Coagulation and Clot Breakdown

Coagul ation Simplified …

Published by ACKNOWLEDGEMENTS CONTENTS

We gratefully acknowledge the support and funding provided by the Ontario Ministry of 1. The Basics of Coagulation and Clot Breakdown ...... 4–7 Health and Long-Term Care. 2. Routine Coagulation Tests ...... 8–17 Special thanks to the past contributors and material reviewers of the first edition. Evaluating coagulation in the laboratory ...... 8 Sample collection for coagulation testing ...... 9 Prothrombin Time (PT) ...... 10 Thanks also to: International Normalized Ratio (INR) ...... 11 s Dale Roddick, photographer, Sunnybrook Health Sciences Centre Activated Partial Thromboplastin Time (APTT) ...... 12 Thrombin Time (TT) ...... 13 s Doug Nicholson, photographer, Sunnybrook Health Sciences Centre Fibrinogen ...... 14 s Reena Manohar, graphic artist, Sunnybrook Health Sciences Centre D-dimer ...... 15 s The ECAT Foundation Anti-Xa assay ...... 16 Summary ...... 17 CLOT-ED Images used or modified with permission from the ECAT Foundation, The Netherlands. 3. Anticoagulant Drugs ...... 18–25 Unfractionated Heparin (UFH) ...... 18 We hope you enjoy the second edition of Bloody Easy: Coagulation Simplified . Like the first Low Molecular Weight Heparins (LMWHs) ...... 19 edition we hope to provide basic foundational learning in coagulation and the assessment Fondaparinux ...... 20 of bleeding disorders and coagulopathies. Updates include, new direct oral anticoagulants Warfarin ...... 21 and reversal strategies for these drugs, in elective and urgent situations, in Chapter 3. New Direct Thrombin Inhibitors (DTI) ...... 23 extended half-life replacement products for hemophilia are now included in Chapter 6. Direct Xa Inhibitors ...... 25

4. Evaluating Abnormal Coagulation Tests ...... 26–29 First Edition, March 2013 Prolonged PT / INR with normal APTT ...... 26 Second Edition, February 2019 Prolonged APTT with normal PT / INR ...... 27 Prolonged APTT and PT / INR ...... 28 Prolonged Thrombin Time (TT) with normal or prolonged APTT and PT / INR ...... 29 General Disclaimer: While the advice and information in this handbook are believed to be true and accurate at 5. Approach to the Evaluation of the Bleeding Patient ...... 30–35 the time of publishing, neither the authors nor the publishers accept any legal responsibility or liability for any errors or omissions in the information provided, or for any of the 6. Diagnosis and Emergency Management of recommendations made. Any decision involving patient care must be based on the judgement Common Bleeding Disorders ...... 36–45 of the attending physician according to the needs and condition of each individual patient. von Willebrand disease (VWD) ...... 36 Disorders of platelet function ...... 38 Hemophilia A and B (Factor VIII and IX deficiency) ...... 40 Factor XI deficiency ...... 43

Key References ...... 45-47

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5 1. Coagulation & Clot Breakdown t o l C 1. ThE BASiCS Of COAGuLATiON AND CLOT BrEAKDOWN & n

n w o o i d t k a l a u e r g a B o C

. Secondary hemostasis, ﬁbrin clot formation and stabilization: 4. Inhibition of coagulation = inhibition of thrombin generation and fibrin 1 clot breakdown (fibrinolysis):

Contact Factors (HMWK, Prekallikrein) inhibition of thrombin generation INITIATION s At the same time that a clot is being formed, the clotting process also starts to shut itself oﬀ to limit the extent of the thrombus formed. FXII FXIIa Tissue Factor s PROPAGATION FVIIa Thrombin binds to the membrane receptor thrombomodulin and activates Protein C to FXI FXIa Activated Protein C (APC). Ca 2+ TF - VIIa complex s APC combines with its cofactor Protein S which then inhibits Factors Va and VIIIa, slowing FIX FIXa down the coagulation process. FVIII FVIIIa Ca2 + +PL s Thrombin bound to thrombomodulin becomes inactive and can no longer activate procoagulant factors or platelets. FX FXa s The endogenous anticoagulant, antithrombin inhibits the activity of thrombin as well 2+ FV FVa Ca +PL as several of the other activated factors, primarily Factor Xa. Prothrombin Thrombin (FII) (FIIa) fibrinolysis AMPLIFICATION s Tissue plasminogen activator (t-PA) converts plasminogen to plasmin which breaks down cross-linked fibrin to several fibrin degradation products, the smallest of which is D-dimer. Soluble Fibrinogen s Thrombin activatable fibrinolysis inhibitor (TAFI) inhibits the formation of plasmin and Fibrin suppresses fibrinolysis.

s Fibrin Clot Formation FXIIIa Anti-plasmin and plasminogen activator inhibitor-1 (PAI-1) inhibit plasmin and t-PA and Stabilization respectively.

Insoluble TAFI Cross-Linked Fibrin Plasminogen Antiplasmin

t-PA

PAI-1 Plasmin

Fibrin(ogen) Fibrin Clot Degradation Products

D-dimer

6 7 2. rOuTiNE COAGuLATiON TESTS Elena Brnjac & rita Selby

Sodium Citrate Tube Evaluating coagulation in the laboratory Sample collection for coagulation testing (Blue Top) s In the coagulation laboratory, the coagulation factors are divided into: s To assess coagulation “in vitro,” the laboratory measures the time • Extrinsic pathway factors (Factor VII) taken to form a clot. s t

s s

Blood is collected into a blue top tube containing sodium citrate e e T

• Intrinsic pathway factors (Factors XII, XI, IX, VIII) n i n t

anticoagulant (which chelates calcium) to prevent blood clotting o i u t o

• Common Pathway factors (Factors X, V, II, Fibrinogen) a l r

in the tube during transport. u . 2 g a o ATTENTION C s Memorizing which factors belong to the extrinsic, intrinsic and common pathways Sodium Citrate Tube Coagulation testing respectively will make evaluating the causes of abnormal coagulation tests easier. (Blue Top) MUST only be sent in a sodium citrate Centrifugation (blue top) tube. Intrinsic Pathway Extrinsic Pathway ! XII XI VII IX Tissue Factor s Plasma (the liquid component of blood that contains the clotting VIII factors) is then separated from the platelets (phospholipid source) APTT X PT Intrinsic Extrinsic by centrifugation. + Common V Pathway + s Common II Common Later we will see how adding back phospholipids and calcium is important in standardizing routine coagulation tests.

