Acquired hemophilia

from Wikipedia, the free encyclopedia
Classification according to ICD-10
D68.3 Hemorrhagic diathesis due to anticoagulants and antibodies
- multiplication of anti-VIIIa
ICD-10 online (WHO version 2019)

The acquired hemophilia is a rare coagulation disorder of the blood, which is the sudden appearance of most pronounced bleeding occurs in previously unremarkable patients. The bleeding tendency is often life-threatening and the treatment of this disease is extremely expensive. Acquired hemophilia is caused by antibodies that are directed against the body's own coagulation factor VIII and block its function. They are therefore autoantibodies and differ from the alloantibodies that occur, for example, in patients with severe haemophilia A as an immune reaction to substitution therapy with factor VIII concentrates.

Acquired factor VIII autoantibodies are mostly polyclonal or oligoclonal , the inhibition of factor VIII function depends on the target epitopes on the factor VIII molecule. The inhibition can be complete (plasma factor VIII activity <5%) or incomplete (decreased but measurable plasma factor VIII activity).

Epidemiology

The incidence of factor VIII inhibitors is between 0.2 and 1.0 / million / year. The disease occurs mainly in old age, there is no gender dependency. The most comprehensive investigation of the underlying causes is still the historical work by Green and Lechner from 1982 (Table 1). These data have been confirmed in recent studies (, Baudo - EACH Registry).

Malignant diseases can be associated with the occurrence of factor VIII antibodies. Therefore, at least in suspicious patients, an appropriate tumor search should be carried out.

Pregnancy-associated factor VIII inhibitors are rare but well known and always reversible. They mostly occur post partum. If a factor VIII antibody manifests prepartally, the newborn child should also be examined for any tendency to bleed, since anti-F VIII autoantibodies of the IgG type cross the placenta and theoretically can also block the child's factor VIII.

Causes of Acquired Factor VIII Autoantibodies

A distinction is made between the following causes:

clinic

The most important clinical feature of factor VIII inhibitors is the sudden occurrence of a spontaneous bleeding tendency in previously unremarkable patients. These are mostly skin, soft tissue and muscle hematomas , especially psoas hematomas are common. The bleeding tendency does not correlate with the factor VIII level or the antibody titer. Bleeding requiring transfusion occurs in 87% of cases, the mortality from bleeding is 10–20%. With adequate hemostatic therapy, fatal bleeding is rare. Acquired hemophilia is a rare condition and is therefore often recognized too late or not at all. Therefore, appropriate laboratory diagnostics must be carried out in patients with an unclear severe bleeding tendency.

Surgical interventions (e.g. for hematoma drainage) should be strictly avoided (except when there is a danger to life), as they make lengthy and extremely expensive substitution therapy necessary. Virtually all hematomas resorb spontaneously after an efficient hemostasis has been restored. Treatment should be carried out according to standardized rules in consultation with a center specializing in blood coagulation disorders.

Laboratory diagnostics

In routine laboratory striking an isolated extension is aPTT (in all test systems used detectable), with normal prothrombin time . Such a constellation must be further clarified in bleeding patients. The following examination is used for this purpose:

Algorithm for the diagnosis of acquired factor VIII antibodies

  • Repetition of aPTT, PTZ, fibrinogen to rule out incorrect determinations
  • Thrombin time to rule out heparin effects or contamination
  • Anti-Xa activity to exclude an effect of low molecular weight heparin
  • Exchange attempt (1: 1 mixture of the patient's plasma with normal plasma) to detect a circulating inhibitor
  • aPTT determination directly after mixing and after two hours of incubation at 37 ° C, to distinguish it from lupus anticoagulants
  • Single factor analysis: coagulation factors VIII, IX, XI, XII
  • Bethesda assay , possibly Nijmegen modification

A reduction in factor VIII activity with simultaneous detection of inhibition confirms the diagnosis of an F. VIII antibody. Due to the kinetics and the temperature dependence of most of these antibodies, but also the varying degrees of inhibition, quantifying the inhibitor titer with the Bethesda method can be problematic. It is quite possible that a high inhibitor titer is calculated and plasma factor VIII activities of> 10% can still be measured.

therapy

Factor VIII autoantibodies have spontaneous remission rates of about 38% within 10 months. Due to the frequent, often pronounced tendency to bleed, which can have a mortality of up to 20%, therapy is nevertheless necessary.

