Heparin-induced thrombocytopenia

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Classification according to ICD-10
D69.5 Secondary thrombocytopenia
ICD-10 online (WHO version 2019)

The heparin-induced thrombocytopenia (HIT) is a disease by the administration of at heparin , an agent for inhibiting blood coagulation , the number of platelets drops (platelets). There are two types of HIT.

Heparin-induced thrombocytopenia type I

HIT type 1 (HIT1) manifests itself in the first few days of heparin treatment. It is represented by a moderate decrease in the number of blood platelets, which regresses spontaneously after a few days. This phenomenon is based on a direct activation of the platelets by the drug. Therapy is not necessary. Usually the platelets do not fall below 80,000 / μL.

Heparin-induced thrombocytopenia type II

HIT type II (HIT2) is based on the formation of antibodies against heparin / protein complexes. Due to its negative charge , the active ingredient binds to numerous proteins. The complex of heparin and platelet factor 4 is considered to be the most important disease-causing factor . Platelet factor 4 is a highly positively charged protein that is released from blood platelets. Some patients develop antibodies against the drug / protein complex - the antigen . After binding to the complex, the antibodies bind with their Fc part to a receptor on the platelet. This causes the platelets to clump together and become activated. This results in thromboses in the venous and arterial system. Inactivation of the coagulation with a tendency to bleed can occur extremely rarely. The first antibodies can be measured six to twenty days after the start of heparin administration.

The occurrence of HIT type II depends on the duration of the heparin treatment; it is less common for less than five days. A high dose also increases the risk of this complication. Furthermore, the molecular size of the active ingredient is a factor. With a larger chain length, more platelet factor can be bound per molecule of heparin, which in turn increases the immunogenicity of the complex. Long-chain, unfractionated heparin has a thirty-fold higher risk of HIT type 2 than low molecular weight heparin. The origin of the heparin can also influence the development of HIT. Antibody formation occurs more frequently when heparin is obtained from pigs than with active ingredient from cattle. Studies also indicate an increased risk in female patients. In therapy with non-fractionated heparin, the incidence of HIT type 2 is between 0.5 and 5% after an administration period of five days.

diagnosis

Upon first contact with heparin, after the latency period, the platelet count drops rapidly to less than half of the initial value over the course of one to two days. If the patient had previously come into contact with heparin and antibodies, this can happen without latency and with an even faster course.

Not all patients with platelet depletion have HIT2. The severity and time course of thrombocytopenia, the occurrence of thrombosis, and the presence of other conditions that may explain thrombopenia determine the likelihood that it is actually HIT2. This can be estimated with the 4T score .

4T score

2 points 1 point 0 points
Thrombocytopenia Decrease in platelet count by> 50% AND the lowest value is 20 - 100 / nl Decrease by 30-50% OR the lowest value is 10-20 / nl Drop by <30% OR the lowest value is <10 / nl
Timing Decrease between days 5 and 10 after starting therapy or
on days 0-1 after prior exposure in the last 30 days 		Decrease after day 10 or
on day 0-1 after pre-exposure in the last 30 to 100 days 		Drop before day 5 without prior exposure
thrombosis New thrombosis, skin necrosis, or systemic reaction to heparin Increasing or recurring thrombosis, suspected thrombosis or reddening of the skin at the injection site No symptoms
Alternative cause of thrombopenia no possible clearly present

This score results in up to 8 points. With a value of up to 3 points, a HIT2 is unlikely, 4 to 5 points are considered to be the medium probability, from 6 points it is very likely. A low probability according to this score has a negative predictive value of 0.998, the positive predictive value of a medium or high score is 0.14 or 0.64 and justifies further clarification and a precautionary change in therapy.

Antibody detection

In principle, it is not possible to confirm the diagnosis with laboratory tests, but there is, among other things, an ELISA test with which the antibodies can be detected in approx. 90–95% of cases. However, depending on the test, antibodies are detected in 5-50% of cases without ever having a HIT. A new method is the lateral flow immunoassay, with which antibodies are found similarly to ELISA, with apparently fewer false-positive results. The serotonin release test is used as the reference method. Donor platelets are incubated with radioactively labeled C14 serotonin, which they absorb. The mixture is then mixed with patient serum and heparin. The serotonin release measured via the radioactivity serves as an indicator for the presence of HIT antibodies. In Germany, the heparin-induced platelet activation assay (HIPA) has also become established. In this test, donor platelets are also incubated with patient serum and heparin. The degree of platelet activation is the turbidity of the sample mixture compared to a reference sample. In some cases, when the heparin is injected under the skin, bleeding skin necrosis can be seen at the injection site. HIT is comparatively well secured if the platelet count increases significantly again 12–48 hours after stopping the heparin and starting an alternative anticoagulant.

