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Haemostasis&Bleeding disorders

BYBY

Prof.DrProf.Dr. . Mervat Atfy MohamedMervat Atfy Mohamed

Objectives/Outline

Definitions Review pathophysiology of bleeding

Provide a framework for differential diagnosis of purpura

Brief discussion of some of the more common presentations and their management

Purpura

Hemorrhage into skin or mucous membrane

Due to:1. Loss of vascular integrity2. Platelet problems

Number Function

3. Clotting factor deficiency

Purpuric lesions

Petechiae capillary hemorrhages, purple macular lesions 2mm develop in areas of increased venous pressure

Purpura – 2mm-1cm

Ecchymoses – > 1cm, often tender

Non-blanching, may be raised

PlateletPlatelet

platelet platelet countcount

bleeding bleeding timetime

< 8 min< 8 min Platelet Platelet functionfunction

CoagulationCoagulation

ACTACT

PTPT

aPTTaPTT

thrombin thrombin timetime

fibrinogenfibrinogen

90-130 sec90-130 sec

12-15 sec12-15 sec

35-45 sec35-45 sec

< 14 sec< 14 sec

250-500 250-500 mg/dLmg/dL

Monitor Monitor heparinheparin

Extrinsic & Extrinsic & finalfinal

Intrinsic & Intrinsic & finalfinal

Final commonFinal common

↓↓in DICin DIC

FibrinolysisFibrinolysis

FDPFDP

d-dimerd-dimer↑↑during during fibrinolysisfibrinolysis

Hemostasis requires normal:

vessels platelets coagulation pathway components

Coagulation factor disorders

Inherited bleeding disorders

Hemophilia A and B vonWillebrands disease Other factor

deficiencies

Acquired bleeding disorders

Liver disease Vitamin K

deficiency/warfarin overdose

DIC

Hemostasis

Arteriolar vasoconstriction Formation of platelet plug

Activation of coagulation cascade Formation of permanent plug

Secondary Hemostasis

Primary Hemostasis

Four reasons for Cell based model

1. Congenital deficiency of XII, HMW kininogen and pre-kallikrein have prolonged PTT but NO BLEEDING PHENOTYPE.

2. These components are NOT required for hemostasis in vivo

3. TF/VIIa activates not only X but also VIII and IX

4. XI deficiency is not associated with bleeding phenotype

Cell Based coagulation model

TF bearing cells Adventital cells Myo-epithelial cells Endothelial cells

3 phases Initiation Priming Propagation

Initiation

TF bearing cells exposed to plasma

VII binds to TF and is activated VIIa Xa TF/VIIa IXa

TF/VIIa/Xa binds Va converts Prothrombin to Thrombin

Small amount of Thrombin Activate platelets accelerant

Priming

Release of granules containing V Cleaved to Va Formation of VIIIa

Propagation Activated platelets rapidly bind

V/VIII/IX Formation of VIII/IXa complex MAJOR activator of X Major prothrombin activator

Screening tests for bleeding disorders

Prothrombin time Measures function of VII, X,

Prothrombin, fibrinogen Prolonged when V, VII, X fall below

50% And when prothrombin level falls to

<30% Vit K dependent proteins:

Prothrombin, V, VII, X, Proteins C and S Warfarin, Liver Failure

Screening tests for bleeding disorders

aPTT Detects decrease in XII, XI, IX, VIII AS WELL AS Fibrinogen, prothrombin, V and X Heparin

Hemophilia

X linked recessive Deficiency of Factor VIII Degrees of severity:

Mild : 5% - 30% Moderate : 2% - 5% Severe : <2%

Prolonged PTT. Normal PT, vWf, BT

Hemophilia A and BHemophilia A Hemophilia B

Coagulation factor deficiency Factor VIII Factor IX

Inheritance X-linked X-linkedrecessive recessive

Incidence 1/10,000 males 1/50,000 males

Severity Related to factor level<1% - Severe - spontaneous bleeding1-5% - Moderate - bleeding with mild injury5-25% - Mild - bleeding with surgery or trauma

Complications Soft tissue bleeding

Hemophilia

Clinical manifestations (hemophilia A & B indistinguishable)

Hemarthrosis (most common)Fixed joints

Soft tissue hematomas (e.g., muscle)Muscle atrophyShortened tendons

Other sites of bleedingUrinary tractCNS, neck (may be life-threatening)

Prolonged bleeding after surgery or dental extractions

Treatment of hemophilia A

Intermediate purity plasma products Virucidally treated May contain von Willebrand factor

High purity (monoclonal) plasma products Virucidally treated No functional von Willebrand factor

Recombinant factor VIII Virus free/No apparent risk No functional von Willebrand factor

Dosing guidelines for hemophilia A

Mild bleeding Target: 30% dosing q8-12h; 1-2 days (15U/kg) Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria

Major bleeding Target: 80-100% q8-12h; 7-14 days (50U/kg) CNS trauma, hemorrhage, lumbar puncture Surgery Retroperitoneal hemorrhage GI bleeding

Adjunctive therapy amino caproic acid (Amicar) or DDAVP (for mild disease only)

Complications of therapy

Formation of inhibitors (antibodies) 10-15% of severe hemophilia A patients 1-2% of severe hemophilia B patients

Viral infections Hepatitis B Human parvovirus Hepatitis C Hepatitis A HIV Other

Treatment of hemophilia B Agent

High purity factor IX Recombinant human factor IX

Dose Initial dose: 100U/kg Subsequent: 50 U/kg every 24 hours

Von Willebrand disease

Most common congenital bleeding disorder

Bleeding is usually mild Etiology of bleeding

Platelet aggregation Major carrier for VIII

Types

von Willebrand DiseaseClinical features

von Willebrand factor Carrier of factor VIIIAnchors platelets to

subendothelium Bridge between platelets

Inheritance Autosomal dominant

Incidence 1/10,000

Clinical features Mucocutaneous bleeding

Laboratory evaluation of von Willebrand disease

Classification Type 1 Partial quantitative deficiency Type 2 Qualitative deficiency Type 3 Total quantitative deficiency

