Malignancy-Associated Coagulopathy:

Size: px

Start display at page:

Download "Malignancy-Associated Coagulopathy:"

Ashley Doyle
6 years ago
Views:

1 Malignancy-Associated Coagulopathy: Recognition and Laboratory Diagnosis Aneel A. Ashrani, M.D., M.S MFMER slide-1

2 Disclosures Relevant Financial Relationship -NONE Off-Label and/or Investigational Uses -NONE 2016 MFMER slide-2

3 Malignancy Associated Coagulopathy Activation of coagulation Venous and arterial thrombosis Disseminated intravascular coagulation and fibrinolysis (DIC/ICF) Hyperfibrinolysis Immune mediated FVIII inhibitor Acquired von Willebrand syndrome FV inhibitor Therapy related coagulopathy Coagulation factor depletion L-aspariginase Drug induced thrombotic microangiopathy Gemcitabine Endothelial dysfunction Thalidomide Bevacizumab Platelet activation/ dysfunction Heparin induced thrombocytopenia Ibrutinib 2016 MFMER slide-3

4 Case 1: 59 year old female 2016 MFMER slide-4

5 Case 1: 59 year old female Stage III serous adenocarcinoma of the ovary s/p total abdominal hysterectomy and bilateral salpingo-oophorectomy on paclitaxel and carboplatin 2016 MFMER slide-5

6 Case 1: 59 year old female Stage III serous adenocarcinoma of the ovary s/p total abdominal hysterectomy and bilateral salpingo-oophorectomy on paclitaxel and carboplatin Post-Influenza vaccine extensive ecchymosis No prior history of excessive bleeding or bruising Hemoglobin 8.7 g/dl 5.7 g/dl (platelets normal) 2016 MFMER slide-6

7 Case 1: 59 year old female Stage III serous adenocarcinoma of the ovary s/p total abdominal hysterectomy and bilateral salpingo-oophorectomy on paclitaxel and carboplatin Post-Influenza vaccine extensive ecchymosis No prior history of excessive bleeding or bruising Hemoglobin 8.7 g/dl 5.7 g/dl (platelets normal) PT: 11.7 sec (Ref: ) APTT: 75 sec (Ref: 25 37) 2016 MFMER slide-7

8 Prolonged PT or APTT (75 sec) Mixing study with normal plasma (39 sec) Correction (factor deficiency) No correction (inhibitor) Clotting factor assays to identify deficiency Determine type of inhibitor Drug: Heparin, IIa inhibitor, Xa inhibitor Specific factor inhibitor (FVIII: <1%) Titer: 7 BU Nonspecific inhibitor (e.g., lupus anticoagulant) Adapted from Mayo Clinic Proc.; Kamal, A.H., 2007;82(7): with permission from Elsevier MFMER slide-8

9 Acquired Factor VIII Inhibitor Neutralizing autoantibodies against factor VIII Prevalence: ~1.5 cases/million/year Most common in the elderly Median age (IQR): 73.9 yrs. ( ) Collins, P.W., et al. Blood. 2007;109: Knoebl, P., et al. J Thromb Haemost 2012; 10: MFMER slide-9

10 Acquired Factor VIII Inhibitor Neutralizing autoantibodies against factor VIII Prevalence: ~1.5 cases/million/year Most common in the elderly Median age (IQR): 73.9 yrs. ( ) Underlying disorder No. of patients Idiopathic 51.9% Malignancy 11.8% Autoimmune diseases 11.6% Pregnancy 8.5% Infections 3.8% Drug induced 3.4% MGUS 2.6% Collins, P.W., et al. Blood. 2007;109: Knoebl, P., et al. J Thromb Haemost 2012; 10: MFMER slide-10

11 Clinical Presentation Knoebl, P., et al. J Thromb Haemost 2012; 10: MFMER slide-11

12 Clinical Presentation Majority of patients bleed (95%) Spontaneous bleed: 77% Subcutaneous: 53% Deep muscle or retroperitoneal bleed: 50% Mucosal bleeding:32% Joint bleeds: 5% Severe bleed: 70% Knoebl, P., et al. J Thromb Haemost 2012; 10: MFMER slide-12

