Coagulation and liver disease - c.ymcdn.comc.ymcdn.com/sites/okosteo.site-ym.com/resource/resmgr/115lectures/... · Coagulation and liver disease ... •Basic concepts in hemostasis

4/24/2015

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Coagulation and liver disease

Germán F. Barbosa-Hernandez M.D.

Oklahoma Osteopathic Association’s Annual Convention

Financial Disclosures

• No financial disclosures to declare

Objectives

• Basic concepts in hemostasis

• Changes in hemostasis with liver cirrhosis

• Review of coagulation tests and their applicability

• New products available

• Practical clinical recommendations

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Clinical Problems

• Hepatitis C and B

• Alcoholic cirrhosis

• PBC, PSC, HCC

• NASH

• Acute liver failure

• Paracentesis

• Esophageal varices

• TIPS

• Dental extractions

• Liver transplant

• Elevated ICP

• Portal vein, Hepatic artery thrombosis

• DVT and PE

Hemostasis

• Complex apparatus

• Not entirely understood

• Interaction of multiple organs

• Regional and systemic variations

Hemostasis – classic view

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Hemostasis – Cell Based Model

• Step 1 Primary Hemostasis

– Initial plug of vascular breach

– Activated platelet

– Thrombin burst

– Initial critical step


• Step 2 Coagulation

– Intrinsic and extrinsic pathways

– Fibrin mesh construction

– Clot fortification


• Step 3 Fibrinolysis– Controls propagation

of fibrin mesh– Once vascular repair

is complete, breaks down fibrin mesh

Northup, P. G. and S. H. Caldwell (2013). "Coagulation in liver disease: a guide for the clinician." ClinGastroenterol Hepatol 11(9): 1064-1074.

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Hemostasis

Pro-Coagulation

• Liver Dependent• Coagulation Factors

• Clearance activated tPa, α2-antiplasmin.

• Liver Independent• Tissue Factor

• Factor VIII

• Factor vW

• Platelets number and function

Anti-Coagulation

• Liver Dependent• Protein C, S, AT III,

clearance of activated Factors. (Modulators)

• Plasminogen(Fibrinolysis)

• Liver Independent• tPa (Fibrinolysis)

• Tissue factor path inhibitor (Modulator)

Hemostasis – Balanced system

Changes with Liver Disease

• Pro-Coagulation changes

• Anti-coagulation changes

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• Primary Hemostasis

– Endothelium:

• Poor flow

• Chronic inflammation

• Decrease in thrombomodulin

Northup, P. G., et al. (2008). "Hypercoagulation and thrombophilia in liver disease." J Thromb Haemost 6(1): 2-9



– Platelet adhesion

• Increase in platelet adhesion molecules (vWF)

• Splenic sequestration and platelet dysfunction

Wannhoff, A., et al. (2014). "Effects of increased von Willebrand factor levels on primary hemostasis in thrombocytopenic patients with liver cirrhosis." PLoS One 9(11): e112583.



– Platelet activation and thrombin burst:

• Normal production in plasma from ESLD patients, when assay includes thrombomodulin

• Normalized inVitrowhen platelets 55-100k

Tripodi, A., et al. (2006). "Thrombin generation in patients with cirrhosis: the role of platelets." Hepatology 44(2): 440-445.

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• Fibrin mesh:

– Low anti-coagulantionfactors

• II, V, VII, IX, X, and XI

– Low protein C, S, AT3,

– Low clearance of activated factors

– Low coagulation factors

– Abnormal polymerization: Excess abnormal fibrinogen and low F-XIII


• Fibrinolysis:

– Decrease clearance activated tPa, α2-antiplasmin.

– Low levels of plasminogen


• The rebalanced state

– Liver disease is at the tipping point due to less reserve

– Although compensatory mechanisms are active, the capacity to adjust to insults to the system is diminished, and small perturbation can overcome compensatory mechanisms

Lisman, T., et al. (2010). "Hemostasis and thrombosis in patients with liver disease: the ups and downs." J Hepatol 53(2): 362-371.

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Changes with Liver Disease –Re-balanced System

Liver Transplant Case

• 59yo M admitted to the hospital for HE, N/V, diarrhea, hyperbilli and anemia

• s/p OLT for cirrhosis secondary to HCV type 1

• Post OLT has been c/b recurrent HCV in the form of fibrosising cholestatic HCV but no rejection. On triple therapy, could not be completed due to side effects.