Fibrinogen Fibrin Clot s Some common problems that may result in spurious coagulation Plasma test results are: Buy C oat • Blood collected into incorrect type of tube (not a sodium citrate Red s Here is another picture to help with memorizing the coagulation cascade without the tube) Cells Roman numerals: • Incorrect plasma to citrate ratio (e.g., underfilling of tube or 8 5 patient’s hematocrit > 0.55 L / L) 12 11 9 10 2 1 • Heparin contamination of sample (e.g., incorrect order of Thrombin Fibrinogen PTT sample collection or sample collected from central lines) • Clotting in tube from traumatic venipuncture or inadequate 7 INR mixing • Hemodilution of sample

• The common pathway factors can be memorized by thinking of the denominations of dollars in Canada: factors 10, 5, 2 and 1 • The PT / INR pathway starts with factor 7 and includes the common pathway factors • The APTT pathway starts from the left at factor 12, counts backwards to factor 8 (skipping factor 10) and includes the common pathway factors

8 9 2. rOuTiNE COAGuLATiON TESTS

Prothrombin Time (PT) International Normalized Ratio (INR) s The PT is used to assess deficiencies or Extrinsic s The International Normalized Ratio (INR) was developed to standardize the PT to allow inhibitors of the extrinsic pathway Pathway for monitoring of oral vitamin K antagonist therapy (e.g., warfarin) across diﬀerent labs. s t

factors (Factor VII) and common s s

The PT in seconds is used to calculate the INR. e e T

n i pathway factors (Factors X, V, II, VII n t s o i u

Each lot of PT reagent needs to have an International Sensitivity Index (ISI) determined / t o

Fibrinogen). a l r

u Common assigned, which indicates how sensitive the reagent is to deficiencies in the Vitamin K . 2 g a

Pathway dependent factors compared to the World Health Organization reference standard. o C X s The INR is the ratio of the patient’s PT value over the geometric mean of the PT (generated from a minimum of 20 normal volunteers) and raised to the power of the ISI of the reagent V used to obtain the PT: II INR = (PT of patient / geometric mean normal PT) ISI

Fibrinogen Fibrin Clot

ISI s Measurement of PT: PT reagent contains a source of tissue factor (also known as thromboplastin), phospholipids Patient PT and calcium chloride. Plasma is warmed to 37 ° C. Pre-warmed PT reagent is added and the INR = time in seconds for clot formation is measured. Mean Normal PT s The PT is dependent on the reagent and instrument used and will vary between laboratories. A normal PT is approximately 9-15 seconds.

Time for clot formation 9 - 15 seconds

Incubate at 37 ˚C

0.1 mL Thromboplastin + Ca ++

0.05 mL Plasma

10 11 2. rOuTiNE COAGuLATiON TESTS

Activated Partial Thromboplastin Time (APTT) Thrombin Time (TT) s s The APTT is used to assess deficiencies Intrinsic The TT is used to assess deficiencies or dysfunction of fibrinogen or the presence of or inhibitors of the intrinsic pathway Pathway an inhibitor of thrombin (Factor IIa). The most common cause for TT prolongation is s t

factors (Factors XII, XI, IX, VIII) and anticoagulant drug therapy (e.g., heparin or direct thrombin inhibitor). Other causes s

e e T

XII n i common pathway factors (Factors X, include quantitative or qualitative fibrinogen abnormalities and increased products of clot n t o i XI u t o

V, II, Fibrinogen). breakdown (e.g., fibrin degradation products in disseminated intravascular coagulation). a l r

u IX Common . 2 g

Pathway a VIII o C X II V II Fibrinogen Fibrin Clot Fibrinogen Fibrin Clot

s Measurement of APTT: s Measurement of TT: The APTT reagent contains a contact activator (e.g., silica, ellagic acid or kaolin) and The patient’s plasma is warmed at 37 ° C and thrombin reagent is added. The time in seconds phospholipids but does not contain tissue factor or calcium chloride. The intrinsic factors that it takes for the plasma to clot is measured. are “activated” when patient plasma is mixed with APTT reagent and incubated at 37 ° C. s The TT is dependent on the reagent and instrument used and will vary between laboratories. Calcium chloride is added and the time in seconds for the plasma to clot is measured. s Since the APTT reagent lacks tissue factor it is a “partial thromboplastin” and the test is called an activated partial thromboplastin time. Time for clot formation s The APTT is dependent on the reagent and instrument used and will vary between measured laboratories. A normal APTT is approximately 25-35 seconds.

Incubate at 37 ˚C Time for clot formation 25 - 35 seconds 0.1 mL Thrombin

0.2 mL Diluted Plasma

0.1 mL CaCI 2

Incubate at 37 ˚C

0.1 mL Contact Activator + PL

0.1 mL Plasma

12 13 2. rOuTiNE COAGuLATiON TESTS

Fibrinogen D-Dimer s The fibrinogen assay assesses fibrinogen activity. s D-dimers are breakdown products generated by the action of plasmin on cross-linked s Hypofibrinogenemia is usually acquired due to loss of fibrinogen (e.g., bleeding), fibrin. A D-dimer contains two cross-linked D fragments. s t s

consumption (e.g., hyperfibrinolysis after traumatic injury, disseminated intravascular e e T

n i n t

coagulation) or decreased production (e.g., severe liver disease). Other rare causes include Fibrinogen o i u t o a l r

congenital hypofibrinogenemia and dysfibrinogenemia (an abnormal fibrinogen). u . 2 g

Fibrin Monomer a s Fibrinogen is an acute phase reactant and may be non-specifically elevated with acute or Thrombin o C

chronic inflammation. Fibrin Polymer s Measurement of ﬁbrinogen based on the Clauss method: FXIII FXIIIa The plasma is diluted with a physiological buﬀer, warmed to 37 ° C and a high concentration Cross-linked Fibrin of thrombin is added. The thrombin cleaves fibrinogen to fibrin monomers which polymerize. D E D D E D The time in seconds for the plasma to clot is measured. The time in seconds is inversely Plasmin proportional to fibrinogen activity which is obtained from a standard calibration curve. E D D E D D E The longer the clotting time, the lower the concentration of fibrinogen in the sample. D-dimer D-dimer

s A negative D-dimer can be used to rule out venous thromboembolism (VTE) in selected

) outpatients (those with low to moderate clinical probability of VTE). Ideally, D-dimer s

d 50.0 n should only be used as part of a validated VTE diagnostic algorithm. o c

e 16.7 s s (

An elevated D-dimer is not specific to thrombosis and may be associated with a host of e 9.5 m

i 8.0 other non-specific diseases or inflammatory states (e.g., recent surgery or trauma, cancer, T Patient

g 5.1

n acute or chronic infectious or inflammatory diseases, disseminated intravascular i t t

o coagulation, healthy elderly, normal pregnancy, etc.). l C 1 s Measurement of D-dimer: 0.1 1.0 3.0 5.0 6.0 9.0 There are several diﬀerent assays available to measure D-dimer. These include qualitative Fibrinogen (g/L) (positive or negative), semi-quantitative or quantitative methods, such as ELISA (Enzyme Linked Immunosorbent Assay) or LIA (Latex Immunoassay) which use a monoclonal antibody to various epitopes of D-dimer. Quantitative D-dimer measurements obtained by s The Clauss fibrinogen activity is a standardized test as laboratories use a WHO calibrated the various assays are not standardized due to the variability in the monoclonal antibody plasma for the calibration curve. While there may be small diﬀerences in the reference used. D-dimer results must be interpreted based on the assay used. ranges between laboratories, the reference range will be approximately 1.5-4 g / L. s Reporting units vary between assays, e.g., DDU (D-dimer units) or FEU (Fibrinogen equivalent units).

