Resident RoundsResident Rounds

February 5, 2004February 5, 2004

Disorders of HemostasisDisorders of HemostasisResident RoundsResident RoundsFebruary 5, 2004.February 5, 2004.

Case Case

4 yo with gums that bleed for 30 mins after 4 yo with gums that bleed for 30 mins after brushing teeth.brushing teeth. Also had spontaneous epistaxis last weekAlso had spontaneous epistaxis last week Unwell 2 weeks agoUnwell 2 weeks ago You notice petichiae around her underwear You notice petichiae around her underwear

elasticelastic ????

CBCCBC Plt 3Plt 3

ITPITP

Children 2-6Children 2-6 viral prodrome usually within 3 weeks of onsetviral prodrome usually within 3 weeks of onset Plts usually <20Plts usually <20

What do you expect their INR/PTT to be?What do you expect their INR/PTT to be? Bleeding time?Bleeding time?

90% recovery90% recovery IVIgG and steroidsIVIgG and steroids splenectomysplenectomy

Normal CoagulationNormal Coagulation

Depends on interaction ofDepends on interaction of VasculatureVasculature PlateletsPlatelets Coagulation cascade.Coagulation cascade.

Case Case

33 yo G2P1 LMP 08/05 est GA 24/4033 yo G2P1 LMP 08/05 est GA 24/40 Presents vomiting with abdominal painPresents vomiting with abdominal pain BP 130/90, 105, 20, sats 99%BP 130/90, 105, 20, sats 99% Jaundiced, tender RUQJaundiced, tender RUQ LabsLabs

Hb 90, PLT 80, inc ALT/AST/biliHb 90, PLT 80, inc ALT/AST/bili Coags normalCoags normal Dx??Dx??

Platelets and CoagulationPlatelets and Coagulation

Disruption of endothelial Disruption of endothelial layer and exposes layer and exposes consituent materialconsituent material

Platelets attach to Platelets attach to constituent constituent componentscomponents

Platelet secretionPlatelet secretionPlatelet activation and Platelet activation and

aggregationaggregation

Platelet DisordersPlatelet Disorders

DestructionDecreased Production

Sequestration

Immune Non-immune

IPT TTPDICHELLPSepsis

splenomegaly

Marrow failure

Quantitative Qualitative

ASA, plavixrena and hepatic disease,vWD

Case Case

12 yo girl with menhorrhagia for 5 days12 yo girl with menhorrhagia for 5 days Hx of von WillebrandsHx of von Willebrands

PalePale HR 110, BP 90/60HR 110, BP 90/60 Hb 60Hb 60

Management plan?Management plan?

Von Willebrand’s Von Willebrand’s DiseaseDisease

Defect in primary hemostasisDefect in primary hemostasis QuantitativeQuantitative (type 1 and 3) and (type 1 and 3) and qualitativequalitative (Type (Type

2)2)

Refers to many different platelet defectsRefers to many different platelet defects Quantitative defects of vWF most commonQuantitative defects of vWF most common

and mild disease is MC (approx 80%)and mild disease is MC (approx 80%) vWF activity reduced 20-50% normalvWF activity reduced 20-50% normal

Most with type 1 vWF will be asymptomatic Most with type 1 vWF will be asymptomatic unless challenged by surgery or traumaunless challenged by surgery or trauma

vWFvWF

large multimeric glycoprotein that functions as large multimeric glycoprotein that functions as the carrier protein for factor VIII the carrier protein for factor VIII

vWF also is required for normal platelet vWF also is required for normal platelet adhesion. As such, vWF functions in both adhesion. As such, vWF functions in both primary (involving platelet adhesion) and primary (involving platelet adhesion) and secondary (involving FVIII) hemostasis. secondary (involving FVIII) hemostasis. In primary hemostasis, vWF binds on platelets to its In primary hemostasis, vWF binds on platelets to its

specific receptor glycoprotein Ib and acts as an specific receptor glycoprotein Ib and acts as an adhesive bridge between the platelets and damaged adhesive bridge between the platelets and damaged subendothelium at the site of vascular injury. subendothelium at the site of vascular injury.

