Heparin-induced thrombocytopenia associated with thrombotic microangiopathy

J.-D. Studt; I. Binet; G. Nair; U. Schanz

doi:10.5482/HAMO-13-03-0012

Hämostaseologie, Table of Contents

Hamostaseologie 2013; 33(02): 160-163
DOI: 10.5482/HAMO-13-03-0012

Original article

Schattauer GmbH

Heparin-induced thrombocytopenia associated with thrombotic microangiopathy

Heparin-induzierte Thrombozytopenie assoziiert mit thrombotischen Mikroangiopathien

J.-D. Studt

¹Division of Haematology, University Hospital Zürich, Switzerland

,

I. Binet

²Division of Nephrology/Transplantation Medicine, Kantonsspital St. Gallen, Switzerland

,

G. Nair

¹Division of Haematology, University Hospital Zürich, Switzerland

,

U. Schanz

¹Division of Haematology, University Hospital Zürich, Switzerland

› Author Affiliations

Abstract

Summary

Some cases of thrombotic microangiopathy (TMA) are refractory to plasma exchange therapy (PE) with persistence or recurrence of thrombocytopenia. We report two patients suffering from TMA of different aetiologies (associated with disseminated malignancy, typical haemolytic uraemic syndrome) with recurrent or persistent thrombocytopenia despite adequate therapy including PE. Since both patients were exposed to unfractionated heparin, heparin-induced thrombocytopenia (HIT) was suspected as a cause. Pretest probabilities for HIT were intermediate. ELISA for PF4/heparin antibodies was strongly positive in both cases, and HIT was confirmed by heparin-induced platelet activation assay. Anticoagulation with lepirudin was initiated, with subsequent rapid increase of the platelet count.

TMA might represent a predisposition for HIT. This could be due to TMA-related platelet activation with increased PF4 release. In TMA patients exposed to heparin and with refractory or rapidly recurrent thrombocytopenia HIT should always be considered as a possible cause.

Zusammenfassung

Bei einem Teil der Patienten mit thrombotischen Mikroangiopathien (TMA) kommt es trotz adäquater Therapie einschliesslich Plasmaaustauschs (PE) zur Persistenz oder zum Wiederauftreten der Thrombozytopenie. Wir berichten über zwei Patienten mit TMA (bei disseminiertem Tumorleiden, typisches hämolytisch-urämisches Syndrom), bei denen ein solcher Verlauf zu beobachten war. Beide hatten unfraktioniertes Heparin erhalten. Wir vermuteten daher eine Heparin-induzierte Thrombozytopenie (HIT) und errechneten eine intermediäre Vortestwahrscheinlichkeit für diese. Im ELISA waren Antikörper gegen PF4/Heparin nachzuweisen. Das Vorliegen einer HIT wurde mittels eines funktionellen Tests bestätigt (Heparin-induzierte Plättchenaktivierung). Nachfolgend war unter Therapie mit Lepirudin eine rasche Normalisierung der Thrombozytenzahl zu verzeichnen.

Wir vermuten, dass TMA das Auftreten einer HIT begünstigen, möglicherweise infolge einer TMA-bedingt gesteigerten Plättchenaktivierung und konsekutiv vermehrten PF4-Freisetzung. Persistiert oder rezidiviert eine Thrombozytopenie bei heparinexponierten Patienten mit TMA, so sollte eine HIT als mögliche Ursache stets bedacht werden.

Keywords

Thrombotic microangiopathy - TMA - thrombocytopenia - heparin - heparin-induced thrombocytopenia - HIT

Schlüsselwörter

Thrombotische Mikroangiopathie - TMA - Thrombozytopenie - Heparin - Heparin-induzierte Thrombozytopenie - HIT