13 Clinical Presentation Majority of patients bleed (95%) Spontaneous bleed: 77% Subcutaneous: 53% Deep muscle or retroperitoneal bleed: 50% Mucosal bleeding:32% Joint bleeds: 5% Severe bleed: 70% Mortality at final follow-up: 28% Median (IRQ) time after diagnosis: 75 days (25 240) Mortality secondary to the bleed: 3% Mortality secondary to the immunosuppression: 3% Knoebl, P., et al. J Thromb Haemost 2012; 10: MFMER slide-13

14 Cancer and FVIII Inhibitors No association with specific tumor type 60% solid tumors (lung, prostate, head/neck) May be autoimmune reaction to tumor tumor antigen similar to FVIII? Standard treatment chemotherapy, radiation, & surgery do not usually eradicate inhibitors Inhibitor is not a marker of tumor recurrence Hauser and Lechner. Thromb Haemost 1999;82: MFMER slide-14

15 Treatment Strategies Dual Objectives Management Strategies Acute Management Long-term Strategy Stop the Bleeding Eradicate Inhibitor 2016 MFMER slide-15

16 Acute Management of Bleeding Bleeding controlled in 80% of patients treated with a first-line hemostatic agent Hemostatic agent No. of patients treated % Response Bypassing agent % rfviia % apcc 60 93% Replacement therapy 69 70% FVIII 55 70% DDAVP 14 64% Thrombotic events similar between rfviia (2.9%) and apcc (4.8%). Baudo, F., et al. Blood. 2012;120(1): 39-46) 2016 MFMER slide-16

17 Inhibitor Eradication: Efficacy and Safety Collins, P, et al. Blood. 2012;120(1): MFMER slide-17

18 Inhibitor Eradication: Efficacy and Safety Regimen N CR (%) Relapse (%) Any AE (%) Mortality (%) Steroids alone % 11% 25% 28% Steroids + cyclophosphamide 83 80% 10% 41% 33% Rituxan based regimens 51 61% 3% 37% 20% Collins, P, et al. Blood. 2012;120(1): MFMER slide-18

19 Inhibitor Eradication: Efficacy and Safety Regimen N CR (%) Relapse (%) Any AE (%) Mortality (%) Steroids alone % 11% 25% 28% Steroids + cyclophosphamide 83 80% 10% 41% 33% Rituxan based regimens 51 61% 3% 37% 20% Cyclophosphamide+steroids versus steroids alone OR 95% CI CR at final follow-up Alive at final follow-up: Alive and in CR Collins, P, et al. Blood. 2012;120(1): MFMER slide-19

20 Case 1: Outcome Acute bleed management: Transfused 4 units PRBCs FEIBA 75 units/kg q12 hours Inhibitor management: Prednisone 1mg/kg/day Factor VIII (%) Inhibitor titer (BU) 0 Oct Nov Dec Jan Feb Mar 2016 MFMER slide-20

21 Case 2: 51 year old female 2016 MFMER slide-21

22 Case 2: 51 year old female No prior personal or family history of bleeding Iron deficiency anemia, celiac disease and recurrent GI bleeding No improvement with gluten-free diet or small bowel resection 2016 MFMER slide-22

23 Case 2: 51 year old female No prior personal or family history of bleeding Iron deficiency anemia, celiac disease and recurrent GI bleeding No improvement with gluten-free diet or small bowel resection 3-year history of frequent epistaxis, unexplained bruises and prolonged bleeding with minor nicks/ cuts 2016 MFMER slide-23

24 Case 2: 51 year old female No prior personal or family history of bleeding Iron deficiency anemia, celiac disease and recurrent GI bleeding No improvement with gluten-free diet or small bowel resection 3-year history of frequent epistaxis, unexplained bruises and prolonged bleeding with minor nicks/ cuts APTT: 35 sec (Ref: 21 33); APTT mix: 30 sec 2016 MFMER slide-24

25 Case 2: 51 year old female No prior personal or family history of bleeding Iron deficiency anemia, celiac disease and recurrent GI bleeding No improvement with gluten-free diet or small bowel resection 3-year history of frequent epistaxis, unexplained bruises and prolonged bleeding with minor nicks/ cuts APTT: 35 sec (Ref: 21 33); APTT mix: 30 sec Von Willebrand disease profile: FVIII: 28% vwf antigen: 18% Ristocetin cofactor: <12% Normal vwf multimer distribution Ristocetin inhibitor screen: Negative 2016 MFMER slide-25