14 15 2. rOuTiNE COAGuLATiON TESTS

Anti-Xa assay Summary s An Anti-Xa assay can be used to measure the ATTENTION s In the coagulation laboratory, the coagulation factors ATTENTION anticoagulant activity of an anticoagulant that inhibits Check that your coagulation are divided into: Reference ranges for common s t

clotting Factor Xa such as heparin, low molecular weight laboratory has validated the s

e e

coagulation tests vary between T

• Extrinsic pathway factors (Factor VII) n i heparin (LMWH), fondaparinux or direct Xa inhibitors Anti-Xa assay for the n t

laboratories due to instrument / o i u t

anticoagulant that • Intrinsic pathway factors (Factors XII, XI, IX, VIII) o (rivaroxaban, apixaban and edoxaban). a l reagent differences. r

u ! . you wish to monitor. 2 ! g s Measurement of Anti-Xa activity: • Common pathway factors (Factors X, V, II, a o A known amount of Factor Xa is added in excess to the plasma sample containing the drug. fibrinogen) C A complex forms between the drug and factor Xa. A chromogenic substrate is added which s The PT is most sensitive to the extrinsic and common pathway factors and the APTT to hydrolyses the unbound or “residual” factor Xa and the release of colour is measured at a the intrinsic and common pathway factors. specific wavelength as an optical density (OD). The OD is converted to a drug concentration s The PT and PTT can be normal in mild factor deficiencies. reported in international units (IU) or ng/mL using a drug-specific calibration curve. s The thrombin time is most sensitive to fibrinogen and presence of inhibitors of thrombin s The therapeutic level of the Anti-Xa assay is specific for the drug being assessed. (Factor IIa). s The Anti-Xa assay only assesses the inhibition of factor Xa. Patient Plasma Excess Factor Xa Drug Drug + Xa Xa Xa Xa Xa Intrinsic Pathway Extrinsic Pathway Incubate XII XI VII Residual Factor Xa Drug Xa IX Tissue Factor + Xa Xa Xa Drug Xa VIII Add Chromogenic Substrate APTT X PT Intrinsic Extrinsic + Common V Pathway + Release of Colour Common Common (measured as optical density) II

Fibrinogen Fibrin Clot Calibration Curve y t

) 0.5 i s n i n e m / D

S l

B 0.3 a c A Patient i t m p ( O 12 Anti-Xa (IU/mL or ng/mL) 16 17 3. ANTiCOAGuLANT DruGS Yulia Lin, rita Selby, Carolyne Elbaz

Unfractionated Heparin (UFH) Low Molecular Weight Heparins (LMWHs)

s Unfractionated heparin is a Intrinsic Pathway Extrinsic Pathway s LMWHs are produced by “fractionating” Intrinsic Pathway Extrinsic Pathway mixture of varying chain lengths XII heparin molecules into smaller chain XII of glycosaminoglycans derived XI VII lengths. XI VII IX IX from pig intestine. VIII s LMWHs are “indirect” anticoagulants. VIII X X s It is an “indirect” anticoagulant. It Common V Pathway They exert their anticoagulant eﬀect Common V Pathway exerts its anticoagulant eﬀect by II by combining with antithrombin (via II combining with antithrombin (via 5 saccharide units – pentasaccharide) 5 saccharide units – pentasaccharide) Fibrinogen Fibrin Clot and inhibiting only the coagulation Fibrinogen Fibrin Clot and inhibiting the coagulation factors factors Xa and IIa.

IIa, Xa, IXa, XIa and XIIa. s t LMWHs are administered subcutaneously (SC). n a l

s u s

It can be administered either intravenously (IV) or subcutaneously (SC). s ATTENTION g

Several preparations are commercially available – g a u o r c

s i

Consider measuring anti-Xa levels D UFH can be monitored using the APTT or the anti-Xa assay. dalteparin, enoxaparin, nadroparin, tinzaparin, etc. t n A

in the following populations: s They vary in their relative inhibition of factors Xa .

Half-life is 60-90 minutes; half-life for SC heparin is longer. 3 and IIa also known as the Xa:IIa ratio. • CrCl < 30 mL / minute s Elective reversal. • Weight < 40kg s LMWHs generally do not require lab monitoring but ! • Discontinue IV unfractionated heparin 4 hours prior to the planned procedure if they are monitored, then the anti-Xa assay is used • Weight > 100kg s Urgent reversal in the setting of significant bleeding. (NOT the APTT). • Pregnancy • Antidote: Protamine s Half-life is 3-6 hours. LMWHs are renally cleared • Administer 1 mg of protamine per 100 units of unfractionated heparin given in the last therefore the half-life will be prolonged in patients with renal failure. 2-2.5 hours s Elective reversal. • Adverse effects of protamine: hypotension, hypersensitivity • Discontinue LMWH 12-24 hours prior to planned procedure depending on the dose of the LMWH, the specific procedure and renal function s Urgent reversal. • Andexanet alpha (pending approval) may be effective for reversal of LMWH • Protamine may reverse the antithrombin (IIa) activity of LMWH but will not reverse the anti-Xa activity. Furthermore, protamine would only affect the intravascular LMWH, not the subcutaneous depot

18 19 3. ANTiCOAGuLANT DruGS

Fondaparinux Warfarin

s Fondaparinux is a synthetic Intrinsic Pathway Extrinsic Pathway s Warfarin is an oral Vitamin K Intrinsic Pathway Extrinsic Pathway pentasaccharide. XII antagonist. XII XI VII XI VII s s Fondaparinux is an “indirect” IX Clotting factors II, VII, IX and X IX anticoagulant. It exerts its VIII as well as natural anticoagulant VIII X X anticoagulant eﬀect by combining Common V Pathway proteins, Protein C and Protein S, Common V Pathway with antithrombin. The fondaparinux- II require the action of Vitamin K II antithrombin complex inhibits only to become activated so that they coagulation factor Xa. Fibrinogen Fibrin Clot may participate in coagulation. Fibrinogen Fibrin Clot s It is administered subcutaneously (SC). By inhibiting Vitamin K, warfarin

prevents the activation of these factors. t s n Fondaparinux generally does not require lab monitoring, but if it is monitored, the a l

s u s

It is monitored using the PT which is converted to an INR. g

anti-Xa assay is used (NOT the APTT). g a u o r c

s i D s Individual doses vary and the dose is adjusted to prolong the INR into a therapeutic range. t

Half-life is 17-21 hours. It is renally cleared so the half-life will be prolonged in patients n A

with renal failure. • Target INR = 2.5 (range = 2.0-3.0) for most indications requiring therapeutic 3 s Elective reversal. anticoagulation • For most procedures, stop prophylactic fondaparinux 24 hours before and therapeutic • Target INR = 3.0 (range = 2.5-3.5) for therapeutic anticoagulation for mechanical fondaparinux 1-2 days before if renal function is normal mitral valves s s Urgent reversal. Patient INR can be measured by sending a citrated plasma sample to the lab (blue top tube) or using a drop of whole blood from a finger-prick using point-of-care devices. • Andexanet alpha (pending approval) may have a role in reversal of fondaparinux s Half-life is 36-42 hours. • Protamine has no eﬀect • There is no evidence to support the use of tranexamic acid, PCCs, FEIBA or recombinant activated VIIa

