A 69-year-old man with metastatic pancreatic cancer presented with coagulopathy, hypotension, and melena. He had been receiving enoxaparin for DVT but now had markedly elevated PT and aPTT due to accumulation of enoxaparin from renal impairment, vitamin K deficiency from poor nutrition, and possible DIC. Hematology recommended administering protamine to reverse the effects of enoxaparin, 4-factor prothrombin complex concentrate to correct the coagulopathy, and continued vitamin K to address the deficiency. The patient's coagulopathy improved after these interventions but his renal function did not.

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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Moheimani and Jackson, ISRN Hematology, 2011
Anticoagulant Mechanisms

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. 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. 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. 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. LMWH and Renal Dysfunction
Becker et al., Am Heart J., 2002

18. 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

19. 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

20. 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

21. 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

23. 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

24. 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

25. 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

26. 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 ?

27. 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

28. 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

29. 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

30. 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)

31. Case Follow-Up, Cont’d

32. 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)

33. 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

34. #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

35. Special Thanks
• Dr. Gerald Soff
• Dr. Rekha Parameswaran
• Dr. Simon Mantha
• Dr. Jacob Glass
• …and MSKCC and WCMC hematology
co-fellows !

36. THANK YOU !!!