Download PDF
Onkologische Welt 2012; 03(01): 05-11
DOI: 10.1055/s-0038-1630917
Review
Schattauer GmbH

Acute phase after haematopoietic stem cell transplantation

Bleeding and thrombotic complicationsDie akute Phase nach StammzelltransplantationBlutungen und thrombotische Komplikationen
L. Graf
1   Stem Cell Transplant Team and Division of Haematology, University Hospital Basel, Switzerland
,
M. Stern
1   Stem Cell Transplant Team and Division of Haematology, University Hospital Basel, Switzerland
› Author Affiliations
Further Information

Publication History

Publication Date:
02 February 2018 (online)

Also available at
    Permissions and Reprints

Summary

The transplantation of allogeneic or autologous haematopoietic stem cells is an established treatment for many malignant and non-malignant diseases of the bone marrow. Intensive cytoreductive regimens administered before transplantation induce prolonged and severe cytopenia of all haematopoietic lineages. Thrombocytopenia leads to an increased risk of bleeding, which may be further aggravated by consumption of plasmatic factors as a result of tumour lysis or after antibody administration. At the same time, patients after transplantation are also at increased risk of thrombotic complications. Endothelial damage induced by radio- and chemotherapy, indwelling catheters, prolonged immobilization and a high incidence of systemic infection all contribute to the frequent occurrence of thromboembolic events in this population.

This review discusses the incidence and risk factors for haemorrhagic and thrombotic complications after stem cell transplantation. Special emphasis is given to complications occurring specifically in the context of transplantation such as diffuse alveolar haemorrhage, haemorrhagic cystitis, veno-occlusive disease, and transplant associated microangiopathy.

Zusammenfassung

Die Transplantation autologer oder allogener hämatopoietischer Stammzellen ist Routine in der Therapie maligner und nicht maligner Knochenmarkserkrankungen. Die zytoreduktive Therapie vor Transplantation induziert in aller Regel eine schwere und prolongierte Zyto penie aller drei Blutzellreihen. Die Thrombozytopenie führt dabei zu einem erhöhten Risiko von Blutungskomplikationen. Dieses Risiko kann zusätzlich verstärkt werden durch Veränderungen der plasmatischen Gerinnung als Folge einer Tumorlyse oder nach einer Antikörpertherapie. Patienten nach Transplantation erleiden auch häufig thrombotische Komplikationen. Chemo- und Radiotherapie-induzierte Endothelschäden, Venenkatheter, Immobilisation und häufige Infektionen tragen alle zu einem erhöhten Risiko von Thrombosen bei.

Diese Übersichtsarbeit diskutiert die Inzidenz und Risikofaktoren für Blutungs- und thrombotische Komplikationen nach Stammzelltransplantation. Dabei wird insbesondere auch auf Komplikationen eingegangen, welche spezifisch nach Transplantation auftreten, wie die diffuse alveoläre Hämorrhagie, die hämorrhagische Zystitis, die Venenverschluss- Krankheit, sowie die Transplantations-assoziierte Mikroangiopathie.

Keywords

Haematopoietic stem cell transplantation - diffuse alveolar haemorrhage - haemorrhagic cystitis - veno-occlusive disease - transplantassociated microangiopathy

Schlüsselwörter:

Stammzelltransplantation - diffuse alveoläre Hämorrhagie - hämorrhagische Zystitis - Venen verschlusskrankheit - transplantationsassoziierte Mikroangiopathie
 

