Coagulopathy Bundarika Suwanawiboon M.D. Yingyong Chinthammitr M.D. Theera Ruchutrakool M.D. Division of Hematology Department of Medicine Faculty of medicine

CoagulopathyCoagulopathy

Bundarika Suwanawiboon M.D. Yingyong Chinthammitr M.D.Theera Ruchutrakool M.D.

Division of HematologyDepartment of Medicine Faculty of medicineSiriraj HospitalBangkok Thailand 10700

CoagulopathyCoagulopathy

Bundarika Suwanawiboon M.D.

Yingyong Chinthammitr M.D.

Theera Ruchutrakool M.D.

CoagulopathyCoagulopathyOutline

Basic of Normal Hemostasis (35 minutes) Theera

Clinical and Laboratory Approach to

Bleeding Patients (35 minutes)

Bundarika

Management of Bleeding Patients

(35 minutes)

Yingyong

Question and answer (15minutes) All

Normal HemostasisNormal Hemostasis

Normal hemostasis Blood vessel Platelet Coagulation factors Fibrinolytic system Natural anticoagulants

Red blood cellPlatelet



Von Willebrand factor


















Von Willebrand factorFibrin polymer






Normal hemostasis Blood vessel Platelet Coagulation factors Fibrinolytic system Natural anticoagulants

Blood vesselBlood vessel Endothelium Connective tissue or collagen


Blood vesselBlood vessel Endothelium


Antithrombotic Effect

Thrombomodulin Platelet derived relaxing

factor (PDRF) Prostacyclin (PGI2) Tissue plasminogen

activator

Thrombogenesis

von Willebrand factor Tissue thromboplastin Endothelin





Collagen direct bind and activate platelet Release von Willebrand factor to bind platelet


PlateletPlatelet Adhesion

via glycoprotein (GP) Shape change

from disc to ameboid form Release

ADP, thromboxane A2, vWF Aggregation

via glycoprotein (GP)


PlateletPlatelet

ligand receptor

adhesion vWF GP Ib/IX/V

collagen GP Ia/IIa

aggregation fibrinogen GP IIb/IIIa


PlateletPlatelet

Platelet plug formation and vasoconstriction

Primary hemostatic plug formation which is enough to stop bleeding from

small and shallow wound

Factor XII HMWK/PK

Factor XI Factor XIa

Factor IX Factor IXa Factor VIIaFactor VIIIa Tissue factor

Factor X Factor Xa Factor XFactor Va

Prothrombin Thrombin

Fibrinogen Fibrin

Normal HemostasisNormal HemostasisCoagulation pathwayCoagulation pathway

Factor XII HMWK/PK





Fibrinogen Fibrin


Common pathway

Intrinsic pathway

Extrinsic pathway

Factor XII HMWK/PK





Fibrinogen Fibrin

Normal HemostasisNormal HemostasisCoagulation pathwayCoagulation pathway

Normal HemostasisNormal Hemostasis Factor XII HMWK/PK





Fibrinogen Fibrin

heparin

Activated proteinC

ProteinC

Protein S

antithrombin

Natural anticoagulantNatural anticoagulant

High Molecular Weight Kininogen (HMWK)Prekallekrein (PK)F.XII

Tissue plasminogen activator (t-PA)Urokinase

Plasminogen PlasminFibrin polymer

Fibrin degradation products (FDP)

Normal HemostasisNormal HemostasisFibrinolytic systemFibrinolytic system

Streptokinase


““New concept !”New concept !”

Cell-based model of coagulation

1. Initiation

3. Propagation

IIa

IIa

2. Amplificatio

n

Hemostasis occurs on two surfaces:TF- bearing cells and platelet


TF

VIIa

TF-expressing cell

TF

VIIa

Activated platelet

platelet

X

Va

Xa

prothrombin

thrombin

VIII/vWF VIIIa

V

XI XIa

Va

prothrombinthrombin

X

Xa

Va

IX

IXa

IXa

VIIIa

IXXIa

Hoffman M et al. Blood Coagul Fibrinolysis. 1998; 9(suppl 1): S61-S65.

