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Hematology Case Conference:
69 y/o Man with Metastatic
Pancreatic Adenocarcinoma
Presenting with Coagulopathy
September 24...
Presentation of Case
• 69 y/o man originally from China:
• August 2014: Diagnosed with locally advanced
pancreas cancer; t...
Case, Cont’d
• 6/21/15: CT C/A/P: Hepatic metastases,
likely peritoneal carcinomatosis, DVT of
left common iliac vein/dist...
Case, Cont’d
• Presents to the UCC 7/15; family reports
the following symptoms:
– Poor oral intake at home, minimal in pas...
Case Cont’d: Progression
• PMH: HTN, HLD, hypothyroidism, DM on insulin
(as complication of malignancy)
• SHx: Originally ...
Relevant Exam Findings
• VS: BP 96/56 (as low as 80s/40s during assessment), HR
88 (as high as low 100s during assessment)...
Case Presentation, cont’d
• Initial labs in UCC:
134 102 69
5.8 20 3.8
(1.0)
12714.7 242
(9.1)
8.8
27.3
8.1
2.6
4.9
Diff: ...
Case Information Summary
69 yo Chinese man with progressive metastatic
pancreatic adenocarcinoma, on enoxaparin for DVT,
n...
Impressions at Bedside
• Hypovolemia leading to AKI accumulation
of enoxaparin
• Poor oral intake leading to ↓vitamin K
•...
In addition to GI and ICU consultation,
how would you approach this patient’s
coagulopathy? (may select multiple
intervent...
Moheimani and Jackson, ISRN Hematology, 2011
Anticoagulant Mechanisms
UFH Mechanism
• 4-30 kDa (mean 15 kDa)
• Enhances binding of
antithrombin (AT) to
thrombin (IIa) and
activated factor X (X...
LMWH: Mechanism
• Mean size 4.5 kDa
(~70% are 2-8 kDa)
• Larger fragments can
bind Xa and IIa, but
smaller fragments
canno...
PK Considerations
• UFH: Hepatic and reticuloendothelial
metabolism; some renal elimination, though little
as active fragm...
LMWH Accumulation in
Setting of ↓GFR
• Retrospective data show ↑ total and major
bleeding events in patients with renal
dy...
LMWH and Renal Dysfunction
Becker et al., Am Heart J., 2002
Protamine: An Introduction
• Originally isolated from the sperm of
salmon and other fish
• Fully reverses the effects of U...
Protamine and LMWH, cont’d
• In healthy volunteers
receiving UFH or
LMWH (both IV),
protamine abrogated
anti-IIa effects i...
After SC LMWH, protamine ↓anti-Xa activity to 38% of peak levels, but at
3h, substantial rebound of anti-Xa (64% of peak) ...
Effectiveness of Protamine in
Reversing LMWH-Associated Bleeding
• Unsurprisingly, limited body of literature
• Retrospect...
Protamine in Reversing LMWH-
Associated Bleeding, Cont’d
• 34 yo woman with enoxaparin
overdose (anti-Xa level 8.3 IU/mL) ...
Protamine Dosing Guide
Unfractionated heparin
• 1 mg protamine
neutralizes approximately
100 units of UFH
• Example: 50 mg...
Protamine Hypersensitivity
• Boxed warning: Rare hypotension,
noncardiogenic pulmonary edema, pulmonary
vasoconstriction o...
Reason for ↑ PT?
• PT may be increased in setting of high
doses of UFH (inhibition of fibrinogen-to-
fibrin conversion); l...
Management of Vitamin K
Deficiency
• Adequate intake: 120 mcg/d (men); 90 mcg/d (women)
• Vitamin K replacement: IV and PO...
Case Follow-Up
• Hematology recommendations:
– Protamine 120 mg IV x1, Kcentra 50 units/kg
IV x1, cont. vitamin K 10 mg IV...
Case Follow-Up, Cont’d
• Rapid improvement in PT/aPTT following
administration of protamine and Kcentra
• CXR w/possible c...
Case Follow-Up, Cont’d
• No significant improvement observed in
BUN/Cr/UOP
• Melena slowed after correction of coagulopath...
Case Follow-Up, Cont’d
Case Follow-Up, Cont’d
• After further interdisciplinary discussions
regarding poor prognosis and multi-organ
system dysfu...
Concluding Pearls
• Despite its limitations, given some evidence
of efficacy and limited alternatives, consider
protamine ...
#HemeConsultsMatter
• Unfortunately, coagulopathy was one of the few
reversible issues in this gentleman, but this may
hav...