Diagnostic tests:

vonWillebrand typeAssay 1 2 3

vWF antigen Normal

vWF activity Multimer analysis Normal Normal

Absent

Treatment of von Willebrand diseaseVaries by Classification Cryoprecipitate

Source of fibrinogen, factor VIII and VWF Only plasma fraction that consistently contains VWF

multimers Correction of bleeding time is variable

DDAVP (Deamino-8-arginine vasopressin) Increases plasma VWF levels by stimulating secretion from

endothelium Duration of response is variable Used for type 1 disease Dosage 0.3 µg/kg q 12 hr IV

Factor VIII concentrate (Humate-P) Virally inactivated product Used for type 2 and 3

Type I vW disease

Autosomal dominant Normal vWF Quantitative decrease Normal PT Mildly prolonged aPTT

Rx of vW disease

DDAVP Cryoprecipitate Monitor VIII levels

DDAVP

1-Deamino, 8 D-arginine vasopressin

Rx for mild Hemophilia A , vW disease

Increases plasma fVIII, vWf from endogenous sorces

Amount of increase = factor transfusion

Useful for platelet dysfunction secondary to aspirin, dextran, ticlopidine

0.3- 0.4 mcg/kg Onset 30 min, peak 90-120 min

Cryoprecipitate

useful in treating factor deficiency (hemophilia A), von Willebrand's disease, and hypofibrinogenemia

uremic bleeding Each 5- to 15-mL unit contains more than

80 units of factor VIII and about 200 mg of fibrinogen.

Because the proteins mentioned previously are in relatively high concentration, a smaller volume may be given than would be required if plasma were used. Cryoprecipitate is usually administered as a transfusion of 10 single units.

NovoSeven

Recombinant f VIIa Activates X and IX (conversion of

prothrombin to thrombin) $$$$ Not FDA approved Anecdotal miraculous rescues

Heparin

Blocks Xa by binding to AT-III and thrombin.

Load 80 mg/kg Infusion 18 mg/kg Cleared from blood in 6hrs Neutralized by protamine 100u of Heparin = 1mg of

protamine

HIT

Heparin induced thrombocytopenia

Formation of IgG against Heparin- PF4 complexes

Upto 5% of patients Onset 4-5 days, but earlier if prior

exposure Can occur with flushes, heparin

bonded catheters also

LMW Heparins

More selective anti-Xa activity Less bleeding complications Do not affect PT Measure anti Xa activity <1% incidence of HIT

Enoxaparin

LMW heparin Porcine intestinal submucosa Binds to and accelerates AT-III

activity

Fondaparinux (Erixtra)

Synthetic pentasaccharide 5 sugar AT-III binding site similar

to Heparin 1000x more potent Very low- no incidence of HIT Cannot be given in CRI

Vitamin K

Necessary for addition of carboxyglutamate residues to the clotting factors synthesized in the liver.

Sites of Calcium binding Prothrombin, VII, IX, X drugs- cephalosporins, quinolones 5mg iv slowly corrects deficit in 6

hrs 10-25 mcg /day sq or im x 3days

Vitamin K deficiency

Source of vitamin K Green vegetablesSynthesized by

intestinal flora

Required for synthesis Factors II, VII, IX ,XProtein C and S

Causes of deficiency MalnutritionBiliary obstruction

MalabsorptionAntibiotic therapy

Treatment Vitamin KFresh frozen plasma

Vitamin K deficiency due to warfarin overdoseManaging high INR values

Clinical situation Guidelines

INR therapeutic-5 Lower or omit next dose;Resume therapy when INR is therapeutic

INR 5-9; no bleeding Lower or omit next dose;Resume therapy when INR is therapeutic

Omit dose and give vitamin K (1-2.5mg po)

Rapid reversal: vitamin K 2-4 mg po (repeat)

INR >9; no bleeding Omit dose; vitamin K 3-5 mg po; repeat as necessaryResume therapy at lower dose when INR therapeutic

Chest 2001:119;22-38s (supplement)

Vitamin K deficiency due to warfarin overdoseManaging high INR values in bleeding patients

Clinical situation Guidelines

INR > 20; serious bleeding Omit warfarinAny life-threatening bleeding Vitamin K 10 mg slow IV infusion

FFP ± factor rhVIIa (depending on urgency)Repeat vitamin K injections every 12 hrs as needed

Warfarin

DIC

Consumption coagulopathy Systemic thromb-hemorrhagic

disorder Etiology:

Gram negative sepsis, crush injuries, amniotic fluid embolism, hemolysis, massive transfusion

Activation of clotting and fibrinolysis

Microvascular thrombosis, sequestration of platelets

Pathogenesis of DIC

Coagulation Fibrinolysis

Fibrinogen

FibrinMonomers

FibrinClot

(intravascular)

Fibrin(ogen)Degradation

Products

Plasmin

Thrombin Plasmin

Release of thromboplastic material intocirculation

Consumption ofcoagulation factors;

presence of FDPs aPTT PT TT

Fibrinogen

Presence of plasmin FDP

Intravascular clot Platelets

Schistocytes

Common clinical conditionsassociated with DIC

Sepsis

Trauma Head injury Fat embolism

Malignancy

Obstetrical complications Amniotic fluid embolism Abruptio placentae

Vascular disorders

Reaction to toxin (e.g. snake venom, drugs)

Immunologic disorders Severe allergic reaction Transplant rejection

DIC

Low fibrinogen High FDP Low platelets Elevated D-dimer

Disseminated Intravascular Coagulation (DIC)Mechanism

Systemic activationof coagulation

Intravasculardeposition of fibrin

Depletion of plateletsand coagulation factors

BleedingThrombosis of smalland midsize vesselswith organ failure

DICTreatment approaches

Treatment of underlying disorder

Anticoagulation with heparin

Platelet transfusion

Fresh frozen plasma

Liver Disease

Decreased synthesis of II, VII, IX, X, XI, and fibrinogenProlongation of PT, aPTT and Thrombin Time

Often complicated byGastritis, esophageal varices, DIC

TreatmentFresh-frozen plasma infusion (immediate but

temporary effect)Vitamin K (usually ineffective)

Stopping the bleeding

Direct pressure. More direct pressure. Pack. Pack.

