Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT:...
Transcript of Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT:...
![Page 1: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/1.jpg)
©2016 MFMER | slide-1 ©2016 MFMER | slide-1
Malignancy-Associated Coagulopathy: Recognition and Laboratory Diagnosis
Aneel A. Ashrani, M.D., M.S.
![Page 2: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/2.jpg)
©2016 MFMER | slide-2
Disclosures
Relevant Financial Relationship -NONE
Off-Label and/or Investigational Uses -NONE
![Page 3: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/3.jpg)
©2016 MFMER | slide-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
![Page 4: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/4.jpg)
©2016 MFMER | slide-4
Case 1: • 59-year-old female with stage III serous
adenocarcinoma of the ovary • s/p total abdominal hysterectomy and bilateral
salpingo-oophorectomy and receiving paclitaxel and carboplatin
• Influenza vaccine administered in the right deltoid region
• Severe pain and swelling in the right shoulder; swelling and ecchymosis in the arm extending down to the wrist
• No prior history of excessive bleeding or bruising
![Page 5: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/5.jpg)
©2016 MFMER | slide-5
Case 1 (contd.)
• Hemoglobin 8.7 g/dL → 5.7 g/dL
• Platelets: 403,000/mm3
• PT: 11.7 sec (Ref: 8.4 – 12.0)
• APTT: 75 sec (Ref: 25 – 37)
• Ultrasound of right upper extremity: soft tissue fluid collection; no DVT
![Page 6: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/6.jpg)
©2016 MFMER | slide-6
Prolonged PT or APTT
Mixing study with normal plasma
Correction (factor deficiency)
No correction (inhibitor)
Clotting factor assays to identify deficiency
Determine type of inhibitor
Nonspecific inhibitor (e.g., lupus anticoagulant
Specific factor inhibitor (e.g., FVIII, FV)
Drug: Heparin, IIa inhibitor, Xa inhibitor
Adapted from Mayo Clinic Proc.; Kamal, A.H., 2007;82(7):864-873 with permission from Elsevier http://www.elsevier.com
![Page 7: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/7.jpg)
©2016 MFMER | slide-7
Case 1 (contd.) • Hemoglobin 8.7 g/dL → 5.7 g/dL
• Platelets: 403,000/mm3
• PT: 11.7 sec (Ref: 8.4 – 12.0)
• APTT: 75 sec (Ref: 25 – 37) • APTT Mix: 39 sec • Platelet neutralization procedure: 82 sec
• DRVVT: 1.2 • DRVVT Mix: 1.0
• Factor VIII: <1% • Factor VIII inhibitor titer: 7 Bethesda Units
![Page 8: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/8.jpg)
©2016 MFMER | slide-8
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. (61.4–80.4)
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: 1870-1877 Knoebl, P. , et al. J Thromb Haemost 2012; 10: 622–31
![Page 9: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/9.jpg)
©2016 MFMER | slide-9
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: 622–31
![Page 10: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/10.jpg)
©2016 MFMER | slide-10
Hauser and Lechner. Thromb Haemost 1999;82:1005.
Cancer and FVIII Inhibitors • Not associated with specific type of tumor
• Two-thirds of associated malignancies are solid tumors
• Most frequent primary: lung, prostate, head/neck
• Male:female ratio ≈ 3:1
• Median age of onset = 69 yrs
• May be autoimmune reaction to tumor → tumor antigen similar to FVIII?
![Page 11: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/11.jpg)
©2016 MFMER | slide-11
Solid Tumors and FVIII Inhibitors
• Standard treatment → chemotherapy, radiation, & surgery do not usually eradicate inhibitors
• Inhibitor is not a marker of tumor recurrence
Hauser and Lechner. Thromb Haemost 1999;82:1005.
![Page 12: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/12.jpg)
©2016 MFMER | slide-12
Treatment Strategies Dual Objectives
Management Strategies
Acute Management
Long-term Strategy
Stop the Bleeding
Eradicate Inhibitor
![Page 13: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/13.jpg)
©2016 MFMER | slide-13
Acute Management of Bleeding
Hemostatic agent No. of patients treated % Response Bypassing agent 219 92%
rFVIIa 159 91% aPCC 60 93%
Replacement therapy 69 70% FVIII 55 70% DDAVP 14 64%
Baudo, F., et al. Blood. 2012;120(1): 39-46)
Thrombotic events similar between rFVIIa (2.9%) and aPCC (4.8%).
