US Food and Drug Administration and is not available in the United States.

Although aprotinin has been successfully used to reduce blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass during coronary artery bypass grafting surgery, its safety relative to other antifibrinolytic drugs has been called into question. The Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) randomly assigned 2331 high-risk cardiac surgical patients to receive aprotinin, tranexamic acid, or aminocaproic acid [110]. While aprotinin was associated with a reduction in massive bleeding compared with the other two agents, it was also associated with a significantly higher risk of death, which has led to the recommendation that aprotinin not be used to prevent excessive bleeding in cardiac surgery. This subject is discussed in depth separately. (See "Early noncardiac complications of coronary artery bypass graft surgery", section on 'Antifibrinolytic agents'.)

Therapies for hypofibrinolytic states — Hypofibrinolytic states are generally treated, if necessary, by downregulating clot formation with an anticoagulant. Indications and choice of drug are discussed in separate topic reviews. (See "Hemostatic abnormalities in patients with liver disease", section on 'Venous thromboembolism (VTE)' and "Venous thromboembolism: Initiation of anticoagulation".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acquired bleeding disorders" and "Society guideline links: Rare inherited bleeding disorders".)

SUMMARY AND RECOMMENDATIONS

●Fibrinolytic system – Fibrinolysis, the enzymatic dissolution of fibrin clots, is essential for maintaining blood vessel patency and completing the healing process after vascular injury (figure 1). Fibrinolysis is mediated by plasmin, an enzyme for which synthesis, activity, and clearance are tightly regulated by activators, inhibitors, and other regulatory proteins (table 1). (See 'Overview of the fibrinolytic system' above.)

●Clinical presentations – Fibrinolytic disorders, resulting from heritable or acquired abnormalities in the expression of fibrinolytic system components, are rare causes of bleeding or thrombosis, depending on whether they increase or decrease plasmin activity:

•Bleeding – Hyperfibrinolysis can cause bleeding, typically manifested as delayed bleeding after trauma or surgery or bleeding in the oropharyngeal or gynecologic mucosa or other characteristic sites (peri-umbilical, intramedullary). Causes include excess tissue-type or urinary-type plasminogen activator (tPA or uPA [urokinase]) or deficiencies of alpha-2-antiplasmin, plasminogen activator inhibitor (PAI-1), or thrombin-activatable fibrinolysis inhibitor (TAFI). PAI-1 deficiency is also associated with pregnancy loss. Quebec platelet disorder is a congenital platelet disorder in which tandem duplication of PLAU, the gene that encodes uPA, causes excessive production of uPA within platelet alpha granules. (See 'Disorders with excess bleeding' above.)

•Thrombosis – Hypofibrinolysis can cause thrombosis. Causes include tPA or uPA deficiency or overexpression of PAI-1 or TAFI. (See 'Thrombotic disorders' above.)

•Pseudomembranes – Plasminogen deficiency can cause poor wound healing and formation of fibrin-rich mucosal pseudomembranes. (See "Plasminogen deficiency".)

●Evaluation – Generally, an evaluation is pursued if the presentation is suggestive of a fibrinolytic disorder and initial laboratory testing for more common causes of bleeding or thrombosis is unrevealing. (See 'Evaluation for abnormal fibrinolysis' above.)

•Laboratory testing – Hyperfibrinolysis may be associated with normal or prolonged plasma clotting times (table 2). Tests such as the euglobulin clot lysis time (ECLT) or thromboelastography (TEG) may be helpful, although these can be challenging to perform and interpret. Consultation with a specialist is recommended to assist with test selection and interpretation of results. (See 'Laboratory assays' above.)

•Differential diagnosis – The differential diagnosis in an otherwise healthy individual includes von Willebrand disease (VWD), which also causes mucosal bleeding, and factor XIII deficiency, which also causes delayed bleeding. The differential diagnosis in an ill individual includes disseminated intravascular coagulation (DIC) and liver disease. Assessment of the clinical response to antifibrinolytic therapy can also be helpful in diagnosis. (See "Approach to the adult with a suspected bleeding disorder" and "Overview of the causes of venous thrombosis".)

●Management – Management depends on the cause of the disorder and severity of presentation. Treatment of the underlying cause is important in acquired disorders. (See 'Treatment of the underlying disorder' above.)

•Hyperfibrinolysis and bleeding – Hyperfibrinolytic states with bleeding can be treated with antifibrinolytic agents (tranexamic acid [TXA] or aminocaproic acid [epsilon-aminocaproic acid; EACA]) if DIC has been excluded. (See 'Therapies for hyperfibrinolytic states' above.)

•Hypofibrinolysis and thrombosis – Hypofibrinolytic states with thrombosis can be treated with anticoagulation. For plasminogen deficiency, plasminogen replacement therapy can be used. (See 'Therapies for hypofibrinolytic states' above and "Plasminogen deficiency".)