26 Case 2: 51 year old female No prior personal or family history of bleeding Iron deficiency anemia, celiac disease and recurrent GI bleeding No improvement with gluten-free diet or small bowel resection 3-year history of frequent epistaxis, unexplained bruises and prolonged bleeding with minor nicks/ cuts APTT: 35 sec (Ref: 21 33); APTT mix: 30 sec Von Willebrand disease profile: FVIII: 28% vwf antigen: 18% Ristocetin cofactor: <12% Normal vwf multimer distribution Ristocetin inhibitor screen: Negative SPEP: 0.5 g/dl IgG lambda monoclonal paraprotein; MGUS 2016 MFMER slide-26

27 Acquired von Willebrand Syndrome: Pathogenesis Autoantibodies Interfering with platelet or collagen binding Increasing VWF clearance Sequestration/adsorption of high-molecular-weight vwf Multiple myeloma Essential thrombocythemia Proteolytic cleavage of VWF Shear stress-induced vwf unfolding Aortic valve stenosis LVAD Pancreatitis, liver cirrhosis, leukemia Decreased synthesis Hypothyroidism Tiede, A., et al. Blood. 2011;117(25): MFMER slide-27

28 Diagnostic Tests Initial assays for AvWS are same as for vwd (Profile approach) Additional useful assays: vwf propeptide? Increased propeptide/ vwf:ag ratio reflects accelerated clearance of vwf Increased ratio also seen in subset of patients with type 1 vwd Autoantibodies: No standard assays Neutralizing antibodies seen in minority of AvWS Mixing studies of VWF:Activity Non-neutralizing antibodies accelerate vwf clearance ELISA assay 2016 MFMER slide-28

29 Treatment Federici AB, et al. Blood. 1998; 92 (8): Tiede, A., et al. Blood. 2011;117(25): MFMER slide-29

30 Treatment DDAVP: Overall response rate: 32% Response transient and vary by underlying disorder Low response: Cardiovascular, MPN Higher response: Autoimmune, Lymphoproliferative disorders, neoplastic, MGUS Federici AB, et al. Blood. 1998; 92 (8): Tiede, A., et al. Blood. 2011;117(25): MFMER slide-30

31 Treatment DDAVP: Overall response rate: 32% Response transient and vary by underlying disorder Low response: Cardiovascular, MPN Higher response: Autoimmune, Lymphoproliferative disorders, neoplastic, MGUS vwf containing concentrate: Half-life short, especially in patients with MGUS or inhibitors Federici AB, et al. Blood. 1998; 92 (8): Tiede, A., et al. Blood. 2011;117(25): MFMER slide-31

32 Treatment DDAVP: Overall response rate: 32% Response transient and vary by underlying disorder Low response: Cardiovascular, MPN Higher response: Autoimmune, Lymphoproliferative disorders, neoplastic, MGUS vwf containing concentrate: Half-life short, especially in patients with MGUS or inhibitors IVIG: Effective in patients with IgG-MGUS associated AVWS Peak effect in 4 days with slow return to baseline within 21 days Federici AB, et al. Blood. 1998; 92 (8): Tiede, A., et al. Blood. 2011;117(25): MFMER slide-32

33 Treatment DDAVP: Overall response rate: 32% Response transient and vary by underlying disorder Low response: Cardiovascular, MPN Higher response: Autoimmune, Lymphoproliferative disorders, neoplastic, MGUS vwf containing concentrate: Half-life short, especially in patients with MGUS or inhibitors IVIG: Effective in patients with IgG-MGUS associated AVWS Peak effect in 4 days with slow return to baseline within 21 days Plasmapheresis: Deplete autoantibodies or paraproteins Federici AB, et al. Blood. 1998; 92 (8): Tiede, A., et al. Blood. 2011;117(25): MFMER slide-33

34 Treatment DDAVP: Overall response rate: 32% Response transient and vary by underlying disorder Low response: Cardiovascular, MPN Higher response: Autoimmune, Lymphoproliferative disorders, neoplastic, MGUS vwf containing concentrate: Half-life short, especially in patients with MGUS or inhibitors IVIG: Effective in patients with IgG-MGUS associated AVWS Peak effect in 4 days with slow return to baseline within 21 days Plasmapheresis: Deplete autoantibodies or paraproteins Antifibrinolytics: Federici AB, et al. Blood. 1998; 92 (8): Tiede, A., et al. Blood. 2011;117(25): MFMER slide-34

