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Hypercoagulability and Thrombosis

Hypercoagulability and Thrombosis. Maria Domenica Cappellini Erika Poggiali University of Milan and Policlinico Foundation IRCCS Milan, Italy. Clinical challenges in NTDT. Iron overload Hypercoagulability. Iron overload Hypercoagulability. Hypercoagulability.

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Hypercoagulability and Thrombosis

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  1. Hypercoagulability and Thrombosis Maria DomenicaCappellini Erika Poggiali University of Milan and Policlinico Foundation IRCCSMilan, Italy

  2. Clinical challenges in NTDT • Iron overload • Hypercoagulability • Ironoverload • Hypercoagulability

  3. Hypercoagulability Why are we so concerned?

  4. Epidemiology of thromboembolismin thalassaemia patients TI = β-thalassaemiaintermedia; TM = β-thalassaemia major; VT = venous thrombosis; PE = pulmonary embolism; AT = arterial thrombosis;N/A = not available. Taher A, et al. Blood Rev 2008;22:283-92.

  5. Taher A, et al. ThrombHaemost. 2006;96:488-91.

  6. Thromboembolicevents Type of event • Risk factors for developing thrombosis in TI were • age (> 20 years) • previous thrombotic event • family history • splenectomy Thromboembolic events (%) DVT = deep vein thrombosis; PE = pulmonary embolism;PVT = portal vein thrombosis; STP = superficial thrombophlebitis. • Patients (N = 8,860) • 6,670 with TM • 2,190 with TI • 146 (1.65%) thrombotic events • 61 (0.9%) with TM • 85 (3.9%) with TI Taher A, et al. ThrombHaemost. 2006;96:488-91.

  7. Can we redefine thalassaemia as a hypercoagulable state?

  8. Pathophysiology of Thalassaemia Extravascular haemolysis + Ineffective erythropoiesis Release into the peripheral circulation of damaged RBCs and erythroid precursors Pulmonaryhypertension (PHT) and thromboembolicevents (TEE)

  9. Pathophysiologyofthrombosis in NTDT • Cellular factors • Platelet activation • Pathology and alteration in red blood cells • Endothelial cells and peripheral blood activation (microparticles) • Nitric oxide • Splenectomy • Inherited and acquired coagulation defects • Other factors Cappellini MD, et al. Ann N Y Acad Sci 2010;1202:231-6.

  10. Nitric oxide • Hallmark of haemolysis • ↓ Levels leading to vasoconstriction • Peripheral • blood elements • Expression of endothelial adhesion molecules and tissue factor on endothelial cells (ELAM-1, ICAM-1, vWF, VCAM-1) • Formation of microparticles • RBCs • Formation of reactive oxygen species • Expression of negatively charged phospholipids • Enhanced cohesiveness and aggregability Hypercoagulability • Thrombophilia • No role for prothrombotic mutations • Decreased levels of antithrombin III, protein C, and protein S • Anti-phospholipid antibodies • Platelets • Increased platelet aggregation • Increased expression of activation markers • Presence of platelet morphologic abnormalities Hypercoagulability • Splenectomy • High platelet counts and hyperactivity • High levels of negatively charged RBCs • Other factors • Cardiac dysfunction • Hepatic dysfunction • Endocrine dysfunction Cappellini MD, et al. Ann N Y Acad Sci 2010;1202:231-6.

  11. Platelet activation Winichagoon P, et al. Asian J Trop Med Public Health 1981;12:556–60. Del Principe D, et al. Br J Hematol 1993;84:111–7. Ruf A, et al. Br J Hematol 1997;98:51–6. Eldor A, et al. Am J Hematol 1989;32:94–9.

  12. Pathology and alteration in red blood cells

  13. Endothelial cells and peripheral blood activation Haemolysis Butthep P, et al. Thromb Hemost 1995;74:1045–9. Butthep P, et al. Southeast Asian J Trop Med Public Health 1997;28(Suppl. 3):141A–8A. Hovav T, et al. Br J Hematol 1999;106:178–81.