• MELD Score: 38

• PMH: DM2, He also had an episode of SVT treated with adenosine.

Liver Transplant Case –Pre-Anhepatic

Platelet hypocoagulability

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Liver Transplant Case - Pre-Anhepatic

Liver Transplant Case - Pre-Anhepatic

Liver Transplant Case –Anhepatic phase

• Consumption Coagulopathy

– Constant activation of intrinsic pathway

– Deficiency of AT III

• Progressively increased fibrinolysis

– Rapid rise in tPa levels

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Liver Transplant Case –Anhepatic phase

Secondary fibrinolysis secondary to hypercoagulable state, normal reaction time, platelet hypocoagulability

Liver Transplant Case – Reperfusion

• Pro- coagulation– Post-reperfusion syndrome: sudden and

temporary activation of the coagulation system

– Low flow state

• Anti-coagulation– Consumed AT III

• Fibrinolysis – Most pronounced immediately before and after

reperfusion, recovery is fast


Secondary fibrinolysis secondary to hypercoagulable state, normal reaction time, platelet hypocoagulability

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Liver Transplant Case – Cardiac Arrest

Liver Transplant Case –PostOperative Course

• Brain Function: AOx2, delirious and violent, requires help for ADL, weak and deconditioned, dysphagia.

• New Liver Function: No new issues. Tolerating immunosuppression.

• Kidney Function: Estimated GFR: >60, however AKI requiring HD on 09/25.

• Heart Function: NSR, No new findings on echo.

Liver Transplant Case –PostOperative Course

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Bleeding and Clotting Risk?

• Clinical evaluation

• Laboratory tests

• Nature of the procedure

• Institutional and practice guidelines

Laboratory Tests

• Things you usually check

– Low platelet count

– High INR (low 2,5,7,9,10)

– Low fibrinogen

– Normal PTT

• Things you usually don’t check

– High vWF and VIIIa

– Low levels of protein C and antithrombin III

– Elevated levels of plasminogen

Laboratory Tests

• Not widely used:– TEG

– Sonorheometry

– PFA-100

– Anti-Xa assay

– Bedside whole-blood clotting times

• Experimental– Endogenous thrombin potential

– Euglobin lysis time

– Procoagulant micoparticles assays

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Laboratory Tests - INR

• INR is a poor predictor of bleeding• 121 ESLD patients• Thrombocytopenia

– <150k in 84%– <75k in 51%

• 50 of these underwent procedures– 10 (20%) bled– All had platelets <75k

• INR >1.5 was not associated w/ bleeding• 2U of FFP pre-procedure is of little benefit for INR 1.5 – 1.7

Giannini, E. G., et al. (2010). "Incidence of bleeding following invasive procedures in patients with thrombocytopenia and advanced liver disease." Clin Gastroenterol Hepatol 8(10): 899-902; quiz e109


• Numerous studies affirming lack of utility– Percutaneous, laparoscopic and open liver biopsy,

renal biopsy

– Paracentesis

– Colonoscopy and polypectomy

– PEG

– Dental extractions

– Bronchoscopy

– Arteriography and angioplasty


• Problems with INR

– Designed for warfarin therapy

– Variability across different labs

– Better indicator of progression of disease (protein synthesis), not risk of bleeding

Trotter, J. F., et al. (2004). "Specific laboratory methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation." Liver Transpl 10(8): 995-1000.

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Laboratory Tests – Fibrinogen

• Low levels of fibrinogen– Common in stable non-bleeding patients

– Low grade DIC: • Not a common feature of stable liver cirrhosis

• Laboratory findings suggestive of DIC are predominantly a reflection of decreased hepatic clearance of activation products.

– Acute phase reactant

Ben-Ari, Z., et al. (1999). "Disseminated intravascular coagulation in liver cirrhosis: fact or fiction?" Am J Gastroenterol 94(10): 2977-2982

Laboratory Tests - TEG

• Advantages

– Time tested for quick diagnosis and guidance of coagulation issues

– Can detect hypercoagulability, however it can miss some patients

– Can detect primary and secondary fibrinolysis

– Can detect platelet function inhibition

Laboratory Tests - TEG

• Disadvantages

– Rotational shear not natural

– Whole blood test, fast turnaround of samples

– Might miss some hyper-coagulable patients

– Not validated outside of the OR or acute settings

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Laboratory Tests – Whole blood clotting times

• Advantages– Low cost, supplies universally available, red top tube

– Tip gently… no running liquid…• Good clot at 20min… mild or no coagulopathy

• Clot at <10 min… hyper-coagulable test – In combination with abnormal hypo-coagulable lab values. ej.

