Clinical Disorders of Fibrinolysis

Daphne B. Stewart

Charles W. Francis

Victor J. Marder

Excessive promotion or inhibition of fibrinolysis interferes with the hemostatic balance and can lead to clinical bleeding or thrombosis. Hyperfibrinolytic mechanisms leading to premature lysis of hemostatic clots may result in significant bleeding disorders. Conversely, if impaired fibrinolysis slows clot dissolution, local clot formation occurs unimpeded, and a procoagulant state ensues. The importance of the fibrinolytic enzyme system is underscored by the observations that constitutional abnormalities in plasminogen,¹^,²^,³ plasminogen activators (PAs),⁴ or their release,⁵ are associated with an increased risk for thrombosis, whereas defects in PA inhibitors⁶ and α₂-antiplasmin (AP)⁷ are associated with an increased bleeding risk. Disorders impairing and promoting fibrinolysis occur as inherited disorders, which are rare and typically caused by a single molecular defect. Acquired disorders are more common, and heightened or impaired fibrinolysis may be the primary or contributing mechanism to bleeding or thrombotic events that occur in the course of an underlying systemic disorder or as the result of pharmacologic therapy. Clinical management requires an appreciation of the potential for pathologic bleeding or clotting; the use of appropriate, sensitive diagnostic tests; and rational use of medical therapies.

‘ HYPERFIBRINOLYSIS WITH BLEEDING

Inherited Disorders of Fibrinolysis with Bleeding

α₂-Antiplasmin Deficiency

Inherited deficiency of α₂-AP is a rare autosomal recessive condition characterized by clinical bleeding due to premature dissolution of hemostatic plugs, typically seen as rebleeding following trauma or invasive procedures (Table 56.1).⁸^,⁹^,¹⁰^,¹¹ AP inhibits fibrinolysis by forming a stable inactive complex with plasmin, by binding to the lysine-binding site of plasminogen and competitively inhibiting plasminogen binding to fibrin, and by covalent binding to fibrin via FXIIIa to prevent fibrinolysis by plasmin.¹² In patients with clinical evidence of the disorder, typical screening coagulation tests are normal, but the euglobulin clot lysis time (ECLT) is short due to uninhibited plasmin activity. A mouse knockout model of AP deficiency demonstrates enhanced endogenous fibrinolytic activity, but the mice, unlike humans, do not have an overt bleeding tendency, reflecting the presence of compensatory mechanisms.¹³ The gene for AP has been mapped to chromosome 17,¹⁴ and several mutations causing congenital deficiency have been elucidated.¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹ Type I deficiency represents a quantitative disorder, with similar decreases in functional and immunologic assays, while type II deficiency results from a structural change causing lower activity than antigen concentration.²⁰

Homozygous type I AP deficiency was first reported in 1978⁸ in a patient with severe lifelong bleeding complications that included hemothorax, hemarthrosis, gingival bleeding, easy bruising, and prolonged bleeding after minor injury. Only 40 cases have been reported; the phenotype is variable, with the most severely affected patients symptomatic in childhood, even presenting with umbilical hemorrhage.²¹ Intramedullary hematoma in the diaphyses of long bones represents a unique site of bleeding.²² Individuals with heterozygous AP deficiencymay be asymptomatic or exhibit a mild bleeding tendency that worsens with advancing age,²³^,²⁴^,²⁵ mostly following trauma, dental extraction, or surgery. Homozygous AP deficiency patients generally have <10% normal AP and heterozygotes have levels of 20% to 50%.²³^,²⁶

Treatment with the antifibrinolytic agents tranexamic acid (TXA) or epsilon aminocaproic acid (EACA) can prevent bleeding during and after invasive procedures and is effective for treating acute bleeding episodes.²¹^,²⁷^,²⁸ While no standard protocol exists, Morimoto et al. suggests using TXA 7.5 mg/kg orally 3 hours prior to dental extraction and then every 6 hours for 7 days. For dental extractions requiring gingival incisions or removal of bone, six patients were treated with infusion of TXA, 1.5 mg/kg/h followed by oral dosing once hemostasis was obtained.²⁷ Infusion of fresh-frozen plasma (FFP) provides adequate and lasting treatment levels, as the in vivo half-life is >20 hours,²⁸ although solvent or detergent treatment of plasma inactivates AP.²⁹

