Disorders of fibrinolysis

Inhibitors of fibrinolysis (deficiency leads to bleeding)

• Plasminogen activator inhibitor 1 (PAI-1): the physiologic inhibitor of tPA.
• TAFI (thrombin-activatable fibrinolysis inhibitor): activated by thrombin; TAFIa blocks recruitment of plasminogen and tPA to the clot (by removing lysine residues from fibrin fragments), thereby slowing fibrinolysis.
• Alpha-2-antiplasmin: the physiologic inhibitor of plasmin.
• Lp(a) lipoprotein: consists of apoprotein(a) plus apolipoprotein B-100. Apoprotein(a) has Kringle domains (also present in plasminogen, which help binding to fibrin), so Lp(a) can competitively inhibit plasminogen binding to fibrin → inhibition of fibrinolysis and clot stabilization. Lp(a) also increases PAI-2 in monocytes (↓ fibrinolysis) and decreases TFPI (→ ↑ FVII activation), promoting clotting.

Inducers of fibrinolysis (increase leads to bleeding; uPA equals Quebec): plasminogen/plasmin and tPA/uPA. (TXA and aminocaproic acid are antifibrinolytics, and D-dimer is a cross-linked fibrin degradation marker, not inducers.)

• Plasminogen: precursor to plasmin. Plasmin (the end product) cleaves fibrin.
• tPA / uPA (urokinase): cleave plasminogen to plasmin. Recombinant fibrin-specific tPAs: tenecteplase, reteplase, alteplase.
• Tranexamic acid (TXA): blocks the fibrin-binding (Kringle) sites on plasminogen, preventing activation of plasminogen to plasmin and blocking plasmin proteolytic activity. TXA is a second-line option in hereditary angioedema; its benefit is attributed to reduced plasmin-mediated activation of the contact (bradykinin-generating) pathway, not to raising C1-INH (attenuated androgens like danazol raise C1-INH). HAE is bradykinin-mediated.
• Aminocaproic acid (Amicar): binds competitively to plasminogen, blocking its binding to fibrin and the subsequent conversion to plasmin, inhibiting fibrinolysis.
• D-dimer: two D domains from adjacent fibrin monomers cross-linked by activated factor XIII (FXIIIa). Because D-dimer comes from cross-linked fibrin (not fibrinogen), an elevated level indicates increased cross-linked fibrin formation and degradation; it is nonspecific and does not by itself establish intravascular thrombosis or DIC.

Hyperfibrinolysis (bleeding)

• α2-antiplasmin deficiency: severe delayed bleeding after trauma or surgery; treat with TXA or aminocaproic acid.
• PAI-1 deficiency: delayed bleeding (PAI-1 inhibits tPA; when absent, fibrinolysis is unrestrained).
• Acquired hyperfibrinolysis:
  • L-asparaginase (treats ALL): depletes plasminogen and α2-antiplasmin → bleeding and thrombosis.
  • Severe liver disease: reduced α2-antiplasmin synthesis.
  • Acute promyelocytic leukemia (APL): hyperfibrinolytic plus DIC; aggressive cryoprecipitate and platelets plus ATRA.
  • Snake venom envenomation: procoagulant or fibrinogenolytic.
  • Massive trauma (esp. head injury): hyperfibrinolysis is common (TXA in CRASH-2/CRASH-3).
  • Postpartum hemorrhage (PPH): WOMAN trial, TXA reduces death due to bleeding (not all-cause mortality), especially if given within 3 hours.
  • Prostate or pancreatic cancer with DIC: increased urokinase; can be hyperfibrinolytic.

Evaluation of hyperfibrinolysis

• Bleeding pattern: delayed bleeding after trauma, surgery, or dental procedures, and bleeding in areas of high fibrinolytic activity: mucocutaneous (epistaxis, dental bleeding), heavy menstrual bleeding, intramedullary (diaphyseal) bleeding in the medullary cavity of long bones, peri-umbilical bleeding, and pregnancy loss or preterm birth (associated with PAI-1 deficiency).

• Differential: von Willebrand disease, factor XIII deficiency (a disorder of fibrin cross-linking), DIC (intravascular clotting and fibrinolysis), and liver disease.