INR>3

• Disadvantages– Time consuming, unable to differentiate between

platelet and factor deficiency

– Difficult to diagnose fibrinolysis

Laboratory Tests – PFA-100

• Not calibrated for thrombocytopenia

• Not studied extensively in liver disease

Laboratory Tests - Experimental

• Sonorheometry

–Advantages

• Same as TEG

• More accurate detection of patients at risk for clotting events and effectiveness of DVT prophylaxis

• More user friendly

–Disadvantages

• Experimental

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Laboratory Tests - Experimental

• Endogenous thrombin potential• Euglobin lysis time• Microparticles

– Platelet derived– Tend to vary with severity of disease, More prevalent in

Child C– Tend to be higher by flow cytometry in hypercoagulable

patients

Owens, A. P., 3rd and N. Mackman (2011). "Microparticles in hemostasis and thrombosis." Circ Res 108(10): 1284-1297

Correction of Coagulation

• FFP• Cryoprecipitate• Platelet• Aminocaproic acid• LMWH• Warfarin• Desmopressin• PCC• FVIIa• Eltrombopag

Correction of Coagulation - FFP

• Prepared from a single unit of blood

• Contains all of the coagulation proteins

• Through storage and thawing processes, 40% degradation of coagulation factors

• INR = 1.3

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Correction of Coagulation - FFP

• Limitations of FFP to correct INR– Half life of FVII in plasma is 5h

• Bottleneck of the system

– Correction of INR from 3.0 to 1.5 would require 2000ml (10u FFP). • Degradation of FVII of the first unit would likely be present

by the time the 5-6th unit is being administered.

– “only 50% of patients with an INR of 1.7 showed a significant change in INR with FFP transfusion”.

Holland, L. L. and J. P. Brooks (2006). "Toward rational fresh frozen plasma transfusion: The effect of plasma transfusion on coagulation test results." Am J Clin Pathol 126(1): 133-139.

Correction of Coagulation - Cryo

• Cryoprecipitate good option for the complications with RBC transfusion:

– Low fibrinogen, vWF, FXIII, Protein C

• Byproduct from thawing FFP

• Contains concentrated factor VIII, fibrinogen, XIII, vWF and others

Correction of Coagulation - LMWH

• Higher potency in cirrhotic – Increases with severity despite having low levels of

Antithrombin III – More severe, more frail balance, same dose increased effect

• Anti Xa not useful. – Experimental use of Endogenous thrombin potential

Senzolo, M., et al. (2012). "Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis." J Thromb Haemost 10(9): 1823-1829.

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• Aminocaproic acid:

– Prophylactic low dose 5 min after reperfusion

• rFVIIa:

– Fulminant failure + need for bolt

– Cannot be recommended for general use

• Warfarin

– Narrow therapeutic regimen

– High rate of complications


• PCC: Factors II, VII, IX and X, as well as protein C and S

– Currently being studied as a supplement for liver transplants, trauma, cardiac and brain surgery

– Quick reversal of warfarin, and newer oral anticoagulants

• FEIBA: Factor eight inhibitor bypass activity: proenzymes of the prothrombin complex factors, prothrombin, FVII, FIX and FX,


• Eltrombopag reduced the need for platelet transfusions in patients with chronic liver disease who were undergoing elective invasive procedures, but it was associated with an increased incidence of portal-vein thrombosis, as compared with placebo

Afdhal, N. H., et al. (2012). "Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia." N Engl J Med 367(8): 716-724.

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Clinical Recommendations


• 60yo F pre-transplant evaluation

• ESLD, CKD/dialysis

• Full mouth extraction

• MELD 20, s/p TIPS and s/p Esophageal varices banding no bleeding

• Htc 27, INR 2.1, and platelets 43k

• Delayed to get platelets and FFP through a mediport

• s/p 4x FFP and 4x Plt.

• Now pushed till 3am…

• EBL 100cc… no complications, normal TEG.