The therapy is based on 3 measures:

  • Hemostasis; in acutely bleeding patients or before absolutely necessary surgical interventions
  • Elimination of the antibody; to enable substitution with factor VIII concentrates
  • Prevention of antibody replication

Hemostasis

A hemostatic therapy is indicated only in patients who are clinically provide a strong tendency to bleed or have large hematoma at critical locations, or as prophylaxis in surgical interventions (. Eg central venous catheters). Other patients, especially those with measurable F. VIII levels (> 10%), usually do not need hemostatically effective therapy.

The following drugs can be used (the recommended prices are based on a patient weighing 70 kg per treatment day):

Recombinant Activated Factor VIIa

Dosage: 90 µg / kg body weight every 2–3 hours, the intervals extended to 4, 6, 8 or 12 hours depending on the clinical improvement in the bleeding tendency. The drug must be given at short intervals and is very expensive (approx. € 5,942 for the minimum dose | 1 × 90 µg / kg |). The advantage is the hemostatic effect that sets in quickly in 90% of patients; however, the risk of arterial thrombosis increases in patients with pre-existing cardiovascular diseases.

Activated prothrombin complex

Dosage: 50-100 U / kg BW iv. (max. 200E / kg body weight / day) every 6–12 hours. The advantage is the rapid onset (max. Thrombin generation after 15–30 minutes), the reliable haemostatic effect (90.5% bleeding stop after 24 hours), the long duration of action combined with a lower dosing frequency (8–12 hours thrombin generation with one dose ) as well as the significantly lower costs.

Costs - (list price according to Lauer estimate: 1.19 € / E; as of April 2010):

  • Max. Dose / day (2 × 100 U / kg) = approx. € 16,660 (2 × 100E × 70 kg × 1.19 €)
  • Standard dose / day (2 × 50-75 U / kg) = approx. € 10,829 (2 × 65E × 70 kg × € 1.19)
  • Lowest dose / day (1 × 50 U / kg) = approx. € 4,165 (1 × 50E × 70 kg × € 1.19)

Human factor VIII concentrates

Dosage: 3 × daily 100–200 U / kg body weight iv (e.g. 3 × 5000 U), then according to plasma F. VIII levels. Objective: valley level> 30% if there is a strong bleeding tendency,> 10% if there is little bleeding tendency. If the inhibitor titer is unclear, give a test dose of 5000 U and determine recovery. If the F. VIII level rises well, treatment can be continued with F. VIII concentrate. Advantages: cheaper than Novoseven or activated prothrombin complex concentrate (FEIBA); In addition, an excess of antigen (F. VIII level> 50–80%) can probably accelerate the elimination of antibodies. Disadvantage: only effective with antibody titers <approx. 5 BU / ml. A “booster effect” (anamnestic response), as it is known in real haemophiles with high-responding inhibitors, never occurs with F. VIII autoantibodies.

Costs:

  • full dose (3 × 200 U / kg) = approx. € 36,330.00
  • Standard dose (3 × 5000 U / kg) = approx. € 18,165.00
  • lowest dose (1 × 2000 U) = approx. € 1,730.00

Antibody Elimination

Rapid removal of the antibody from the circulation with the aim of lowering the titer below approx. 5 BU / ml enables substitution therapy to be switched to (significantly cheaper) F. VIII concentrates; spontaneous F. -VIII increase (patient's own F. VIII production).

Immune adsorption

The most efficient method is immunoadsorption on immobilized anti-human immunoglobulin antibodies (Therasorb®). With this system, 7 liters of plasma can be treated per day and the antibody titer reduced within a few days. Immune adsorption can be carried out via good peripheral veins, which is an advantage, since central venous access can be problematic because of the tendency to bleed.

Immunoadsorption to immobilized staphylococcal protein A is also efficient. Depending on availability, one of these two immunoadsorption processes can be selected.