  • References

  • 1 Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813-1826.
    CrossrefPubMedGoogle Scholar
  • 2 Korbling M, Freireich EJ. Twenty-five years of peripheral blood stem cell transplantation. Blood 2011; 117: 6411-6416.
    CrossrefPubMedGoogle Scholar
  • 3 Nadir Y, Brenner B. Hemorrhagic and thrombotic complications in bone marrow transplant recipients. Thromb Res 2007; 120 (02) S92-S98.
    CrossrefPubMedGoogle Scholar
  • 4 Carreras E, Diaz-Ricart M. The role of the endothelium in the short-term complications of hematopoietic SCT. Bone Marrow Transplant. 2011 doi:10.1038/bmt.2011.65.
    PubMedGoogle Scholar
  • 5 Palomo M, Diaz-Ricart M, Carbo C. et al. Endothelial dysfunction after hematopoietic stem cell transplantation: role of the conditioning regimen and the type of transplantation. Biol Blood Marrow Transplant 2010; 16: 985-993.
    CrossrefPubMedGoogle Scholar
  • 6 Tichelli A, Gratwohl A. Vascular endothelium as ‘novel’ target of graft-versus-host disease. Best Pract Res Clin Haematol 2008; 21: 139-148.
    CrossrefPubMedGoogle Scholar
  • 7 Nadir Y, Hoffman R, Brenner B. Drug-related thrombosis in hematologic malignancies. Rev Clin Exp Hematol 2004; 8: E4.
    PubMedGoogle Scholar
  • 8 Gordon B, Haire W, Kessinger A. et al. High frequency of antithrombin 3 and protein C deficiency following autologous bone marrow transplantation for lymphoma. Bone Marrow Transplant 1991; 8: 497-502.
    PubMedGoogle Scholar
  • 9 Collins P, Roderick A, O’Brien D. et al. Factor VIIa and other haemostatic variables following bone marrow transplantation. Thromb Haemost 1994; 72: 28-32.
    PubMedGoogle Scholar
  • 10 Collins PW, Gutteridge CN, O’Driscoll A. et al. Von Willebrand factor as a marker of endothelial cell activation following BMT. Bone Marrow Transplant 1992; 10: 499-506.
    PubMedGoogle Scholar
  • 11 Salat C, Holler E, Reinhardt B. et al. Parameters of the fibrinolytic system in patients undergoing BMT: elevation of PAI-1 in veno-occlusive disease. Bone Marrow Transplant 1994; 14: 747-750.
    PubMedGoogle Scholar
  • 12 Klerk CP, Smorenburg SM, Otten HM. et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005; 23: 2130-2135.
    CrossrefPubMedGoogle Scholar
  • 13 Kakkar AK, Levine MN, Kadziola Z. et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol 2004; 22: 1944-1948.
    CrossrefPubMedGoogle Scholar
  • 14 Gerber DE, Segal JB, Levy MY. et al. The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention. Blood 2008; 112: 504-510.
    CrossrefPubMedGoogle Scholar
  • 15 Pihusch R, Salat C, Schmidt E. et al. Hemostatic complications in bone marrow transplantation: a retrospective analysis of 447 patients. Transplantation 2002; 74: 1303-1309.
    CrossrefPubMedGoogle Scholar
  • 16 Holler E, Kolb HJ, Greinix H. et al. Bleeding events and mortality in SCT patients: a retrospective study of hematopoietic SCT patients with organ dysfunctions due to severe sepsis or GVHD. Bone Marrow Transplant 2009; 43: 491-497.
    CrossrefPubMedGoogle Scholar
  • 17 Pihusch M. Bleeding complications after hematopoietic stem cell transplantation. Semin Hematol 2004; 41 1 Suppl 1 93-100.
    PubMedGoogle Scholar
  • 18 Nevo S, Vogelsang GB. Acute bleeding complications in patients after bone marrow transplantation. Curr Opin Hematol 2001; 8: 319-325.
    CrossrefPubMedGoogle Scholar
  • 19 Rysler C, Stoffel N, Buser A. et al. Effect of betablockers, Ca2+ antagonists, and benzodiazepines on bleeding incidence in patients with chemotherapy induced thrombocytopenia. Platelets 2010; 21: 77-83.
    CrossrefPubMedGoogle Scholar
  • 20 Dominietto A, Raiola AM, van Lint MT. et al. Factors influencing haematological recovery after allogeneic haemopoietic stem cell transplants: graftversus- host disease, donor type, cytomegalovirus infections and cell dose. Br J Haematol 2001; 112: 219-227.
    CrossrefPubMedGoogle Scholar
  • 21 Najima Y, Ohashi K, Miyazawa M. et al. Intracranial hemorrhage following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2009; 84: 298-301.
    CrossrefPubMedGoogle Scholar
  • 22 Socie G, Schmoor C, Bethge WA. et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATGFresenius. Blood 2011; 117: 6375-6382.
    CrossrefPubMedGoogle Scholar