Pack. Electrocautery. Ligate vessel

Methylcellulose Gelfoam

Absorbable Liquefies in 2-5

days Serves as a scaffold

for coagulation

Microfibrillar collagen

Decellularized bovine source Stimulates latelet adhesion Stops venous ooze Absorbed in 90 days

Thrombin + Gelfoam + CaCl

Thrombin for cleavage/activation Gelfoam as matrix Very useful in vascular surgery

Fibrin glue

Tiseel FDA approved in 1998 Concentrated fibrinogen and f VIII Thrombin and calcium Aprotinin to prevent clot

dissolution Takes time to prepare Good for diffuse oozing, needle

punctures, parenchymal injuries

Hemostasis:

BV Injury

PlateletPlateletAggregation

PlateletActivation

Blood VesselBlood Vessel Constriction

CoagulationCoagulation Cascade

Stable Hemostatic Plug

Fibrin formation

Reduced

Blood flow

Tissue Factor

Primary hemostatic plug

Neural

Lab Tests•CBC-Plt•BT,(CT)•PT•PTT

Plt StudyMorphologyFunctionAntibody

Hemostasis 1. Vascular phase : vasoconstriction,

immediately 2. Platelet phase : adhesion &

aggregation, several seconds after 3. Coagulation phase : later, contains extrinsic

& intrinsic pathways 4. Metabolic (fibrinolytic) phase: release

antithrombotic agent

primary

secondary

Hemostasis The intrinsic pathway : Initiated through surface contact activation of factor

XII by exposed subendothelial tissues--collagen The extrinsic pathway : Initiated through tissue thromboplastin released by

injured tissue, which activates factor VII

Antihemophilic factor; von Willebrand factor, VWF

Plasma thromboplastin component, PTC; Christmas factor

Antihemophilic factor; von Willebrand factor, VWF

Gla domain: activated by vit. K and NADH

Antithrombotic agent

Postaglandin: secretion by endothelial cell Antithrombin III (AT III): main Antithrombotic

agent Protein C: inactivate factor V and VIII with

protein S Plasmin: activated by urokinase and

streptokinase from plasminogen

primary

secondary

Etiology of bleeding disorder

1. Nonthrombocytopenia 2. Thrombocytopenia purpuras 3. Disorders of coagulation

Etiology of bleeding disorder

Nonthrombocytopenia 1. vascular wall alteration : infection,

chemical, allergy 2. Disorder of platelet function : Genetic defects (bernard-soulier disease:

glycoprotein, GP-Ib dysfunction with VWF) Aspirin, NSAIDs, broad-spectrum

antibiotics(Ampicillin, Penicillin, Gentamycin, Vancomycin)

Autoimmue disease

Adjunctive drug therapy for bleeding

Fresh frozen plasmaCryoprecipitateEpsilon-amino-caproic acid (Amicar)DDAVPRecombinant human factor VIIa (Novoseven)

Clinical Features of Bleeding Disorders

Platelet Coagulation disorders factor disorders

Site of bleeding Skin Deep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract)

Petechiae Yes No

Ecchymoses (“bruises”) Small, superficial Large, deep

Hemarthrosis / muscle bleeding Extremely rare Common

Bleeding after cuts & scratches Yes No

Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe

Correct surgical bleeding

ACT

elevated normal

Protamine 25-50mg PLT 0.1 u/kg

ACT

elevated

normal

Heparin level

yes

no

protamineCoagulation profile

FDP >32mcg/kg TEG abnormal clot lysis

fibrinolysis

FFP 5-10ml/kg CP 0.2-0.4u/kg EACA

PLT<70000

thrombocytopenia

PLT 0.1u/kg

bleeding time >20min

PLT dysfunction

Fibrinogen < 100mg/dL TEG abnormalhypofibrinogenemia

FFP 5-10ml/kg CP 0.2-0.4u/kg

aPTT >1.3x PT >1.5x

Anesthesiologist’s manual of surgical procedures

Fresh frozen plasma

Content - plasma (decreased factor V and VIII) Indications

Multiple coagulation deficiencies (liver disease, trauma) DIC Warfarin reversal Coagulation deficiency (factor XI or VII)

Dose (225 ml/unit) 10-15 ml/kg

Note Viral screened product ABO compatible

Cryoprecipitate

Prepared from FFP Content

Factor VIII, von Willebrand factor, fibrinogen Indications

Fibrinogen deficiency Uremia von Willebrand disease

Dose (1 unit = 1 bag) 1-2 units/10 kg body weight

Etiology of bleeding disorders

Thrombotic Thrombocytopenia purpuras (TTP)：血栓性血小板低下紫斑

1. primary 2. secondary : Chemicals, ex: mitomycin C Physical agent (radiation)

Systemic disease (leukemia)Character:1. 1.Thrombocytopenia 2. Micro-angiopathic hemolytic

anemia(MAHA) 3. Fever 4. Hyporenal function 5. Neural systemic desturbance due to ischemic