20 21 3. ANTiCOAGuLANT DruGS

Warfarin (continued) Direct Thrombin Inhibitors (DTIs) s Elective reversal. s DTIs are synthetically derived and directly inhibit thrombin (Factor IIa). They are • Stop warfarin 5 days before major invasive procedure called “direct” because unlike heparin, LMWH and fondaparinux, they do not require antithrombin to inhibit their target. • Note: bridging therapy may be considered for selected patients at high risk for thrombosis s Urgent reversal. Intrinsic Pathway Extrinsic Pathway XII • Antidotes: XI VII – Vitamin K IX VIII u IV vitamin K acts more quickly than the oral ATTENTION X route (6-12 hours vs. 18-24 hours) Vitamin K should not be Common V Pathway

administered subcutaneously. II n a u Vitamin K works quickly because it activates l u s g g factors and does not require synthesis of Fibrinogen Fibrin Clot a u o r c i D ! t new factors n A

– Prothrombin complex concentrates (PCCs) (Octaplex, Beriplex) 3 s u PCCs contain vitamin K dependent clotting factors (II, VII, IX, X, Protein C and S) DTIs include intravenously administered drugs like argatroban, bivalirudin and lepirudin and a small amount of heparin which are used primarily in the treatment of Heparin-Induced Thrombocytopenia (HIT). DTIs also include the oral drug dabigatran which is used for the prevention of stroke u Contraindicated in patients with heparin-induced thrombocytopenia related to non-valvular atrial fibrillation and in the prophylaxis and treatment of venous • For emergent reversal of warfarin (reversal within 6 hours), give vitamin K 5-10mg IV thromboembolism. and PCCs. At present, a PCC dose of 1000 IU is recommended for INR 1.5-3.0 s Dabigatran does not require routine monitoring. Since the drug inhibits thrombin, • If urgent reversal is not required, vitamin K alone may be administered APTT, TT and PT may be variably aﬀected. s Half-life of dabigatran is 15 hours (12-18 hours). ATTENTION Dabigatran is contraindicated • Renally cleared so half-life will be prolonged in in patients with CrCl patients with renal failure < 30 mL / minute. s Elective reversal of direct thrombin inhbitors ! DRUG RENAL MINOR MODERATE RISK MAjOR SURGERy (dose regimen) FUNCTION PROCEDURES SURGERy INCLUDING (12-25% residual NEURAXIAL anticoagulant PROCEDURE effect acceptable) (<10% residual drug effect acceptable) Dabigatran BiD CrCl ≥50 mL / min Last dose Last dose Last dose day -1 day -2 day -3 Dabigatran BiD CrCl 30- Last dose Last dose Last dose 49 mL / min day -1 day -3 day -5

22 23 3. ANTiCOAGuLANT DruGS

Direct Thrombin Inhibitors (continued) s Half-life: Rivaroxaban 7-8 hours; apixaban 8-12 hours; edoxaban 10-14 hours. s Urgent reversal of dabigatran. • Partially renally cleared so half-life will be prolonged in patients with renal failure • Antidote: Idarucizumab 5g IV administered in two boluses of 2.5g no more than s Elective reversal. 15 minutes apart DRUG RENAL MINOR MODERATE RISK MAjOR SURGERy • Activated charcoal if ingested within 2 hours (dose regimen) FUNCTION PROCEDURES SURGERy INCLUDING • Hydration to correct pre-renal dysfunction (12-25% residual NEURAXIAL anticoagulant PROCEDURE • There is no definitive evidence to support the use of tranexamic acid, PCCs, FEIBA or effect acceptable) (<10% residual drug recombinant factor VIIa effect acceptable) • Consult an expert in hematology or transfusion medicine rivaroxaban OD CrCl ≥30 mL / min Last dose Last dose Last dose

day -1 day -2 day -3 t n a l u s Apixaban BiD CrCl ≥30 mL / min Last dose Last dose Last dose g g a u o r c i

day -1 day -2 day -3 D t n A

Edoxaban OD CrCl ≥30 mL / min Last dose Last dose Last dose 3 day -1 day -2 day -3

s Urgent reversal. • Antidote: Andexanet alfa (pending approval) Direct Xa inhibitors • There is no definitive evidence to support the use of tranexamic acid, PCCs, FEIBA or s Direct factor Xa inhibitors are Intrinsic Pathway Extrinsic Pathway recombinant factor VIIa synthetically derived and directly XII • For life threatening bleed, consider PCC (Octaplex or Beriplex) 1500-2000 units IV STAT inhibit Factor Xa. They are called XI VII IX • Consult an expert in hematology or transfusion medicine “direct” because unlike heparin, LMWH VIII and fondaparinux, they do not require X antithrombin to inhibit their target. Common V Pathway II s Direct Xa inhibitors include rivaroxaban, apixaban and edoxaban, Fibrinogen Fibrin Clot which are used for the prevention of stroke related to non-valvular atrial fibrillation and in the prophylaxis and / or treatment of venous thromboembolism. Other factor Xa inhibitors are under development.

s Rivaroxaban, apixaban and edoxaban do not require ATTENTION routine monitoring. Since the drug inhibits factor Xa, PT Rivaroxaban, apixaban and and APTT may be variably aﬀected. The eﬀect of these edoxaban are contraindicated drugs can be measured using the anti-Xa assay. in patients with CrCl < 30 mL / minute. ! 24 25 4. EVALuATiNG ABNOrMAL COAGuLATiON TESTS Karen Moffat

Prolonged PT / INR with normal APTT Prolonged APTT with normal PT / INR

If the PT / INR is prolonged but the Intrinsic Pathway Extrinsic Pathway If the APTT is prolonged but Intrinsic Pathway Extrinsic Pathway APTT is not, the probable cause is XII the PT / INR is not, the probable XII related to Factor VII (FVII). XI VII cause is related to the intrinsic XI VII IX pathway – either Factors VIII, IX, XI IX VIII What is the diﬀerential diagnosis? VIII X or the contact factors (Factor XII, X Common V Pathway s Congenital deficiency of FVII. Prekallikrein or High Molecular Common V Pathway II Weight Kininogen). s Acquired deficiency of FVII. II Fibrinogen Fibrin Clot • Early warfarin therapy or early What is the diﬀerential Fibrinogen Fibrin Clot vitamin K deficiency (FVII has diagnosis? the shortest half-life of the s Congenital deficiency of Factors VIII, IX, XI or contact factors – usually a vitamin K dependent factors so FVII levels will be lower single factor deficiency. than the other Vitamin K dependent factors (IX, X and II) early on in the course of warfarin therapy or Vitamin K deficiency) • Deficiencies of Factors VIII and IX are generally associated with bleeding • Early liver disease • von Willebrand’s disease can have low factor VIII and be variably associated with bleeding s PT may be elevated in the presence of a DTI (e.g., dabigatran) or anti-Xa (e.g., rivaroxaban, l apixaban, edoxban). • Factor XI deficiency is variably associated with bleeding a s m r t s o

s • Contact factor deficiencies can profoundly elevate the APTT but do not result in a e n

Specific inhibitors to FVII can occur but are exceptionally rare. T

b n A

bleeding tendency o i g t n i a l s t

To distinguish between factor deﬁciency and inhibitor u Acquired causes of prolonged APTT may be due to inhibitors – either specific or non- a g u l a a

s specific. o v

Perform an immediate 50:50 mix. This test is performed by combining 1 part patient plasma C E

