Introduction
Acquired coagulation inhibitors are antibodies that neutralize the coagulation factors' activity and fasten their clearance by uniting with the coagulation factors. Alloantibodies are inhibitors that occur in patients with acquired deficiencies of coagulation factors. In contrast, autoantibodies develop spontaneously in individuals who have had normal coagulation factor function earlier. The latter category is inclusive of inhibitors against coagulation factors I to XIII.
What Are Acquired Inhibitors of Coagulation?
Acquired coagulation inhibitors occur due to the depletion or inhibition of a coagulation factor. These inhibitors are most commonly directed against factor VIII (FVIII) and Von Willebrand factor (VWF), and inhibitors against other coagulation factors are only occasionally reported.
What Are the Clinical Features Associated With Acquired Inhibitors of Coagulation?
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An acquired inhibitor should be considered in patients with recent onset of abnormal bleeding. Patients usually present to clinicians with limited experience of the disorder, and diagnosis and appropriate treatment are often delayed. Severe and life-threatening bleeding is common in AHA (acquired hemophilia A), although, in contrast, no hemostatic treatment is required in 25 to 33 % of cases.
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The clinical features of AHA differ from those of congenital hemophilia because bruising, retroperitoneal, muscle, gastrointestinal and urogenital bleeding are common, whereas haemarthrosis is uncommon.
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Fatality is associated with gastrointestinal, intracranial, and retroperitoneal bleeds.
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Compartment syndromes and critical compression of nerves and blood vessels may be seen.
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Acquired hemophilia A has been reported in association with anticoagulation, and antiplatelet agents, and diagnosis, may be delayed because the bleeding is assumed to be caused by these agents.
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Excessive bruising or unexpected bleeding in patients on anticoagulants should be further investigated.
How Are Acquired Inhibitors of Coagulation Diagnosed?
Diagnosis of acquired coagulation factor inhibitors, and their differentiation from other coagulation abnormalities, requires specialized investigation, often necessitating referral to a reference laboratory. When investigating abnormal clotting times in patients presenting with bleeding, it is essential to exclude treatment with anticoagulant therapy.
FVIII inhibitors depend on time and temperature, and combining studies with normal plasma can demonstrate inhibition on incubation that does not occur instantly after combining. Inhibitors to other coagulation factors have not been reported to be time-dependent. Enzyme-linked immunosorbent assay (ELISA)-based assays have been reported for FVIII inhibitor detection, which may avoid interference by LAs. Chromogenic FVIII assays may be used because LAs do not interfere with this assay.
How Are Acquired Inhibitors of Coagulation Treated?
Treatment and management of acquired inhibitors of coagulation are mentioned as follows:
1. Avoiding Iatrogenic Bleeding-
Patients should not be exposed to invasive procedures unless essential because uncontrollable bleeding may result even from minor procedures.
2. Treatment of Bleeding in AHA-
Treatment of bleeding should be supervised by a clinician experienced in the treatment of patients with inhibitors because bleeds may be very severe, and prompt hemostatic control is required to reduce morbidity and mortality.
3. Bypassing Agents-
Most data on the treatment of bleeds for patients with FVIII inhibitors relate to congenital hemophilia and focus on haemarthrosis. The autoantibodies that cause AHA have different properties than the alloantibodies associated with congenital hemophilia, and the bleeding pattern differs. In particular, haemarthrosis is uncommon. Data derived from patients with genetic inhibitors cannot necessarily be extrapolated to AHA.
4. Factor VIII and Desmopressin-
After matching for bleed and patient characteristics, the likelihood of hemostatic failure was lower with bypassing agents compared to FVIII or Desmopressin.
5. Human FVIII-
Even though the inhibitor titer may be modest, most AHA patients are resistant to human FVIII, and the Bethesda assay does not accurately predict FVIII recovery. Normally, human FVIII is neutralized by a rapid early parabolic drop to a low level, occasionally followed by a less rapid, second disappearance phase, leaving a relatively low residual FVIII activity that may last for a few hours. The FVIII level cannot predict the clinical reaction.
6. Human Factor VIII and Immunoadsorption-
High-dose human FVIII (100 IU/kg/day) in combination with immunoadsorption may result in hemostatic FVIII levels and high-speed control of unmanageable bleeding, even with high anti-FVIII inhibitor titer levels. This treatment strategy may be helpful as first-line therapy or if bypassing agents have failed, although it is available in only a minimal number of centers.