Bleeding controlled in 80% of patients treated with a first-line hemostatic agent
![Page 14: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/14.jpg)
©2016 MFMER | slide-14
Inhibitor Eradication: Efficacy and Safety Regimen N CR (%) Relapse (%) Stable CR (%) Steroids alone 142 58% 11% 48% Steroids + cyclophosphamide 83 80% 10% 70% Rituxan based regimens 51 61% 3% 59%
Regimen N Any AE (%) Infection Mortality (%) Steroids alone 142 25% 16% 28% Steroids + cyclophosphamide 83 41% 27% 33% Rituxan based regimens 51 37% 12% 20%
Cyclophosphamide+steroids versus steroids alone OR 95% CI
CR at final follow-up 3.16 1.20-8.31 Alive at final follow-up: 0.91 0.45-1.82 Alive and in CR 1.26 0.64-2.48
Collins, P, et al. Blood. 2012;120(1):47-55
![Page 15: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/15.jpg)
©2016 MFMER | slide-15
Case 1 (contd.)
• Acute bleed management: • Transfused 4 units PRBCs • FEIBA 75 units/kg q12
hours
• Inhibitor management: • Prednisone 1mg/kg/day
0
10
20
30
40
50
60
Oct Nov Dec Jan Feb Mar
Factor VIII (%) Inhibitor titer (BU)
Tiede, A, et al. Blood. 2015;125(7):1091-1097
Low FVIII at presentation is associated with a lower response rate to immunosuppression Partial response achieved on steroids alone within <21 days is more common in patients with FVIII >1 IU/dL and inhibitor concentration <20 BU/mL
![Page 16: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/16.jpg)
©2016 MFMER | slide-16
![Page 17: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/17.jpg)
©2016 MFMER | slide-17
Case 2 • 51-year-old female with iron deficiency anemia underwent
colonoscopy with polypectomy • About two weeks later, she had hematochezia with
hemoglobin drop to 5.5 g/dL • Required 4 units of PRBCs
• As serology for celiac disease were positive, she underwent upper GI endoscopy with biopsies
• Biopsies were consistent with celiac disease • She then started having melanotic stools, requiring
PRBC transfusions
• Despite gluten-free diet, she continued to be anemic requiring PRBC transfusion
![Page 18: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/18.jpg)
©2016 MFMER | slide-18
Case 2 (contd.) • A capsule study suggested that the proximal jejunum may
be the site of bleeding • She then underwent small bowel resection • She continued to have melanotic stools and was
persistently anemic
• Over the last three years, she has had frequent epistaxis, unexplained bruises and prolonged bleeding with minor nicks/ cuts
• Prior to that, no issues with excessive bleeding/ bruising
• Hemoglobin: 10.3 g/dL
• Platelets: 443,000/ mm3
• Leukocyte count: 9200/ mm3
![Page 19: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/19.jpg)
©2016 MFMER | slide-19
Patient 2 (contd.) • PT: 8.4 sec (Ref: 8.3 – 10.8)
• APTT: 35 sec (Ref: 21 – 33) • APTT mix: 30 sec • Platelet neutralization procedure: 37 sec
• FVIII: 28%
• vWF antigen: 18%
• Ristocetin cofactor: <12%
• vWF multimer analysis: Normal vWF multimer distribution
• Ristocetin inhibitor screen: Negative
![Page 20: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/20.jpg)
©2016 MFMER | slide-20
Patient 2 (contd.) • Platelet function analyzer (PFA100):
• Collagen/Epinephrine closure time: >267 sec • Collagen/ADP: >166 sec
• Platelet aggregation studies: • Arachidonate: Normal • ADP: Normal • Epinephrine: Normal • Collagen: Normal • Ristocetin: Decreased
• SPEP: 0.5 g/dL IgG lambda monoclonal paraprotein • Lambda free light chain: 9.9 mg/dL (UNL: 2.6 mg/dL)
![Page 21: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/21.jpg)
©2016 MFMER | slide-21
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):6777-6785
![Page 22: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/22.jpg)
©2016 MFMER | slide-22
Differentiating AvWS from Congenital vWD In favor of AvWS In favor of vWD
Personal history • Late onset of bleeding • Uneventful prior surgeries
• Early onset of bleeding • No uneventful surgery or no
previous high-risk situations Family history • Negative • Positive AVWS-associated disorder
• Present • Absent
Laboratory evaluation • Presence of inhibitor or VWF-binding antibodies
• VWF gene mutation