35 What About Long-Term Management of AvWS? Treatment of the underlying disorder should be considered whenever possible Response to therapy for underlying lymphoproliferative disorders and multiple myeloma: 35-70% Response to cytoreductive therapy for underlying MPN: ~85% MGUS usually unresponsive to steroids and chemotherapy Cannot eradicate slowly proliferating plasma cell clones? Bortezomib Ojeda-Uribe M, et al. Am J Hematol. 2010;85(5): MFMER slide-35

36 Case 2: Outcome 2016 MFMER slide-36

37 Case 2: Outcome DDAVP (0.3 mcg/kg x 1) % FVIII:C vwf:ag vwf:rco Time (hours) 2016 MFMER slide-37

38 Case 2: Outcome DDAVP (0.3 mcg/kg x 1) IV IgG (1 g/kg x 1) % FVIII:C vwf:ag vwf:rco Time (hours) % vwf:rco FVIII:C vwf:ag Time (Days) 2016 MFMER slide-38

39 Case 3: 54 year old male 2016 MFMER slide-39

40 Case 3: 54 year old male Stage IV peripheral T-cell lymphoma (liver involvement) Bilirubin: 16 mg/dl 2016 MFMER slide-40

41 Case 3: 54 year old male Stage IV peripheral T-cell lymphoma (liver involvement) Bilirubin: 16 mg/dl Gemcitabine, Solu-Medrol, and cisplatin: x 2 cycles 2016 MFMER slide-41

42 Case 3: 54 year old male Stage IV peripheral T-cell lymphoma (liver involvement) Bilirubin: 16 mg/dl Gemcitabine, Solu-Medrol, and cisplatin: x 2 cycles Liver function tests improved significantly 2016 MFMER slide-42

43 Case 3: 54 year old male Stage IV peripheral T-cell lymphoma (liver involvement) Bilirubin: 16 mg/dl Gemcitabine, Solu-Medrol, and cisplatin: x 2 cycles Liver function tests improved significantly 2016 MFMER slide-43

cisplatin: x 2 cycles Liver function tests improved significantly

44 Case 3: 54 year old male Stage IV peripheral T-cell lymphoma (liver involvement) Bilirubin: 16 mg/dl Gemcitabine, Solu-Medrol, and cisplatin: x 2 cycles Liver function tests improved significantly Overall significant improvement, but with new skeletal lesions 2016 MFMER slide-44

45 Case 3 (contd.) 2016 MFMER slide-45

46 Case 3 (contd.) He then received first cycle of CHOP-etoposide When due for the second cycle: Fever up to 103 o F and sweats Right arm pain and swelling (PICC line in right arm) ROS negative 2016 MFMER slide-46

47 Case 3 (contd.) He then received first cycle of CHOP-etoposide When due for the second cycle: Fever up to 103 o F and sweats Right arm pain and swelling (PICC line in right arm) ROS negative Lactate: 2.9 Uric Acid: 8.1 LDH: 324 Bilirubin: 1.6 AST 64 Alk phosphatase: 527 CXR: No infiltrate Cultures: negative 2016 MFMER slide-47

48 Case 3 (contd.) 2016 MFMER slide-48

49 Case 3 (contd.) Right UE ultrasound: Acute DVT in the right subclavian, axillary, and brachial veins Enoxaparin 1mg/kg q12h 2016 MFMER slide-49

50 Case 3 (contd.) Right UE ultrasound: Acute DVT in the right subclavian, axillary, and brachial veins Enoxaparin 1mg/kg q12h Persistent fevers, despite negative infection work up Lymphoma? 2016 MFMER slide-50

51 Case 3 (contd.) Right UE ultrasound: Acute DVT in the right subclavian, axillary, and brachial veins Enoxaparin 1mg/kg q12h Persistent fevers, despite negative infection work up Lymphoma? 2016 MFMER slide-51

52 Case 3 (contd.) Right UE ultrasound: Acute DVT in the right subclavian, axillary, and brachial veins Enoxaparin 1mg/kg q12h Persistent fevers, despite negative infection work up Lymphoma? PET-CT scan: Mixed response Increased activity in the right cardiophrenic recess but with improvement in other lesions 2016 MFMER slide-52

