Bleeding Emergencies. Gregory W. Hendey, MD, FACEP Professor of Clinical Emergency Medicine UCSF Fresno

Transcription

1 Bleeding Emergencies Gregory W. Hendey, MD, FACEP Professor of Clinical Emergency Medicine UCSF Fresno

2 Objectives To discuss indications and agents used for reversal of coagulopathy To apply those principles in clinical situations Supratherapeutic coumadin, ICH, Heparin, Thrombocytopenia, Hemophilia, Massive transfusion

3 General approach: Stop the bleeding Replace RBCs if needed Correct coagulopathy Blood products (Plts, FFP, cryo) Clotting factors (VII, VIII, IX, PCC) Reversal agents (Vit K, Protamine)

4 Hemostasis: opposing forces Pro-thrombotic Clotting factors, platelets Anti-thrombotic Protein C, S, Antithrombin, Plasmin

5 Hemostasis Injury Primary: Platelet plug Activated, sticky, GP IIb/IIIa receptors Secondary: Clot Clotting factors, fibrin cement

6 Clotting cascade Intrinsic pathway XII, XI, etc Extrinsic pathway VII Factor X Factor II (Prothrombin--Thrombin) Factor I (Fibrinogen--Fibrin)

7 Anti-thrombotics: Anti-platelet (# or fxn) ASA, Clopidogrel, IIb/IIIa inhibitors Disease (ITP, EtOH, Cancer, CKD, DIC) Anti-coagulants Coumadin, Heparin, new agents Fibrinolytics Disease (EtOH, liver ds, dilution, DIC)

8 Pro-thrombotic tools: Platelets: Platelet transfusion ddavp Clotting factors: FFP, Cryo, Factors (VII, VIII, IX, PCC) Protamine Vit K Amino caproic acid

9 Reversing coagulopathy: What is the deficit? Platelet or clotting factors What is the clinical situation? Life-threatening hemorrhage Abnormal lab with no bleeding Why is patient anti-coagulated? Side effects / cost of correction?

10 1) Coumadin Inhibits vit K dependent synthesis II, VII, IX, X, Protein C,S Prolongs Prothrombin Time, INR Not PTT (Partial Thromboplastin Time) Anticoagulation DVT, PE Stroke prevention A-fib, Mechanical heart valve

11 The reason for anti-coagulation matters... Annual risk of thrombotic complication WITHOUT coumadin: Lone Afib 1% High risk Afib 12% Bjork-Shiley aortic valve 23% St. Jude mitral valve 22% Multiple prosthetic valves 91%

12 A little history ranchers bleeding cows Sweet clover / mold in silos 1940 s Karl Link dicoumarin Paid by Wisc Alumni Research Fund Named it Warfarin. Rat poison Dupont patented Coumadin

13 What if the INR is high? Am Coll Chest Physicians guidelines INR < 5, no bleeding Hold 1 dose, recheck, restart lower INR 5-9, no bleeding Hold 1-2, recheck, restart lower Optional: Vit K mg po

14 ACCP guidelines INR > 9, no bleeding Hold, give Vit K mg po, Recheck, restart lower when therapeutic Major bleeding (with elevated INR) Hold coumadin (Admit patient) Vitamin K 10 mg IV (q12h) FFP, PCC, FVII depending on situation

15 Example 1: 56 yo M, on coumadin for aortic valve, INR = 6, no bleeding, VS nl ACCP guidelines: Hold 1-2 doses Recheck INR 1-2 days, restart lower Optional: Vit K mg po

16 Example 2: 60 yo alcoholic F, GI bleeding, BP=80, Hgb=7.0, INR=6 ACCP guidelines: Hold coumadin Vitamin K 10 mg IV (q12h) FFP, PCC, FVII depending on situation (PRBC, supportive care)

17 FFP: Approximately 250 cc Room temp, clotting factors degrade in 1 week Frozen, shelf life = 1 year Dose = 10 cc/kg (2-3 units) Takes hours to normalize INR

18 Prothrombin complex concentrate (PCC) Factors II, VII, IX, X Hemophiliacs with inhibitors Super-therapeutic coumadin with life-threatening bleeding Thromboembolic complications US: Profilnine SD, Bebulin VH U/kg ($1,500-$3,000)