Clinical Recommendations –Prognosis

• SBP mortality / episode 40%

• GI Bleed: 30% mortality with each episode

• Hepatorenal syndrome, type I: median survival 2 weeks

• Versus survival with LT: 80% at 3yrs

Arora, G. and E. B. Keeffe (2008). "Management of chronic liver failure until liver transplantation." Med Clin North Am 92(4): 839-860, ix

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Clinical Recommendations –Prognosis

• With development of ascites: 50% two year survival

• Ascites refractory of diuretics: 25% one year survival

Fernandez, J., et al. (2002). "Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis." Hepatology35(1): 140-148.

Clinical Recommendations - Decision

• MELD <11: proceed with elective surgery

• MELD 12-19 or Child B: complete transplant work-up, “these patients should preferably have surgery at an institution with liver transplant center”

• MELD >20 or Child C: postpone elective surgery until after transplant

Teh, S. H., et al. (2007). "Risk factors for mortality after surgery in patients with cirrhosis." Gastroenterology 132(4): 1261-1269.


• Acute liver failure

– Despite profound elevation in INR, minimal global effects on hemostasis

– Prophylactic correction not recommended except if active bleeding

– High risk procedures

• Single rFVIIa dose (40μg/Kg)

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Clinical Recommendations –Bleeding Risk

• There are no good measures of bleeding risk before invasive procedures

• Decision to proceed with elective or semi-elective procedures– Not solely on INR and platelet count

– Severity of comorbidities

– Urgency of procedures

– Access to mechanical hemostatic maneuvers

– Ability to detect bleeding early


• Pre-procedure Prophylaxis– For truly elective procedures, delay during acute

events that might upset the rebalanced state• Acute infection, severe acute alcoholic hepatitis,

uremia.

– For dental extractions, FFP vs nasal desmopressin• As effective and more convenient

– Platelet count >50-60k probably more appropriate for prophylaxis than INR alone• No added benefit when platelets >100k


• Pre-procedure Prophylaxis

– Protocol transfusions to correct INR are not helpful and are possibly harmful

– rVIIa has not been shown to be beneficial in preventing bleeding complications

• Acute liver failure patient requiring ICP monitoring (40mcg/kg)

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• Pre-procedure Prophylaxis

– Society of interventional Radiology:

• Correction of INR>2.0 with FFP for moderate to high-risk procedures


• Active Bleeding

– Transfuse to Hb>7

• Avoid overtransfusion injuries

– Transfuse to Platelets >50-100

• Will use 2-3 units in most decompensated cirrhotics

– Fibrinogen >100-150

– Correct INR if bleeding persists

• About 10cc/kg of FFP

• Large volume FFP might make pHTN worst


• Active Bleeding

– With microvascular bleeding assess for hyperfibrinolysis (TEG)

– rVIIa in special rare cases with thrombosis caveat

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• Esophageal Variceal Bleeding – Most common bleeding event in ESLD

– Risk factors are hemodynamic and mechanic• pHTN gradient, varix size, appearance and severity of

ESLD

• Not necessarily coagulopathy

– No specific recommendations for correction of anticoagulation before banding• Non-selective B-blocker for primary bleeding

prophylaxis

Clinical Recommendations –Clotting Risk

• There are no good measures of clotting risk • Decreased protein C

– Levels similar to those with congenital deficiency– Worsens with severity of cirrhosis

• Increased FVIII – FVIII: Protein C ratio: became more unfavorable

toward coagulation with increasing child scores.

• Resistance to Thrombomodulin

Tripodi, A., et al. (2009). "An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis." Gastroenterology 137(6): 2105-2111.


• Deep Venous Thrombosis (DVT)– Platelet count, INR and MELD: poor predictors of DVT

and PE– Low albumin level <2.8g/dL, rough indicator– Consider medical prophylaxis in inpatients

• Do not assume hospitalized patient is auto-anticoagulated

– Treatment should follow the same protocol and similar doses as PE

Northup, P. G., et al. (2008). "Hypercoagulation and thrombophilia in liver disease." J Thromb Haemost 6(1): 2-9

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• Portal Vein Thrombosis (PVT)

– PVT is a frequent (10–20%) complication of liver cirrhosis

• Highest risk, is malignancy, 6 month screening in all HCC patients

• No evidence to support chronic anticoagulant therapy in asymptomatic patients– Bleeding risk is substantial, benefit of removing an

asymptomatic PVT in cirrhosis is highly uncertain.