53 Case 3 (contd.) 2016 MFMER slide-53

54 Case 3 (contd.) Hemoglobin: 7.6 g/dl WBC: 2800/mm 3 Platelets: 68,000/mm MFMER slide-54

55 Case 3 (contd.) Hemoglobin: 7.6 g/dl WBC: 2800/mm 3 Platelets: 68,000/mm 3 PT: 18.1 sec (Ref: ) APTT: 56 sec (Ref: 28 38) 2016 MFMER slide-55

56 Case 3 (contd.) Hemoglobin: 7.6 g/dl WBC: 2800/mm 3 Platelets: 68,000/mm 3 PT: 18.1 sec (Ref: ) APTT: 56 sec (Ref: 28 38) Coagulation factors II, V, IX, X, XI, XII low; factor VII, VIII normal 2016 MFMER slide-56

57 Case 3 (contd.) Hemoglobin: 7.6 g/dl WBC: 2800/mm 3 Platelets: 68,000/mm 3 PT: 18.1 sec (Ref: ) APTT: 56 sec (Ref: 28 38) Coagulation factors II, V, IX, X, XI, XII low; factor VII, VIII normal Fibrinogen: 107 mg/dl (Ref: ) D-Dimer: 1545 ng/ml (Ref: <250) Soluble fibrin monomer complex (SFMC): 52 mcg/ml (Ref: <8) 2016 MFMER slide-57

58 Disseminated Intravascular Coagulation and Fibrinolysis (DIC/ ICF) Persistent intravascular activation of coagulation leading to fibrin formation and deposition inducing consumption of coagulation factors and platelets Can present as thrombosis or bleeding DIC is a clinical and laboratory diagnosis, based on findings of coagulopathy and/or fibrinolysis No single laboratory test can accurately confirm or eliminate the diagnosis 2016 MFMER slide-58

59 DIC Pathophysiology UNDERLYING CONDITION Activation of intravascular coagulation Platelet consumption Coagulation factor consumption Fibrin deposition fibrinolysis Endothelial damage Platelets PT APTT D-Dimer SFMC MAHA Impaired coagulation Thrombosis BLEEDING ORGAN ISCHEMIA 2016 MFMER slide-59

60 Acute versus Chronic DIC Parameter Acute (Decompensated) DIC Chronic (Compensated) DIC Underlying condition Trauma, sepsis, malignancy (esp. APL), ABO-incompatible blood transfusion Malignancy (esp. pancreatic, gastric, ovarian, brain tumors Presentation Bleeding Venous or arterial thromboembolism Platelet count Decreased Variable PT Prolonged Normal aptt Prolonged Normal Thrombin time Prolonged Normal or slightly prolonged Fibrinogen Decreased Normal or elevated Factor V Decreased Normal Factor VIII Decreased Normal D-Dimer Elevated Elevated SFMC Elevated Elevated 2016 MFMER slide-60

61 Differential Diagnosis 2016 MFMER slide-61

62 Differential Diagnosis Severe liver disease Thrombotic microangiopathy (TMA) TTP HUS Drug-induced TMA 2016 MFMER slide-62

63 Differential Diagnosis Severe liver disease Thrombotic microangiopathy (TMA) TTP HUS Drug-induced TMA Management 2016 MFMER slide-63

64 Differential Diagnosis Severe liver disease Thrombotic microangiopathy (TMA) TTP HUS Drug-induced TMA Management Treat underlying cause Supportive measures Transfusion support, if necessary PRBCs, platelets Cryoprecipitate, FFP Anticoagulation for thrombotic complications 2016 MFMER slide-64

65 Case 3: Outcome: improvement in DIC with chemotherapy Fibrinogen (mg/dl) Platelet count (x1000/mm3) Cryoprecipitate CHOP-E 2016 MFMER slide-65

66 Case 4: 63 year old female 2016 MFMER slide-66

67 Case 4: 63 year old female History of Stage IA infiltrating ductal breast cancer, s/p surgery, adjuvant chemotherapy and on aromatase inhibitor 2016 MFMER slide-67

68 Case 4: 63 year old female History of Stage IA infiltrating ductal breast cancer, s/p surgery, adjuvant chemotherapy and on aromatase inhibitor Presented with extensive spontaneous ecchymoses, hematuria and soft tissue bleeding CT of the abdomen: non-obstructing renal calculi Incidental multiple lytic and sclerotic lesions in the LS spine and pelvis 2016 MFMER slide-68