19 Recombinant, activated Factor 7 (rfviia) Binds tissue factor coagulation Clotting via extrinsic pathway

20 Concerns: Thromboembolic complications Stroke, MI, arterial thrombus Expense ($10,000)

21 Indications? FDA-approved: Hemophilia A/B with inhibitors Off-label: Intracranial hemorrhage Trauma / Massive transfusion

22 Coumadin alternatives Dabigatran (Pradaxa) Oct 2010 Direct thrombin (II) inhibitor Non-valvular A-fib Rivaroxaban (Xarelto) Nov 2011 Factor Xa inhibitor Apixaban (Eliquis) soon Factor Xa inhibitor

23 Dabigatran (Pradaxa) Expensive ($4 per 150mg, $8/day) Advantages: Predictable; No need to monitor INR Works now (no bridging with heparin) No p450 induction (few interactions)

24 Dabigatran (Pradaxa) vs Coumadin RE-LY trial, NEJM, K pts with non-valvular AF Stroke prevention (1.1% vs 1.7% / yr)* Major bleeding (3.1% vs 3.4%) Lower rate of ICH (.38% vs.1%)* Mortality (3.6% vs 4.1%)

25 Apixaban (Eliquis) vs Coumadin ARISTOTLE trial, NEJM, K pts with AF + other risk factor Stroke prevention (1.3% vs 1.6% / yr)* Major bleeding (2.1% vs 3%)* Lower rate of ICH (.24% vs.47%)* Mortality (3.5% vs 3.9%)*

26 Reversal of coumadin alternatives? No specific reversal FFP, PCC (?) Very little prothrombin (II) Factor X easier to replace Inhibited if drug still present Dialysis?

27 2) Intracerebral Hemorrhage AHA Guideline (2010): Class I,II,III (recommended, not) Level of Evidence A,B,C Correct INR with Vit K, FFP (I,C) Consider PCC (IIa,B) Not rfviia (III,A) Replace Platelets if low (I,C) Replace Plts if on anti-plt drug (IIb,B)

28 ICH and rfviia: Mayer, NEJM, 2005 (phase 2 study): 399 pts, randomized to rfviia or placebo Primary outcome measure: % increase in ICH size at 24 hrs. rfviia pts had less increase in ICH: 14% vs 29% Lower 90d mortality: 18% vs 29% But more major thromboembolic events: 7% vs 2%

29 ICH and rfviia: Mayer, NEJM, 2008 (Phase 3): 841 pts % increase in ICH: 26% placebo; 18%, 11% rfviia groups 90d mortality: 19% placebo; 18% and 21% for rfviia Combined, death or severe disability: 24% placebo; 26% and 29% rfviia

30 rfviia and Head Trauma? Narayan, Neurosurg, 2008: PRDBPCT, Traumatic ICH 97 patients, 38 hospitals Placebo (36) vs 5 doses rfviia (61) No diff in mortality (11% vs 11%) Trends toward less hematoma expansion but more DVTs

31 3) Heparin Binds and increases action of Antithrombin III Unfractionated Half life 60 mins LMWH Half life 4-6 hours

32 Too much heparin? Bleeding? Where / how much? 1) Turn it off 2) Protamine sulfate Binds heparin (complex is inactive) 1 mg per 100 U heparin Less effective for LMWH 1 mg per 1 mg

33 4) Platelets Bleeding? Where / how much? Problem: Number, function, or both? 1) Stop anti-platelet meds 2) Platelet transfusion 3) ddavp

34 Anti-platelet agents Aspirin Irreversible inhibitor of COX Decreased synth of Thomboxane A2 Clopidogrel Inhibits ADP receptor on Plts Decreased platelet aggregation IIb/IIIa inhibitors Block platelet aggregation

35 Platelet transfusion: Main treatment for anti-platelet drugs Random donor Plt unit = 25-50cc Room temp, 5 days Increase Plt count by 5-8K Typical dose: 6-10 units

36 Apheresis platelet unit Collected from one donor Equal to about 6 random donor units Increases Platelet count by 30-50K Exposure to only one donor Anti-platelet antibodies

37 Indications for Platelets Plts < 50K, with active bleeding Massive transfusion Plts < 10K If due to underproduction Serious bleeding in pts with druginduced platelet dysfunction