With both methods, a special anticoagulation protocol is necessary, on the one hand to prevent coagulation in the extracorporeal circuit (which can destroy the expensive Sepharose columns) and, on the other hand, to avoid exposing the patient to additional anticoagulation. The hemostatic situation is complicated, since during the procedure (which lasts 4 hours) the patient's F. VIII levels can already rise and a procoagulant effect begins. A well-functioning protocol uses a continuous infusion of citrate and heparin for local anticoagulation of the system, as well as a continuous infusion of protamine chloride to antagonize the heparin so that the patient is not exposed to heparin action.

Switch to F. VIII concentrates

After the inhibitor titer has been reduced to below approx. 5 BU / ml by immunoadsorption, the hemostatic therapy can be switched to the cheaper F. VIII concentrates. A tried and tested procedure in practice is to take blood for F. VIII determination immediately after immunoadsorption, then give 5000 units of F. VIII concentrate and measure the F. VIII level again after 1 hour. An increase in the F. VIII values ​​indicates that the inhibitor has been eliminated, and further therapy can be carried out with F. VIII concentrates. For this purpose, F. VIII pre and post values ​​must always be determined once a day and the F. VIII dose and intervals adjusted accordingly. The aim is to achieve F. VIII trough levels of> 50% and <100%.

Plasmapheresis

A plasmapheresis is not as efficient as far immunoadsorption and can have many side effects. This procedure should therefore no longer be used.

High dose immunoglobulins

In analogy to the therapy of autoimmune thrombocytopenia , it has been described that therapy with IgG concentrates (1000 mg / kg body weight on 2 consecutive days) can eliminate the F. VIII autoantibodies for a short time. However, this effect is not constant and only lasts for a short time. The Ig concentrates are expensive and cannot be combined with any planned immune adsorption.

Obtaining an excess of antigen

The administration of F. VIII concentrates to raise the F. VIII level appears to cause the inhibitor to be eliminated more quickly, although the levels required for this are not known. However, continuous values> 50% (valley level) should be sufficient.

Prevention of antibody replication

After eliminating the triggering cause (if possible), the immune process that led to the formation of the F. VIII autoantibodies can be interrupted with immunosuppressive therapy.

Corticosteroids

Therapy with steroids (e.g. prednisolone (Aprednislon®) 1–2 mg / kg / d po. (E.g. 100 mg absolute)) is part of the standard therapy for F. VIII autoantibodies, although no clinical studies on it exist. Caution is advised in patients with diabetes mellitus or impaired glucose tolerance, or in the case of psychological instability ( cortisone psychosis ). The duration of therapy depends on the antibody titer, but should not be longer than 3–4 weeks in the full dose. Therapy should not be stopped suddenly.

Cyclophosphamide

Also Cyclophosphamide is a standard therapy. The dose is 1.5-2.0 mg / kg (z. B. 200 mg absolute) Endoxan® orally per day (possibly after an initial bolus of 1000 mg iv.) And by white blood cell count to titrate. A decrease in leukocytes can be expected approx. 10-14 days after the start of therapy. The main complication of therapy is a significant susceptibility to infection. Immunosuppressive therapy must be carefully monitored and the dose adjusted according to the white blood cell count. Therapy can (and should) be rapidly reduced after normal F. VIII values ​​have been reached (without substitution). Various studies have shown that immunosuppressive therapy is associated with a high rate of side effects. Close monitoring of leukocyte counts and infection parameters or antibiotic screening should therefore be carried out consistently.

Rituximab

The anti-CD20 antibody rituximab destroys all CD20-positive cells, including all immunoglobulin-producing lymphocytes and plasma cells. It has achieved some success in the therapy of autoimmune diseases, and certain successes have also been described with factor VIII autoantibodies. Clinical studies are ongoing for this indication, but no results are yet available. Therefore, this therapy should not yet be used for the routine treatment of F. VIII antibodies. The currently valid protocol comprises 4 infusions of 375 mg / m² Mabthera® each at weekly intervals. The infusions must be administered according to the guidelines provided. Rituximab can (also in the long term) cause an increased susceptibility to infections (especially viral infections - CMV , herpes simplex , herpes zoster , and pneumocystis ). An old, healed HBV infection or an existing hepatitis B can lead to life-threatening reactivations.