Special Thanks
• Dr. Gerald Soff
• Dr. Rekha Parameswaran
• Dr. Simon Mantha
• Dr. Jacob Glass
• …and MSKCC and WCMC hemat...
THANK YOU !!!
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  1. 1. Hematology Case Conference: 69 y/o Man with Metastatic Pancreatic Adenocarcinoma Presenting with Coagulopathy September 24, 2015 Mark B. Geyer, MD Department of Medicine Hematology/Medical Oncology Fellow Memorial Sloan-Kettering Cancer Center MarkGeyerMD
  2. 2. Presentation of Case • 69 y/o man originally from China: • August 2014: Diagnosed with locally advanced pancreas cancer; treated with GTX (gemcitabine, docetaxel, capecitabine)  durable minor response; tolerated well • May 2015: Started concurrent chemoRT; c/b fatigue, anorexia, nausea, abdominal pain • 6/20/15: Hospital admission with lethargy and generalized weakness
  3. 3. Case, Cont’d • 6/21/15: CT C/A/P: Hepatic metastases, likely peritoneal carcinomatosis, DVT of left common iliac vein/distal IVC – Started on enoxaparin 1 mg/kg SC q12h – Discharged home 6/24/15 • 6/27-7/1/15: Readmitted with lethargy, generalized weakness, poor PO intake; hospice referral discussed, but declined by patient and family
  4. 4. Case, Cont’d • Presents to the UCC 7/15; family reports the following symptoms: – Poor oral intake at home, minimal in past 2 weeks – Bedbound, less interactive, more confused – Abdomen more distended, increased jaundice – One day of black tarry stools – Has received enoxaparin 1 mg/kg SC q12h (given by family), including 8 hours ago, even after passage of melenic stool
  5. 5. Case Cont’d: Progression • PMH: HTN, HLD, hypothyroidism, DM on insulin (as complication of malignancy) • SHx: Originally from China. Retired mechanic. Lives w/wife in Rockland County. 45 pack year ex-smoker. • FHx: Mother w/colon cancer (dx age 80), first cousin w/pancreas cancer • Home meds: enoxaparin SC, insulin glargine, insulin aspart SS pre-meal, dronabinol, mirtazapine, rosuvastatin, amlodipine, olmesartan, eplerenone, levothyroxine, vit D
  6. 6. Relevant Exam Findings • VS: BP 96/56 (as low as 80s/40s during assessment), HR 88 (as high as low 100s during assessment), T 36.6ºC, RR 20, SaO2 97% RA • GA: Ill-appearing, cachectic, jaundiced, obtunded older man, actively passing large black bowel movement • HEENT: +Scleral icterus, dry mucous membranes • CV: Regular, mild tachycardia • Resp: Limited effort • Abd: Soft, distended, does not grimace to palpation, small ecchymoses at enoxaparin injection sites • Ext: 1-2+ pretibial/pedal edema (L>R) • Neuro: Obtunded, does not follow commands in Chinese or English, tracks visitors, moves all extremities readily
  7. 7. Case Presentation, cont’d • Initial labs in UCC: 134 102 69 5.8 20 3.8 (1.0) 12714.7 242 (9.1) 8.8 27.3 8.1 2.6 4.9 Diff: 88% polys Prior LFTs: T bili 2.9, AST 81, ALT 34, Alb 2.7, Alk Phos 406 4.3 2.2 8.1 7.3 206 72 303 (35 .0) 77.9 96.4 6.96 (1.45) 13.2 194 7.7 24.5 Diff: 87% polys 93.9 94.4 8.38 Hematology Consulted • Repeat labs in UCC: s/p 2L NS IV, vit K 10 mg IV Fibrinogen 237
  8. 8. Case Information Summary 69 yo Chinese man with progressive metastatic pancreatic adenocarcinoma, on enoxaparin for DVT, now with: • Profound fatigue, weakness • Poor oral intake • Encephalopathy • Melenic stools • Hypotension • Significantly elevated PT and aPTT • Marked AKI • Mildly worsening anemia • Worsening hyperbilirubinemia, hypoalbuminemia
  9. 9. Impressions at Bedside • Hypovolemia leading to AKI accumulation of enoxaparin • Poor oral intake leading to ↓vitamin K • POD leading to hyperbilirubinemia, ? ↓liver synthetic function • Likely UGIB exacerbated by coagulopathy • Question of sepsis • Encephalopathy in the setting of all the above
  10. 10. In addition to GI and ICU consultation, how would you approach this patient’s coagulopathy? (may select multiple interventions) (A) Hold enoxaparin (B) Administer protamine (C) Administer further vitamin K (D) Administer FFP (E) Administer cryoprecipitate (F) Administer 4-factor prothrombin complex concentrate
