the power to congeal is the power to heal

MSHP Annual Meeting 2018 #MASHP18

Blood Factor Products 1

The Power to Congeal is the Power to HealBlood Factor Products

Monica V. Mahoney, PharmD, BCPS AQ-ID

Brian Spoelhof, PharmD, BCPS

Clinical Specialist Lead – Medicine

Boston Medical Center

mmPharmD

Conflict of Interest

• The presenter has no actual or potential conflicts of interest to disclose

• This presentation discussed non-FDA approved uses medications



Learning Objectives

1. List the components of the coagulation cascade

2. Describe the effect of pharmaceutical products on coagulation

3. Develop a plan utilizing blood factors in a patient with coagulopathy

A Battle of the Ages

Coagulation Hemorrhage



Understanding Hemostasis and Coagulation: A Brief History

• Thrombus• Term in ancient Greece, Rome Byzantine Empires

• Congealed blood, breast milk, kidney stones

• 4th- 5th Century B.C.E. • Hippocrates: Four Humors, “Solid blood”

• Plato: “fibers” of blood that progressive thicken

• Aristotle: Fibers are from the earth

• 5th Century C.E.• Aetius of Amida: Early clot removal

Tsoucalas, G. et al (2017). Current Pharmaceutical Design, 23(9), 1275–1278.

Modern Day Understanding

• First proposed 1964

• Classical coagulation cascade• Extrinsic

• Extravascular elements

• Tissue Factor

• Intrinsic• Intravascular elements

• (-) charge, non-physiologic

• Common Pathway• Final steps of coagulation

Bunn, H. F. et al (2017). Overview of Hemostasis Pathophysiology of Blood Disorders, 2e. Bakeer, M. S. (2016). Journal of Clinical & Experimental Cardiology, 7(10).



Factors Simplified: ExtrinsicIntrinsic Extrinsic

Common

Xa

IIa

Fibrinogen → Fibrin

TF:VIIa

Tissue Damage

Adapted From: Bunn, H. F. et al (2017). Overview of Hemostasis Pathophysiology of Blood Disorders, 2e.

Factors Simplified: IntrinsicIntrinsic Extrinsic

Common

Xa

IIa


VIIIa:IXa

IXa

VIIIa




Factors Simplified: A Unified ApproachIntrinsic Extrinsic

Common

Xa

IIa


VIIIa:IXa

IXa

TF:VIIa

Tissue Damage

VIIIa

XIa


Va

VIIIa

Va:Xa

Homeostasis of Hemostasis

• Antithrombin inactivates IIa, IXa, and Xa

• Proteins C and S inactivate Va and VIIIa

• Tissue plasminogen activator degrades fibrin clots



Labs

Defects Measured PT aPTT (TT)

Factor V, X, prothrombin↑ ↑ ↔

Factor VII ↑ ↔ ↔

Factors XII, XI, IX, or VIII↔ ↑ ↔

Fibrinogen or thrombin

inhibitor↑ ↑ ↑

Bunn, H. F. et al (2017). Overview of Hemostasis Pathophysiology of Blood Disorders, 2e.

Prothrombin Time (PT), Partial Thromboplastin Time (PTT) Thrombin Time (TT)

Active Learning Question

Complete the following statements:

1) Factor IIa, also known as __________, is an important part of the __________ pathway that converts __________ to fibrin.

2) When __________is released by damaged tissue it activates the ___________ pathway of coagulation

1) Factor VIIIa and factor IXa form a complex to active factor ____ which the first in turn activates __________ to _________.




Complete the following statements:

1) Factor IIa, also known as thrombin, is an important part of the commonpathway that converts fibrinogen to fibrin.

2) When tissue factor is released by damaged tissue it activates the extrinsic pathway of coagulation

3) Factor VIIIa and factor IXa form a complex to active factor X which the first in turn activates prothrombin to thrombin.