38 ddavp (desmopressin) Synthetic vasopressin, ADH IV, oral, nasal Increases vwf Protein critical in platelet aggregation Mostly used for central DI, vwds Uremia,? Adjunct for Anti-platelet drugs 0.3 mcg/kg IV over mins

39 5) Fibrinolytics Major bleeding after TPA 1) Stop TPA infusion 2) Preserve Fibrin Cryoprecipitate Amino caproic acid (Amicar) Tranexamic acid 3) Reverse other anti-thrombotics Vit K, Protamine, Platelets, etc

40 Cryoprecipitate: One unit from one donor (25 cc) Rich in Fibrinogen, VIII, vwf Major use: Fibrinogen depletion (DIC) in ICU

41 Amino caproic acid (Amicar) Lysine derivative, inhibits Plasmin Post op, hyphema, abruption Fibrinolysis gone bad 4-5 g IV or po, then 1 g/hr x 8 hrs

42 Tranexamic acid Lysine derivative, inhibits Plasmin 8x more activity than EACA Cardiac, vascular, ortho surgery Fibrinolysis gone bad 10 mg/kg IV

43 6) Hemophilia A (VIII deficiency), B (IX) X-linked recessive Extremely rare in females Jews recognized in 2 nd century A.D. Exemption from circumcision if 2 older brothers had bled to death after circumcision

44 Royal disease Queen Victoria of England (1800s) Carrier, 9 kids One son with ds, 2 daughter carriers Married into Russian, German, Spanish royal families

45 Treatment 1950 s: whole blood, animal plasma Most died before age s: cryo, factor concentrates 1980 s: hepatitis and HIV Half the hemophiliacs HIV positive 1990 s: highly purified, recombinant

46 Factor 8, 9 concentrate: Hemophilia A (VIII), B (IX) Heat treated, purified concentrate Recombinant

47 Dose calculation: Moderate bleed: 50% activity Severe: 100%, admit, repeat Plasma = 50 cc/kg 70 kg x 50 cc/kg = 3500 u (100%) Factor 9: double it Twice the volume of distribution

48 Example: 20 yo Hemo A: shoulder pain Dx: Hemarthrosis Moderate bleed, target 50% Factor VIII No tests 70 kg x 50 cc/kg x 50% = 1750 units (Round up) Sling, analgesics, close follow up

49 7) Massive transfusion Definition: Entire blood volume in 24 hrs (75 cc/kg, 5L, 10 units PRBC) 5 units in 3 hrs + ongoing hemorrhage Problems: Coagulopathy, DIC Hypothermia Acidosis Hypocalcemia (citrate toxicity)

50 Coagulopathy: Multi-factorial Dilution Hypothermia, acidosis 2 approaches: 1) treat problems as they arise 2) treat prophylactically (Protocol) 5 PRBC / 5 U FFP / 1 apheresis Plts Approximates Whole blood No randomized trials

51 Ho, Can J Surg, 2005: Mathematical model Ongoing loss, various ratios of transfxn Assumptions: 30% blood loss, IVF, 2 U PRBC Clotting factors already 50% Only way to maintain or catch up is 1:1 or higher (more FFP)

52 n Vary PRBC:FFP 3:1, 2:1, 1:1

53 Ho, Can J Surg, 2005 (cont): n Only way to maintain or catch up is 1:1 or higher (more FFP)

54 Borgman, J Trauma, 2007: Retro, 246 pts, > 10 U PRBC Higher FFP:PRBC, higher survival Low ratio (1:8) Survival 35% High ratio (1:1.4) Survival 81% Supports 1:1 massive transfusion

55 Holcomb, Ann Surg, 2008: Retro, 466 massive transfusion pts High FFP:PRBC ratio (>1:2) vs low 30 day survival: 60% vs 40% Same effect with Plt:PRBC ratio Recommended 1:1:1

56 Massive Transfusion Pack 5 U PRBC (O-negative) 5 U FFP (AB, pre-thawed) 1 U Apheresis Platelets

57 Summary Indications and agents used for reversal of coagulopathy Clinical situations Supratherapeutic coumadin ICH, Heparin, Thrombocytopenia Hemophilia, Massive transfusion

58 Thank you! And don t worry... All bleeding eventually stops!