TF

VIIa

TF-expressing cell

TF

VIIa

Activated platelet

platelet

X

Va

Xa

prothrombin

thrombin

VIII/vWF VIIIa

V

XI XIa

Va

prothrombin thrombin

X

Xa

Va

IX

IXa

IXa

VIIIa

IXXIa

Hoffman M et al. Blood Coagul Fibrinolysis. 1998;9(suppl 1):S61-S65.

Cell-based model “Three overlapping phases”

Initiation phase “TF-bearing cell to generate F.Xa,

F.IXa and (little amount of) thrombin”

Amplification phase“Gererate cofactor F.V and F.VIII by

little amount of thrombin from initiation phase”

Propagation phase“Large amount of thrombin production

(burst of thrombin) on activated platelet”

Approach to Hemostatic Disorders:

Clinical and Laboratory Approach

Bundarika Suwanawiboon, M.D.

Division of Hematology

Department of Medicine

What is the diagnosis?What is the diagnosis?

Clinical Evaluation of Bleeding PatientsClinical Evaluation of Bleeding Patients

“80% of correct diagnosis can be made by history taking and physical examination.”

History TakingHistory Taking

Identify if the bleeding problem is due toLocal vs. systemic defect

Location: single vs. multiple sitesSeverity: Spontaneous? Appropriate to trauma?

Hereditary vs. acquired disorderOnsetFamily historyUnderlying diseaseMedication

Primary vs. secondary hemostatic disoder

Deep Deep ecchymosis,

hematoma

Rare

Retroperitoneal hematoma, hemarthrosis

Superficial Petechiae, superficial

ecchymosis

Common

Rare

Sites Skin

Mucosal

Others

DelayedImmediateOnset

Secondary HemostasisPrimary Hemostasis

Primary Hemostatic defect Secondary Hemostatic defect

Laboratory Investigation of Laboratory Investigation of Hemostatic DisordersHemostatic Disorders

Assessment of Primary HemostasisAssessment of Primary Hemostasis

PlateletComplete blood count (CBC)Bleeding time/ PFA-100Platelet aggregation study

Blood vesselBleeding time

von Willebrand factor (vWF)Bleeding timevWF Antigen, vWF: RCO, vWF multimer, FVIII

Complete Blood Count (CBC)Complete Blood Count (CBC)

Platelet number Normal platelet count: 150,000 –400,000/uL

> 100,000/uL Bleeding unlikely

< 20,000/uL ↑ risk for spontaneous

bleeding

Must exclude pseudothrombocytopenia

Assess for platelet morphology

Bernard-Soulier Syndrome

Giant platelet

Thrombocytopenia

Pseudothrombocytopenia

Etiology of ThrombocytopeniaEtiology of Thrombocytopenia

Decreased Production

• Hypoproliferation

• Ineffective Thrombopoiesis

• Aplastic Anemia, Amegakaryocytic

thrombocytopenia, infection, toxins, drugs

Infiltrative marrow disease, TAR

• Megaloblastic anemia

Increased Destruction

• Immune

• Non-immune

• Alloimmune, Autoimmune: ITP, SLE

• DIC, TTP, HUS

Others

• Splenic sequestration

• Dilutional

• Hypersplenism

• Massive blood transfusion

Bleeding TimeBleeding Time

Bleeding Time: InterpretationBleeding Time: Interpretation

Normal value* : 1-9 minProlonged bleeding time:

Thrombocytopenia/ anemia (Hct < 20%)Hereditary platelet dysfunctionvon Willebrand diseaseSevere hypofibrinogenemiaBlood vessels disordersUremiaMyeloproliferative disordersMedication: Aspirin, NSAIDs,other antiplatelet drugs

Platelet Aggregation StudyPlatelet Aggregation Study

Normal Platelet ResponseNormal Platelet Response

Arterioscler Thromb Vasc Biol 2000 20:285

Epinephrine ADP Collagen Ristocetin Arachidonic

acid

Normal +++ +++ +++ +++ +++

Glanzmann’s - - - +++ -

Thrombasthenia

Bernard-Soulier +++ +++ +++ - +++

Syndrome

Storage Pool + +* +* +++ ++

Disease (no secondary wave)

