Non-overt disseminated intravascular coagulation in patients during treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation

Weber, Michael; Hansen, Arne; Zabelina, Tatjana; Eifrig, B.; Hossfeld, Dieter K.; Zander, Axel R.

doi:10.1038/sj.bmt.1703921

Cited by 24 publications

(13 citation statements)

References 28 publications

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“…This relates to the use of ATG, which was included in the conditioning therapy in the unrelated transplants and causes non-overt DIC according to an earlier report. 23 Although the recipients of sibling transplants were given steroid prophylaxis early on, no major differences were observed between the two types of donors after SCT. Interestingly, early after transplantation, F1 þ 2 levels were twofold higher, but the activity of fibrinolysis was simultaneously weaker in the SCT recipients of peripheral blood than in those of BM.…”

Section: Discussionmentioning

confidence: 99%

Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD

Pinomäki

Volin

Joutsi‐Korhonen

et al. 2009

Bone Marrow Transplant

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The evolution of coagulation and fibrinolysis has not been thoroughly evaluated in allogeneic SCT. In this pilot study, we characterized the adaptive mechanisms of coagulation and fibrinolysis during allogeneic SCT and 3-month followup and studied possible associations with outcome, including acute GVHD. Thirty patients underwent SCT for a haematological malignancy after myeloablative conditioning. Nineteen patients received the transplant from an HLAidentical sibling and 11 from an unrelated donor. GVHD prophylaxis consisted of CYA and MTX, with methylprednisolone in sibling transplants. Serial coagulation and fibrinolytic activity markers were assessed, including prothrombin fragments 1 þ 2 (F1 þ 2), thrombin time, D-dimer, tissue-type plasminogen-activator (tPA) and plasminogenactivator inhibitor (PAI-1). Early during conditioning therapy, F1 þ 2 and D-dimer increased threefold indicating thrombin generation and fibrin turnover. TPA activity peaked before engraftment, concurring with diminished PAI-1. At 10 days after transplantation shortened thrombin time (o15 s), F1 þ 2 exceeding 0.7 nmol/L and PAI-1 3.0 IU/mL were associated with the development of GVHD. In conclusion, early maladaptation, that is, upregulated thrombin generation and inhibition of fibrinolysis, occurred in one-third of the SCT patients associating with the development of GVHD, a finding suggesting an interplay between coagulation and immunology during SCT.

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Section: Discussionmentioning

confidence: 99%

Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD

Pinomäki

Volin

Joutsi‐Korhonen

et al. 2009

Bone Marrow Transplant

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“…The latter is commonly referred to as nonovert disseminated intravascular coagulopathy (9), as laboratory evidence reproducibly denotes thrombopenia and elevated plasma markers of hypercoagulability during ATG treatment (6,10), whereas clinically apparent thrombosis or bleeding complications occur less frequently (6,8). The exact mechanisms underlying this phenomenon are not yet known.…”

Section: Introductionmentioning

confidence: 99%

“…The exact mechanisms underlying this phenomenon are not yet known. Previous studies have suggested that ATG treatment induces a cytokinemediated release of tissue factor (TF) into the circulation (6). Recently, Langer et al showed that ATG binding to monocytes resulted in rapid complement-dependent TF decryption and activation of the extrinsic coagulation pathway (11).…”

Section: Introductionmentioning

confidence: 99%

“…Whereas ATG treatment is highly effective, it can be complicated by coagulation activation (5)(6)(7)(8). The latter is commonly referred to as nonovert disseminated intravascular coagulopathy (9), as laboratory evidence reproducibly denotes thrombopenia and elevated plasma markers of hypercoagulability during ATG treatment (6,10), whereas clinically apparent thrombosis or bleeding complications occur less frequently (6,8).…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of Platelet Activation and Hypercoagulability by Antithymocyte Globulins (ATG)