7. Desmopressin-
Desmopressin may be helpful in treating minor bleeds, but careful laboratory and clinical response monitoring are required.
8. Porcine FVIII-
In AHA, the inhibitor titer to porcine FVIII is usually five to ten percent that of the human titer, and so porcine FVIII may achieve hemostasis in situations where human FVIII is ineffective. Plasma-derived porcine FVIII has proven efficacy in AHA but is no longer available. The use of a recombinant B-domain deleted porcine FVIII is currently under investigation in AHA.
9. Tranexamic Acid-
Tranexamic acid is a helpful adjunct therapy, especially for mucosal bleeds. It should be considered for all bleeds apart from renal tract bleeding. Concerns about the concomitant use of Tranexamic acid with FEIBA exist, but reports of complications are very rare, and many clinicians use Tranexamic acid in combination with FEIBA. Topical Tranexamic acid may be helpful for oral or skin bleeding.
10. Intravenous Immunoglobulin-
The use of intravenous immunoglobulin (IVIG) as an adjunct to other hemostatic measures is approved for patients with acquired inhibitors of coagulation factors and life or limb-threatening hemorrhage that has failed to respond to other therapies.
11. Management of Invasive Procedures-
Treatment options include the use of bypassing agents or immunoadsorption with FVIII infusions. Hemostasis cannot be guaranteed, and life-threatening bleeding may result.
12. Thrombosis-
Treatment with either rFVIIa or FEIBA is associated with arterial and venous thrombosis, and the incidence of thrombosis appears to be higher than when these agents are used in congenital hemophilia A.
13. Eradication of the Inhibitor in AHA-
Immunosuppression to eradicate an inhibitor should be started as soon as the diagnosis has been made to reduce the time a patient is at risk of bleeding, although hemostatic control should be the priority in the acute setting. The choice of immunosuppressive regimen needs to be taken into account; patients should be monitored closely for evidence of infection.
14. Immunosuppressive Regimens-
Routine first-line treatment in many centers is with either steroids alone or steroids combined with a cytotoxic agent.
15. Steroids and Cytotoxic Agents-
Patients treated with Prednisone alone were compared to those treated with Prednisone and oral Cyclophosphamide.
16. Rituximab-
Rituximab is becoming a common treatment for AHA, but there is no data to support the contention that alone, or with other agents, it results in more patients achieving remission or a more rapid response to treatment.
17. Calcineurin Inhibitors-
The combination of Ciclosporin or Tacrolimus and steroids has been reported as a successful first-line treatment with stable remission.
18. Factor VIII Immune Tolerance-
FVIII, in conjunction with immunosuppressive agents, has been reported. The lack of controls in these studies means that the role of FVIII is difficult to assess.
19. Adverse Events-
Adverse events like high infection rates, diabetes mellitus (a metabolic disease that causes elevated blood sugar levels), neutropenia (a low count of neutropenia, which is a type of white blood cell), and psychiatric problems are highly common.
20. Second-line Immunosuppressive Therapy-
Failure of first-line therapy should be considered after three to five weeks when there is no increase in the FVIII levels, and the inhibitor titer does not drop. In patients not responding to first-line steroids, a cytotoxic agent, a calcineurin inhibitor, or Rituximab can be considered. If a patient fails first-line treatment with Rituximab, then steroids, cytotoxic agents, or calcineurin inhibitors may be successful. Mycophenolate mofetil may be a useful alternative, although there are no reports in the literature of using this drug in AHA. Resistant cases may respond to high dose FVIII, immunosuppression, immunoadsorption, or more intensive combination chemotherapy.
Conclusion
Acquired inhibitors of coagulation are significantly rarer than the congenital forms of the disease. The acquired inhibitors are autoantibodies that neutralize the target coagulation activity, often interfering with binding to phospholipid surfaces. Acquired von Willebrand syndrome (AVWS) is a rare acquired bleeding disorder presenting in adulthood. Bleeding is the main presenting symptom of acquired coagulation disorders and is often severe or life-threatening, constituting a medical emergency. Management includes rapid and accurate diagnosis, control of bleeding, investigation for an underlying cause, and eradication of the inhibitor by immunomodulation. The diagnosis should be suspected in a patient with a suggestive clinical presentation and prolongation of the activated partial prothrombin time (APTT) or another suggestive coagulation abnormality.