. with 1 part normal plasma. A PT is performed on the 50:50 mix. • Specific inhibitors are directed against specific factors (commonly against Factor VIII) 4 s If the PT prolongation corrects on mixing the prolongation is likely due to a factor deficiency • Non-specific inhibitors may be drugs (e.g., heparin, rivaroxaban, apixaban, edoxaban) (due to replacement of factor(s) from the normal plasma). If it does not correct the or antiphospholipid antibodies that target coagulation proteins bound to phospholipids prolongation is likely due to an inhibitor. A partial correction may represent multiple factor (also known as lupus anticoagulants) deficiencies or an inhibitor. • The APTT may also be elevated in patients on direct thrombin inhibitors (DTI) (e.g., dabigatran, argatroban, bivalirudin)

To distinguish between factor deﬁciency and inhibitor s Perform an immediate 50:50 mix. This test is performed by combining 1 part patient’s sample with 1 part normal plasma. Run an APTT on the 50:50 mix. s If the APTT prolongation corrects on mixing it is likely due to a factor deficiency (due to replacement of factor(s) from the normal plasma). If it does not correct the prolongation is likely due to an inhibitor. A partial correction may represent multiple factor deficiencies or an inhibitor.

26 27 4. EVALuATiNG ABNOrMAL COAGuLATiON TESTS

Prolonged APTT and PT / INR Prolonged Thrombin time (TT) with normal or prolonged APTT and PT / INR

If the PT / INR and the APTT are both Intrinsic Pathway Extrinsic Pathway If the thrombin time is prolonged, Intrinsic Pathway Extrinsic Pathway prolonged, there could be multiple XII the probable cause is related to XII factors affected in the intrinsic and XI VII either thrombin (Factor IIa) or XI VII IX extrinsic pathways or a single factor fibrinogen. IX VIII VIII deficiency in the common pathway – X The PT / INR and APTT are not X Factors X, V, II (prothrombin) or a Common V Pathway sensitive to mild to moderate Common V Pathway severe deficiency of fibrinogen. II deficiencies of fibrinogen; the II TT may be the only prolonged What is the differential diagnosis? Fibrinogen Fibrin Clot screening test in those instances. Fibrinogen Fibrin Clot s Congenital deficiency of Factors X, V, II or fibrinogen – usually a single What is the differential factor deficiency. diagnosis? • Deficiencies of Factors X, V, II or fibrinogen may be associated with bleeding depending on s Congenital deficiency of fibrinogen (hypofibrinogenemia or afibrinogenemia) the severity of the phenotype or a qualitative abnormality (dysfibrinogenemia). s Acquired causes. s Acquired causes. l

• Non-specific inhibitors - drugs (e.g., excessive doses of heparin, direct thrombin inhibitors • Drugs (e.g., heparin, direct thrombin inhibitors) a s m r t

or direct Xa inhibitors) or antiphospholipid antibodies that target coagulation proteins s o

• Specific inhibitors directed to either factor II or fibrinogen (extremely rare) e n T

bound to phospholipid (also known as lupus anticoagulants) b n A

o i • Consumptive coagulopathy (e.g. disseminated intravascular coagulation) due to g t n i a l • Specific inhibitors directed to a factor within the common pathway t u increased fibrin degradation products in the circulation that interfere with fibrin a g u l a a

• Severe vitamin K deficiency (low vitamin K dependent factors II, VII, IX and X) polymerization o v C E

. • Supratherapeutic warfarin therapy (low vitamin K dependent factors II, VII, IX and X) • Acquired hypofibrinogenemia 4 • Severe liver disease (due to impaired production of multiple coagulation factors) – Severe liver disease • Consumptive coagulopathy (e.g., disseminated intravascular coagulation) due to – Massive hemorrhage increased consumption of multiple coagulation factors – May occur with systemic t-PA treatment • Isolated Factor X deficiency (e.g., associated with systemic amyloidosis) • Severe depletion of fibrinogen due to massive hemorrhage or fibrinolysis • Hemodilution (post operative sample, massive transfusion, pre-analytical causes) As previously discussed, an immediate 50:50 mix may help in providing clues as to whether the cause of the prolongation is due to a factor deficiency or an inhibitor. However, specific factor levels and inhibitor studies will be more informative.

28 29 5. APPrOACh TO ThE EVALuATiON Of ThE BLEEDiNG PATiENT Paula James

History s The history is the most important tool in determining ATTENTION s A congenital bleeding disorder would more often be associated with a lifelong history the pre-test probability of the existence of a bleeding The bleeding history is the of excessive bleeding or bruising and a positive family history for bleeding; however, disorder and helping to distinguish congenital from most important predictor the lack of family history does not rule out a congenital bleeding disorder. acquired causes. of a bleeding disorder. s Standardized bleeding assessment tools (BATs) should ATTENTION s Details to inquire about on history. ! be used to assess bleeding risk. An example is the Standardized bleeding • Onset of bleeding – spontaneous or with hemostatic challenges (dental extractions, condensed MCMDM-1 VWD bleeding questionnaire assessment tools (BATs) should be surgery, postpartum) for von Willebrand disease and platelet function used to assess bleeding risk. disorders. • Location of bleeding – skin, mucous membranes, muscles, joints ! s The condensed MCMDM-1 may be useful in the • Pattern of bleeding – bruises, petechiae, hematomas prediction of operative bleeding, however prospective, • Duration and severity of bleeding episode peri-operative validation studies have not been done. • Menstrual history • Treatments / interventions required to stop bleeding – local pressure, cautery / packing for nosebleeds, other interventions Physical Examination s • History or symptoms of anemia / iron deficiency – fatigue, prior iron supplementation Should include examination of: • Previous blood transfusions • Skin – pallor, jaundice, size and location of bruises, petechiae, hematomas, telangiectasia • Medication history • Hepatosplenomegaly and lymphadenopathy • Family history of bleeding problems • Joints – range of motion, evidence of hypermobility

t f n o

e i n t o a i t P

a g u l n i a d v e E

e . l 5 B

30 31 5. APPrOACh TO ThE EVALuATiON Of ThE BLEEDiNG PATiENT

Diagnostic Approach Investigations s Congenital causes of bleeding include: s Initial investigations should be directed by the history and include: • von Willebrand disease (VWD) • CBC and peripheral blood film • Platelet function disorders (PFD) • PT / INR and APTT • Hemophilia A and B • + / - Thrombin time • Factor XI deficiency • + / - Fibrinogen • Other coagulation factor deficiencies • + / - Hepatic, renal function • Collagen vascular disorders (Ehlers Danlos Syndrome) • + / - Ferritin • Hypo / dysfibrinogenemia s The initial investigations may be normal in both VWD and PFD. VWD is the most common congenital cause of bleeding. s Subsequent investigations will depend on the clinical history and initial test results and may include: s Acquired causes of bleeding include: • von Willebrand screen • Medications (e.g., antiplatelet agents, anticoagulants, antidepressants, anticonvulsants) • Testing of specific coagulation factors • Hepatic or renal disease • Platelet function testing • ITP (immune thrombocytopenia purpura) s Ideally, specialized investigations should be done under the supervision of a hematologist. • Bone marrow disorders • Acquired coagulation factor deficiencies (Factor VIII, von Willebrand Factor) • Cushing’s syndrome ATTENTION Medications are the most common acquired cause of bleeding. A bleeding time is no longer recommended for the investigation of bleeding disorders. ATTENTION !

t f n o

VWD is the most common e i n t o a i

congenital cause of bleeding. t P

a g u l

Medications are the most n i a d v e common acquired cause E

e . l 5

! B of bleeding.