Treatment response • Remission after treatment of underlying disorder
• Response to IVIG (in IgG-MGUS-associated AVWS)
• Short-lived response to VWF containing concentrates or desmopressin
• Normal recovery and half-life of VWF-containing concentrate
• Sustained response to desmopressin
Tiede, A., et al. Blood. 2011;117(25):6777-6785
![Page 23: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/23.jpg)
©2016 MFMER | slide-23
Diagnostic Tests • Initial assays for AvWS are same as for vWD
• FVIII:C • VWF:Antigen • VWF:Activity or VWF:RCo • VWF:Collagen Binding
• vWF multimer analysis
• 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
![Page 24: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/24.jpg)
©2016 MFMER | slide-24
• 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:
Treatment
Federici AB, et al. Blood. 1998; 92 (8): 2707-2711 Tiede, A., et al. Blood. 2011;117(25):6777-6785.
![Page 25: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/25.jpg)
©2016 MFMER | slide-25
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):396
![Page 26: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/26.jpg)
©2016 MFMER | slide-26
Case 2 (contd.)
DDAVP (0.3 mcg/kg x 1)
0 10 20 30 40 50 60 70 80 90
100
0 1 2 3 4
%
Time (hours)
FVIII:C vWF:Ag vWF:RCo
IV IgG (1 g/kg x 1)
0
50
100
150
200
0 2 4 6 8 10 12 14 16 18 20 Time (Days)
vWF:RCo FVIII:C vWF:Ag
![Page 27: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/27.jpg)
©2016 MFMER | slide-27
Case 3 • 54-year-old male with peripheral
stage IV peripheral T-cell lymphoma
• Bilirubin: 16 mg/dL • alkaline phosphatase: 916 U/L • ALT 503 U/L; AST 405 U/L
• He was treated with two cycles of gemcitabine, Solu-Medrol, and cisplatin
• Liver function tests improved significantly
• Overall significant improvement, but with new skeletal lesions
![Page 28: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/28.jpg)
©2016 MFMER | slide-28
Case 3 (contd.) • He then received first cycle of CHOP-etoposide
• When due for the second cycle: • Fever up to 103oF and sweats • Right arm pain and swelling (PICC line in right arm) • ROS negative
7.3
19.5 80 4.5
125 3.6
84 1.2 30 85
24
Lactate: 2.9 Uric Acid: 8.1 LDH: 324 UA: negative
Bilirubin: 1.6 AST 64 Alk phosphatase: 527
CXR: No infiltrate Cultures: negative
![Page 29: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/29.jpg)
©2016 MFMER | slide-29
![Page 30: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/30.jpg)
©2016 MFMER | slide-30
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
![Page 31: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/31.jpg)
©2016 MFMER | slide-31
Case 3 (contd.) • Hemoglobin: 7.6 g/dL
• WBC: 2800/mm3
• Platelets: 68,000/mm3
• PT: 18.1 sec (Ref: 9.5 – 13.8)
• APTT: 56 sec
• Fibrinogen: 107 mg/dL (Ref: 200 – 375)
• D-Dimer: 1545 ng/ml (Ref: <250)
• Soluble fibrin monomer complex (SFMC): 52 mcg/ml (Ref: <8)
![Page 32: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/32.jpg)
©2016 MFMER | slide-32
Case 3 (contd.) Coagulation factor Value Reference range Fibrinogen 58 200 – 375 mg/dL Factor II 36 75 – 145% Factor V 69 70 – 165% Factor VII 77 65 – 180% Factor VIII 168 55 – 200% Factor IX 44 65 – 140% Factor X 44 70 – 150% Factor XI 32 55 – 150% Factor XII 37 55 – 180%
![Page 33: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/33.jpg)
©2016 MFMER | slide-33
• 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
Disseminated Intravascular Coagulation and Fibrinolysis (DIC/ ICF)
![Page 34: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/34.jpg)
©2016 MFMER | slide-34
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
DIC Pathophysiology
![Page 35: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/35.jpg)
©2016 MFMER | slide-35
Acute versus Chronic DIC Parameter Acute (Decompensated) DIC Chronic (Decompensated) 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
![Page 36: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/36.jpg)
©2016 MFMER | slide-36
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
![Page 37: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/37.jpg)
©2016 MFMER | slide-37
Case 3 (contd.)