  • 23 Pihusch R, Holler E, Muhlbayer D. et al. The impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation. Bone Marrow Transplant 2002; 30: 347-354.
    CrossrefPubMedGoogle Scholar
  • 24 Majhail NS, Parks K, Defor TE, Weisdorf DJ. Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes. Biol Blood Marrow Transplant 2006; 12: 1038-1046.
    CrossrefPubMedGoogle Scholar
  • 25 Lewis ID, DeFor T, Weisdorf DJ. Increasing incidence of diffuse alveolar hemorrhage following allogeneic bone marrow transplantation: cryptic etiology and uncertain therapy. Bone Marrow Transplant 2000; 26: 539-543.
    CrossrefPubMedGoogle Scholar
  • 26 Afessa B, Tefferi A, Litzow MR, Peters SG. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002; 166: 1364-1368.
    CrossrefPubMedGoogle Scholar
  • 27 Afessa B, Abdulai RM, Kremers WK. et al. Risk factors and outcome of pulmonary complications after autologous hematopoietic stem cell transplant (HSCT). Chest. 2011 doi: 10.1378/chest.10-2889.
    PubMedGoogle Scholar
  • 28 Raptis A, Mavroudis D, Suffredini A. et al. High-dose corticosteroid therapy for diffuse alveolar hemorrhage in allogeneic bone marrow stem cell transplant recipients. Bone Marrow Transplant 1999; 24: 879-883.
    CrossrefPubMedGoogle Scholar
  • 29 Wanko SO, Broadwater G, Folz RJ, Chao NJ. Diffuse alveolar hemorrhage: retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid. Biol Blood Marrow Transplant 2006; 12: 949-953.
    CrossrefPubMedGoogle Scholar
  • 30 Pastores SM, Papadopoulos E, Voigt L, Halpern NA. Diffuse alveolar hemorrhage after allogeneic hematopoietic stem-cell transplantation: treatment with recombinant factor VIIa. Chest 2003; 124: 2400-2403.
    CrossrefPubMedGoogle Scholar
  • 31 Hicks K, Peng D, Gajewski JL. Treatment of diffuse alveolar hemorrhage after allogeneic bone marrow transplant with recombinant factor VIIa. Bone Marrow Transplant 2002; 30: 975-978.
    CrossrefPubMedGoogle Scholar
  • 32 Estella A, Jareno A, Perez-Bello Fontaina L. Intrapulmonary administration of recombinant activated factor VII in diffuse alveolar haemorrhage: a report of two case stories. Cases J 2008; 1: 150.
    CrossrefPubMedGoogle Scholar
  • 33 Heslet L, Nielsen JD, Levi M. et al. Successful pulmonary administration of activated recombinant factor VII in diffuse alveolar hemorrhage. Crit Care 2006; 10: R177.
    CrossrefPubMedGoogle Scholar
  • 34 Silva Lde P, Patah PA, Saliba RM. et al. Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. Haematologica 2010; 95: 1183-1190.
    CrossrefPubMedGoogle Scholar
  • 35 Gorczynska E, Turkiewicz D, Rybka K. et al. Incidence, clinical outcome, and management of virusinduced hemorrhagic cystitis in children and adolescents after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2005; 11: 797-804.
    CrossrefPubMedGoogle Scholar
  • 36 Bogdanovic G, Priftakis P, Giraud G. et al. Association between a high BK virus load in urine samples of patients with graft-versus-host disease and development of hemorrhagic cystitis after hematopoietic stem cell transplantation. J Clin Microbiol 2004; 42: 5394-5396.
    CrossrefPubMedGoogle Scholar
  • 37 Giraud G, Priftakis P, Bogdanovic G. et al. BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated- HLA-mismatched grafts. Bone Marrow Transplant 2008; 41: 737-742.
    CrossrefPubMedGoogle Scholar
  • 38 Leung AY, Yuen KY, Kwong YL. Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant 2005; 36: 929-937.
    CrossrefPubMedGoogle Scholar
  • 39 Dalianis T, Ljungman P. Full myeloablative conditioning and an unrelated HLA mismatched donor increase the risk for BK virus-positive hemorrhagic cystitis in allogeneic hematopoetic stem cell transplanted patients. Anticancer Res 2011; 31: 939-944.
    Google Scholar
  • 40 Cesaro S, Hirsch HH, Faraci M. et al. Cidofovir for BK virus-associated hemorrhagic cystitis: a retrospective study. Clin Infect Dis 2009; 49: 233-240.
    CrossrefPubMedGoogle Scholar
  • 41 Pihusch M, Bacigalupo A, Szer J. et al. Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation. J Thromb Haemost 2005; 3: 1935-1944.
    CrossrefPubMedGoogle Scholar
  • 42 Tsakiris DA, Tichelli A. Thrombotic complications after haematopoietic stem cell transplantation: early and late effects. Best Pract Res Clin Haematol 2009; 22: 137-145.