Blood Factors as Pharmaceutical Agents

• Currently there are 40 approved blood factor approved• Single Factors

• Activated Factor VII, Recombinant• Factor VIII, Human + Recombinant• Factor IX, Human + Recombinant• Von Willebrand's Factor

• Multiple factors• 3 and 4 Factor Prothrombin Complex Concentrate (PCC)• Activated PCC• Factor VIII and von Willebrand’s Factor

• Blood components• Fresh Frozen Plasma• Cryoprecipitate



Blood Factor “Controversies” in Hospitals

• Ownership of blood factors• Blood bank vs pharmacy

• Blood factor preparation• Nursing vs pharmacy vs blood bank

• Acquisition• Consignment vs purchasing

• Dosing• Which dose to use?

A Comparison of Pharmacy vs Blood Bank

• Single center, Quality Improvement Project evaluating pharmacy management of products

• 22 patients in the Pharmacy Group vs 43 patients in the Blood Bank Group

• Results:• Minutes to Administration: 43 [32–65] vs 62 [39–110], p = 0.032

• Revisable anticoagulant: 91% vs 86%

• IV Vitamin K use: 95% vs 77%

• INR above 1.4: 95% vs 79%

• Pt with major bleed: 95% vs 84%

• 33% closer to the appropriate calculated dose

Langstraat, E. at al. (2017).. American Journal of Health-System Pharmacy , 74(17 Supplement 3), S61–S66.



Disorders of Hemostasis

Inherited• Coagulation Factor Deficiencies

• Hemophilia A and B

• Von Willebrand Disease

• Platelet Disorders

• Fibrinolytic Disorders

Acquired• Drug Induced

• Disseminated Intravascular Coagulation

• Liver Disease

Bunn, H. F. et al (2017). Overview of Hemostasis Pathophysiology of Blood Disorders, 2e.

History Hemophilia

• 2nd - 12th Century• Records exempting a child from

circumcision

• Exemptions for all siblings with common mother

• 10th Century• Males of one village dying of

hemorrhage

• 18th Century• First medically detailed cases

• Hemophilia term coined 1828

Ingram, G. I. (1976). Journal of Clinical Pathology, 29(6), 469–479.



Hemophilia Overview

• Hemophilia A• Factor VIII Deficiency

• X-link recessive

• 1 in 5,000 male births

• Hemophilia B• Factor IX Deficiency

• X-link recessive

• 1 in 30,000 male births

Escobar, M. A. et al (2015) Williams Hematology, 9e. New York, NY: McGraw-Hill Education.

Hemophilia Classification

Classification Factor VIII Level Clinical Features

Severe ≤1% of normal (<1 IU/dL)

Spontaneous hemorrhage from early infancy

Frequent spontaneous hemarthroses and other

hemorrhages, requiring clotting factor replacement

Moderate 1–5% of normal (1–5 IU/dL)

Hemorrhage secondary to trauma or surgery

Occasional spontaneous hemarthroses

Mild 6–40% of normal (6–40 IU/dL)

Hemorrhage secondary to trauma or surgery

Rare spontaneous hemorrhage

Srivastava, A. et al (2013). Haemophilia : The Official Journal of the World Federation of Hemophilia, 19(1), e1-47.



Hemophilia Treatment

Factor replacement is cornerstone of therapy

• Episodic Treatment• Acute treatment for clinically relevant bleeding

• Prophylaxis• Primary: Absence of joint disease, before the age of 3, and before the second major

joint bleed

• Secondary: Absence of joint disease and after the second major joint bleed

• Tertiary: After the presence of joint disease

• Intermittent Prophylaxis• Short term prophylaxis prior to surgery, or repeated bleeding


Prophylaxis

• For patients with severe disease to reduce bleeding episodes and joint disease

• Maintain factor levels > 1 IU/dL

• Two common prophylactic strategies:• 25 – 40 IU/kg dose 2 – 3 times weekly

• 15 – 30 IU/kg dose 2 – 3 times weekly

• Cochrane Systematic review comparing on-demand vs prophylaxis• Reduces joint complications in children

• Insufficient evidence prophylaxis reduces bleeding

Iorio, A . Etal (2011). The Cochrane Database of Systematic Reviews, (9)Srivastava, A. et al (2013). Haemophilia : The Official Journal of the World Federation of Hemophilia, 19(1), e1-47.