69 Case 4: 63 year old female History of Stage IA infiltrating ductal breast cancer, s/p surgery, adjuvant chemotherapy and on aromatase inhibitor Presented with extensive spontaneous ecchymoses, hematuria and soft tissue bleeding CT of the abdomen: non-obstructing renal calculi Incidental multiple lytic and sclerotic lesions in the LS spine and pelvis No prior history suggestive of a bleeding disorder 2016 MFMER slide-69

70 Case 4 (contd.) 2016 MFMER slide-70

71 Case 4 (contd.) Hemoglobin 9.4 g/dl WBC 7900/ mm 3 Platelets 192,000/mm MFMER slide-71

72 Case 4 (contd.) Hemoglobin 9.4 g/dl WBC 7900/ mm 3 Platelets 192,000/mm 3 Prothrombin time 10.5 sec (Ref: ) aptt 30 sec (Ref: 21-33) Thrombin time 24 sec (Ref: 16-25) 2016 MFMER slide-72

73 Case 4 (contd.) Hemoglobin 9.4 g/dl WBC 7900/ mm 3 Platelets 192,000/mm 3 Prothrombin time 10.5 sec (Ref: ) aptt 30 sec (Ref: 21-33) Thrombin time 24 sec (Ref: 16-25) Coagulation factors II, V, VII, VIII, IX, X, XI, XII normal 2016 MFMER slide-73

74 Case 4 (contd.) Hemoglobin 9.4 g/dl WBC 7900/ mm 3 Platelets 192,000/mm 3 Prothrombin time 10.5 sec (Ref: ) aptt 30 sec (Ref: 21-33) Thrombin time 24 sec (Ref: 16-25) Coagulation factors II, V, VII, VIII, IX, X, XI, XII normal Von Willebrand factor (vwf) antigen and vwf activity normal 2016 MFMER slide-74

75 Case 4 (contd.) Hemoglobin 9.4 g/dl WBC 7900/ mm 3 Platelets 192,000/mm 3 Prothrombin time 10.5 sec (Ref: ) aptt 30 sec (Ref: 21-33) Thrombin time 24 sec (Ref: 16-25) Coagulation factors II, V, VII, VIII, IX, X, XI, XII normal Von Willebrand factor (vwf) antigen and vwf activity normal Platelet aggregation studies and PFA100 assays normal 2016 MFMER slide-75

76 Case 4 (contd.): Now What? 2016 MFMER slide-76

77 Case 4 (contd.): Now What? Fibrinogen (Clauss) 159 mg/dl D-dimer >20000 ng/ml <250 Soluble Fibrin Monomer Negative 2016 MFMER slide-77

78 Case 4 (contd.): Now What? Fibrinogen (Clauss) 159 mg/dl D-dimer >20000 ng/ml <250 Soluble Fibrin Monomer Negative Factor XIII screen Clot dissolved before testing could be completed 2016 MFMER slide-78

79 Case 4 (contd.): Now What? Fibrinogen (Clauss) 159 mg/dl D-dimer >20000 ng/ml <250 Soluble Fibrin Monomer Negative Factor XIII screen Clot dissolved before testing could be completed Clot solubility test for XIII screen Normally, a clot is stable for 2 hours in 5M urea or 2% acetic acid, while in factor XIII deficiency the clot is unstable and dissolves in minutes 2016 MFMER slide-79

80 Case 4 (contd.): Now What? Fibrinogen (Clauss) 159 mg/dl D-dimer >20000 ng/ml <250 Soluble Fibrin Monomer Negative Factor XIII screen Clot dissolved before testing could be completed Clot solubility test for XIII screen Normally, a clot is stable for 2 hours in 5M urea or 2% acetic acid, while in factor XIII deficiency the clot is unstable and dissolves in minutes Plasminogen activity 34% Alpha-2 antiplasmin 35% MFMER slide-80

81 Fibrinolysis Tissue plasminogen activator (t-pa) Plasminogen activator inhibitor 1 and 2 Urokinase PLASMINOGEN PLASMIN Factor XIa, XIIa, Kallikrein α 2 -antiplasmin α 2 -macroglobulin FIBRINOGEN FIBRIN FIBRIN DEGRADATION PRODUCTS Thrombin Thrombin activable fibrinolysis inhibitor 2016 MFMER slide-81