0
50
100
150
200
250
300 Fibrinogen (mg/dL) Platelet count (x1000/mm3)
CHOP-E
Cryoprecipitate
![Page 38: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/38.jpg)
©2016 MFMER | slide-38
![Page 39: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/39.jpg)
©2016 MFMER | slide-39
Case 4 • 63-year-old female with history of Stage IA, ER & PR
positive, HER-2 negative infiltrating ductal breast cancer presented with extensive spontaneous ecchymoses
• Status post mastectomy, followed by six cycles of CMF, and was on letrozole for the prior three years
• Subsequently, she developed hematuria and soft tissue bleeding
• CT of the abdomen: non-obstructing renal calculi • Incidentally, multiple lytic and sclerotic lesions
noted in the LS spine and pelvis
• No prior history suggestive of a bleeding disorder
![Page 40: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/40.jpg)
©2016 MFMER | slide-40
Case 4 (contd.) Hemoglobin 9.4 g/dL WBC 7900/ mm3
Platelets 192,000/mm3
Smear No schistocytes
Prothrombin time 10.5 sec (Ref: 8.3-10.8) aPTT 30 sec (Ref: 21-33) Thrombin time 24 sec (Ref: 16-25)
![Page 41: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/41.jpg)
©2016 MFMER | slide-41
Case 4 (contd.): Coagulation Factors Factor Activity Reference range (%)
Factor II 171% 70-130 Factor V 124% 60-145 Factor VII 108% 50-160 Factor VIII 171% 55-200 Factor IX 107% 60-140 Factor X 67% 60-140 Factor XI 81% 60-140 Factor XII 125% 60-160 vWF Ag 206% 55-200 vWF activity 208% 55-200
![Page 42: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/42.jpg)
©2016 MFMER | slide-42
Case 4 (contd.): Platelet Function Assays
Agonist Value Reference Arachidonate Normal ADP Normal Epinephrine Normal Collagen Normal Ristocetin Normal
PFA Col/Epi 147 sec 70-165 sec PFA Col/ADP 92 sec 50-115 sec
![Page 43: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/43.jpg)
©2016 MFMER | slide-43
Case 4 (contd.): Now What? Fibrinogen (Clauss) 159 mg/dL 200-430 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% 75-140 Alpha-2 antiplasmin 35% 80-140
![Page 44: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/44.jpg)
©2016 MFMER | slide-44
Fibrinolysis PLASMINOGEN
PLASMIN
FIBRIN FIBRIN DEGRADATION PRODUCTS
FIBRINOGEN
Thrombin Thrombin activable fibrinolysis inhibitor
α2-antiplasmin
α2-macroglobulin
Factor XIa, XIIa, Kallikrein
Tissue plasminogen activator (t-PA)
Urokinase
Plasminogen activator inhibitor 1 and 2
![Page 45: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/45.jpg)
©2016 MFMER | slide-45
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
![Page 46: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/46.jpg)
©2016 MFMER | slide-46
Case 4 (contd.) • Bone marrow biopsy: Involvement by metastatic
adenocarcinoma • Morphologically and immunophenotypically consistent with
breast primary • Immunohistochemistry for t-PA on bone marrow: t-PA
expression in ER/PR–positive cells
• 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
![Page 47: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/47.jpg)
©2016 MFMER | slide-47
![Page 48: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/48.jpg)
©2016 MFMER | slide-48
Case 5 • 17 year old male diagnosed with T-cell
acute lymphoblastic leukemia (ALL)
• Remission induction regimen included: • Intrathecal cytarabine: Day 1 • Vincristine: Days 1, 8, 15, 22 • Prednisone: Days 1-28 • Daunorubicin: Days 1, 8, 15, 22 • PEG Asparaginase: Day 4 • Intrathecal methotrexate: Days 8, 29
• Day 8: Received intrathecal methotrexate • Soon following LP, he complained of
back pain that progressively worsened • By evening, developed lower
extremity weakness
![Page 49: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/49.jpg)
©2016 MFMER | slide-49
Case 5 (contd.)