Full Text

References

References
1 Alberio L, Kimmerle A, Baumann S. et al. Rapid determination of anti-heparin/platelet factor 4 antibody titers in the diagnosis of heparin-induced thrombocytopenia. Am J Med 2003; 114: 528-536.
2 Booth KK, Terrell DR, Vesely SK, George JN. Systemic infections mimicking thrombotic thrombocytopenic purpura. Am J Hematol 2011; 86: 743-751.
3 Douglas KW, Pollock KG, Young D. Infection frequently triggers thrombotic microangiopathy in patients with preexisting risk factors: a single-institution experience. J Clin Apheresis 2010; 25: 47-53.
4 Fontana S, Gerritsen H, Kremer JHovinga. et al. Microangiopathic haemolytic anaemia in metastasizing malignant tumours is not associated with a severe deficiency of the von Willebrand factor-cleaving protease. Br J Haematol 2001; 113: 100-202.
5 George JN, Terrell DR, Vesely SK. et al. Thrombotic microangiopathic syndroms associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer. Presse Med 2012; 41: 177-188.
6 Greinacher A, Althaus K, Krauel K, Selleng S. Heparin-induced thrombocytopenia. Hämostaseologie 2010; 30: 17-28.
7 Greinacher A, Alban S, Omer-Adam MA. et al. Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low molecular weight-heparin, and fondaparinux in different clinical settings. Thromb Res 2008; 122: 211-220.
8 Güngör T, Furlan M, Lämmle B. et al. Acquired deficiency of von Willebrand factor-cleaving protease in a patient suffering from acute systemic lupus erythematosus. Rheumatology 2001; 40: 940-942.
9 Howard MA, Williams LA, Terrell DR. et al. Complications of plasma exchange in patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: An additional study of 57 consecutive patients, 2002-2005. Transfusion 2006; 46: 154-156.
10 Kojouri K, George JN. Thrombotic microangiopathy following allogeneic hematopoietic stem cell transplantation. Curr Opin Oncol 2007; 19: 148-154.
11 Kokame K, Nobe Y, Kokubo Y. et al. FRETSVWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol 2005; 129: 93-100.
12 Kowalska MA, Rauova L, Poncz M. Role of the platelet chemokine platelet factor 4 (PF4) in hemostasis and thrombosis. Thromb Res 2010; 125: 292-29.
13 Kremer JAHovinga, Meyer SC. Current management of thrombotic thrombocytopenic purpura. Curr Opin Hematol 2008; 15: 445-450.
14 Kremer JAHovinga, Mottini M, Lämmle B. Measurement of ADAMTS-13 activity in plasma by the FRETS-VWF73 assay: comparison with other assay methods. J Thromb Haemost 2006; 04: 1146-1148.
15 Kremer JAHovinga, Vesely SK, Terrell DR. et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010; 115: 1500-1511.
16 Lubenow N, Hinz P. Thomaschewski et al. The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia. Blood 2010; 115: 1797-1803.
17 McMinn JR, Thomas IA, Terrell DR. et al. Complications of plasma exchange in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a study of 78 additional patients. Transfusion 2003; 43: 415.
18 Moake JL. Thrombotic thrombocytopenia purpura and other thrombotic microangiopathies. Best Pract Res Clin Haematol 2009; 22: 567-576.
19 Nellen V, Sulzer I, Barizzi G. et al. Rapid exclusion or confirmation of heparin-induced thrombocytopenia: a single-center experience with 1291 patients. Haematologica 2012; 97: 98.
20 Nguyen L, Terrell DR, Duvall D. et al. Complications of plasma exchange in patients treated for thrombotic thrombocytopenic purpura. An additional study of 43 consecutive patients, 2005 to 2008. Transfusion 2009; 49: 394.
21 Rizv MA, Vesely SK, George JN. Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome. Transfusion 2000; 40: 896-901.
22 Schaller M, Sulzer I, Mansouri M. et al. Anti-ADAMTS13 inhibitor boosting during plasma exchange therapy in acquired TTP as a result of a general dysregulation of the immune response. Hämostaseologie 2012; 32: A18.
23 Scully M, Hunt BJ, Benjamin S. et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol 2012; 158: 323-335.
24 Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003; 121: 535-555.
25 Warkentin TE, Cook RJ, Marder VJ, Greinacher A. Anti-PF4/heparin antibody formation postorthopedic surgery thromboprophylaxis: the role of non-drug risk factors and evidence for a stoichiometry-based model of immunization. J Thromb Haemost 2010; 08: 504-512.
26 Warkentin TE, Greinacher A, Gruel Y. et al. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost 2011; 09: 2498-2500.
27 Warkentin TE, Levine MN, Hirsh J. et al. Heparininduced thrombocytopenia in patients treated with low-molecular-weight-heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-1335.
28 Warkentin TE, Sheppard JA, Horsewood P. et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96: 1703-1708.
29 Yagi H, Konno M, Kinoshita S. et al. Plasma of patients with Upshaw-Schulman syndrome, a congenital deficiency of von Willebrand factor-cleaving protease activity, enhances the aggregation of normal platelets under high shear stress. Br J Haematol 2001; 115: 991-997.