Aspirin + ++ + ++ -

Effect

von Willebrand Factorvon Willebrand Factor

Synthesized in endothelial cells and megakaryocytes

Two important functions:Carrier protein for plasma FVIII

Ligand binding to platelet GPIb receptor to initiate platelet adhesion

Primary Hemostasis: vWFPrimary Hemostasis: vWF

Arterioscler Thromb Vasc Biol 2000 20:285

von Willebrand Factor Panelvon Willebrand Factor Panel

vWF antigen

vWF ristocetin cofactor activity

vWF multimer analysis

FVIII level

vWD Laboratory DiagnosisvWD Laboratory Diagnosis

Test/Type 1 2A 2B 2M 2N 3

BT N or ↑ ↑ ↑ N or ↑ ↑ ↑ N ↑↑↑↑

vWF:Ag ↓ ↓ ↓ ↓ or N ↓ or N ↓↓↓↓

vWFR:Co ↓ ↓↓↓ ↓↓ ↓ ↓ or N ↓↓↓↓

LD-RIPA - - ↑ - - -

FVIII N or ↓ N or ↓ N or ↓ N ↓↓↓ ↓↓↓

Multimer N but ↓ abnormal abnormal N but ↓ N but ↓ absent

vWF Multimer AnalysisvWF Multimer Analysis

Hoffmann. 4th Ed.Hematology Basic Principles and Practice

Assessment of Secondary HemostasisAssessment of Secondary Hemostasis

Screening tests:PT

aPTT

Mixing study

Additional TestsFibrinogen

Thrombin Time

Reptilase time

Coagulation factor assays

D-dimer

Fibrin Degradation Product

Euglobulin lysis time

Accurate Sample Collection is the KeyAccurate Sample Collection is the Key

Always use 3.2% sodium citrate tube and sent to the lab immediately.

Fill tube to the proper level.

(anticoagulant to plasma ratio = 1:9)

Modification may be required based on Hct Sodium citrate (ml) = (100 – Hct pt) x 0.5 / 55*

* normal plasma vol.

XII XIIa

XI XIaHMWK

IXaIXVIIIa/PL

Tenase

Ca++X Xa

II IIaVa/PL

Ca++

Fibrinogen Fibrin

X-linkedFibrin

XIIIa

Intrinsic Pathway Extrinsic Pathway

Common Pathway

XII XIIa

XIHK/PK

IXa/IX

VIIIaVIIa/TF

VIIVIIa

TF

Ca++X Xa

II IIaVa/PL

Ca++

Fibrinogen Fibrin

XIa

Prothrombin Time (PT)Prothrombin Time (PT)

PT : test extrinsic and common pathway

Activated Partial Thromboplastin Time Activated Partial Thromboplastin Time (aPTT)(aPTT)

aPTT : test intrinsic and common pathway

Mixing StudyMixing Study

+

0% 100%

50%

<35%

Correctable

Normal coagulation

time

Uncorrectable

prolonged coagulation

time

Deficiency

Inhibitor

Prolonged PT or aPTT occurs when coagulation factor < 35-40%

Interpretation of Abnormal Interpretation of Abnormal CoagulogramCoagulogram

Isolated prolonged PT

Isolated prolonaged aPTT

Prolonged PT and aPTT

Isolated prolonged PT

Mixing study

Correctable Uncorrectable Deficiency Inhibitor

Hereditary: FVII FVII (rare) Lupus anticoagulant Acquired: Early liver impairment

Vitamin K antagonist Vitamin K deficiency

Isolated prolonged aPTT

Bleeding No bleeding

Mixing study Mixing study

Correctable Uncorrectable Correctable Uncorrectable

Deficiency Inhibitor Deficiency Inhibitor

Factor VIII /vWD Factor VIII Factor XII Factor XIIFactor IX Factor IX HMWK HMWKFactor XI Factor XI Prekallekrein Prekallekrein Heparin Lupus anticoagulant

Acquired FVIII inhibitor

Prolonged aPTT and PT

Mixing study

Correctable Uncorrectable

- FII,FV or FX deficiency - FII, V, or X inhibitor - FV and VIII deficiency - Lupus anticoagulant - Liver disease - LAC + Factor inhibitor - Vitamin K antagonist - Vitamin K deficiency - DIC