32 33 5. APPrOACh TO ThE EVALuATiON Of ThE BLEEDiNG PATiENT

here is an example of a bleeding assessment tool validated for the assessment of VWD and platelet function disorders:

The Condensed MCMDM-1 VWD Bleeding Questionnaire has been validated for Other VWD and PFD s For VWD, a bleeding score ≥ 4 has a sensitivity = 100%, specificity = 87%, positive s The bleeding score is determined by scoring the worst episode for each symptom (each predictive value (PPV) = 20%, negative predictive value (NPV) = 100%. (Bowman, 2008) row) and then summing all of the rows together. s For PFD, a bleeding score ≥ 4 has a sensitivity = 86%, specificity = 65%, PPV = 50% and s “Consultation only” refers to a patient consulting a medical professional (doctor, nurse, NPV = 92%. (James, 2011) dentist) because of a bleeding symptom where no treatment was given.

CLINICAL SITUATION -1 01 23 4 Epistaxis No or trivial > 5 per year or more than Consultation only Packing or cauterization or Blood transfusion or replacement (≤ 5 per year) 10 minutes antifibrinolytic therapy or desmopressin Cutaneous No or trivial (≤ 1 cm) > 1 cm and no trauma Consultation only Bleeding from No or trivial > 5 per year or more than Consultation only Surgical hemostasis Blood transfusion or replacement minor wounds (≤ 5 per year) 5 minutes therapy or desmopressin Oral cavity No Reported, no consultation Consultation only Surgical hemostasis or Blood transfusion or replacement antifibrinolytic therapy or desmopressin Gastrointestinal No Associated with ulcer, Spontaneous Surgical hemostasis, blood bleeding portal hypertension, transfusion, replacement therapy, hemorrhoids, desmopressin, antifibrinolytic angiodysplasia Tooth extraction No bleeding in at None done or no Reported, no Consultation only Resuturing or packing Blood transfusion or replacement least 2 extractions bleeding in 1 extraction consultation therapy or desmopressin Surgery No bleeding in at None done or no Reported, no Consultation only Surgical hemostasis or Blood transfusion or replacement least 2 surgeries bleeding in 1 surgery consultation antifibrinolytic therapy or desmopressin

t f

Menorrhagia No Consultation only Antifibrinolytics, oral Dilation & curettage, iron therapy, Blood transfusion or replacement n o

e i n contraceptive pill use ablation therapy or desmopressin t o a i t P

a g u l Postpartum No bleeding in at None done or no Consultation only Dilation & curettage, iron Blood transfusion or replacement Hysterectomy n i a d v e hemorrhage least 2 deliveries bleeding in 1 delivery therapy, antifibrinolytics therapy or desmopressin E

e . l 5 Muscle hematomas Never Post trauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, Spontaneous or traumatic, B requiring desmopressin or requiring surgical intervention or replacement therapy blood transfusion hemarthrosis Never Post trauma, no therapy Spontaneous, no therapy Spontaneous or traumatic, Spontaneous or traumatic, requiring desmopressin or requiring surgical intervention or replacement therapy blood transfusion Central nervous Never Subdural, any intervention Intracerebral, any intervention system bleeding

34 35 6. DiAGNOSiS AND EMErGENCY MANAGEMENT Of COMMON BLEEDiNG DiSOrDErS Michelle Sholzberg

von Willebrand Disease (VWD) Diagnosis: Deﬁnition s Bleeding history with a bleeding assessment tool (BAT). GPllb / llla s von Willebrand factor (VWF) adheres s CBC – subtype 2B can also have a low platelet count.

platelets to exposed subendothelial s Dense granules APTT may be prolonged (but not always). collagen and also acts as a protective Platelet s carrier of Factor VIII. PT / INR is normal. s VWD Screen: s von Willebrand’s disease = Alpha granules Inherited quantitative deficiency GPlb / IX Endothelium • VWF antigen = VWF quantity assessment Collagen VWF Injury site OR qualitative dysfunction of VWF. collagen exposed • VWF activity = VWF quality assessment s Autosomal inheritance. • Factor VIII activity = VWF protective carrier assessment • Men and women are both s If BAT and VWD screen are positive – refer to hematologist for additional testing to aﬀected determine subtype. s Three types: • Type 1: partial quantitative deficiency of VWF Management – Most common form s Prevent bleeding. • Type 2: qualitative defect of VWF • Avoid trauma – including IM injections, arterial punctures, contact sports – 4 subtypes: 2A, 2B, 2M, 2N • Type 3: quantitative absence of VWF • Avoid antiplatelet agents (e.g., aspirin, clopidogrel) and regular NSAIDs – Rare severe form • Increase VWF / FVIII activity prior to invasive procedures (e.g., dental work) • Most patients do not require prophylactic therapy on a regular basis Clinical Presentation s If suspect serious bleeding or trauma – treat first, investigate later. s Mucosal bleeding (e.g., heavy menstrual bleeding, post-partum hemorrhage, • Ask patient if he / she has a wallet card with diagnosis or therapy recommendations GI hemorrhage), easy bruising are most common symptoms. • Consult Hematology or Hemophilia centre for advice (www.ahcdc.ca, s Excessive and prolonged post-operative bleeding. www.hemophilia.ca) s Bleeding into muscles, joints, CNS – rare, mainly in Type 3 VWD. • Type 1: DDAVP 0.3 mcg / kg IV or SC (dose cap 20 mcg / dose in Canada; no dose cap in other countries) for patients with a proven previous response – If DDAVP non-responder or response unknown, then consider plasma-derived purified VWF / Factor VIII concentrate IV • Type 2: usually plasma-derived purified VWF / FVIII concentrate IV g n i

• Type 3: plasma-derived purified VWF / FVIII concentrate IV d e s e l r e B

• Tranexamic acid (Cyclokapron) 25 mg / kg po q8h for mucosal bleeding d n r o o s i • If VWF / Factor VIII concentrate indicated, consult product monograph for dosing m D m o C

. 6

36 37 6. DiAGNOSiS AND EMErGENCY MANAGEMENT Of COMMON BLEEDiNG DiSOrDErS

Disorders of Platelet Function Diagnosis: Deﬁnition s Bleeding history with bleeding assessment tool (BAT).