Acute Treatment of Active Bleeding

Setting PhaseFVIII

(IU/dL)FIX

(IU/dL)Duration

(d)

CNS bleeding Initial 80 – 100 60 – 80 1 – 7

Maintenance 50 30 8 – 21

Deep laceration N/A 80 – 100 60 – 80 5 – 7

Major Surgery Pre-op 80 – 100 60 – 80

Post-op 60 – 80 40 – 60 1 – 3

40 – 60 30 – 50 4 – 6

30 – 50 20 – 40 7 – 14

Minor Surgery Pre-op 50 – 80 50 – 80

30 – 80 30 – 80 1 – 5

Factor VIII1 unit/kg = 2 unit/dL ↑Typically Q8H

Factor IX1 unit/kg = 1 unit/dL ↑Typically Q12H


Other Agents

Hemophilia A and B

• Fresh Frozen Plasma (FFP)• 1 mL of FFP = 1 unit of factor

activity• Use generally not recommended,

if avoidable

• Tranexamic acid• Most commonly used topically in

dental procedures• Not to be combined with activated

prothrombin complexes

Hemophilia A

• Cryoprecipitate• Contains FVIII, von Willebrand’s

factor, fibrinogen, FXIII

• 70 – 80 U FVIII

• Desmopressin• Dose of 0.3 mcg/kg can boost FVIII

level by 3 – 6 times

• Not all patients will respond




Complications of Drug Therapy

• Historically, high rates of infections through blood and blood factors infusion

• 50% HIV

• 44% HCV

• Cost

• Development of Inhibitors• Rapid development (20 – 50 days)

• Mostly in children• 30% Hemophilia A

• 5% Hemophilia B

Coppola, A et al (2010). Journal of Blood Medicine, 1, 183–195. National Hemophilia AssociationEvatt, B. L. (2006). Journal of Thrombosis and Haemostasis : JTH, 4(11), 2295–301.

Management of Factor Inhibitors

• Low Responding Inhibitors • Lower affinity for factor; less inhibition• Increase dose

• High Responding Inhibitors• Higher affinity for factor; more inhibition• FEIBA or rVIIa

• Immune Tolerance Induction• High dose, and continuous exposure• Concomitant immunosuppression

• Emicizumab• New agent approved 12/17• Monoclonal ab that binds IX and X

Coppola, A et al (2010). Journal of Blood Medicine, 1, 183–195.



Cost Impact In Hemophilia

• Factor VIII $1.8 – 2.2 per unit

• Factor IX $1.6 – 1.9 per unit

• 60 kg patient with hemophilia A• Prophylaxis: 30 units/kg factor VIII

three times per week• Over $500,000 per year

• Major Surgery• ~$100,000

Chen, S.-L. (2016). The American Journal of Managed Care, 22(5 Suppl), s126-33.

• Prophylactic vs on-demand• Short term, 1- 2 year study

• Annual cost $ 292K vs 185 K

• ~92% drug costs

• $ 3,500 lower non-drug costs

• Lower number of ED visits

• Cost-effectiveness analysis• Increase of 14.8 quality adjusted

life years (QALY)

• Similar cost per QALY $ 48,982 vs 48,990

Von Willebrand's Disease

• Von Willebrand Factor (vWF)• Large multimer protein with no catalytic properties

• Chaperone for factor VIII to prevent degradation

• Enables platelets to adhere to injured vasculature

• Release activate of V2 receptor

• Variability in severity and type of disease• Type 1: Reduction of circulating vWF and factor VIII to 15 – 60%

• Type 2a: Cannot form large multimers, unable to bind platelets

• Type 2b: Multimers too large, bind to platelets causing thrombocytopenia

• Type 3: Less then 5% circulating vWF, often mimics symptoms of Hemophilia A




A 75 kg 25 yo male with Hemophilia A presents s/p mechanical fall. CT of the head demonstrates a large right subdural hematoma with a 5 mm midline shift.

1) What factor is this patient deficient in?

2) What do you want to know before factor replacement?

3) Assuming the patient has an undetectable factor VIII level what initial dose do you give?