Plasminogen Activator Inhibitor-1 Deficiency

Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of tissue-type plasminogen activator (t-PA) and urokinasetype plasminogen activator (u-PA), physiologically limiting fibrinolysis to a thrombus by generating irreversible, inactive complexes. Congenital PAI-1 deficiency may be quantitative or qualitative and is characterized by recurrent bleeding, primarily after surgery or trauma.³⁰^,³¹^,³²^,³³^,³⁴^,³⁵ As with AP deficiency, screening coagulation tests are normal; the ECLT is short (<2 hours); and fibrinogen, plasminogen, and AP levels are reduced to variable degrees. Diagnosis may be aided by demonstrating PAI-1 activity of <1 U/mL combined with elevated plasmin-AP complexes.³⁶

Quantitative deficiency in a family of 26 affected individuals was linked to a frameshift mutation,³³ and those individuals who were homozygous for the mutation had mild to moderate bleeding symptoms (epistaxis, menorrhagia, bleeding following trauma), while heterozygotes tolerated surgery without bleeding.³³ The incidence is perhaps underestimated, as low PAI-1 levels (<1 U/mL) have been found in 23% of patients investigated for a bleeding tendency³⁷ Bleeding can be treated effectively with antifibrinolytic medications.

Table 56.1 Hyperfibrinolysis with bleeding

Inherited Disorders	Clinical Characteristics
AP deficiency	Premature lysis of hemostatic plugs Autosomal recessive, chromosome 17 Homozygous: severe bleeding Short lysis time, decreased plasmin-AP complexes, and fibrinogen Prophylaxis and treatment: FFP, antifibrinolytics
PAI-1 deficiency	Homozygous deficiency with moderate to severe bleeding Absent PAI-1, short lysis time, low fibrinogen, and plasminogen Increased plasmin-AP complexes Treat with antifibrinolytics
Elevated t-PA	Continuous plasmin activation Short lysis time, decreased fibrinogen Elevated circulating t-PA Treat with antifibrinolytics
Quebec platelet disorder	Excess u-PA in platelet granules released into hemostatic plugs causing premature lysis Increased copy number of u-PA gene Moderate to severe delayed bleeding Treat with antifibrinolytics
Factor XIII deficiency	Non-cross-linked fibrin undergoes premature fibrinolysis Increased clot solubility, low FXIII Severe delayed bleeding Prophylaxis and treatment: FFP, FXIII concentrate, antifibrinolytics
A cquired Disorders
Cirrhosis	Hyperfibrinolysis exacerbates bleeding tendency, increases mortality Impaired clearance of t-PA Impaired synthesis of AP, PAI-1, TAFI Pronounced fibrinolysis during anhepatic phase of orthotopic liver transplant Primary hyperfibrinolysis Circulating t-PA due to endothelial release or infusion Rapidly cleared If DIC absent, may treat with antifibrinolytics
APL	Blasts release t-PA, u-PA, elastase Dense surface expression of annexin II on blasts enhances t-PA activation of plasmin ATRA decreases annexin II expression
Menorrhagia (normal uterine anatomy)	Increased t-PA in endometrium with high local fibrinolysis Antifibrinolytic treatment decreases bleeding Progesterone intrauterine device (IUD) decreases bleeding
FXIII deficiency	Consumption or immune clearance May be medication related: isoniazid (INH) Treat with: FFP, FXIII concentrate, antifibrinolytics, immune suppression
Trauma	Increased fibrinolysis with severe hypoperfusion Degree of fibrinolysis correlates with mortality Early volume resuscitation with FFP may benefit
FFP, fresh-frozen plasma; u-PA, urokinase plasminogen activator; AF, antifibrinolytics; TAFI, thrombin-activatable fibrinolysis inhibitor; DIC, disseminated intravascular coagulation; ATRA, all-trans retiπnoic acid.