Čumpelik

Gerossier

Jin

et al. 2015

American Journal of Transplantation

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T cell depletion with antithymocyte globulins (ATG) can be complicated by thrombopenia and hypercoagulability. The underlying mechanism is still unclear. We found that binding of ATG to platelets caused platelet aggregation, a-granule release, membrane phosphatidylserine exposure and the rapid release of procoagulant platelet microvesicles (MV). Platelet activation and MV release were complement-dependent and required membrane insertion of C5b-8 but not stable lytic pore formation by C5b-9. ATG also activated platelets via binding to the low-affinity Fc gamma receptor FcgRII. However, only complement inhibition but not blockade of FcgRII prevented MV release and subsequent thrombin activation in plasma. In 19 hematopoietic stem cell and kidney transplant patients, ATG treatment resulted in thrombopenia and increased plasma levels of d-dimer and thrombin-antithrombin complexes. Flow cytometric analysis of complement fragments on platelet MV in patient plasma confirmed dose-dependent complement activation by ATG. However, the rapid rise in MV numbers observed in vitro was not seen during ATG treatment. In vitro experiments suggested that this was due to adherence of C3b-tagged MV to red blood cells via complement receptor CR1. These data suggest a clinically relevant link between complement activation and thrombin generation and offer a potential mechanism underlying ATG-induced hypercoagulability.

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“…Antithymocyte globulin (ATG) is a polyclonal horse or rabbit IgG with pleiotropic cellular effects that is used to prevent or treat allograft rejection and graft-versus-host disease. 27 On the basis of our previous observation that ATG induces low-grade disseminated intravascular coagulation in patients undergoing hematopoietic stem cell transplantation, 28 we were interested in further defining the effects of ATG on cells implicated in the initiation of coagulation in vivo. In this report, we show that binding of rabbit ATG to monocytic cells triggers a nonlytic complement cascade that is sufficient to rapidly activate TF procoagulant activity in a PDI-dependent manner.…”

mentioning

confidence: 99%

Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase

Länger

Spath

Fischer

et al. 2013

Blood

102

108

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Key Points• ATG induces monocyte TF procoagulant activity dependent on complement activation but independent of de novo protein synthesis.• TF decryption requires oxidation of cell surface PDI following C5 activation and phosphatidylserine membrane exposure following C7 insertion.Lymphocyte depletion with antithymocyte globulin (ATG) can be complicated by systemic coagulation activation. We found that ATG activated tissue factor procoagulant activity (TF PCA) on monocytic cells more potently than other stimuli that decrypt TF, including cell disruption, TF pathway inhibitor inhibition, and calcium ionophore treatment. Induction of TF PCA by ATG was dependent on lipid raft integrity and complement activation. We showed that ATG-mediated TF activation required complement activation until assembly of the C5b-7 membrane insertion complex, but not lytic pore formation by the membrane attack complex C5b-9. Consistently, induction of TF PCA by ATG did not require maximal phosphatidylserine membrane exposure and was not correlated with the magnitude of complement-induced lytic cell injury. Blockade of free thiols, an inhibitory monoclonal antibody to protein disulfide isomerase (PDI), and the small-molecule PDI antagonist quercetin-3-rutinoside prevented ATG-mediated TF activation, and C5 complement activation resulted in oxidation of cell surface PDI. This rapid and potent mechanism of cellular TF activation represents a novel connection between the complement system and cell surface PDI-mediated thiol-disulfide exchange. Delineation of this clinically relevant mechanism of activation of the extrinsic coagulation pathway during immunosuppressive therapy with ATG may have broader implications for vascular thrombosis associated with inflammatory disorders. (Blood. 2013;121(12):2324-2335

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Non-overt disseminated intravascular coagulation in patients during treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation

Cited by 24 publications

References 28 publications

Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD

Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD

Mechanism of Platelet Activation and Hypercoagulability by Antithymocyte Globulins (ATG)

Rapid activation of monocyte tissue factor by antithymocyte globulin is dependent on complement and protein disulfide isomerase

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