  11. 11. Moheimani and Jackson, ISRN Hematology, 2011 Anticoagulant Mechanisms
  12. 12. UFH Mechanism • 4-30 kDa (mean 15 kDa) • Enhances binding of antithrombin (AT) to thrombin (IIa) and activated factor X (Xa) • By inactivating thrombin, also inhibits thrombin- induced activation of Plts, V, VIII, XI, XIII • Anti-Xa to Anti-IIa ratio of nearly 1:1 Weitz, NEJM, 1997
  13. 13. LMWH: Mechanism • Mean size 4.5 kDa (~70% are 2-8 kDa) • Larger fragments can bind Xa and IIa, but smaller fragments cannot bind IIa • Xa inactivation is nearly as good • Anti-Xa to Anti-IIa ratio of 2:1 to 4:1 Weitz, NEJM, 1997
  14. 14. PK Considerations • UFH: Hepatic and reticuloendothelial metabolism; some renal elimination, though little as active fragments – Extensive and variable binding to plasma proteins – Rapid, saturable phase of hepatic uptake – Slower phase of renal clearance • Enoxaparin: Hepatic metabolism; longer heparin chains (and anti-IIa activity) more rapidly cleared; ↓binding to heparin binding proteins than UFH, ↑ dependence on renal elimination, some as active fragments
  15. 15. LMWH Accumulation in Setting of ↓GFR • Retrospective data show ↑ total and major bleeding events in patients with renal dysfunction treated with LMWH • Data from patients enrolled on a TIMI study using therapeutic doses of enoxaparin for NSTEMI show ↑anti-Xa levels among those with renal impairment, and trend toward ↑ bleeding Gerlach et al., Pharmacotherapy, 2000 Becker et al., Am Heart J., 2002
  16. 16. LMWH and Renal Dysfunction Becker et al., Am Heart J., 2002
  17. 17. Protamine: An Introduction • Originally isolated from the sperm of salmon and other fish • Fully reverses the effects of UFH via dissociation of the heparin-AT complex (reverses anti-IIa, anti-Xa, aPTT)  complexes to form a stable salt • Protamine appears to reverse the anti-IIa effects of LMWH fully, but the anti-Xa effects less efficiently
  18. 18. Protamine and LMWH, cont’d • In healthy volunteers receiving UFH or LMWH (both IV), protamine abrogated anti-IIa effects in both groups, but only ~80% of anti-Xa effects in the LMWH group Holst et al., Blood Coagul Fibrinolysis, 1994
  19. 19. After SC LMWH, protamine ↓anti-Xa activity to 38% of peak levels, but at 3h, substantial rebound of anti-Xa (64% of peak) and anti-IIa (54% of peak) was observed, as well as rebound in aPTT Protamine and LMWH, cont’d Holst et al., Blood Coagul Fibrinolysis, 1994
  20. 20. Effectiveness of Protamine in Reversing LMWH-Associated Bleeding • Unsurprisingly, limited body of literature • Retrospective series of 18 patients from the UK receiving protamine after LMWH: – 14 pts w/active bleeding: 4 w/continued bleeding s/p protamine (including one w/liver disease), 2 not easily evaluable, 8 with arrest of bleeding – 4 pts needing emergency surgery within 12h of LMWH (including a neonate with anti-Xa level 2.96): no bleeding complications after protamine – Of the 4 adult pts with anti-Xa levels >1.0 IU/mL before protamine, 2 experienced cont’d bleeding van Veen et al., Blood Coagul Fibrinolysis, 2011
  21. 21. Protamine in Reversing LMWH- Associated Bleeding, Cont’d • 34 yo woman with enoxaparin overdose (anti-Xa level 8.3 IU/mL) in setting of suicide attempt: – Given protamine 50 mg IV x1 at 25 hrs after admission (and rFVIIa), after RP hematomas developed, without clear rapid improvement in anti-Xa levels • 64 yo man on oral a/c admitted with SDH inadvertently received enoxaparin 1 mg/kg (peak anti-Xa 1.02, ↓ to 0.77 at 15 minutes after protamine 20 mg IV x1, then ↓ to 0.63 and 0.57 following two further doses of protamine 20 mg at 2h, 4h, with ongoing intracranial bleeding observed Byrne and Zumberg, Blood Coagul Fibrinolysis, 2012; Makris et al., Br J Haematol, 2000