s s Platelet disorders can occur on Platelet Structure Important to exclude anti-platelet medication (e.g., aspirin, clopidogrel, NSAIDs) the basis of defects in the platelet GPllb / llla or concurrent disease (e.g., chronic kidney disease). membrane, receptors or granules. s CBC and blood film: some disorders are also associated with a low platelet count or • Membrane surface promotes Alpha granules Dense granules abnormal platelet morphology. activation of blood clotting s If BAT screen is positive – refer to hematologist for platelet function testing. Membrane • Receptors allow the platelet to phospholipid interact with the blood vessel surface wall, other blood cells and Management coagulation factors (thrombin, GPlb / IX s Depends on the particular disorder and on the severity of bleeding. VWF and fibrinogen) s Prevent bleeding. • Granule contents are released • Avoid trauma – including IM injections, arterial punctures, contact sports when platelets are activated Inherited platelet disorders can • Avoid antiplatelet agents (e.g., aspirin, clopidogrel) and regular NSAIDs s Can be inherited or acquired. be divided into several groups: • Most patients do not require prophylactic therapy on a regular basis s Autosomal inheritance. 1. Disorders of platelet adhesion (e.g., Bernard Soulier syndrome) s If suspect serious bleeding or trauma – treat first, investigate later. • Men and women are 2. Disorders of platelet aggregation • Ask patient if he / she has a wallet card with diagnosis or therapy recommendations both aﬀected (e.g., Glanzmann thrombasthenia) • Consult Hematology or Hemophilia centre for advice (www.ahcdc.ca, 3. Disorders of platelet granules www.hemophilia.ca) Clinical Presentation (e.g., gray platelet syndrome) • Options may include: s Mucosal bleeding (e.g., heavy 4. Disorders of platelet pro-coagulant activity (e.g., Scott syndrome) – DDAVP 0.3 mcg / kg IV or SC (dose cap 20 mcg / dose in Canada; no dose cap in menstrual bleeding, post-partum other countries) hemorrhage), easy bruising are 5. Combined abnormalities of number and function (e.g., MYH9-related disease) most common symptoms. – Tranexamic acid (Cyclokapron) 25 mg / kg po q8h for mucosal bleeding 6. Non-specific abnormalities (most common) s Excessive and prolonged – Platelet transfusion post-operative bleeding. – In cases of life-threatening bleeding, recombinant factor VIIa (Niastase) may be considered g n i d e s e l r e B

d n r o o s i m D m o C

. 6

38 39 6. DiAGNOSiS AND EMErGENCY MANAGEMENT Of COMMON BLEEDiNG DiSOrDErS

Hemophilia A and B (Factor VIII and IX deficiency) Diagnosis Definition s Detailed bleeding and family history. Intrinsic s Hemophilia A = Inherited Factor VIII Pathway s APTT usually prolonged. deficiency. XII s PT / INR is normal. s XI Hemophilia B = Inherited Factor IX s IX Common Low Factor VIII activity in Hemophilia A. deficiency Pathway VIII s Low Factor IX activity in Hemophilia B. s X-linked inheritance. X • Males predominantly affected; V almost always presents in childhood II Management for severely affected males s Prevent bleeding. Fibrinogen Fibrin Clot • Female carriers can be symptomatic • Avoid trauma – including IM injections, arterial punctures, contact sports s 30% have de novo mutation (i.e., negative family history). • Avoid antiplatelet agents (e.g., aspirin, clopidogrel) and regular NSAIDS • Replace missing factor prior to invasive procedures Grades of Severity: • Some patients, especially those with severe hemophilia require prophylactic factor replacement therapy on a regular basis SEVERITy GRADE CLOTTING FACTOR ACTIVITy BLEEDING SyMPTOMS s Coordinate patient care with Hemophilia centre (www.ahcdc.ca, www.hemophilia.ca). Severe <0.01 IU / mL Spontaneous bleeding into joints / muscles s If suspect serious bleeding or trauma – treat first, investigate later. (<1%) Severe bleeding with minimal trauma/surgery • Ask patient if he / she has a wallet card with diagnosis or therapy recommendations Moderate 0.01-0.04 IU / mL Occasional spontaneous bleeding • Consult Hematology or Hemophilia centre for advice (1-4%) Severe bleeding with trauma / surgery • Rest, compression, elevation for affected muscles and joints Mild 0.05-0.40 IU / mL Severe bleeding with major trauma / surgery • Factor replacement therapy if indicated (5-40%) • DDAVP 0.3 mcg / kg IV or SC (dose cap 20 mcg / dose in Canada; no dose cap in other countries) for patients with mild Hemophilia A (not B) and a proven previous response Clinical Presentation • Tranexamic acid (Cyclokapron) 25 mg / kg po q8h for mucosal bleeding s Classically bleed into joints, muscles, soft tissue. • May also have mucosal and CNS bleeds

s g

Excessive and prolonged post-operative n i d

bleeding. e s e l r e B

d n r o o s i m D m o C

. 6

40 41 6. DiAGNOSiS AND EMErGENCY MANAGEMENT Of COMMON BLEEDiNG DiSOrDErS

Hemophilia A and B (continued) Factor XI Deficiency factor replacement Therapy Deﬁnition Intrinsic Pathway s Calculation of factor replacement therapy is based on the baseline level, the desired level s Inherited deficiency of Factor XI. XII for the clinical bleeding situation and the rise in factor expected with replacement. s Autosomal recessive inheritance. XI s Factor VIII replacement: each IU / kg results in 2% rise in Factor VIII activity and has a • Prevalent in Ashkenazi Jewish IX Common Pathway half-life of 8-12 hours for standard product (half-life is longer for extended half-life population VIII products). X s Factor IX replacement: each IU / kg results in 0.5 - 1% rise in Factor IX activity and has a V half-life of 18-24 hours for standard product (half-life is longer for extended half-life Clinical Presentation II products). s Poor correlation between Factor XI levels and bleeding tendency. Fibrinogen Fibrin Clot s Provide the initial dose as below and consult a hematologist (ideally aﬃliated with a hemophilia treatment center for advice on further dosing). s Personal bleeding history is more predictive of future bleeding risk. SITUATION DESIRED FACTOR DOSE OF RECOMBINANT DOSE OF RECOMBINANT s Mucosal bleeding (e.g., heavy menstrual bleeding, GI hemorrhage), easy bruising. LEVEL (IU / ML) FACTOR VIII (IU / KG ) FACTOR IX (IU / KG ) s Excessive and prolonged post-operative bleeding. Minor bleed 0.25-0.35 15-20 25-40 s Spontaneous bleeding is rare. Moderate bleed / 0.35-0.6 20-30 35-70 minor surgery Diagnosis Severe bleed / 0.8-1.0 40-50 80-120 s Detailed bleeding and family history. major surgery s APTT may be prolonged. s PT / INR is normal. Example s Low factor XI activity. s A patient with severe Hemophilia A and a baseline factor of < 0.01 U / mL who weighs 70 kg presents with a major joint hemorrhage. s The desired factor level is 0.8 - 1.0 IU / mL. s The dose of recombinant factor VIII would be 50 IU x 70 kg = 3500 IU. g n i d e s e l r e B