2. Considered to be an emergency 3. Tx: plasma exchange (血漿置換術 ) and glucocortisone

application

Etiology of bleeding disorders

Disorders of coagulation 1. Inherited : Hemophilia A Christmas disease von Willebrandis Disease 2. Acquired : Liver disease Vitamin K deficiency Anticoagulation drugs (heparin,

coumarin) Anemia

Etiology of bleeding disorders

Thrombotic Thrombocytopenia purpuras (TTP)：血栓性血小板低下紫斑

1. primary 2. secondary : Chemicals, ex: mitomycin C Physical agent (radiation)

Systemic disease (leukemia)Character:1. 1.Thrombocytopenia 2. Micro-angiopathic hemolytic

anemia(MAHA) 3. Fever 4. Hyporenal function 5. Neural systemic desturbance due to ischemic

2. Considered to be an emergency 3. Tx: plasma exchange (血漿置換術 ) and glucocortisone

application

Evaluation of bleeding disorders

1. Take history 2. Physical examination 3. Screening clinical laboratory tests 4. Observation of excessive bleeding following

a surgical procedure

Physical examination

Jaundice (黃疸 ) Petechiae (淤點 )： < 0.2 cm Purpura (紫斑 )： 0.2 cm-1 cm Eccymoses (淤斑 )： > 1 cm Spider angioma (蜘蛛斑 ) Oral ulcer Hyperplasia of gingiva Hemarthrosis (關節血腫 )

Platelet count

Test platelet phase: evaluation of platelet function

Normal (140,000 to 400,000/mm3) Thrombocytopenia : < 140,000/mm3 Clinical bleeding problem : <50,000/mm3 Spontaneous bleeding with life theartening :

<20,000/mm3

PT (Prothrombin Time)

Activated by tissue thromboplastin Tests extrinsic ( factor VII ) and common

( I,II,V,X ) pathways Normal ( 11-15sec ) Coumarin therapy- PT at 1.5 to 2.5 time International normalized ratio= INR, (1)

surgery can be done under INR< 3.0 (2) when INR=3.0-3.5, consultation is needed (3) delay surgery when INR>3.5

Activated PTT (aPTT)

Activated by contact activator (kaolin) Tests intrinsic and common pathway Normal ( 25-35 sec ) Heparin therapy- PTT in 50-65 sec range by

promote AT III

TT (Thrombin Time)

Activated by thrombin Tests ability to form initial clot from fibrinogen Normal ( 9 to 13 seconds )

1. No historical bleeding problem

3. Aspirin therapy

4. Coumarin therapy

6. Possible liver disease

7. Chronic leukemia

8. Long term antibiotic therapy

5. Renal dialysis (heparin)

2. History bleeding problem

9. Vascular wall alteration

10. Cancer (fibrinogenolysis)

Following surgical procedure

PT, aPTT, TT, BT

BT, aPTT

PT

aPTT

BT, PT

BT

PT

BT

TT

Dental management of the medically compromised patient

condition

8. thrombocytopenia

2. Coumarin therapy

4. Liver disease

7. Vascular wall defect

9. hemophilia

1. Aspirin therapy

Platelet count

5. leukemia

6. Long term antibiotic

3. Heparin therapy

10. fibrinogenolysis

+

-

+

+

+

-

-

++

-

-

BT

+

-

+

+

+

-

+

++

-

-

PTT

+

++

++

++

-

++

-

-

++

+

PT

+

++

-

++

-

++

-

-

-

+

TT

-

-

-

++

-

++

-

-

-

++

-: normal, +: may be abnormal, ++: abnormal

Patient at low risk

1. patient with no history of bleeding disorders, normal

examinations, no medications associated with bleeding

disorders and normal bleeding parameters

2. patients with nonspecific history of excessive bleeding

with normal bleeding parameters (PT, PTT, BT,

platelet count, are within normal time)

Patient at moderate risk

1. patients in chronic oral anticoagulant therapy

(coumadin) 2. patients on chronic aspirin therapy

Patient at high risk

1. patients with known bleeding disorders Thrombocytopenia Thrombocytopathy Clotting factor defects 2. Patient without known bleeding disorders

found to have abnormal , platelet count, BT, PT, PTT

Dental management of bleeding disorders Replacement therapy : 1. platelet concentrate : thrombocytopenia ( 1

unit= 30,000/ uL enough for 1 day ) 2. Fresh frozen plasma : liver disease,

Hemophilia B, vWD type III 3. Factor VIII,IX concentrate : Hemophilia A ( 1

unit /kg can add 2%, so 50 unit /kg add 100% ) 4. Factor IX concentrate : Hemophilia B 5. 1-desamino-8-darginine vesopressin (DDAVP)

: Hemophilia A, vWD type I, II

Antifibrinolytic therapy: 1. E-aminocaproic acid (EACA, Plaslloid) 2. Tranexamic acid (AMCA, Transamin)

Heparin (anticoagulant)

Complex inhibited ( IXa, Xa, XIa, XIIa ) Used in deep vein thrombosis , renal dialysis Rapid onset, Duration 4-6hrs ( given IV ) Monitoring by aPTT: 50-65 sec Discontinue 6 hrs before surgery then

reinstituting therapy 6-12hrs post –op Protamine sulfate can reverse the effect

Coumarin (Vit k anatagonist)

Inhibit Vit K action (Factor II,VII,IX,X) Used venous thrombosis, cerebrovascular

disease Duration haft-life 40hrs Monitored by PT : INR 1.5-2.5 PT>2.5, reduction coumarin dosage ( 2-3

days ) Vit. K can reverse the effect

Local hemostatic methods

splints, pressure packs, sutures; gelfoam with thrombin, surgicel, oxycel, microfibrillar collagen(avitene), topical AHF

Aspirin (antiplatelet)