82 Hyperfibrinolysis Primary Increased fibrinolytic activity independent of other factors Excess of plasminogen activators Deficiency of fibrinolysis inhibitors Secondary (e.g., DIC) Consequence of activation of coagulation and thrombin generation Stimulates the endothelium to produce increased amounts of t-pa 2016 MFMER slide-82

83 Case 4: Outcome Bone marrow biopsy: Involvement by metastatic adenocarcinoma: Immunohistochemistry for t-pa on bone marrow: t-pa expression in ER/PR positive cells (research assay) Plasma t-pa antigen: >150 ng/ml (Ref:<14.1 ng/ml) Profuse bleeding from the bone marrow biopsy site Hemoglobin 9.4 g/dl 6.4 g/dl 4 units of prbcs ε-aminocaproic acid infusion Weekly paclitaxel Bleeding and bruising improved Naina, H.V., et al. J Clin Oncol. 2010;28:e MFMER slide-83

84 Case 5: 17 year old male 2016 MFMER slide-84

85 Case 5: 17 year old male T-cell acute lymphoblastic leukemia Induction regimen included: Intrathecal cytarabine: Day 1 PEG Asparaginase: Day 4 Intrathecal methotrexate: Days 8, 29 In addition to: Vincristine; Prednisone, Daunorubicin MFMER slide-85

86 Case 5: 17 year old male T-cell acute lymphoblastic leukemia Induction regimen included: Intrathecal cytarabine: Day 1 PEG Asparaginase: Day 4 Intrathecal methotrexate: Days 8, 29 In addition to: Vincristine; Prednisone, Daunorubicin. Day 8: Post-intrathecal methotrexate Progressive back pain and lower extremity weakness 2016 MFMER slide-86

Case 5: 17 year old male T-cell acute lymphoblastic leukemia Induction regimen included: Intrathecal cytarabine: Day 1 PEG Asparaginase: Day 4 Intrathecal methotrexate:

87 Case 5: 17 year old male T-cell acute lymphoblastic leukemia Induction regimen included: Intrathecal cytarabine: Day 1 PEG Asparaginase: Day 4 Intrathecal methotrexate: Days 8, 29 In addition to: Vincristine; Prednisone, Daunorubicin. Day 8: Post-intrathecal methotrexate Progressive back pain and lower extremity weakness 2016 MFMER slide-87

88 Case 5 (contd.) 2016 MFMER slide-88

89 Case 5 (contd.) Lab Prechemo Pre-LP Post-LP Post-cryo + FFP Ref. range Hemoglobin (g/dl) Platelets (x1000/mm3) PT (sec) APTT (sec) Fibrinogen (mg/dl) 326 < MFMER slide-89

90 Case 5 (contd.) Lab Prechemo Pre-LP Post-LP Post-cryo + FFP Ref. range Hemoglobin (g/dl) Platelets (x1000/mm3) PT (sec) APTT (sec) Fibrinogen (mg/dl) 326 < Patient underwent laminoforaminotomies with decompression of T11 through S1 and evacuation of hematoma 2016 MFMER slide-90

91 Case 5 (contd.) Fibrinogen (mg/dl) 200 Cryoprecipitate PEG-Asparaginase MFMER slide-91

92 L-Asparaginase Catalyzes the hydrolysis of L-asparagine (ASN) to L-aspartic acid and ammonia Depletion of the circulating pool of ASN Lymphoblasts typically have low levels of ASN synthetase activity and are dependent on extracellular sources of ASN for protein synthesis Depletion of ASN is associated with cell-cycle arrest in the G1 phase L-Asparaginase also catalyzes the hydrolysis of glutamine (GLU) to glutamic acid, resulting in depletion of circulating levels of GLU Three product types: Native E. coli asparaginase Pegylated form of the E. coli asparaginase (long half life) Erwinia asparaginase (Erwinase) 2016 MFMER slide-92

93 L-Asparaginase: Adverse Effect Profile Allergy/Hypersensitivity Hyperbilirubinemia Elevated liver enzymes Hyperglycemia Pancreatitis Nausea/vomiting Fatigue Neuropathy Pediatric (n=1274) Adult (n=76) Hypofibrinogenemia CNS ischemia Thrombosis Bleeding Stock, W et al. Leukemia & Lymphoma.2011; 52(12): MFMER slide-93