Supportive therapy

Red cell transfusions should be performed if there are signs of severe anemia (hemoglobin levels below 8.0 g / dL). Any pain relief that may be necessary should only be carried out with drugs that do not affect platelet aggregation (preferably opioids ).

Monitoring

To control the therapy (as efficient as possible substitution for hemostasis, but at the lowest possible cost), on the one hand, the assessment of the clinical situation (bleeding tendency, blood count) and, on the other hand, close-knit laboratory controls are necessary. The best parameter for response to therapy is trough factor VIII level . It can be determined relatively easily and shows the residual F. VIII activity after the last substitution. Determining the recovery (from an F. VIII post value one hour after the last F. VIII substitution) can also provide an indication of the antibodies that are still present. For this reason, an F. VIII level (if possible also a post-value) should be determined daily in patients with F. VIII autoantibodies. APTT values ​​are only sufficient in individual cases (e.g. weekends). The F. VIII values ​​are primarily used to control F. VIII substitution therapy.

The determination of the F. VIII antibody titer is problematic for F. VIII autoantibodies (see above) and no longer provides exact values ​​as soon as F. VIII levels can be measured again. This parameter is therefore only used to estimate whether a substitution with F. VIII concentrates makes sense (for titers <5 BU / ml).

Further controls

  • Blood count: erythrocyte count or Hb to estimate blood loss, leukocytes to control the endoxane dose, platelets to detect a DIC or the endoxane effect
  • Coagulation: prothrombin time, aPTT, fibrinogen; F. VIII activity, F. VIII inhibitor, recovery of F. VIII
  • Blood sugar in cortisone therapy
  • C-reactive protein for detecting infection under immunosuppression
  • LDH , CPK etc. in the case of compartment syndrome or large hematomas
  • General monitoring of hematomas in critical areas (neck, retroperitoneum , ...)

Refractory patients

Immunosuppression

In patients who still do not have normal F. VIII values ​​after 3 months, cortisone should be reduced to a maintenance dose of approx. 12.5 mg / day. Cyclophosphamide should be discontinued because an effect can no longer be expected after such a long time.

Patients who do not bleed should only be observed, as late spontaneous remissions are also possible. Further therapy is only indicated if there is a tendency to bleed. The following strategies exist for this:

Prevention of inhibitor replication

Rituximab (specified above)

Immune tolerance induction

Immune tolerance induction, as it is carried out with inhibitors (alloantibodies) in real haemophilia, is not carried out in acquired haemophilia. This is mainly because the patient produces large amounts of factor VIII anyway and therefore F. VIII antigen is always present. The aim of therapy, however, is to achieve an antigen excess (ie F. VIII levels above 10%) through regular infusion of F. VIII concentrates in order to saturate the inhibitor. For this purpose, a combination with other forms of therapy, e.g. B. intravenous IgG should be considered.

Other immunosuppressants

The following drugs have so far been described for immunosuppression with F. VIII inhibitors:

Treatment of bleeding or surgery

Basically carried out as described above with F. VIII concentrates, Novoseven, FEIBA, DDAVP, local measures, antifibrinolytics .

Forecast and follow-up

If treated correctly, the prognosis for acquired hemophilia is good today. A meta-analysis by Delgado shows that the elimination of the antibody has the greatest impact on survival. Unfavorable prognostic factors were age> 65 years and the presence of underlying malignancies. The administration of immunotherapy, especially protocols containing cyclophosphamide, leads to faster inhibitor elimination, but has a high rate of side effects, including fatal sepsis , especially in elderly or multimorbid patients .

Relapses after complete inhibitor elimination can occur, but are rare and are associated with the course of any underlying underlying disease. Regular follow-up checks should therefore be carried out.

International registers

Patients with acquired coagulation inhibitors and other blood coagulation disorders should be collected in an international registry for research purposes, e.g. B. the International Registry of Rare Bleeding Disorders based in Italy . The European EACH2 register was closed in 2009.