Inhibit cycloxygenase, TxA2 formation Analgesic drug impairs platelet function Aterial thrombosis, MI Tests-BT, aPTT If tests are abnormal , MD should be consulted

before dental surgery is done Stop aspirin for 5 days, substitute alternative

drug in consultation with MD

Thrombocytopenia

Disease in number of circulation platelets Idiopathic thrombocytopenia, secondary

thrombocytopenia TX : is none indicated unless platelets<20000/mm3, or excessive

bleeding TX : Steroid, platelet transfusion

Von Willebrandis Disease

Gene mutation on Von Willebrandis factor; most common Inherited disease in America ( 1% )

Type I : 70%-80%, partial loss on quantity Type II : poor on quality Type III : severe loss on quantity, inactive to

DDAVP

Laboratory evaluation of von Willebrand disease

Classification Type 1 Partial quantitative deficiency Type 2 Qualitative deficiency Type 3 Total quantitative deficiency

Diagnostic tests:

vonWillebrand typeAssay 1 2

3

vWF antigen Normal

vWF activity Multimer analysis Normal Normal

Absent

Hemophilia

Sex-linked recessive trait, X chromosome, male > female

Prolong aPTT, normal BT,PT Hemophilia A (factor VIII deficiency) Hemophilia B or Christmas disease (factor IX

deficiency) Severity of disorder : severe<1%, moderate 1-

5%, mild 6-30% TX : Replacement factors, antifibrinilytic

agents, steroids

Hemophilia-dental management

Preventive dentistry 1. tooth brushing, flossing, rubber cup

prophylaxis & topical fluoride, supragingival scaling 2. without prior replacement therapy Pain control 1. block anesthesia: factor level>50% 2. Avoid aspirin, NSAIDs

Hemophilia-dental management

Orthodontic treatment : 1. no contraindication in well-motivated

patients 2. care with placement of bands and wires Operative dentistry 1. rubber dam to protect tissue against

accidental laceration 2. wedges should be place to protect and

retract papilla

Hemophilia-dental management

Pulp therapy 1. Preferable to extraction 2. Avoid overinstrumentation and overfilling Periodontal therapy 1. no contraindication of probing and

supragingival scaling 2. deep scaling, curettage, surgery need

replacement therapy

Hemophilia-dental management

Oral surgery : 1. Dental extraction: 40%-50% level 2. Maxillofacial surgery (including surgery extraction of impaction teeth): 80-100% 3. Antifribrinilytic therapy & local hemastatic measure 4. do not open lingual tissue in lower molar

regions to avoid hemorrhage track down a endanger

airway

Summary

History, PE, Lab data Consultation with physician Antibiotics to prevent post-op infection Avoid aspirin and NSAIDs Local hemostatic measure is very important

Haemostasis

Hemostasis

1° hemostasis Vasoconstriction & retraction of cut

ends of blood vessels Release of FVIII-vWF Platelets adhere to endothelium granules release ADP, Ca &

ThromboplastinA2 aggregation Stabilization of platelet plug

Coagulation Cascade:

Intrinsic PathIntrinsic Path (12,11,9,8)

Extrinsic PathExtrinsic Path(7)

Fibrinogen Fibrin

CommonCommon PathPath (5,2)

(PT)(aPTT)

(TT)

(F & FDP)

(Factor 10)

(Thrombin)

Coagulation cascade

Vitamin K dependant factorsVitamin K dependant factors

XIIaXIIa

IIa

Intrinsic system (surface contact)Intrinsic system (surface contact)

XIIXII

XIXI XIa

Tissue factorTissue factor

IXIX IXa VIIa VIIVII

VIIIVIII VIIIaVIIIa

Extrinsic system (tissue damage)Extrinsic system (tissue damage)

XX

VV VaVa

IIII

FibrinogenFibrinogen FibrinFibrin

(Thrombin)(Thrombin)IIa

Xa

Laboratory Evaluation of the Coagulation Pathways

Partial thromboplastin time(PTT)

Prothrombin time(PT)

Intrinsic pathway Extrinsic pathway

Common pathwayThrombin time

Thrombin

Surface activating agent (Ellagic acid, kaolin)PhospholipidCalcium

Thromboplastin Tissue factor PhospholipidCalcium

Fibrin clot

Pre-analytic errors

Problems with blue-top tube Partial fill tubes Vacuum leak and citrate

evaporation

Problems with phlebotomy Heparin contamination Wrong label Slow fill Underfill Vigorous shaking

Biological effects• Hct ≥55 or ≤15

• Lipemia, hyperbilirubinemia, hemolysis

Laboratory errors• Delay in testing

• Prolonged incubation at 37°C

• Freeze/thaw deterioration

Initial Evaluation of a Bleeding Patient - 1

Normal PTNormal PTT

Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysis Platelet disorder (2 anti-plasmin def) Vascular disorder Elevated FDPs

Ureasolubility

Normal

Abnormal

Factor XIIIdeficiency

Initial Evaluation of a Bleeding Patient - 2Normal PT

Abnormal PTT

Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab)

Abnormal PTNormal PTT

Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)

Initial Evaluation of a Bleeding Patient - 4

Abnormal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific : Factors V, X, Prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common)

Coagulation factor deficienciesSummary

Sex-linked recessive Factors VIII and IX deficiencies cause bleeding

Prolonged PTT; PT normal

Autosomal recessive (rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding

Prolonged PT and/or PTT

Factor XIII deficiency is associated with bleeding andimpaired wound healing

PT/ PTT normal; clot solubility abnormal

Factor XII, prekallikrein, HMWK deficienciesdo not cause bleeding

Disorders of Hemostasis

Vascular disorders Scurvy, easy bruising,

Platelet disorders Low Number or abnormal function

Coagulation disorders Factor deficiency.