Lab Pre-chemo
Pre-LP Post-LP Post-cryo + FFP
Ref. range
WBC (x1000/mm3) 89.5 5.5 4.1 4.4 3.5 – 10.5
Hemoglobin (g/dL) 13.7 14.9 11.9 10.3 13.5 – 17.5
Platelets (x1000/mm3) 62 155 260 177 150 – 450
PT (sec) 15.7 23.8 13.3 9.5 – 13.8
APTT (sec) 30 59 32 28 – 38
Fibrinogen (mg/dl) 326 <60 127 200 – 375
Antithrombin (%) 45 80 – 130
Patient underwent laminoforaminotomies with decompression of T11 through S1 and evacuation of hematoma
![Page 50: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/50.jpg)
©2016 MFMER | slide-50
Case 5 (contd.)
0
50
100
150
200
250
300
350
Fibrinogen (mg/dL)
PEG-Asparaginase
Cryoprecipitate
![Page 51: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/51.jpg)
©2016 MFMER | slide-51
L Asparaginase • L-Asparaginase: enzyme that catalyzes the hydrolysis of L-asparagine
(ASN) to L-aspartic acid and ammonia, resulting in depletion of the circulating pool of ASN
• Three product types:
Native E. coli asparaginase
Pegylated form of the E. coli asparaginase (long half life)
Erwinia asparaginase (Erwinase)
• 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-Asp is also known to catalyze the hydrolysis of glutamine (GLU) to glutamic acid, resulting in depletion of circulating levels of GLU
![Page 52: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/52.jpg)
©2016 MFMER | slide-52
L-Asparaginase: Adverse Effect Profile
0 10 20 30 40
Bleeding
Thrombosis
CNS ischemia
Hypofibrinogenemia
Neuropathy
Fatigue
Nausea/vomiting
Pancreatitis
Hyperglycemia
Elevated liver enzymes
Hyperbilirubinemia
Allergy/Hypersensitivity
Pediatric (n=1274) Adult (n=76)
Stock, W et al. Leukemia & Lymphoma.2011; 52(12): 2237–2253
![Page 53: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/53.jpg)
©2016 MFMER | slide-53
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): 2237–2253
![Page 54: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/54.jpg)
©2016 MFMER | slide-54
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
![Page 55: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/55.jpg)
©2016 MFMER | slide-55
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
Serially (after administration)
• 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
![Page 56: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/56.jpg)
©2016 MFMER | slide-56
Suggested Replacement Triggers During and After L-Asparaginase Therapy
• Fibrinogen < 100 mg/dl • AT < 60% (normal: 80-120%)
• Dosage should be determined by pre-therapy AT level in order to increase AT level to 80%
• Units required = [desired - baseline AT level] × weight (kg) 1.4
• Confirm restoration of desired level after replacement administered
![Page 57: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/57.jpg)
©2016 MFMER | slide-57
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 of underlying process important for appropriate management of the patient
![Page 58: Malignancy-Associated Coagulopathy...2016/12/07 · • PT: 11.7 sec (Ref: 8.4 – 12.0) • APTT: 75 sec (Ref: 25 – 37) • Ultrasound of right upper extremity: soft tissue fluid](https://reader033.fdocuments.in/reader033/viewer/2022060814/6093595391129f3a942c7b8f/html5/thumbnails/58.jpg)
©2016 MFMER | slide-58
Questions & Discussion