  14. Nitric oxide • Hallmark of haemolysis • ↓ levels leading to vasoconstriction • RBCs • Formation of reactive oxygen species • Expression of negatively charged phospholipids • Enhanced cohesiveness and aggregability • Peripheral • blood elements • Expression of endothelial adhesion molecules and tissue factor on endothelial cells (ELAM-1, ICAM-1, vWF, VCAM-1) • Formation of microparticles Hypercoagulability • Thrombophilia • No role for prothromboticmutations • Decreased levels of antithrombin III, protein C, and protein S • Anti-phospholipid antibodies • Platelets • Increased platelet aggregation • Increased expression of activation markers • Presence of platelet morphologic abnormalities Hypercoagulability • Splenectomy • High platelet counts and hyperactivity • High levels of negatively charged RBCs • Other factors • Cardiac dysfunction • Hepatic dysfunction • Endocrine dysfunction Cappellini MD, et al. Ann N Y Acad Sci 2010;1202:231-6.

  15. The epidemiological data and the clinical experience

  16. OPTIMAL CARE study: incidence and risk factors for thrombosis *RR indicates adjusted relative risk. EMH = extramedullaryhaematopoiesis; CI = confidence interval. Taher AT, et al. Blood. 2010;115:1886-92.

  17. Frequency of thrombosis increases with age in NTDT patients • N = 120 treatment-naive* TI patients 11–20 years > 32 years 21–32 years < 10 years * *= statistically significant trend * * * * * *never received any treatment intervention (splenectomy, transfusion, iron chelation therapy, or HbF-inducing agents).PHT = pulmonary hypertension; HF = heart failure; ALF = abnormal liver function; DM = diabetes mellitus. Taher A, et al. Br J Haematol 2010;150:486-9.

  18. 150 120 90 60 30 0 High prevalence of thromboembolic events, particularly in splenectomized patients Splenectomized patient with TI Non-splenectomized patient with TI Non-splenectomized controls Splenectomized controls Thrombin-generated (nM) 0 10 30 60 90 120 150 Time (s) Thromboembolic events occurred in 24/83 (29%) transfusion-independent patients with TI who had undergone splenectomy Cappellini MD, et al. Br J Haematol. 2000;111:467-73.

  19. OPTIMAL CARE study: patient stratification according to splenectomy and TEE status *All patients who had PE had confirmed DVT. • Three groups of patients identified • Group I, splenectomized patients with a documented TEE (n = 73) • Group II, age- and sex-matched splenectomized patients without TEE (n = 73) • Group III, age- and sex-matched non-splenectomized patients without TEE (n = 73) TEE = thromboembolicevents; DVT = deep vein thrombosis; PE = pulmonary embolism; STP = superficial thrombophlebitis; PVT = portal vein thrombosis. Taher A, et al. J ThrombHaemost. 2010;8:2152-8.

  20. OPTIMAL CARE study: patient stratification according to splenectomy and TEE status (cont.) Hb = total haemoglobin; HbF = fetal haemoglobin; NRBC = nucleated red blood cell; PHT = pulmonary hypertension; HF = heart failure; DM = diabetes mellitus. Taher A, et al. J ThrombHaemost. 2010;8:2152-8.

  21. Time-to-thrombosis (TTT) since splenectomy • The median TTT following splenectomy was 8 years (range 1–33 years) Taher A, et al. J ThrombHaemost. 2010;8:2152-8.

  22. NRBC count < 300 x 106/L ≥ 300 x 106/L 1 1 1 1 0.8 0.8 0.8 0.8 0.6 0.6 0.6 0.6 0.4 0.4 0.4 0.4 0.2 0.2 0.2 0.2 0 0 0 0 0 0 0 0 5 5 5 5 10 10 10 10 15 15 15 15 20 20 20 20 25 25 25 25 30 30 30 30 35 35 35 35 40 40 40 40 Time-to-thrombosis (TTT) since splenectomy(cont.) Time to thrombosis Platelet count < 500 x 109/L ≥ 500 x 109/L Cumulative thrombosis-free survival Cumulative thrombosis-free survival Duration since splenectomy (years) Duration since splenectomy (years) Transfused Yes No Pulmonary hypertension Yes No Cumulative thrombosis-free survival Cumulative thrombosis-free survival Duration since splenectomy (years) Duration since splenectomy (years) Taher A, et al. J ThrombHaemost. 2010;8:2152-8.