Increased t-PA

A congenital hemorrhagic disorder due to increased plasma levels of PA has been described in a few patients, including one with fatal intracranial hemorrhage.⁶^,³⁸ Laboratory findings reflect continuous plasmin activation, as evidenced by elevated plasmin-AP complexes, shortened ECLT, low fibrinogen, and increased plasma t-PA that can be inhibited by specific antibodies.³⁸ Bleeding occurs after surgery, trauma, or dental extraction, although some family members have no clinical bleeding despite laboratory evidence of increased clot lysis. In one report, treatment with EACA or TXA resulted in improvement in laboratory markers of hyperfibrinolysis with normalization of clot lysis times and an increase in fibrinogen and α₂-AP.³⁸

Quebec Platelet Disorder

The Quebec platelet disorder is an autosomal dominant condition characterized by moderate to severe delayed bleeding, typically starting at 12 to 24 hours after hemostatic challenge.³⁹ Affected individuals experience large bruises, joint bleeds, and local bleeding following dental extractions or trauma. The disorder was initially designated as Factor V Quebec because of defi-ciency in platelet factor V content.⁴⁰ Additional platelet defects include reduced count, defective platelet aggregation to epinephrine, and absence of α-granule contents and intrinsic membrane proteins.³⁹^,⁴¹^,⁴²^,⁴³ Platelets of affected individuals show excessive α-granule protein degradation due to excess platelet u-PA, but external membrane, dense granule, and cytoplasmic platelet proteins are not affected.³⁹^,⁴¹^,⁴⁴^,⁴⁵^,⁴⁶ The bleeding state is caused by the excess u-PA that is released into hemostatic plugs, and bleeding episodes may be treated with fibrinolytic inhibitors.⁴⁴^,⁴⁷

Genetic marker analysis links the abnormality to the u-PA gene (PLAU) on chromosome 10; no point mutations have been found,⁴⁸^,⁴⁹ but an increased gene copy number likely accounts for the excess u-PA expression.⁵⁰ It is likely that testing for PLAU amplification will facilitate diagnosis in the future.

Factor XIII Deficiency

Activated factor XIII (FXIII) cross-links fibrin strands and AP to fibrin, thus contributing to fibrin clot stabilization and protection against premature fibrinolysis.⁵¹ Congenital FXIII defi-ciency is associated with severe, lifelong bleeding due to rapid, plasmin-mediated lysis of hemostatic clots. The first described case was a young man with severe bleeding and normal coagulation assays, who had clots that lysed readily; addition of normal plasma corrected the laboratory abnormalities.⁵² Approximately 160 cases have been reported.⁵³ FXIII is a tetramer, formed from dimerization of two A subunits associated with two B subunits (see Chapter 17). Deficient cases typically have absent A subunit in plasma. Patients typically present with delayed bleeding, even from the umbilical stump, and suffer a lifelong predisposition to subcutaneous, intramuscular, and intracranial bleeding; impaired wound healing; and spontaneous abortion.⁵⁴ Bleeding generally is delayed after trauma, compatible with lysis of clots after initial hemostatic plug formation. Intracranial hemorrhage is the most frequent cause of bleeding-associated mortality.⁵³

Routine clotting time assays are normal. Diagnosis is based on solubility of clots in 1% monochloroacetic acid and 5 M urea, and by quantitation of FXIII activity in platelets and plasma. Treatment of acute bleeding episodes may be accomplished by infusion of small volumes of FFP, as control of hemorrhage requires raising

plasma concentration by only a few percent.⁵³ The plasma half-life of FXIII is 11 to 14 days, so prophylactic doses may be infused every 6 weeks. Patients are generally treated with lifelong FFP prophylaxis, with fibrinolytic inhibitors, or with FXIII concentrates. A recombinant product, FXIII-A2 homodimer, has been developed though not yet approved by the FDA⁵⁵ Inhibitors to FXIII resulting from replacement treatment have been reported.⁵⁶