Bleeding Disorders with Bleeding Disorders with Normal PT and aPTTNormal PT and aPTT

Factor XIII deficiency

Dysfibrinogenemia

Mild isolated factor deficiency

-antiplasmin deficiency

Elevated fibrin degradation products

Platelet disorders

Vascular disorders

Further Diagnostic TestsFurther Diagnostic Tests

Specific coagulation factor assay

Coagulation factor inhibitor assay

Lupus anticoagulant panel

Other Tests for Secondary HemostasisOther Tests for Secondary Hemostasis

Fibrinogen

D-dimer

Fibrin(ogen) degradtion product

Thrombin time

Reptilase time

Euglobulin lysis time

FibrinogenFibrinogen

Functional level (200-400 mg/dl)↓ Fibrinogen (esp. < 100 )

DICFibrinolytic therapyPrimary fibrinolytic stateCongenital afibrinogenemiaAcquired/congenital dysfibrinogenemia

↑ FibrinogenInflammatory states/acute illnessMay associated with shortened PT/aPTT

D-Dimer

Measured cross-linked fibrin degradation product by plasmin

More sensitive and specific for fibrinolysis than Fibrin(ogen) Degradatioin Product (FDP)

↑ D-dimer:DIC

Acute thromboembolic episodes

Post-trauma or surgery

Malignancy

Fibrin(ogen) Degradation Product

↑ levels inPrimary fibrinolytic syndromes

DIC

After lytic therapy

Acute thromboembolic episodes

After injury/surgery

Thrombin TimeThrombin Time

Thrombin Time (TT)Assess the ability to convert fibrinogen fibrin by adding thrombin to plasma

Prolonged TT:Inhibitor of thrombin: heparin, anti-thrombin antibody

Hypofibrinogenemia or dysfibrinogenemia

Inhibitor of fibrin polymerization: fibrin degradation product, paraprotein

Euglobulin Lysis TimeEuglobulin Lysis Time

Euglobulin fraction of plasma is precipitated by acetic acid and thrombin added.

Lysis of clot is observed.

Normal : > 120 min

Shortened ELT:DIC

Liver disease

Primary fibrinogenolysis: malignancy, e.g. prostate carcinoma

Management of Bleeding Patients

Yingyong Chinthammitr27 June 2007

Objectives

• Efficient practice of replacement therapy

• Management of common bleeding problems

Goal of replacement Rx

• Treatment of bleeding

• Prevention of bleeding before procedure

• Not treat only lab. esp. in irreversible causes of coagulopathy

WB

PRC PRP

FFP PC

CRP Cryo

WB = Whole blood

PRC = Pack Red CellPRP = Platelet-rich plasma

FFP = Fresh frozen plasmaPC = Platelet concentrates(other: apheresis PLT = 4-6 u)

CRP = Cryo-removed plasma,FFP with cryo.-removed

Cryo. = Cryoprecipitate(F VIII 100 u, vWF, Fibrinogen, F XIII)

1 unit

Other products

• Factor concentrates : VIII, IX• Prothrombin complex concentrates (PCC)• Activated PCC (APCC)• DDAVP• Vitamin K injection• Recombinant F VIIa (novoseven)• Tranexamic acid – antifibrinolysis• Fibrin glue – two bottles: Fibrinogen & Thrombin

Recombinant Factor VIIa (NovosevenR)

EFFECTIVE+SAFE but VERY EXPENSIVE

- Hemophilia with inhibitor (alloantibody)- Factor VIII inhibitor (autoantibody)

- Uncontrolled bleeding from coagulopathy (liver failure)- Uncontrolled bleeding from thrombocytopenia- Uncontrolled bleeding from platelet dysfunction (uremia , congenital defect)- Severe surgical and traumatic hemorrhage

