Coagulation

Acquired bleeding disorders

Inhibitors



Last author update: 1 August 2010
Last staff update: 11 October 2022

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PubMed Search: Inhibitors

Kendall Crookston, M.D., Ph.D.
Julie Kim Harrington, M.D.
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Cite this page: Crookston K, Rosenbaum LS, Gober-Wilcox J. Inhibitors. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/coagulationinhibitors.html. Accessed June 3rd, 2023.
Autoimmune based inhibitors in nonhemophiliac patients
Definition / general
  • An acquired hemophilia that occurs after development of an autoantibody directed against a specific coagulation protein in patients with no prior coagulation defect

Epidemiology
  • Incidence of 0.2 to 1.0 per million per year
  • Median age at presentation is 60 - 70 years
  • M = F

Etiology
  • Associated with autoimmune disorders, solid tumors, hematologic malignancies, dermatologic disorders, inflammatory bowel disease, respiratory diseases, diabetes, acute hepatitis (B and C), severe drug reactions, post childbirth
  • 50% occur in patients with no known medical problems

Clinical features
  • Most common inhibitor is antifactor VIII (Semin Thromb Hemost 2009;35:760)
  • Mortality rate of 8 - 22% with severe bleeding in up to 90% of affected individuals
  • Patients present with soft tissue bleeding such as gastrointestinal, urinary tract or intramuscular (versus intra-articular bleeding in hereditary hemophilia)
  • An acquired hemophilia should be suspected in patients with a new onset bleeding disorder accompanied by an isolated prolonged PTT (Curr Gerontol Geriatr Res 2010;2010:927503)
  • Patients should be referred to a hemophilia center with expertise in managing inhibitors (Haematologica 2009;94:566)
  • Poor prognostic factors are advanced age and lack of treatment (Semin Thromb Hemost 2009;35:769)

Laboratory
  • Prolonged PTT that does not correct with mixing studies
    • Note: PTT may initially be normal and then increases after 1 - 2 hours incubation
  • Normal PT
  • A nonlinear curve in a factor assay is often a clue to the presence of an inhibitor
  • The Bethesda assay is performed to detect and quantitate presence of inhibitor by diluting inhibitor patient plasma with pooled normal plasma
    • Each Bethesda unit of inhibitor indicates a decrease of factor VIII concentration in assay by 50% (1 unit → a reduction from 100% to 50%, 2 units → to 25%, 3 units → 12.5%, etc.)

Treatment
  • Prothrombin complex concentrates, recombinant factor VIIa, DDAVP, factor VIII concentrates, immunosuppressive agents, plasmapheresis (variable success) (BMC Res Notes 2010;3:161)

Additional references
Bovine coagulation factor inhibitors
Definition / general
  • Antibodies that develop against bovine proteins after exposure to topical bovine thrombin preparations which can potentially crossreact with corresponding human coagulation factors
  • Antibodies can form against bovine thrombin, factor V / Va and fibrinogen and less commonly against bovine factors VII and X
  • Some fibrin glues contain bovine thrombin and cryoprecipitate (containing human fibrinogen)
  • After use of bovine fibrin glue to achieve hemostasis, 1.7% develop a clinically significant inhibitor

Laboratory
  • Prolonged PT and PTT that does not correct with mixing studies

Case reports

Treatment
  • Steroids, cyclophosphamide, cyclosporine A, IV immunoglobulin
  • Management of acute bleeding includes plasmapheresis, platelet transfusions and immunoabsorption

Differential diagnosis
Factor V inhibitor
Definition / general
  • An acquired alloantibody that develops against factor V that promotes either its increased clearance from the circulation or interference with its coagulation function
  • Most are polyclonal IgG (which may also be associated with IgM or IgA)
  • May behave like factor VIII inhibitor in mixing studies, with increasing PTT or PT after 1 - 2 hours

Epidemiology
  • 20% of cases are idiopathic
  • In one study, 42% of cardiac surgery patients and 20% of neurosurgery patients developed factor V inhibitors after bovine thrombin exposure (Transfusion 2002;42:18)

Sites
  • Mucocutaneous and surgical site bleeding are the most common
  • Hematuria, gastrointestinal bleeding, intracranial bleeding and hemospermia have also been observed

Etiology
  • Most cases of acquired factor V inhibitors are iatrogenic and are caused by exposure to bovine protein (i.e., bovine thrombin preparations)
  • Antibodies are generated as an immune response to bovine factor V which then crossreacts with endogenous factor V
  • Other risk factors associated with factor V inhibitor development include recent surgery, drug exposure (e.g., aminoglycosides, B lactam antibiotics), infections, blood transfusions, autoimmune disorders, malignancy and pregnancy