Mixed/Consumption: DIC

Purpura - Manifestations

Platelet petechiae, mucosal bleeding CNS bleeding in severe cases

Coagulation disorders ecchymoses or hemarthroses

Vascular contusion, ecchymosis, hemorrhage palpable purpura

Clinical manifestations of disordered hemostasis

Clinical Characteristic

Platelet defect Clotting factor deficiency

Site of bleeding Skin, mucous membranes

Deep in soft tissues

Bleeding after minor cuts

Yes Unusual

Petechiae Yes No

Ecchymoses Small, superficial Large, palpable

Hemarthroses, muscle hematomas

Rare Common

Bleeding after surgery

Immediate, mild Delayed, severe

Platelet Coagulation

Petechiae, Purpura Hematoma, Hemarthrosis

Thrombocytopenias

Decreased production Platelet pooling and splenic

sequestration Increased destruction

Plt <100 000 Spontaneous bleeding uncommmon with

plt > 20 000 Bleeding time prolonged, PT/PTT normal

Sites of bleeding in thrombocytopenia

Skin and mucous membranes Petechiae Ecchymosis Hemorrhagic vesicles Gingival bleeding and epistaxis

Menorrhagia Gastrointestinal bleeding Intracranial bleeding

Classification of platelet disorders

Quantitative disorders

Abnormal distribution Dilution effect Decreased production

Increased destruction

Qualitative disorders

Inherited disorders (rare) Acquired disorders

Medications Chronic renal failure Cardiopulmonary

bypass

Associated with bleeding

Immune-mediated thrombocytopenia (ITP)

Most drug-induced thrombocytopenias

Most others

Associated with thrombosis

Thrombotic thrombocytopenic purpura

DIC Trousseau’s syndrome Heparin-associated

thrombocytopenia

Acquired thrombocytopenia with shortened platelet survival

Approach to the thrombocytopenic patient History

Is the patient bleeding? Are there symptoms of a secondary illness? (neoplasm, infection,

autoimmune disease) Is there a history of medications, alcohol use, or recent transfusion? Are there risk factors for HIV infection? Is there a family history of thrombocytopenia? Do the sites of bleeding suggest a platelet defect?

Assess the number and function of platelets CBC with peripheral smear Platelet function study

Platelet function screenResults

Epi ADP Interpretation

Normal Normal Normal platelet function

Abnormal Normal “Aspirin effect”

Abnormal Abnormal Abnormal platelet function

Valvular heart disease

Renal failure

Von Willebrand disease

Platelet transfusions

Source Platelet concentrate (Random donor)

Each donor unit should increase platelet count ~10,000 /µl

Pheresis platelets (Single donor)

Storage Up to 5 days at room temperature

“Platelet trigger” Bone marrow suppressed patient (>10-20,000/µl) Bleeding/surgical patient (>50,000/µl)

Platelet transfusions - complications

Transfusion reactions Higher incidence than in RBC transfusions Related to length of storage/leukocytes/RBC mismatch Bacterial contamination

Platelet transfusion refractoriness Alloimmune destruction of platelets (HLA antigens) Non-immune refractoriness

Microangiopathic hemolytic anemia Coagulopathy Splenic sequestration Fever and infection Medications (Amphotericin, vancomycin, ATG,

Interferons)

Laboratory Evaluation of BleedingOverview

CBC and smear Platelet count ThrombocytopeniaRBC and platelet morphology TTP, DIC, etc.

Coagulation Prothrombin time Extrinsic/common pathwaysPartial thromboplastin time Intrinsic/common pathwaysCoagulation factor assays Specific factor deficiencies50:50 mix Inhibitors (e.g., antibodies)Fibrinogen assay Decreased fibrinogenThrombin time Qualitative/quantitative

fibrinogen defectsFDPs or D-dimer Fibrinolysis (DIC)

Platelet function von Willebrand factor vWDBleeding time In vivo test (non-specific)Platelet function analyzer (PFA) Qualitative platelet disorders

and vWDPlatelet function tests Qualitative platelet disorders

Decreased Production

Malignancies (leukemia, lymphoma, neuroblastoma)

Bone marrow suppression Drug-related (aplastic anemia) Infection

Congenital Fanconi anemia TAR syndrome Wiscott-Aldrich Glycogen storage diseases

Platelet Dysfunction

Congenital Glanzmanns thrombasthenia (GP11b/IIIa

deficiency) Bernard Soulier (vWF receptor

deficiency) Acquired

Drugs (ASA/NSAIDs, lasix, nitrofurantoin) Renal disease Liver disease

Increased Platelet Destruction

Immunologic ITP SLE Isoimmunization (post-transfusion, neonatal) Drug related (heparin, quinine, dig, sulphonamides,

phenytoin) Infection

Sepsis Mechanical

DIC HUS-TTP Giant hemangioma (Kasabach-Merritt) Burns Trauma

Thrombocytopenia (cont’d)

Sequestration Hypersplenism Sickle cell anemia

Dilutional Massive transfusion

Loss of Vascular Integrity

Congenital Disorders of

connective tissue Ehlers-Danlos

syndrome Osteogenesis

imperfecta Marfan’s

Disorders of blood vessels

Hemorrhagic telangiectasia

Acquired Trauma/NAI Scurvy Steroid induced Increased intravascular

pressure coughing vomiting straining

Vasculitis Drug-related Infection

Viral Coxsackie A9, B3 Echoviruses 4,9 Atypical measles

Bacterial Meningococcemia Streptococcal

pharyngitis Septic emboli SBE Gonococcus

Rickettsial Rocky Mountain

spotted fever

Immune-mediated HSP SLE Serum sickness Dysgammaglobulinemia

Coagulation Factor Deficiency

Usually cause larger ecchymoses, deep tissue hemorrhage, and mucosal bleeding

Clotting factor deficiencies Congenital

von Willebrand’s disease Hemophilias Protein C and S deficiencies

Acquired Vitamin K deficiency

Liver disease Malabsorption

Diagnosis

Careful history and focused physical exam are keys to diagnosis

Laboratory tests are confirmatory

History

Present history Onset Location Associated symptoms

Fever Abdominal pain Arthralgias/joint swelling meningismus

History

Recent Viral illness Ill contacts Trauma Medications Immunization Travel

Past history Easy bruising or

bleeding Epistaxis, menorrhagia Excessive bleeding

following circumcision or dental extraction

Family History Bleeding disorders

Physical Exam

Sick vs. not sick Fever Lymph nodes Liver, spleen Joints – arthritis, hemarthrosis