  22. 22. Protamine Dosing Guide Unfractionated heparin • 1 mg protamine neutralizes approximately 100 units of UFH • Example: 50 mg protamine for a patient with hemorrhage after heparin 5000 units IV • When given as IVCI, only heparin given during the preceding ~2-2.5 hrs needs to be considered Enoxaparin (Lovenox ®) • Per package insert, 1 mg protamine sulfate should be administered to neutralize 1 mg Lovenox, if ≤8 hrs since prior dose • 0.5 mg protamine per 1 mg Lovenox if >8 hrs since dose • Consider another 0.5 mg protamine per 1 mg Lovenox if aPTT still prolonged at 2-4 hrs Garcia et al., Chest, 2012
  23. 23. Protamine Hypersensitivity • Boxed warning: Rare hypotension, noncardiogenic pulmonary edema, pulmonary vasoconstriction observed with infusion • Vasectomized men may develop antibodies to different sperm antigens – 75% with anti-sperm Abs, 25% with anti-protamine Abs, c/w 10% and 0% in non-vasectomized men in one series • Prior use of protamine-containing drugs (e.g. NPH), fish allergies (for fish-derived protamine) may ↑ risk as well Watson et al., Urology, 1983; Vézina et al., Contraception, 1990
  24. 24. Reason for ↑ PT? • PT may be increased in setting of high doses of UFH (inhibition of fibrinogen-to- fibrin conversion); less commonly observed with LMWH • Vitamin K deficiency due to poor nutrition • Hepatic dysfunction from POD • Component of DIC ?
  25. 25. Management of Vitamin K Deficiency • Adequate intake: 120 mcg/d (men); 90 mcg/d (women) • Vitamin K replacement: IV and PO routes preferred over SC based on higher rates of effectiveness; wide dose ranges reported • Need to consider severity of bleeding, need for emergency procedures in addition to PT/INR itself • ACCP guidelines for patients with major bleeding in the setting of a VKA: vitamin K 5-10 mg IV, 4-factor PCC (e.g. Kcentra) • Kcentra labeling in setting of INR >6: 50 units/kg x1 (factor IX activity) Hirsh et al., Chest, 2008 Dezee et al., Arch Int Med 2006
  26. 26. Case Follow-Up • Hematology recommendations: – Protamine 120 mg IV x1, Kcentra 50 units/kg IV x1, cont. vitamin K 10 mg IV daily x3 days – Recheck PT/aPTT/fibrinogen at 4h after Kcentra and protamine administration – CBCs w/PT/aTT/fibrinogen q4-6h – Consideration of PRBCs – Consideration of IVC filter • DNR/DNI status confirmed
  27. 27. Case Follow-Up, Cont’d • Rapid improvement in PT/aPTT following administration of protamine and Kcentra • CXR w/possible consolidation in RML and RLL; empiric abx started
  28. 28. Case Follow-Up, Cont’d • No significant improvement observed in BUN/Cr/UOP • Melena slowed after correction of coagulopathy • Abdominal USG showed new main and R portal vein thrombosis (a/c deferred) • Transient mild improvement in responsiveness, followed by subsequent decline • Family decided against invasive measures (IVC filter, EGD)
  29. 29. Case Follow-Up, Cont’d
  30. 30. Case Follow-Up, Cont’d • After further interdisciplinary discussions regarding poor prognosis and multi-organ system dysfunction, his family agreed to comfort measures only • Died as an inpatient on the afternoon of 7/20/15 (had been admitted 7/15/15)
  31. 31. Concluding Pearls • Despite its limitations, given some evidence of efficacy and limited alternatives, consider protamine in the setting of severe bleeding associated with LMWH • In an unstable patient with life-threatening bleeding and deficiencies in the vitamin K- dependent coagulation factors, consider the use of 4-factor PCCs in addition to vitamin K
  32. 32. #HemeConsultsMatter • Unfortunately, coagulopathy was one of the few reversible issues in this gentleman, but this may have helped to stabilize his GI bleeding and allow for more thoughtful discussions of goals of care • Family, team appreciative
  33. 33. Special Thanks • Dr. Gerald Soff • Dr. Rekha Parameswaran • Dr. Simon Mantha • Dr. Jacob Glass • …and MSKCC and WCMC hematology co-fellows !
  34. 34. THANK YOU !!!

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