94 Thrombosis and Bleeding L-Asparaginase leads to asparagine depletion Decreased synthesis of: Fibrinogen Plasminogen Antithrombin (AT), protein C, and protein S AT and fibrinogen are particularly affected Reduction in AT and protein C leads to thrombosis Patients with AT <70% are at high risk for thrombosis Depletion of fibrinogen is associated with increased bleeding Patients with fibrinogen <100 mg/dl are at high risk of hemorrhage Stock, W et al. Leukemia & Lymphoma.2011; 52(12): MFMER slide-94

95 Risk Factors for Thrombosis Increasing age Pediatric patients: 5% Adult patients: 34% Adults > 30 years: 42% Presence of indwelling venous catheters Oral contraceptives Prednisone versus dexamethasone therapy Lower thrombosis rates reported for dexamethasone Inherited thrombotic diathesis e.g., factor V Leiden, protein S deficiency, protein C deficiency Stock, W et al. Leukemia & Lymphoma.2011; 52(12): MFMER slide-95

96 Suggested Monitoring During L- Asparaginase Rx 2016 MFMER slide-96

97 Suggested Monitoring During L- Asparaginase Rx Baseline (before first dose) 2016 MFMER slide-97

98 Suggested Monitoring During L- Asparaginase Rx Baseline (before first dose) APTT, PT, AT and fibrinogen Prolonged APTT: r/o LAC or heparin or factor deficiency Prolonged PT: r/o Vitamin K deficiency, liver disease, DIC 2016 MFMER slide-98

99 Suggested Monitoring During L- Asparaginase Rx Baseline (before first dose) Serially (after administration) APTT, PT, AT and fibrinogen Prolonged APTT: r/o LAC or heparin or factor deficiency Prolonged PT: r/o Vitamin K deficiency, liver disease, DIC 2016 MFMER slide-99

100 Suggested Monitoring During L- Asparaginase Rx Baseline (before first dose) Serially (after administration) APTT, PT, AT and fibrinogen Prolonged APTT: r/o LAC or heparin or factor deficiency Prolonged PT: r/o Vitamin K deficiency, liver disease, DIC APTT, PT, AT and fibrinogen Twice weekly after last dose of L-asparaginase until there is no evidence of ongoing coagulation factor depletion. This is typically one week after L-asparaginase but may be up to 3 or more weeks after the pegylated form 2016 MFMER slide-100

101 Suggested Monitoring During L- Asparaginase Rx Baseline (before first dose) Serially (after administration) APTT, PT, AT and fibrinogen Prolonged APTT: r/o LAC or heparin or factor deficiency Prolonged PT: r/o Vitamin K deficiency, liver disease, DIC APTT, PT, AT and fibrinogen Twice weekly after last dose of L-asparaginase until there is no evidence of ongoing coagulation factor depletion. This is typically one week after L-asparaginase but may be up to 3 or more weeks after the pegylated form Suggested replacement triggers during and after L-asparaginase therapy: Fibrinogen < 100 mg/dl AT < 60% (normal: %) 2016 MFMER slide-101

102 Summary 2016 MFMER slide-102

103 Summary Multiple presentations of cancer coagulopathy Asymptomatic laboratory abnormality Bleeding disorder Thrombotic disorder 2016 MFMER slide-103

104 Summary Multiple presentations of cancer coagulopathy Asymptomatic laboratory abnormality Bleeding disorder Thrombotic disorder Variable mechanisms of cancer coagulopathy Activation of coagulation and fibrinolysis Immune mediated Endothelial damage Therapy related Platelet dysfunction 2016 MFMER slide-104

105 Summary Multiple presentations of cancer coagulopathy Asymptomatic laboratory abnormality Bleeding disorder Thrombotic disorder Variable mechanisms of cancer coagulopathy Activation of coagulation and fibrinolysis Immune mediated Endothelial damage Therapy related Platelet dysfunction Recognition and appropriate laboratory testing critical for optimal management of the patient 2016 MFMER slide-105

106 Questions & Discussion 2016 MFMER slide-106

Acquired Inhibitors of Coagulation

Acquired Inhibitors of Coagulation Christine L Kempton, MD, MSc Emory University Disclosures for In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research