Physical exam - Skin

Are lesions petechial, purpuric or ecchymotic?

Palpable purpura Vasculitis – HSP, RMSF, SLE Embolic lesions, meningococcemia, bacterial

endocarditis Location

Isolated petechiae above nipple line often associated with crying, coughing, vomiting

Purpura in dependent areas with HSP Ecchymoses on upper extremities,, or with

recognizable pattern –

Investigations - initial

CBC, peripheral smear Hgb - Blood loss, hemolysis Plt - thrombocytopenia WBC - Sepsis, leukemia

Prothrombin Time extrinsic and common pathway Factors II, V, VII, X

PTT intrinsic and common pathway all factors except VII and XIII

Specific tests

Factor Level Assays Fibrin, FSP, D-dimer Bleeding time - test of platelet function platelet aggregation - ADP, epinephrine,

collagen, and ristocetin

Cases

Case1 - 2 year old presents with purpuric rash

Acting otherwise well, eating normally

No fever, no weight loss, no systemic Sx

Recovered from a URI Rash is not itchy and is

flat No regular medications No hospitalizations or

chronic illnesses

Idiopathic Thrombocytopenic Purpura

Most common platelet disorder in children (5/100,000 prevalence)

Isolated thrombocytopenia (often < 20 000)

No associated conditions that may cause thrombocytopenia

Peak age 2-4 Male = female

ITP -pathophysiology

Development of IgG Abs to plt membrane glycoproteins as a result of an unbalanced response to an infectious agent or autoimmunity

Sequestration by splenic macrophages 70% cases occur 1-4 weeks following viral

illness VZV, EBV, influenza common causes

ITP - Clinical presentation

Usually acute, sudden onset with history of viral illness in the several weeks preceeding onset

Petechiae, purpura, and easy bruising

Epistaxis, gingival bleeding and menorrhagia are common

ICH very rare

Diagnosis

Hx, PE, CBC and peripheral smear Isolated thrombocytopenia

Bone marrow ex will show megakaryocytes hyperplasia (increased plt production)

Clinical course

Self limiting in 80-90% cases Normalize within months ↑ plt 5-7 days

Serious bleeding in 2-4% Epistaxis, GI, hematuria, menorrhagia ICH - 0.1-0.5%

Plt<10,000, NSAIDs, head trauma, Chronic 10-20%

ED Management – if severe bleeding

No controlled studies to guide management Transfusions of PRBC to HGB > 10 Transfusions of platelets (0.2unit/ kg) Corticosteroids

Prednisone 1-2mg/kg/d x 1-2wk, then taper Methylprednisolone 30mg/kg (max 1g) IV over 30

min QD x3 IgG

IvIG 1g/kg/d over 3 hrs x 2days Anti-Rh D (only if Rh+)

Rhogam 40-80ug/kg single dose over 5 min Splenectomy

Management if not bleeding

80% resolve spontaneously Treatment does shorten duration of

profound thrombocytopenia, but doesn’t alter clinical course

HSP

Vasculitis

Case 2

6 yo boy c/o periumbilical abdominal pain and rash x 2/7

Also c/o knee and ankle pain

Recently recovered from Grp A Strep infection

Henoch Schönlein Purpura

Palpable purpura Arthritis Abdominal pain +/-Glomerulonephritis Most common in spring 75% cases occur between ages 2-11 Often follows URI (grp A strep,

mycoplasma, VZV, EBV, parvovirus B19) Insect stings

HSP - pathophysiology

Exact cause unknown IgA mediated systemic vasculitis of

small vessels of skin, GIT, kidneys, synovium

HSP – Clinical features

Gradual or acute onset Blanching macules or papules on buttocks and

lower extremities that evolve into palpable purpura

Younger children - face, torso and extremities Arthritis of large joints (65-85%) 50% will have GI symptoms

Crampy abdominal pain +/- hematochezia Intussusception, bowel infarct, pancreatitis

25-50% develop glomerulonephritis Self limited, CRF in 1%

HSP - Diagnosis

Clinical diagnosis CBC, Urea, Cr, urine analysis DDx

Meningococcemia Rheumatic fever Rocky Mountain spotted fever Bacterial endocarditis Juvenile rheumatoid arthritis Systemic lupus erythematosis Reactive arthritis

HSP- Treatment

No specific Tx Majority resolve over 2-4 wks Symptomatic treatment of arthritis,

malaise, fever – acetaminophen or NSAIDs*

If severe abdo pain: prednisone 1-2mg/kg/d

Case 3

13 year boy c/o fever,, myalgias

Developed rash that started on hands and feet, now all over

Recent travel to camp in Colorado

Rocky Mountain Spotted Fever

1-2 weeks after bite by tick infected with Rickettsia rickettsii

fever, headache, myalgias, nausea, vomiting

petechial rash that begins on day 2-6 of fever

Starts on palms and soles and spreads centripedally over the torso within hours

Vasculitis 2º to rickettsial invasion of endothelial cells

RMSF - Epidemiology

SE and South Central US

Between April and October

Most common in under 15 yrs

Not contagious

RMSF - Treatment

Tx based on clinical suspicion

Abx, supportive care, +/- steroids <8 chloramphenicol 50mg/kg/day x 7-10 d 8 doxycycline 100mg PO BID x 7-10 d