Web links

Literature / sources

  1. ↑ a b c d J. Delgado: Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. In: Brit.J. Haematol. 2003; 121, pp. 21-35.
  2. ↑ a b c d D. Green, K. Lechner. A survey of 215 non-hemophilic patients with inhibitors to Factor VIII. In: Thromb Haemost . 1981; 45 (3), pp. 200-203. PMID 6792737 .
  3. ^ I. Hauser, K. Lechner: Solid tumors and factor VIII antibodies. In: Thromb Haemost. 1999; 82 (3), pp. 1005-1007. [1]  ( Page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: Toter Link / www.schattauer.de  
  4. ^ I. Hauser, B. Schneider, K. Lechner: Post-partum factor VIII inhibitors. A review of the literature with special reference to the value of steroid and immunosuppressive treatment. In: Thromb Haemost. 1995; 73 (1), pp. 1-5. PMID 7740477
  5. ↑ Specialist information on NovoSeven, as of December 2013 (PDF; 100 kB)
  6. ↑ P. Collins, F. Baudo, A. Huth-Kühne, J. Ingerslev, CM Kessler, ME Castellano, M. Shima, J. St-Louis, H. Lévesque: Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. . In: BMC research notes. Volume 3, 2010, p. 161, ISSN  1756-0500 . doi: 10.1186 / 1756-0500-3-161 . PMID 20529258 . PMC 2896368 (free full text).
  7. ↑ a b c d Specialist information Feiba NF 500E factor VIII inhibitor bypassing activity (PDF)  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: Toter Link / baxter.de  
  8. ↑ a b c d Specialist information Feiba NF 1000E Factor VIII Inhibitor Bypassing Activity (PDF)  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice.@1@ 2Template: Toter Link / baxter.de  
  9. ↑ a b K. Váradi et al .: Monitoring the Bioavailability of FEIBA with a Thrombin Generation Assay. In: J Thromb Haemost . 2003; 1, pp. 2374-2380.
  10. ↑ J. Aster Mark et al .: A randomized comparison of bypassing agents in hemophilia complicated by at inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. (PDF)
  11. ↑ Lauer estimate
  12. ↑ M. Jansen, S. Schmaldienst, I. Pabinger, WH Hörl, K. Derfler, P. Knöbl: Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb). In: Brit.J. Haematol. 2001; 112, pp. 91-97.
  13. ^ H. Zeitler, G. Ulrich-Merzenich, L. Hess, E. Konsek, C. Unkrig, P. Walger, H. Vetter, HH Brackmann: Treatment of acquired hemophilia by the Bonn-Malmo Protocol: documentation of an in vivo immunomodulating concept. In: Blood . 2005 Mar 15; 105 (6), pp. 2287-2293.
  14. ^ S. Schmaldienst, A. Goldammer, S. Spitzauer, K. Derfler, WH Hörl, P. Knöbl: Local anticoagulation of the extracorporeal circuit with heparin and subsequent neutralization with protamine during immunoadsorption. In: Am. J. Kidney Dis. 2000; 36, pp. 490-497.
  15. ^ WR Sperr, K. Lechner, I. Pabinger: Rituximab for the treatment of acquired antibodies to factor VIII. In: Haematologica . 2007 Jan; 92 (1), pp. 66-71.
  16. Jump up ↑ O. Lambotte, J. Dautremer, B. Guillet, T. Boutekedjiret, M. Dreyfus, R. Kotb, P. Le Bras, JF Delfraissy, T. Lambert, C. Goujard: Acquired hemophilia in older people: a poor prognosis despite intensive care. In: J Am Geriatr Soc. 2007 Oct; 55 (10), pp. 1682-1685.
  17. ↑ PW Collins, S. Hirsch, TP Baglin, G. Dolan, J. Hanley, M. Makris, DM Keeling, R. Liesner, SA Brown, CR Hay; UK Haemophilia Center Doctors 'Organization: Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Center Doctors' Organization. In: Blood. 2007 Mar 1; 109 (5), pp. 1870-1877.
  18. ^ International Registry of Rare Bleeding Disorders
  19. ↑ http://www.each2registry.org/  ( page no longer available , search in web archives )  Info: The link was automatically marked as defective. Please check the link according to the instructions and then remove this notice. European Acquired Hemophilia Registry@1@ 2Template: Dead Link / www.each2registry.org