Bleeding disorders due to hyperfibrinolysis

• tPA / uPA excess: metabolized by the liver, so in liver disease accumulation of tPA/uPA can cause bleeding. Congenital overexpression of tPA/uPA is very rare.
• Quebec platelet disorder: congenital platelet disorder with excessive uPA production (tandem duplication of PLAU, the gene encoding uPA) within platelet alpha granules. Patients have premature clot lysis (from increased uPA) and low platelet factor V (about 20% of total blood FV is stored in platelet alpha granules; the increased uPA depletes it). Labs: mild thrombocytopenia is common, platelet aggregation studies can be abnormal, and platelet factor V, fibrinogen, and uPA analysis plus genetic testing confirm the diagnosis. Moderate to severe bleeding 12 to 24 hours after surgery, dental procedures, or trauma, plus poor wound healing and heavy menstrual bleeding. Treat with preprocedural TXA or aminocaproic acid.
• Alpha-2-antiplasmin deficiency: enhanced plasmin activity and fibrinolysis. Normal PT/aPTT and platelet function; diagnose with a specific alpha-2-antiplasmin activity assay (a normal euglobulin clot lysis time does not exclude it, as the assay is method-dependent and insensitive). Delayed bleeding after surgery or dental work. Treat with plasma transfusion and/or oral antifibrinolytics. Acquired causes: severe liver disease (decreased synthesis), nephrotic syndrome (increased renal excretion), DIC (increased consumption), and following thrombolytic therapy (depletion); also amyloidosis, APML, malignancy, abdominal aortic aneurysm, and head injury.
• PAI-1 deficiency: normally PAI-1 inhibits conversion of plasminogen to plasmin, so deficiency yields increased plasmin and a hyperfibrinolytic state. Very rare. Heterozygotes have no bleeding; homozygotes have increased delayed bleeding, plus obstetric complications such as miscarriage, antepartum or postpartum bleeding, and preterm birth (not specific; recurrent pregnancy loss is also classic for severe factor XIII deficiency), cardiac fibrosis, and delayed wound healing. Diagnosis by plasma PAI-1 antigen and activity (shortened euglobulin clot lysis time). Treat with preprocedural TXA or aminocaproic acid.
• 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 cirrhosis (decreased synthesis). Hyperfibrinolysis can also complicate factor VIII, IX, or XI deficiencies, due to decreased thrombin generation and consequently decreased activation of TAFI to TAFIa.
• Hyperfibrinolytic states:
  • DIC (enhanced-fibrinolytic type, e.g., APL and some cancers): hyperfibrinolysis from increased tPA (endothelium) or uPA (cancer cells), leading to consumption and decreased alpha-2-antiplasmin. Fibrinolysis in DIC is variable, and sepsis-associated DIC usually has suppressed fibrinolysis (increased PAI-1).
  • Thrombolytic therapy: tPA (fibrin-specific) or streptokinase/urokinase (non-fibrin-specific) lead to consumption and decreased alpha-2-antiplasmin, plasminogen, and fibrinogen.
  • Cardiopulmonary bypass.
  • Heat stroke: increased fibrinolysis with bleeding, typically accompanied by multiple coagulation abnormalities.

Antifibrinolytic agents

• Tranexamic acid (TXA): lysine analog; binds plasminogen lysine sites → blocks plasmin activation. Adult dose: PO 1.3 g TID for menorrhagia; IV 1 g over 10 min then 1 g over 8 hr (CRASH-2 trauma protocol); 1 g IV bolus for PPH (WOMAN). Renal-cleared; reduce dose for renal impairment per label (oral LYSTEDA steps down once serum creatinine >1.4 mg/dL), not only at CrCl <30.
• Aminocaproic acid (Amicar): similar mechanism, about 10× less potent with a short half-life (about 2 hours), hence frequent dosing. PO/IV 4 to 5 g loading then 1 g/hr.
• Aprotinin: serine protease inhibitor; withdrawn 2007 (BART trial: increased mortality in cardiac surgery vs lysine analogs).
• TXA cautions and contraindications: active intravascular thrombosis, severe renal impairment (dose-adjust), and urinary tract bleeding (concern for clot retention and obstruction in the renal pelvis). Avoid in DIC with active thrombosis, since antifibrinolytics can precipitate thrombosis.

Hypofibrinolysis and thrombotic disorders

• PAI-1 elevation: associated with metabolic syndrome and VTE. Numerous studies link elevated PAI-1 with venous and arterial thrombosis, septic shock, and multiorgan failure, but these findings are mainly research rather than clinical care.
• Plasminogen deficiency: rare, autosomal recessive (PLG variants). Poor wound healing and fibrin-rich pseudomembranes, classically ligneous conjunctivitis (woody pseudomembranes on the eyes), with hydrocephalus and infertility described. Note: the bulk of evidence suggests plasminogen deficiency is not itself a risk factor for thrombosis. Treatment: plasminogen replacement (plasminogen, human-tvmh; Ryplazim), FDA approved June 2021 for plasminogen deficiency type 1 (hypoplasminogenemia).
• tPA or uPA deficiency: very rare, with no congenital cases in the literature; antibodies to tPA can occur in APLS.
• TAFI overexpression: a potential risk factor for thrombosis.
• Lp(a) lipoprotein elevation: a modified form of LDL that may be prothrombotic. Apoprotein(a) Kringle domains competitively inhibit plasminogen binding to fibrin, and Lp(a) increases PAI-2 and decreases TFPI, promoting clotting. Data are conflicting: one meta-analysis found a plasma Lp(a) level >30 mg/dL to be an independent risk factor for VTE, while another study found very little difference between VTE patients and controls.

High yield

• TXA in trauma (CRASH-2): lower mortality if given <3 hours from injury.
• TXA in head trauma (CRASH-3): benefit in mild to moderate TBI.
• TXA in PPH (WOMAN): reduces death from bleeding by about 20% overall (about 30% when given within 3 hours of birth).
• APL hyperfibrinolytic DIC: aggressive cryoprecipitate and platelets; start ATRA before genetics return.
• L-asparaginase toxicity: depletes plasminogen, antithrombin, and fibrinogen → both bleeding AND thrombosis (esp. CNS).
• Plasminogen deficiency = ligneous conjunctivitis (rare).
• Quebec platelet disorder = PLAU duplication, excess platelet uPA, low platelet factor V; delayed post-procedural bleeding responsive to antifibrinolytics.
• Do NOT give antifibrinolytics in DIC with active thrombosis (risk of precipitating thrombosis).