Acquired Disorders of Fibrinolysis with Bleeding

Cirrhosis

Severe liver disease is frequently complicated by clinically significant bleeding, due to a combination of decreased synthesis and/or clearance of coagulation factors and inhibitors, and thrombocytopenia caused by splenic sequestration and marrow insufficiency (Table 56.1). Accelerated fibrinolysis is common; in some cases this may represent the predominant hemostatic abnormality and is attributable to impaired clearance of t-PA and decreased synthesis of fibrinolytic inhibitors.¹¹ Although elevated plasma levels of D-dimer suggest disseminated intravascular coagulation (DIC), macrovascular and microvascular thrombosis is less common in advanced cirrhosis compared with other conditions associated with DIC⁵⁷ Rather, an accelerated fibrinolytic state typically exists, identified by a rapid ECLT, increased plasma t-PA, and decreased AP and PAI-1.⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶² Elevated D-dimer levels are likely the result of degradation of plasma-soluble cross-linked fibrin.⁶³ Chronic systemic hyperfi-brinolysis is present in 30% to 46% of patients with cirrhosis and is more prevalent with greater severity of liver failure.⁶⁴ In a study of 112 cirrhotic patients with esophageal varices but without clinical upper gastrointestinal bleeding who were followed for 3 years, multivariate analysis indicated that elevated t-PA and D-dimer were the only markers predictive of bleeding.⁶⁵ In another study of 86 patients with cirrhosis, 31% showed a rapid ECLT, which was proportional to the severity of hepatic dysfunction.⁶⁶ Treatment with fibrinolytic inhibitors such as EACA and TXA may be useful in patients with cirrhosis, particularly those with mucosal or gastrointestinal bleeding, but there are no prospective controlled studies to validate clinical observations.

Pathologic hyperfibrinolysis may contribute to severe hemorrhage in some cases of orthotopic liver transplantation (OLT), especially during the anhepatic phase of surgery.⁶⁷^,⁶⁸ Accelerated fibrinolysis during OLT has been associated with increased plasma t-PA, depletion of fibrinogen and AP, and elevated fibrin degradation products.⁶⁹ Both systemic release and reduced hepatic clearance of t-PA contribute to accelerated fibrinolysis, which improves after revascularization of the transplanted liver. Treatment with fibrinolytic inhibitors can be useful. In a double-blind, randomized, placebo-controlled study of 45 patients, those who received TXA had less intraoperative blood loss and reduced intraoperative need for plasma, platelets, and cryoprecipitate.⁷⁰ Porte et al.⁷¹ showed in a double-blind study of OLT recipients that treatment with aprotinin reduced blood loss with no increase in thrombosis or mortality.

Primary (Systemic) Hyperfibrinolysis

Primary systemic hyperfibrinolysis follows the widespread endothelial release or the exogenous infusion of t-PA, which leads to hemostatic plug dissolution and bleeding at sites of
vascular injury. Disparate clinical conditions may cause systemic hyperfibrinolysis, for example, the bleeding symptoms of dengue infection in which plasminogen is activated by the virus⁷²^,⁷³ and heat stroke, characterized by an elevated body temperature, an exaggerated acute-phase response and multiorgan failure,⁷⁴ which may present as a hemorrhagic diathesis.⁷⁵ A similar transient clinical bleeding disorder may occur acutely after coronary artery bypass grafting surgery,⁷⁶^,⁷⁷ or following the infusion of t-PA to achieve therapeutic thrombolysis. Laboratory findings of hyperfibrinolysis, including increased t-PA and D-dimer, decreased plasminogen, and increased plasmin-AP complexes, likely reflect an exaggerated release of endothelial cell t-PA causing this primary hemorrhagic disorder, without the thrombotic events that characterize DIC syndromes (see Chapter 98). The hemorrhage may be transient and self-limited, reflecting clearance of t-PA, and in the absence of concomitant DIC, therapy may be limited to an antifibrinolytic agent and replacement of consumed factors, especially fibrinogen. In most cases, t-PA release is of limited duration, and therapeutic intervention is directed to the underlying condition.

Secondary Fibrinolysis in DIC: Microcirculatory activation of fibrinolysis may be a secondary response to the marked hemostatic activation and microvascular thrombotic occlusion of DIC and serves an important compensatory function in maintaining vascular patency (see Chapter 98). The bleeding that complicates DIC is primarily due to consumption of procoagulant factors and platelets, and this local fibrinolytic response usually does not reach the systemic level of primary hyperfibrinolysis. Pharmacologic inhibition of the compensatory fibrinolysis of DIC with antifibrinolytic therapy must be considered carefully, since local activation of fibrinolysis serves the crucial role of maintaining microvascular patency in patients with DIC. Fibrinolytic inhibition may exacerbate thrombosis and worsen or precipitate ischemic symptoms.⁷⁸^,⁷⁹