Goal: 100 units/dL

Increase: 100 units/dL

Weight Based Dose: 50 units/kg

Total Dose: 3,750 units

Emergency Hospitalizations for Adverse Drug Events in Older Americans• Primary Endpoint:

• Hospitalizations after an emergency department visit for an adverse event due to medications

• Patients 65 or older

• Top offending Medications (71.2%)• Oral hypoglycemics (10.7%)

• Oral antiplatelets (13.3%)

• Insulins (13.9%)

• Warfarin (33.3%)

N Engl J Med. 2011 Nov 24;365(21):2002-12



Ganetsky, M. (2015). Journal of Emergency Medicine, 49(5), 693–697.

A Trend Over Time

Anticoagulation Review

• Warfarin• Vitamin K dependent factors• II, VII, IX, X, Protein C + S

• Heparin• Inhibits II, X

• Low Molecular Weight Heparins• Inhibits X > II

• Factor Xa Inhibitors• Inhibit X

• Direct Thrombin Inhibitors• Inhibits II



Anticoagulant Reversal Agents

Anticoagulant Reversal Agents

Warfarin • Vitamin KAND• PCCOR• Fresh Frozen Plasma

Heparin + LMWH • Protamine

Factor Xa Inhibitors • PCCOR• activated PCC

Dabigatran • Idarucizumab

Other DTIs • No available reversal agents

Warfarin Reversal with Blood products

• rFVIIa vs 3 Factor PCC• Δ INR: 1.2 vs 1.5 (p =0.14)

• ≤ 1.5: 33.8% vs 23% p=0.001

4 Factor vs plasma

• 3 Factor PCC + rFVIIa vs 4 Factor PCC

• Post-INR: 0.8 versus 1.3 (p < .01)

• Higher thromboembolic complications and mortality

Chapman, S. A. et al (2014). World Journal of Emergency Surgery : WJES, 9, 27. Barton, C. et al. (2018). American Journal of Surgery. Goldstein, J. N . Et al (2015). Lancet (London, England), 385(9982), 2077–87.



Dosing of 4 Factor PCC in Warfarin Associated Bleeds• Traditional Dosing

• 2 – <4: 25 units/kg, max 2,500 units• 4 – 6: 35 units/kg, max 3,500 units• > 6: 50 units/kg, max 5,000 units

• A case for lower INRs in certain cases• The neurocritical care society recommends an INR < 1.4• Goal for several studies evaluating 4 Factor PCC

• Fixed Dosing of 4 Factor PCC• Typically between 500 and 1,500 units• Limited to small studies• Primary benefits are reduction in time to administration and cost avoidance

Frontera, J. A. et al(2016). Neurocritical Care, 24(1), 6–46.Kcentra® [package insert]. Kankabee, IL. CSL Behring LLC;2013Abdoellakhan, R. A. et al (2017). Neurocritical Care, 26(1), 64–69. Klein, L. et al (2015). The American Journal of Emergency Medicine, 33(9), 1213–8.

Direct Oral Anticoagulants Blood Product Reversal• Eerenberg and colleagues: 4 Factor PCC vs Placebo

• Double blind, placebo controlled, crossover study in healthy volunteers

• Dose of 50 units/kg• Rivaroxaban successfully reversed

• Dabigatran not reversed

• Marlu and colleagues: 4 Factor PCC vs FEIBA vs rFVIIa• Double blind, placebo controlled, crossover study in healthy volunteers

• Escalating doses• 4 Factor PCC: Reverse rivaroxaban

• FEIBA: Reverses both dabigatran and rivaroxaban

• rVIIa: May reverse dabigatran dabigatran

Circulation. 2011 Oct 4;124(14):1573-9. Epub 2011 Sep 6Eerenberg, E. S. et al. (2011) Circulation, 124(14), 1573–9. Marlu, R.,et al (2012). Thrombosis and Haemostasis, 108(2), 217–24.