• Portal Vein Thrombosis (PVT)– May worsen its clinical course by favoring

gastrointestinal bleeding and mesenteric infarction.• Treatment (LWMH) only in life-threatening thrombosis of the

extra-hepatic portal district (acute or subacute, superior mesenteric and splenic veins)

• Anticoagulation should be considered in patients with occlusive PVT awaiting transplantation

• Esophageal varices must be resolved before therapy

Fimognari, F. L. and F. Violi (2008). "Portal vein thrombosis in liver cirrhosis." Intern Emerg Med 3(3): 213-218.


• Post-transplant hepatic artery thrombosis

– Devastating injury: Loss of graft

– Risk factors:

• Graft/surgery related: lengthy benchwork present and reperfusion time.

• Recipient related: male, increase cold ischemia time, pre-existing DVT, albumin <2.5

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Clinical Recommendations –IntraOperative Management

• Restrictive fluid regimen decreases portal venous pressure

• Phenylephrine helps to maintain arterial BP without increasing portal venous pressure

• Suggest surgical alternatives

– Laparoscopic verus open

Klinck, J. R. and L. T. Pan (2012). "Lessons from liver transplantation." Anaesthesia 67(10): 1067-1071.

Clinical Recommendations -IntraOperative Management

• Aggressive infection prevention measures

– Sterile techniques

– Remove / avoid central access

– Discontinue foley ASAP

• Maintain renal function / avoid nephrotoxic agents

Thank You

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References

1. Afdhal, N.H., et al., Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med, 2012. 367(8): p. 716-24.

2. Arora, G. and E.B. Keeffe, Management of chronic liver failure until liver transplantation. Med Clin North Am, 2008. 92(4): p. 839-60, ix.

3. Ben-Ari, Z., et al., Disseminated intravascular coagulation in liver cirrhosis: fact or fiction? Am J Gastroenterol, 1999. 94(10): p. 2977-82.

4. Fernandez, J., et al., Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology, 2002. 35(1): p. 140-8.

5. Fimognari, F.L. and F. Violi, Portal vein thrombosis in liver cirrhosis. Intern Emerg Med, 2008. 3(3): p. 213-8.

6. Giannini, E.G., et al., Incidence of bleeding following invasive procedures in patients with thrombocytopenia and advanced liver disease. Clin Gastroenterol Hepatol, 2010. 8(10): p. 899-902; quiz e109.

7. Holland, L.L. and J.P. Brooks, Toward rational fresh frozen plasma transfusion: The effect of plasma transfusion on coagulation test results. Am J Clin Pathol, 2006. 126(1): p. 133-9.

8. Lisman, T., et al., Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol, 2010. 53(2): p. 362-71.

9. Northup, P.G., et al., Hypercoagulation and thrombophilia in liver disease. J Thromb Haemost, 2008. 6(1): p. 2-9.

10. Northup, P.G. and S.H. Caldwell, Coagulation in liver disease: a guide for the clinician. ClinGastroenterol Hepatol, 2013. 11(9): p. 1064-74.

References

11. Owens, A.P., 3rd and N. Mackman, Microparticles in hemostasis and thrombosis. Circ Res, 2011. 108(10): p. 1284-97.

12. Senzolo, M., et al., Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis. J Thromb Haemost, 2012. 10(9): p. 1823-9.

13. Tripodi, A., et al., Thrombin generation in plasma from patients with cirrhosis supplemented with normal plasma: considerations on the efficacy of treatment with fresh-frozen plasma. Intern Emerg Med, 2012. 7(2): p. 139-44.

14. Wannhoff, A., et al., Effects of increased von Willebrand factor levels on primary hemostasis in thrombocytopenic patients with liver cirrhosis. PLoS One, 2014. 9(11): p. e112583.

15. Teh, S.H., et al., Risk factors for mortality after surgery in patients with cirrhosis.Gastroenterology, 2007. 132(4): p. 1261-9.

16. Trotter, J.F., et al., Specific laboratory methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation. Liver Transpl, 2004. 10(8): p. 995-1000.

17. Tripodi, A., et al., An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology, 2009. 137(6): p. 2105-11.

18. Tripodi, A., et al., Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology, 2006. 44(2): p. 440-5.

19. Klinck, J.R. and L.T. Pan, Lessons from liver transplantation. Anaesthesia, 2012. 67(10): p. 1067-71.

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Coagulation and liver disease - c.ymcdn.comc.ymcdn.com/sites/okosteo.site-ym.com/resource/resmgr/115lectures/... · Coagulation and liver disease ... •Basic concepts in hemostasis