Clinical features
  • Highly variable
  • Bleeding is typically severe and frequently fatal, however, in some instances there may be little to no bleeding
  • Inhibitors usually manifest 7 - 10 days postoperatively and then disappear within 8 - 10 weeks
    • Noniatrogenic inhibitors may persist for significantly longer periods
  • The titer of the inhibitor correlates with clinical severity
  • Bovine thrombin associated factor V inhibitors are often accompanied by antibodies to other coagulation proteins such as fibrinogen, prothrombin and thrombin

Laboratory
  • Prolongation of PT and PTT with failure to correct with mixing studies
  • A nonlinear curve in a factor assay is often a clue to the presence of an inhibitor
  • Thrombin times may be prolonged if thrombin inhibitor is also present
  • The Bethesda assay is performed to detect and quantitate the presence of inhibitor by diluting inhibitor patient plasma with pooled normal plasma
  • Each Bethesda unit indicates a decrease of factor V concentration in the assay by 50% (1 unit → reduction from 100% to 50%, 2 units → to 25%, 3 units → to 12.5%, etc.)
  • The Nijmegen assay is also used (Thromb Haemost 1995;73:247)

Prognostic factors
  • Noniatrogenic inhibitors are associated with more severe bleeding and fatal outcomes

Case reports

Treatment
  • Steroids, cyclophosphamide, cyclosporine A, IV immunoglobulin
  • Management of acute bleeding includes plasmapheresis, platelet transfusions and immunoabsorption

Differential diagnosis
  • May behave like factor VIII inhibitor in mixing studies, with increasing PTT or PT after 1 - 2 hours
  • Combined factor V / factor VIII deficiency

Additional references
Factor VIII inhibitor
Definition / general
  • An acquired antifactor VIII alloantibody, "antibody produced by one individual that reacts with alloantigens of another individual of the same species," that develops following infusion of factor VIII concentrates (plasma derived and recombinant) causing either increased clearance from the circulation or interference with coagulation function (e.g., inhibition of interaction of factor VIII with phospholipid, etc.)

Terminology
  • When challenged with factor VIII concentrate, inhibitor patients are either low or high responders:
    • Low responders are patients who develop a low titer of inhibitor (< 5 Bethesda Units [BU])
      • 50% of inhibitors are low titer and transient
    • High responders are patients who develop a high titer of inhibitor (> 5 BU)
  • Bypassing agents are coagulation factor treatment products that do not contain factor VIII

Epidemiology
  • Develops in 10 - 20% of patients with severe hemophilia A after infusion of factor VIII containing products, less often with mild / moderate disease
  • Rarely occurs de novo in patients without hereditary hemophilia, causing acquired hemophilia A (Autoimmune based inhibitors)
  • Risk factors for development of inhibitors:
    • Specific factor VIII genotype (i.e., major deletions or rearrangements have higher risk than those with small deletions or missense mutations)
    • Increased severity of hemophilia A (most likely due to more aggressive treatment)
    • Younger age
    • Race (blacks and Hispanics more affected than whites)
    • Family history of factor VIII inhibitors

Sites
  • Typically associated with intra-articular and soft tissue bleeding, similar to hemophilia B

Etiology
  • Multiple genetic and environmental factors (see Epidemiology)

Clinical features
  • Occurs after at least one infusion of factor concentrate, at a median of 9 - 12 exposures
  • Are predominantly polyclonal IgG but isolated instances of IgM and IgA have been reported
  • Titer of inhibitor often increases after treatment with factor VIII containing products
    • This does not happen with autoimmune factor VIII inhibitor
  • The presence of an inhibitor should be suspected when a hemophilia patient shows a decreased response to replacement therapy (i.e., when a sufficient dose of factor concentrate does not control an acute bleeding episode)

Laboratory
  • Prolonged PTT that does not correct with mixing studies
    • Note: PTT may initially be normal and then increase after 1 - 2 hours incubation
  • Normal PT
  • A nonlinear curve in a factor assay is often a clue to the presence of an inhibitor
  • The Bethesda assay is performed to detect and quantitate the presence of inhibitor by diluting inhibitor patient plasma with pooled normal plasma
    • Each Bethesda unit indicates a decrease of factor VIII concentration in assay by 50% (1 unit reduction from 100% to 50%, 2 units → to 25%, 3 units → 12.5%, etc.)
  • The Nijmegen assay is also used (Thromb Haemost 1995;73:247)

Prognostic factors
  • Patients with high titer inhibitor (> 5 BU) are less likely to respond to treatment
  • Factor VIII genotypes that includes large gene deletions, inversions, nonsense and splice site mutations show less response to treatment (J Thromb Haemost 2009;7:1809)
  • Data is inconclusive regarding relative inhibitor risk of plasma derived versus recombinant factor concentrates: both can lead to formation