therapy

If HIT type II is first suspected, heparin should be discontinued immediately in order to avoid potentially life-threatening complications (venous and arterial thromboses can lead to pulmonary embolism and infarcts). In order to continue treating the underlying disease, but essentially to prevent the fatal circulatory disorders associated with HIT, you must immediately switch to another anticoagulant. The hepatically eliminated argatroban is the drug of choice and has no relevant side effects in addition to the naturally increased tendency to bleed. An alternative is the heparinoid danaparoid , which has a similar structure to heparin. Therefore, before using the latter, it would first have to be clarified whether the antibodies responsible for HIT also cross-react with danaparoid (<10%). Danaparoid treatment must also be controlled by determining a coagulation factor that the drug inhibits. The advantage of the danaparoid, however, is that it can be injected subcutaneously (under the skin), while argatroban and lepirudin must be given continuously intravenously (via an indwelling cannula). The treatment with argatroban and hirudin, which directly inhibit the thrombin necessary for coagulation , can be monitored less laboriously via the routine aPTT value. Oral anticoagulants such as phenprocoumon , warfarin and acenocoumarol , which inhibit vitamin K as a vitamin required for blood clotting, cannot be used in the first two weeks of HIT type II, as necrotic disorders can occur as a side effect. Oral anticoagulation is then possible and usually makes sense. The administration of platelet aggregation inhibitors such as acetylsalicylic acid has not shown any decisive effectiveness in the stage of thrombosis development. The selective anti-Xa inhibitor fondaparinux , a pentasaccharide, should not be used in acute situations due to the lack of approval. Although isolated HIT-II cases have been published in fondaparinux patients in the past, due to the lack of cross-reactivity between fondaparinux and HIT-II sera, it can be ruled out that Fondaparinux itself could trigger HIT-II. The use of fondaparinux in anamnestic HIT-II patients (at least three months after diagnosis) is therefore the antithrombotic of first choice.

forecast

The lethality of HIT type II in connection with the occurrence of thrombotic complications is around 30%.

literature

  • A. Greinacher et al .: Heparin-induced thrombocytopenia. In: Dtsch Arztebl. Volume 100, Issue 34-35, 2003, pp. A 2220-2229.
  • J. Braun, R. Preuss: Clinical Guide Intensive Care Medicine. 5th edition. Urban & Fischer, 2002, ISBN 3-437-41202-7 .
  • Drug Commission of the German Medical Association, "UAW-News - International": Heparin-induced thrombocytopenia under Fondaparinux. In: Dtsch Arztebl. Volume 105, No. 30, 2008, pp. A-1626 / B-1402 / C-1370.

References

  1. ↑ Wolfgang Gerok: The internal medicine. 11th edition. Stuttgart 2007, p. 95; Heiner Greten : Internal Medicine. 12th edition. Stuttgart 2005, p. 383f.
  2. ↑ Souza-Offtermatt, Staubach, Sterk, Udolph: Intensive Surgery Course . 1st edition. Elsevier, Munich 2004, p. 103.
  3. ↑ Wolfgang Gerok: The internal medicine. 11th edition. Stuttgart, 2007, p. 95; Heiner Greten: Internal Medicine. 12th edition. Stuttgart 2005, p. 383f; Bettina Kemkes-Matthes: Heparin-Induced Thrombocytopenia. Bremen 1999, p. 13f.
  4. ↑ Gerd Herold: Internal Medicine. Cologne, 2011, p. 804.
  5. ↑ Wolfgang Gerok: The internal medicine. 11th edition. Stuttgart 2007, p. 95; Report on a study on risk for women: TE Warkentin, JA Sheppard, CS Sigouin, T. Kohlmann, P. Eichler, A. Greinacher: Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. In: Blood . Volume 108, 2006, pp. 2937-2941. PMID 16857993 ; Bettina Kemkes-Matthes: Heparin-Induced Thrombocytopenia. Bremen 1999, p. 27.
  6. ↑ GK Lo, D. Juhl, TE Warkentin, CS Sigouin, P. Eichler, A. Greinacher: Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin ‐ induced thrombocytopenia in two clinical settings . In: Journal of Thrombosis and Hemostasis . tape 4 , no. 4 , April 2006, p. 759-765 , doi : 10.1111 / j.1538-7836.2006.01787.x .
  7. ↑ A. Cuker, PA Gimotty, MA Crowther, TE Warkentin: Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis . In: Blood . tape 120 , no. 20 , September 2012, p. 4160-4167 , doi : 10.1182 / blood-2012-07-443051 , PMID 22990018 , PMC 3501714 (free full text).
  8. ↑ A. Cuker et al .: American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia . In: Blood Advances . tape 2 , no. 22 , 2018, p. 3360-3392 , doi : 10.1182 / bloodadvances.2018024489 .
  9. ↑ UJ Sachs, J. von Hesberg, S. Santoso, G. Bein, T. Bakchoul: Evaluation of a new nanoparticle-based lateral-flow immunoassay for the exclusion of heparin-induced thrombocytopenia (HIT). In: Thromb Haemost . Volume 106, No. 6, Oct 2011, pp. 1197-1202.
  10. ↑ Wolfgang Gerok: The internal medicine. 11th edition. Stuttgart 2007, p. 95; Heiner Greten: Internal Medicine. 12th edition. Stuttgart 2005, p. 384; Bettina Kemkes-Matthes: Heparin-Induced Thrombocytopenia. Bremen 1999, p. 32ff; LL Gottschling, C. Alaniz: Thrombosis resulting from heparin therapy. In: Pharmacotherapy. Volume 16, No. 3, May-Jun 1996, pp. 469-472. PMID 8726609
  11. ↑ AWMF online: Guideline on the prophylaxis of venous thromboembolism , guideline register number: 003/001, pdf on the website of the Working Group of Scientific Medical Societies , accessed on November 11, 2018.
  12. ↑ Heiner Greten: Internal Medicine. 12th edition. Stuttgart 2005, p. 384.
  13. ↑ I. Elalamy, C. Lecrubier, F. Potevin, M. Abdelouahed, L. Bara, JP Marie, M. Samama: Absence of in vitro cross-reaction of pentasaccharide with the plasma heparin-dependent factor of twenty-five patients with heparin-associated thrombocytopenia. In: Thromb. Haemost. Volume 74, 1995, pp. 1384-1395.
  14. ↑ Heiner Greten: Internal Medicine. 12th edition. Stuttgart 2005, p. 383f.