d n r o o s i m D m o C

. 6

42 43 6. DiAGNOSiS AND EMErGENCY MANAGEMENT Of COMMON BLEEDiNG DiSOrDErS

Management Key References s Prevent bleeding. • Avoid trauma – including IM injections, arterial punctures, contact sports Chapter 1: The Basics of Coagulation and Clot Breakdown Cox K, Price V, Kahr WH. Inherited platelet disorders: a clinical approach to diagnosis and management. Expert • Avoid antiplatelet agents (e.g., aspirin, clopidogrel) and regular NSAIDs Rev Hematol 2011;4:455-72. • Increase FXI activity prior to invasive procedures (e.g., dental work) Hoffman M. A cell-based model of coagulation and the role of factor VIIa. Blood Rev 2003 Sep;17 Suppl 1:S1-5. • Most patients do not require prophylactic therapy on a regular basis Luchtman-Jones L, Broze GJ. The Current Status of Coagulation. Annals of Medicine 1995;27:47-52. s Coordinate patient care with Hemophilia centre (www.ahcdc.ca, www.hemophilia.ca). s If suspect serious bleeding or trauma – treat first, investigate later. Chapter 2: Routine Coagulation Tests CLSI. One-Stage Prothrombin Time (PT) Test and Activated Partial Thromboplastin Time (APTT) Test; Approved • Ask patient if he / she has a wallet card that dictates therapy Guideline—Second Edition. CLSI document H47-A2. Wayne, PA: Clinical and Laboratory Standards Institute; 2008. • Treatment options: Johnston M. Monitoring heparin therapy. In Quality in Laboratory Hemostasis and Thrombosis. Ed Kitchen S, Olson JD, – Plasma derived Factor XI concentrate Preston FE. 2009. West Sussex: Blackwell Publishing Ltd. Pg 170-78. Kitchen S, McCraw A, Echenagucia M. Diagnosis of Hemophilia and Other Bleeding Disorders. A laboratory manual. 2nd ed. – If Factor XI concentrate not available, frozen plasma Montreal: World Federation of Hemophilia; 2008. Available at http://www1.wfh.org/publication/files/pdf-1283.pdf. • Tranexamic acid (Cyclokapron) 25 mg / kg po q8h for mucosal bleeding Accessed 25 Feb 2013. • DDAVP 0.3 mcg / kg IV or SC (dose cap 20 mcg / dose in Canada, no dose cap in other Tripodi A. Monitoring oral anticoagulant therapy. In Quality in Laboratory Hemostasis and Thrombosis. Ed Kitchen S, countries) Olson JD, Preston FE. 2009. West Sussex: Blackwell Publishing Ltd. Pg 179-89. Tripodi A. D-dimer testing in laboratory practice. Clin Chem 2011 Sep;57 (9):1256-62. Wells PS. The role of qualitative D-dimer assays, clinical probability, and noninvasive imaging tests for the diagnosis of deep vein thrombosis and pulmonary embolism. Semin Vasc Med 2005 Nov;5 (4):340-50.

Chapter 3: Anticoagulant Drugs Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 Feb;141(2 Suppl):e44S-88S Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman MH, Dunn AS, Kunz R. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 Feb;141(2 Suppl):e326S-50S Elmer J, Wittels KA. Emergency reversal of pentasaccharide anticoagulants: a systematic review of the literature. Transfusion Med 2012 Apr;22(2):108-15. Garcia DA, Baglin TP, Weitz JI, Samama MM; American College of Chest Physicians. Parenteral Anticoagulants. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 Feb;141(2 Suppl):e24S-43S. Majeed, A., Agren, A., Holmstrom, M., Bruzelius, M., Chaireti, R., Odeberg, J., Hempel, E., Magnusson, M., Frisk, T., & Schulman, S. (2017). Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood, 130(15), 1706-1712. National Advisory Committee on Blood and Blood Products. Recommendations for the use of prothrombin complex concentrates in Canada. 2011. Available at http://www.nacblood.ca/resources/guidelines/PCC.html. Accessed 25 Feb 2013.

44 45 Key References (continued)

Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to Hayward CP, Moffat KA, Raby A, Israels S, Plumhoff E, Flynn G, Zehnder JL. Development of North American consensus switch. Blood 2012 Mar 29;119(13):3016-23. guidelines for medical laboratories that perform and interpret platelet function testing using light transmission aggregometry. Am J Clin Pathol 2010 Dec;134(6):955-63. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012;120:2954-62. Lillicrap, D. The basic science, diagnosis, and clinical management of von Willebrand disease. Treatment of Hemophilia No. 35. Montreal: World Federation of Hemophilia, 2008. Available at http://www1.wfh.org/publication/files/pdf- Thrombosis Canada. (2018). Clinical Guide. NOACs/DOACs: Peri-operative management, 1–7. 1180.pdf. Accessed 25 Feb 2013. http://thrombosiscanada.ca/wp-content/uploads/2018/05/NOACs-DOACs-Perioperative-Management-2018May17.pdf Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, useful Website: Yawn BP. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Thrombosis Canada. Available from: https://thrombosiscanada.ca/ Lung and Blood Institute (NHLBI) Expert Panel report (USA). Hemophilia 2008 Mar;14(2):171-232 Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A; Treatment Guidelines Working Group on Behalf of The World Federation of Hemophilia. Guidelines Chapter 4: Evaluating Abnormal Coagulation Tests for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47. Lippi G, Pasalic L, Favaloro EJ. Detection of mild inherited disorders of blood coagulation: current options and personal World Federation of Hemophilia. Guidelines for the Management of Hemophilia (2nd Edition), 2012. Available at recommendations. Expert Rev Hematol. 2015 8(4):527-542. https://www1.wfh.org/publication/files/pdf-1472.pdf. Accessed November 27, 2018. Rydz N, James PD. Approach to the diagnosis and management of common bleeding disorders. Semin Thromb Hemost useful Websites: 2012 Oct;38(7):711-19. Association of Hemophilia Clinic Directors of Canada. Available from: http://www.ahcdc.ca/ Samuelson B, Cuker A, Siegal DM, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: A systematic review. Chest. 2017 151(1):127-138. Canadian Hemophilia Society. Available from: http://www.hemophilia.ca/ Verhovesk M, Moffat KA, Hayward CPM. Laboratory testing for fibrinogen abnormalities. Am J Hematol. 2008 83(12): World Federation of Hemophilia. Available from: www.wfh.org 928-31.

Chapter 5: Approach to the Evaluation of the Bleeding Patient Bowman M, Mundell G, Grabell J, Hopman WM, Rapson D, Lillicrap D, James P. Generation and Validation of the Condensed MCMDM1-VWD Bleeding Questionnaire. J Thromb Haemost 2008 Dec;6(12):2062-66. James P, Bowman M, Grabell J, Dwyre L, Rapson D. Prospective Validation of the Condensed MCMDM1-VWD Bleeding Questionnaire for Platelet Function Disorders. J Thromb Haemost 2011; 9 (Suppl 2), p 549, P-WE-092. useful Website: Clinical and Molecular Hemostasis Research Group: Available at http://www.path.queensu.ca/labs/james/bq.htm

Chapter 6: Diagnosis and Management of Common Bleeding Disorders American Society of Hematology. Clinical Practice Guideline on the Evaluation and Management of von Willebrand Disease (VWD). Quick Reference Guide, 2012. Assessed November 27, 2018. Bolton-Maggs PHB. Factor XI deficiency. 3rd ed. Treatment of Hemophilia No. 16. Montreal: World Federation of Hemophilia; 2008. Available at http://www1.wfh.org/publication/files/pdf-1141.pdf. Accessed 25 Feb 2013. To order this resource, please visit the Transfusion Ontario website : www.transfusionontario.org Cox K, Price V, Kahr WH. Inherited platelet disorders: a clinical approach to diagnosis and management. Expert Rev Hematol 2011;4:455-72.

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