Case reports

Treatment
  • Acute bleeding episodes can be treated with high dose human factor VIII for low titer patients (to overwhelm inhibitor) or porcine factor VIII (if no cross reactivity with inhibitor)
  • For high-titer inhibitors, factor VIII bypassing agents (prothrombin complex concentrates, FEIBA or recombinant factor VIIa (J Thromb Haemost 2004;2:899)
  • FEIBA can also be used for minor or major surgical procedures (Haemophilia 2009;15:1300)
  • Immunosuppression for autoimmune based inhibitors, with a possible role for plasmapheresis

Differential diagnosis
  • Lupus-like anticoagulant:
    • Occasionally can cause a false positive inhibitor screen by prolonging the PTT and leading to a nonlinear curve in a factor assay

Additional references
Factor IX inhibitor
Definition / general
  • An acquired antifactor IX alloantibody ("antibody produced by one individual that reacts with alloantigens of another individual of the same species") that develops following infusion of factor IX concentrates (plasma derived and recombinant) causing either increased clearance from the circulation or interference with coagulation function (e.g., inhibition of interaction of factor IX with phospholipid, etc.)

Terminology
  • When challenged with factor IX concentrate, inhibitor patients are either low or high responders
  • Low responders are patients who develop a low titer of inhibitor (< 5 Bethesda Units [BU])
    • 50% of inhibitors are low titer and transient
  • Bypassing agents are coagulation factor treatment products that do not contain factor IX

Epidemiology
  • Develops in 1.5 - 3% of patients with severe hemophilia B after transfusion of factor IX containing products, less commonly with mild / moderate disease
  • The lower inhibitor rate in hemophilia B is due to the lower proportion of severe cases of hemophilia B (~30%) compared with hemophilia A (~60%)
  • Rarely arises in nonhemophilia patients with autoimmune disorders causing acquired hemophilia B
  • Risk factors for development of inhibitors:
    • Specific factor IX genotype (i.e., major deletions or nonsense mutations have higher risk than those with small deletions or missense mutations)
    • Increased severity of hemophilia B (most likely due to more aggressive treatment)
    • Younger age
    • Race (particularly individuals of Scandinavian descent)
    • Family history of factor IX inhibitors

Sites
  • Typically associated with intra-articular and soft tissue bleeding, similar to hemophilia A

Etiology
  • Multiple genetic and environmental factors (see Epidemiology)

Clinical features
  • Occurs after at least one infusion of factor concentrate, at a median of 9 - 12 exposures
  • Antibodies are predominantly polyclonal IgG
  • Titer of inhibitor often increases after treatment with factor IX containing products
  • The presence of an inhibitor should be suspected when a hemophilia patient shows a decreased response to replacement therapy (i.e., when a sufficient dose of factor concentrate does not control an acute bleeding episode)
  • With the development of inhibitors, some patients may experience allergic or anaphylactic reactions following exposure to concentrate

Laboratory
  • Prolonged PTT that does not correct with mixing studies
  • Note:
    • With factor VIII inhibitors, the PTT may initially be normal and then increase after 1 - 2 hours incubation
    • In contrast, factor IX inhibitors immediately inactivate factor IX activity and therefore do not require prolonged incubation
  • Normal PT
  • A nonlinear curve in a factor assay is often a clue to the presence of an inhibitor
  • The Bethesda assay is performed to detect and quantitate the presence of inhibitor by diluting inhibitor patient plasma with pooled normal plasma
  • Each Bethesda unit indicates a decrease of factor IX concentration in assay by 50% (1 unit reduction from 100% to 50%, 2 units → 25%, 3 units → 12.5%, etc.)
  • The Nijmegen assay is also used (Thromb Haemost 1995;73:247)

Prognostic factors
  • Patients with a high titer of inhibitor (> 5 BU) are less likely to respond to treatment
  • Data is inconclusive regarding the relative inhibitor risk of plasma derived versus recombinant factor concentrates
    • Both can lead to formation of inhibitors

Case reports

Treatment
  • Treatment is primarily supportive
    • Aggressive treatment should be aimed at correcting the underlying cause
  • Acute bleeding episodes can be treated with high dose human factor IX for low titer patients (to overwhelm the inhibitor) or porcine factor IX (if no cross reactivity with inhibitor)
  • For high titer inhibitors, factor IX bypassing agents (prothrombin complex concentrates, FEIBA or recombinant factor VIIa (J Thromb Haemost 2004;2:899)
  • FEIBA can also be used for minor or major surgical procedures (Haemophilia 2009;15:1300)
  • For autoimmune based inhibitors, use immunosuppression and possibly plasmapheresis

Differential diagnosis
  • Lupus-like anticoagulant:
    • Occasionally can cause a false positive inhibitor screen by prolonging the PTT and leading to a nonlinear curve in a factor assay

Additional references
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