VIIa

TFPI

Activated Platelet

TF

Va

XI a XaIXa

X II

IIa

IX

IX

Activated platelet

VaVIIIa

IIa

VIII/vWF

XI

XIaPlatelet

Va

V

VIIIa + free vWF

V

TF

Tissue factor--bearing cell

TFTF

VIIaVIIaXaXa

TF TFTF

TF

Va

II

X

TFPI

Activated Platelet

TF

Va

Xa

X II

IIaActivated platelet

Va

IIa

VIII/vWF

XI

XIaPlatelet

Va

V

VIIIa + free vWF

V

TF

Tissue factor--bearing cell

TFTF

VIIaVIIaXaXa

TF TFTF

TF

Va

II

X

VIIa

Fibrin Glue- มี� 2 ขวด คือ

1. Thrombin2. Fibrinogen, F XIII (cryoprecipitate)

Thrombin XIIIaFibrinogen ------------->Fibrin ------> Cross-linked

Fibrin

เติ มี Calcium ใน Thrombin

อาจเติ มี Tranexamic acid ใน Fibrinogen

ใช้� อ�ปกรณ์� two syringes with one air-line

Tranexamic acid

- anti-fibrinolysis- adjunctive Rx in areas with high fibrinolysis (Oral cavity, GI tract, GU tract)- Contraindication : DIC, Thrombosis, Renal bleeding (obstructive uropathy)- IV : 10 mg/kg/dose q 8 h- Oral : 25 mg/kg/dose q 8 hr- Oral wash in dental bleeding

http://content.nejm.org/content/vol356/issue22/images/large/10f1.jpeg

Bleeding

• Thrombocytopenia

• Coagulopathy

• Combined

Platelet level & Bleeding

• > 100,000/mm3 No bleeding tendency• < 100,000/mm3 Bleeding time prolongation• < 50,000/mm3 Bleeding after trauma , surgery• < 10,000/mm3 Spontaneous bleeding• < 5,000/mm3High risk for spontaneous CNS bleeding

• Platelet level

• Platelet function

• Anemia

• Local problem

• Coexisting coagulopathy

Thrombocytopenia & Bleeding

Platelet transfusion

• Symptomatic Rx , not Rx cause• Dose: 1 unit per 10 kg BW• Indication

– Bleeding associated with thrombocytopenia– Prophylaxis, before invasive procedure/surgery

• Contra-indication– TTP (Thrombotic thrombocytopenic

purpura) /HUS (Hemolytic uremic syndrome), HIT (Heparin-induced thrombocytopenia)

Prophylaxis in thrombocytopenia

Condition Threshold

Chronic stable thrombocytopenia (underproduction e.g. aplastic anemia)

<5,000 or No

Post-chemo stable patient <10,000

Unstable (fever or infection or coagulopathy or platelet dysfunction)

<20,000

Invasive procedures, surgery <50,000

Neurosurgery, ocular Sx <100,000

Plasma derivatives: FFP, Cryo.

• No medications added• Return to blood bank if not use within 30 min• Most adverse transfusion reactions occur in the

first 15 min.• Time of transfusion – not exceed 4 hr• Rate in adult (good cardiac

condition) : 200 - 300 mL/hr• NOT for: volume expansion, protein (alb, glob)

nutrient

Cirrhosis• FFP 10-15 ml/kg• Vitamin K 10 mg IV • Pitfalls

– Uncorrected localized bleeding problem e.g. varice, mucosal lesion

– Overdependence on PT – Goal: to correct or prevent bleeding, NotNot to achieve a

normal PT– Timing of FFP therapy before an invasive procedure

- Vitamin K : fat-soluble vitamin- Vitamin K-dependent factors : II,VII,IX,X ; Protein C,S,Z- Vit.K : K1(green vegetables), K2(gut flora), K3(synthetic water-soluble)

Vitamin K deficiency

* Neonatal : hemorrhagic disease of the newborn* Children & Adult : - low intake- absorption defect - cholestasis, fat malabsorption syndrome- broad-spectrum antibiotics (+low intake)



• Vit. K 10 mg IV slowly, sc

• FFP

• Prothrombin complex concentrate (PCC)

HEMARTHROSIS AND HEMOPHILIC ARTHROPATHY

Hemophilia A• Cryoprecipitate• Factor VIII concentrates• FFP• DDAVP

Hemophilia B

• FFP• Cryo. Removed Plasma• F IX concentrates

vWD• DDAVP• Cryoprecipitate• F VIII concentrates • FFP

Rx of Bleeding episodes in Hemophilia

Site Level (%) Rx Length

Joint 30-40 1 dose

Muscle 30-40 1-3 doses

Hematuria 30-40 1 dose

Retroperitoneal 50 5-7 d

GI 50 5-7 d

Neck 100 7-10 d

Intracranial 100 10-14 d

Hemophilia A with hemarthrosis

• 60 kg.