    CrossrefPubMedGoogle Scholar
  • 43 Gonsalves A, Carrier M, Wells PS. et al. Incidence of symptomatic venous thromboembolism following hematopoietic stem cell transplantation. J Thromb Haemost 2008; 6: 1468-1473.
    CrossrefPubMedGoogle Scholar
  • 44 Stoffel N, Rysler C, Buser A. et al. Leukocyte count and risk of thrombosis in patients undergoing haematopoietic stem cell transplantation or intensive chemotherapy. Thromb Haemost 2010; 103: 1228-1232.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Pinomaki A, Volin L, Joutsi-Korhonen L. et al. Early thrombin generation and impaired fibrinolysis after SCT associate with acute GVHD. Bone Marrow Transplant 2010; 45: 730-737.
    CrossrefPubMedGoogle Scholar
  • 46 Pihusch M, Lohse P, Reitberger J. et al. Impact of thrombophilic gene mutations and graft-versushost disease on thromboembolic complications after allogeneic hematopoietic stem-cell transplantation. Transplantation 2004; 78: 911-918.
    CrossrefPubMedGoogle Scholar
  • 47 Abdelkefi A, Ben Romdhane N, Kriaa A. et al. Prevalence of inherited prothrombotic abnormalities and central venous catheter-related thrombosis in haematopoietic stem cell transplants recipients. Bone Marrow Transplant 2005; 36: 885-889.
    CrossrefPubMedGoogle Scholar
  • 48 Lagro SW, Verdonck LF, Borel Rinkes IH, Dekker AW. No effect of nadroparin prophylaxis in the prevention of central venous catheter (CVC)-associated thrombosis in bone marrow transplant recipients. Bone Marrow Transplant 2000; 26: 1103-1106.
    CrossrefPubMedGoogle Scholar
  • 49 Magagnoli M, Masci G, Castagna L. et al. Prophylaxis of central venous catheter-related thrombosis with minidose warfarin in patients treated with high-dose chemotherapy and peripheral-blood stem-cell transplantation: retrospective analysis of 228 cancer patients. Am J Hematol 2006; 81: 1-4.
    CrossrefPubMedGoogle Scholar
  • 50 Ho VT, Revta C, Richardson PG. Hepatic venoocclusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41: 229-237.
    CrossrefPubMedGoogle Scholar
  • 51 Salat C, Holler E, Kolb HJ. et al. Plasminogen activator inhibitor-1 confirms the diagnosis of hepatic veno-occlusive disease in patients with hyperbilirubinemia after bone marrow transplantation. Blood 1997; 89: 2184-2188.
    PubMedGoogle Scholar
  • 52 Richardson PG, Elias AD, Krishnan A. et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood 1998; 92: 737-744.
    PubMedGoogle Scholar
  • 53 Richardson PG, Murakami C, Jin Z. et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood 2002; 100: 4337-4343.
    CrossrefPubMedGoogle Scholar
  • 54 Chalandon Y, Roosnek E, Mermillod B. et al. Prevention of veno-occlusive disease with defibrotide after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2004; 10: 347-354.
    CrossrefPubMedGoogle Scholar
  • 55 Dignan F, Gujral D, Ethell M. et al. Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from venoocclusive disease. Bone Marrow Transplant 2007; 40: 79-82.
    CrossrefPubMedGoogle Scholar
  • 56 Laskin BL, Goebel J, Davies SM, Jodele S. Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy. Blood 2011; 118: 1452-1462.
    CrossrefPubMedGoogle Scholar
  • 57 Ho VT, Cutler C, Carter S. et al. Blood and marrow transplant clinical trials network toxicity committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 571-5715.
    CrossrefPubMedGoogle Scholar
  • 58 Au WY, Ma ES, Lee TL. et al. Successful treatment of thrombotic microangiopathy after haematopoietic stem cell transplantation with rituximab. Br J Haematol 2007; 137: 475-478.
    CrossrefPubMedGoogle Scholar
  • 59 Nurnberger J, Philipp T, Witzke O. et al. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 2009; 360: 542-544.
    CrossrefPubMedGoogle Scholar
  • 60 McDonald GB, Sharma P, Matthews DE. et al. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors. Hepatology 1984; 4: 116-122.
    CrossrefPubMedGoogle Scholar
  • 61 Jones RJ, Lee KS, Beschorner WE. et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation 1987; 44: 778-783.
    CrossrefPubMedGoogle Scholar
  • 62 Ruutu T, Barosi G, Benjamin RJ. et al. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica 2007; 92: 95-100.
    CrossrefPubMedGoogle Scholar