  23. Clinical recommendations for the prevention of thromboembolic events • A guarded approach to splenectomy in β-thalassaemia patients is recommended unless strongly indicated • In already-splenectomized NTDT patients, those at high risk of thrombosis may be identified early by their high NRBC and platelet counts, evidence of PHT, and transfusion naivety • attention should also be paid to the aging NTDT patients • Prospective clinical trials that evaluate the efficacy, safety, and cost-effectiveness of transfusions and anti-platelet and anticoagulant therapy in preventing thromboembolism are necessary • aspirin for stroke prevention and lifelong anticoagulation treatment in patients with a history of thrombotic events Taher AT, et al. Br J Haematol. 2011;152:512-23.

  24. OPTIMAL CARE study: transfusion therapy reduces the risk of complications n = 445 occasionally/regularly transfused patients (N = 584) Taher AT, et al. Blood. 2010;115:1886-92.

  25. OPTIMAL CARE study:transfusion therapy reduces the risk of complications (cont.) • Transfusion therapy was protective for thrombosis, EMH, PHT, HF, cholelithiasis and leg ulcers • Transfusion therapy was associated with an increased risk of iron overload-related endocrinopathy n = 445 occasionally/regularly transfused patients (N = 584). Only significant associations presented. Taher AT, et al. Blood. 2010;115:1886-92.

  26. Indications of RBC transfusion in TI • Hb < 5 g/dL • Declining Hb level with progressive splenic enlargement (> 3 cm/year)* • Poor growth and/or development • Evidence of • bone deformities • clinically relevant tendency to thrombosis • leg ulcers • EMH • PHT • infections • Prior to surgical procedures • Pregnancy Hb = heamoglobin. * At least in periodsof maximal growth and development. Taher A. et al. Blood Reviews 26S (2012); S24-S27.

  27. Initiating transfusion therapyin NTDT patients • The decision to initiate transfusion in these patients is very difficult due to the heterogeneity of the disease • There is no benefit in limiting the quantity or frequency of transfusions once they have begun • Starting transfusions after the third year of life has been shown to increase the risk of alloimmunization • Transfused patients with TI experience fewer TEE, PHT and silent brain infarcts compared to transfusion-naïve patients, due to the correction of the ineffective erythropoiesis and resulting damaged RBCs with thrombogenic potential Taher A. et al. Blood Reviews 26S (2012); S24-S27.

  28. Summary • Thromboembolic events are frequent in β-thalassaemia patients • oxidative damage to RBCs, impacting their membrane properties, resulting in increased aggregation and risk of thromboembolism • risk of thromboembolism increases with age, and is influenced strongly by splenectomy and transfusion navïety • Splenectomyis associated with a high risk of thrombosis, particularly in patients with high NRBC or platelet counts, who are transfusion-naïve • Transfusion therapy reduces the risk of thrombosis in NTDT patients • transfusion iron intake inevitably increases the risk of iron overload, but the benefit of transfusion therapy may greatly outweigh the cost and inconvenience of iron chelation therapy

  29. Summary • Despite various treatment options are available, no clear guidelinesexist: each patient must be assessed individually and assigned a personalized thrombotic risk based on intrinsic and extrinsic factors • Several studies are highlighting the roles of transfusion, iron chelation therapy, and fetal haemoglobininduction(hydroxycarbamide, HU) in the management of NTDT; thus these approaches merit large prospective evaluation • Another approach would be to correct the reactive oxygen species-induced RBC membrane damage using antioxidants, although this approach has not yet been verified in clinical trials

  30. Acknowledgments I would like to thank you for the attention, and all the Congenital Anemia Center Staff for their support Prof. M.D. Cappellini Giovanna Graziadei Irene Motta AlessiaMarconIlariaGandolfi Laura Zanaboni Marianna Giuditta Elena Cassinerio Marta Mazzoleni Claudia CesarettiSilvio De Fazio All the nursing staff

  31. Alteration of the phospholipid “Flip-Flop” mechanism: RBCs with negatively charged phospholipids Adherence of RBCs to endothelial cells is increased • Phosphatidylserine on damaged or senescent RBCsleads to • Recognition by phagocytes • Removal from circulation • Apoptosis Thrombin generation Thrombus formation Fibrin/ platelets Splenectomyfavours persistence of these RBCs in the circulation Courtesy of Dr A. Taher.

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