Delayed treatment may result in DIC, shock, encephalopathy, gastrointestinal bleeding and myocarditis

Meningococcemia

most often seen in children younger than 5 years old

peak attack rate in infants < 6 months

gram-negative diplococcus

spread by respiratory droplets

outbreaks are common after index case exposes others

day care centers, schools, and colleges

Meningococcemia

begins abruptly with fever, lethargy, and rash

Initially the rash may be maculopapular or urticarial

Rapidly becomes purpuric as the disease progresses

15-25% of patients -purpura fulminans syndrome characterized by very large purpuric

lesions secondary to cutaneous hemorrhage and necrosis with DIC

Meningococcemia -Treatment

ABCs, supportive care Abx:

Ceftriaxone 200mg/kg/d IV q6H Vancomycin 60 mg/kg/d IV q6HIf severe B-lactam allergy: Chloramphenicol 75-100mg/kg/d IV q6H Vancomycin 60 mg/kg/d IV q6H

Case 4

5yo male with 3/7 hx watery diarrhea after attending a birthday party

Today developed fever and petechial rash

Looks unwell

Hemolytic Uremic Syndrome

Acute renal failure Microangiopathic hemolytic anemia Thrombocytopenia Fever

90% of cases follow a diarrheal illness Most often E. coli 0157:H7 Also Shigella, Salmonella, Yersinia, and

Campylobacter species From undercooked meats, unpasteurized dairy

HUS - pathophysiology

Verotoxins from bacteria endothelial cell injury cascade of events leading to hyaline microthrombi formation and consumptive thrombocytopenia

TTP seems to have similar pathophysiology but has predominately CNS effects cf predominately renal involvement with HUS

HUS-Tx

Diagnosis is clinical with supportive lab investigations CBC and smear - MAHA, thrombocytopenia PT/PTT, fibrinogen – normal Elevated BUN, Cr E. coli 0157:H7 on stool culture

Treatment - consultation with hematology and nephrology early dialysis, plasma exchange, treatment of

hypertension

Mortality 5-15%

Disorders of Coagulation

von Willebrand’s Disease

Most common inherited bleeding disorder 2 functions of vWF:

plt aggregation at site of injury carrier protein for FVIII

3 phenotypes: Type I - ↓ amount vWF (60-80% cases) Type II – vWF abnormal (10-30%) Type III – no vWF (1-5%)

patients typically present with bruising, menorrhagia, epistaxis or excessive bleeding after surgical procedures

von Willebrand’s Disease

Difficult to diagnose Platelets normal Prolonged bleeding time PTT – may be prolonged vWF activity, levels Factor VIII levels

von Willebrand’s Disease - Tx

DDAVP 0.3 ugkg IV over 30 min or SC 150ug nasal inh Releases FVIII and vWF from

endothelial cells (3-5x ↑ level)* Factor VIII/vWF concentrates Cryoprecipitate 1 bag/ 10kg Aminocaproic acid (Amicar®) Tranexamic acid (Cyclokapron®)

Hemophilia A and B

X-linked recessive Deficiency factor VIII (A) and IX (B) Multiple cutaneous bruises, muscular

bleeding and hemarthroses Prolonged PTT but normal PT and

bleeding time Tx - FFP or factor replacement – Life long

Summary

Bleeding caused by vascular, platelet or clotting factor problems

Broad differential diagnosis Relatively benign to potentially fatal

Most causes can be diagnosed by good history, physical exam and simple laboratory tests

Infections

Viral Atypical measles Congenital rubella Cytomegalovirus Enterovirus HIV Hemorrhagic varicella

Bacterial Meningococcemia Gonnococcemia Pneumococcal sepsis Haemophilus

influenzae sepsis Pseudomonas

aeruginosa sepsis

Rickettsial Rocky Mountain

spotted fever Protozoal

Malaria

BV Injury

PlateletPlateletAggregation

PlateletActivation

Blood VesselBlood Vessel Constriction

CoagulationCoagulation Cascade

Stable Hemostatic Plug

Fibrin formation

Reduced

Blood flow

Contact/ Tissue Factor

Primary hemostatic plug

Neural

Questions?

1. What is the mechanism for the thrombocytopenia in ITP?

2. What is the classic triad associated with hemolytic uremic syndrome?

3. How is hemophilia inherited? 4. Describe some indications for factor VIII

administration in a patient with hemophilia A.

5. What are the functions of von Willebrand factor?

6. What combination of laboratory tests are good screening studies for von Willebrand disease?

7. Why is it important to test for blood type in a person with suspected von Willebrand disease?

8. Name the vitamin K dependent factors. 9. Explain why the addition of normal

plasma to a patient's PTT test, will help to identify a circulating anticoagulant such as the lupus anticoagulant.

1. True/False: Newborns with Down syndrome and elevated white counts and immature forms frequently progress to leukemia.

2. True/False: Factor VIII deficiency is on the vitamin K dependent factors leading to Hemorrhagic disease of the newborn.

3. Rh antibodies in mothers can result from: . . . . . a. previous mismatched transfusions . . . . . b. prior miscarriages . . . . . c. fetal maternal transfusion . . . . . d. all of the above.

4. True/False: Red cell problems are usually seen with abnormalities of white cells and platelets.

5. True/False: Neonatal immune thrombocytopenia can result from maternal auto sensitization or fetal maternal transfusion.

6. True/False: Thalassemia and hemoglobinopathies can present in the neonatal period with severe anemia.