Reversal in Major Bleeds Associated with DOAC

• Dabigatran• First Line: Idarucizumab

• Second line: • Activated PCC dosed at 50 units/kg

OR

• 4 Factor PCC dosed at 50 units/kg

• Factor Xa Inhibitors• First line: 4 Factor PCC dosed at 50 units/kg

• Second line: Activated PCC dosed at 50 units/kg

Other Acquired Coagulopathies

• Liver Disease• PCC effectively reduces INR

• Reduces bleeding complications during procedures

• May not increase risk of thromboembolism

• Not a prolonged effects

• Cardiac Surgery• PCC reduces post-op blood loss and transfusion requirements compared to plasma

• PCC may be associated with a greater risk of AKI

• May be more prothrombotic then in other patient populations

Lesmana, C. R. A., et al (n.d.). Case Reports in Gastroenterology, 10(2), 315–22. Huang, W.-T. et al. (2017). Clinical and Applied Thrombosis/hemostasis , 23(8), 1028–1035.Cappabianca, G. et al. (2016). Critical Care (London, England), 20, 5. Tanaka, K. A. et al. (2014). Journal of Intensive Care, 2(1), 60.




An 62 year old female presents to the ED with right side weakness and slurred speech. A stat head CT is ordered demonstrating a 40 cc intracerebral hemorrhage. You speak with the patients son who tells you that the patient takes medicine “to thin her blood”.

1) What questions do you ask?

2) Assuming the patient is taking warfarin1) What would you use to reverse the patient?

2) The patients INR is 9.7 and she weights 110 kg. How would you dose Kcentra?

3) Assume the patient was actually taking apixaban1) How does this change your plan?

Future Of Blood Factors - Hemophilia

• Reduce immunogenicity of factors

• Extending half life• Adynovate – Pegylated

• Elocate – Linked to Fc region of immunoglobulin

• Afstyla – Better stability with vWF

• Overcoming inhibitors• Nanoparticle encapsulation

• Longer acting rFVIIa products

• Emicizumab

• Gene therapy



Blood Factor Class Human Recombinant Total

Antihemophilic Factor 3 12 15

Coagulation Factor IX 2 6 8

Prothrombin Complex Concentrate 4 4

Antihemophilic Factor/von Willebrand Factor Complex 3 3

Antithrombin 1 1 2

Coagulation Factor VIIa 1 1

Coagulation Factor X 1 1

Coagulation Factor XIII A Subunit 1 1

Factor XIII Concentrate 1 1

Fibrinogen 1 1

Fibrinogen Concentrate 1 1

Protein C Concentrate 1 1

von Willebrand factor 1 1

Total 18 22 40

Info from the FDA Center for Biologics Evaluation and Research

Approval of Blood Factors Over Time

0

5

10

15

20

25

30

35

40

45

1965 1975 1985 1995 2005 2015

Human

Recombinant

Total

Info from the FDA Center for Biologics Evaluation and Research



Future of Blood Factors - Anticoagulation

• Idarucizumab• Monoclonal antibody directly binding dabigatran• Approved• Dose: 2.5 g IV x 2 doses

• Andexanet alpha• Recombinant Xa with no anticoagulant activity• Bind rivaroxaban, apixaban, edoxaban, heparin, LMWH, and fondaparinux• Not yet approved• Dose: 400 – 800 mg bolus followed by a 480 mg – 960 mg infusion

• Ciraparantag• Cationic bonding to all oral and parenteral anticoagulants• Not yet approved

The Role of the Health System Pharmacist

• Safe, effective, and timely administration of blood factor products• Order sets and guidelines to ensure appropriate use, selection, and dosing• Prospective review • Bed side preparation

• Fiscal responsibility• Restrictions, approval pathways

• Blood Factor stewardship at large academic medical center• Standardized to single formulary agent per class• Utilized continuous infusion factor IX• FEIBA over rVIIa in Hemophilia A with inhibitors• Restrict use to approved guidelines• Guideline based treatment in neurosurgery and cardiothoracic surgery

Amerine, L. B. et al (2015). American Journal of Health-System Pharmacy , 72(18), 1579–84.



Conclusion

• The coagulation system is a complex system of interconnected proteins

• Small disruption within the cascade can lead to significant complications

• The mainstay of treatment in Hemophilia is replacing the affected factor

• Anticoagulation induced bleeding is primarily managed with non-specific agents

• There have been several therapies developed over the last 5 years changing the landscape of blood factors

The Power to Congeal is the Power to HealBlood Factor Products

Monica V. Mahoney, PharmD, BCPS AQ-ID

Brian Spoelhof, PharmD, BCPS

Clinical Specialist Lead – Medicine

Boston Medical Center

mmPharmD

the power to congeal is the power to heal

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