• Raise F VIII to 30 %

• 1 u/kg raise 2%

• F VIII half life = 12 hr– Raise 30% -> 15 u/kg = 15x60 = 900 u– Cryo. 9 bags ( cont. ~5 bags q 12 hr)

Hemophilia B with hemarthrosis

• 60 kg.

• Raise F IX to 30 %

• 1 u/kg raise 1%

• F IX half life = 24 hr– Raise 30% -> 30 u/kg = 30x60 = 1800 u– FFP 1800 ml. ( cont. 900 ml. q 24 hr)

Warfarin-associated coagulopathy & bleeding

• Life-threatening Bleeding– withhold warfarin, FFP/PCCs, vit. K 5-10 mg.

i.v., provide medical support (e.g. PRC)

• Major, non-life-threatening Bleeding– withhold warfarin, FFP/PCCs, vit. K 1-10 mg.

i.v., provide medical support (e.g. PRC)

J Thromb Haemost 2006;4:1853-63

Warfarin-associated coagulopathy & NoNo bleeding

– Withhold warfarin– Vit. K 1 mg.– Reintroduce at a

lower dose on the following day

– Recheck INR in < 72 hr

Beware of re-thrombosis from overcorrection

– Withhold warfarin– Vit. K 1 mg. i.v.– Recheck INR in 24

hr

– Withhold warfarin

– Recheck INR in 24-48 hr

INR 4.5-10INR 4.5-10

Identify and correct the cause of elevated INR

INR >10INR >10

J Thromb Haemost 2006;4:1853-63

Heparin

• Unfractionated heparin (prolonged APTT)– Bleeding: hold heparin, protamine (1 mg/100

u heparin)– No bleeding: hold heparin (Hf. life 1 hr)

• LMWH (normal APTT)– Bleeding: protamine (neutralize all anti-IIa but

75% of anti-Xa)

DIC

• Rx cause

• Bleeding– FFP , PLT concentrate– Cryoprecipitate raise fibrinogen > 100 mg/dL

:1 bag/5 kg BW raise fibrinogen 100 mg/dL

Treatment of DIC

* Treat associated disease* Bleeding - Replacement therapy* Thrombosis - heparin : purpura fulminans, acral/dermal ischemia, retained dead fetus syndrome, giant hemangioma, aortic aneurysm without rupture, solid tumor* AT concentrate, APC

Massive blood transfusion

• > Total blood volume in 24 hour

• Dilution and/or consumption of PLT, Coag. Factors

• LAB: platelet, coagulogram, fibrinogen

• PLT > 50,000, PT <1.5 times the midpoint of normal range, Fibrinogen >100 mg/dL : generally adequate for hemostasis

Platelet dysfunction

• Stop Antiplatelet agents before surgery– Aspirin : 7 days (irreversible inhibition)– NSAID : 1-4 days (reversible inhibition)– Clopidogrel : 10 days

Uremic bleedingTreatment Regimen Onset Duration

*PRC /LPB Hct ~30% 1 h While Hct at this level

*EPO 50-100 U/kg Hct 30% Same

(~6 wk)

*Cryoppt. 10 units 1 h 24–36 h[Effective ~ 50%]

*DDAVP 0.3-0.4 mcg/kg 1 h 4 – 8 h IV or SC 2-3 mcg/kg intranasal

*Conjugated 0.6 mkd IV 6 h 14 d (IV)

estrogen 50 mkd po 2 d 5 d (PO)

x 5 days

*Dialysis

Thank you for your attentionThank you for your attention

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Coagulopathy Bundarika Suwanawiboon M.D. Yingyong Chinthammitr M.D. Theera Ruchutrakool M.D. Division of Hematology Department of Medicine Faculty of medicine