Acute Promyelocytic Leukemia

Acute promyelocytic leukemia (APL) represents a malignant clonal expansion of immature myeloid cells characterized by a balanced translocation, t(15;17), and the expression of a chimeric protein derived from the fusion of genes for the nuclear retinoic acid receptor on chromosome 17 and a transcription factor (PML) on chromosome 15.⁸⁰ Before the introduction of therapy with all trans-retinoic acid (ATRA), hemorrhage was a major cause of mortality, occurring in 14% of 268 patients during induction therapy.⁸¹ Thrombocytopenia, DIC, and fibrinolysis may all contribute to the bleeding diathesis.⁸²^,⁸³ Leukemic cells contain t-PA, u-PA, and elastase, and elevated plasma levels of these proteins have been found in patients with accelerated fibrinolysis and APL.⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷ Leukemic blasts also produce inflammatory cytokines (TNF-α, IL-1β⁸⁸^,⁸⁹ that downregulate endothelial anticoagulant properties and upregulate procoagulant tendencies and express annexin II, a cofactor for t-PA-mediated activation of plasminogen to plasmin.⁹⁰^,⁹¹ Surface annexin II, plasminogen, and t-PA may cause plasminemia and hyperfi-brinolytic hemorrhage,⁹⁰ especially as plasmin present on cell surfaces is protected from inhibition by AP.⁹²

Chemotherapy typically exacerbates bleeding,⁷⁹^,⁹³ but ATRA normalizes hemostatic abnormalities in the 1st week of therapy,⁸¹ at least partly by downregulating surface expression of annexin II.⁹⁴ Although studies demonstrating the benefits of fibrinolytic inhibitors were published before the introduction of ATRA for induction therapy, contemporary treatment should focus on the optimal use of ATRA, and fibrinolytic inhibitors should be considered only in patients who are refractory to treatment and who have significant bleeding manifestations. A retrospective analysis of 30 patients with newly diagnosed APL observed that AP was a useful marker of fibrinolysis and hemorrhage risk and permitted treatment of higher risk patients with a coagulopathy protocol of low-dose heparin, EACA, and blood products.⁹⁵

Menorrhagia

Up to one-third of women undergoing hysterectomy for menorrhagia have an anatomically normal uterus.⁹⁶^,⁹⁷ However, increased t-PA is present in the endometrium and menstrual fluid in women with menorrhagia, compared to women with normal menstrual blood loss,⁹⁸ likely explaining the excessive bleeding in some patients. A meta-analysis of seven trials of antifibrinolytic agents (vs. placebo) for menorrhagia found that treatment was associated with a considerable reduction in blood loss.⁹⁶ Antifibrinolytic agents compared to other nonsurgical therapies, including mefenamic acid, norethisterone, and ethamsylate, show a strong, though nonsignificant, trend in favor of antifibrinolytic agents in the participants’ perception of improvement of menstrual blood loss. Increased fibrinolytic activity has been identified in the endometrium of women with an intrauterine device (IUD) associated with menorrhagia, and treatment with antifibrinolytic agents has been effective in reducing menorrhagia.⁹⁹ In contrast to standard IUD, those that release progesterone more effectively mitigate menorrhagia, as shown in a study of 41 women with menorrhagia treated with a levonorgestrel-releasing intrauterine system of whom 100% had resolution of their menorrhagia by 6 months. Endometrial sampling confirmed significant local increases in PAI-1 and endothelial expression of the u-PA receptor, without effect on systemic hemostasis.¹⁰⁰

Amyloidosis

Patients with systemic, monoclonal light-chain amyloidosis may present with bleeding due to acquired factor ×X deficiency¹⁰¹ or hyperfibrinolysis secondary to increased t-PA.¹⁰²^,¹⁰³ Hemorrhage in such patients has also been attributed to amyloid angiopathy, bleeding from the weakened walls of blood vessels infiltrated with amyloid fibrils.¹⁰⁴ The clonal plasma cells responsible for amyloidosis contain u-PA, in contrast to clonal plasma cells from multiple myeloma patients.¹⁰⁵^,¹⁰¹ One report showed resolution of hemorrhage following treatment with nafamostat mesilate, a u-PA inhibitor,¹⁰⁵ and others relate hyperfibrinolysis primarily to deficiency of AP.¹⁰²^,¹⁰³^,¹⁰⁴^,¹⁰⁵^,¹⁰⁶^,¹⁰⁷ Patients with amyloidosis and hyperfibrinolysis often respond well to antifibrinolytic therapy¹⁰¹^,¹⁰²^,¹⁰³^,¹⁰⁶^,¹⁰⁷

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