In secondary hemostasis, vWF protects FVIII from In secondary hemostasis, vWF protects FVIII from degradation and delivers it to the site of injury. degradation and delivers it to the site of injury.

Type 1 vWFType 1 vWF

Mild to moderate decrease in plasma Mild to moderate decrease in plasma levels of vWFlevels of vWF

Proportional decrease in vWF functionProportional decrease in vWF function Proportional decrease in circulating FVIIIProportional decrease in circulating FVIII

Von WillebrandVon Willebrand

Treatment optionsTreatment options Helpful to know Helpful to know

specific sub-type of diseasespecific sub-type of disease Previous response to currently available Previous response to currently available

treatmentstreatments Immediate management depends onImmediate management depends on

Severity of diseaseSeverity of disease Type and location of bleedingType and location of bleeding

Treatment OptionsTreatment Options

DDAVPDDAVP Specific vWF and factor VIII replacement Specific vWF and factor VIII replacement

(Humate-P)(Humate-P) cryoprecipitatecryoprecipitate

DDAVPDDAVP

Use based on observation that epi and stress Use based on observation that epi and stress increase levels of vWF and FVIIIincrease levels of vWF and FVIII

Same effect with vasopressin and synthetic Same effect with vasopressin and synthetic vasopressin (but no pressor effect)vasopressin (but no pressor effect) Can be used IN/IV/IM (IV and IM have same effect)Can be used IN/IV/IM (IV and IM have same effect) 2-3X increase in vWF and FVIII2-3X increase in vWF and FVIII Dose = 0.2mcg/kg IVDose = 0.2mcg/kg IV

NB not effective in Type2/3 disease where pts express an abnormal ptn.NB not effective in Type2/3 disease where pts express an abnormal ptn.

CryoprecipitateCryoprecipitate

plasma fraction that contains factor VIII, plasma fraction that contains factor VIII, vWF, fibrinogen, and fibronectinvWF, fibrinogen, and fibronectin

obtained by harvesting the precipitate that obtained by harvesting the precipitate that forms when frozen plasma is warmed to forms when frozen plasma is warmed to 4°C. 4°C.

1 bag contains approx 100U of vWF and 1 bag contains approx 100U of vWF and FVIII (approx 10x more than FFP)FVIII (approx 10x more than FFP)

Case Case

12yo with hematemesis for last 6hrs12yo with hematemesis for last 6hrs Tells you has “the worst” vonWillebrandsTells you has “the worst” vonWillebrands

Type IIIType III No detectable vWF and markedly reduced FVIIINo detectable vWF and markedly reduced FVIII TreatmentTreatment

Cryo [+/- DDAVP] Cryo [+/- DDAVP]

Case Case

37 yo male twisted knee and fell at work37 yo male twisted knee and fell at work PMHx of HemophiliaPMHx of Hemophilia Unsure of usual factor activityUnsure of usual factor activity

OE tender knee hemarthrosisOE tender knee hemarthrosis

Do you give him factor?Do you give him factor?

How much factor to give?How much factor to give?

What if you’re in High River (and you aint got none?)What if you’re in High River (and you aint got none?)

?cryo?cryo

HemophiliaHemophilia

A – FVIII deficiencyA – FVIII deficiency B – FIX deficiencyB – FIX deficiency X-linked recessiveX-linked recessive 1/3 spontaneous mutation1/3 spontaneous mutation Mild/moderate/severe Mild/moderate/severe based of percent factor based of percent factor

activityactivity >5%, 1-5%, <1% respectively>5%, 1-5%, <1% respectively

MC manifestations MC manifestations hemarthrosis and SC hemarthrosis and SC

HemarthrosisHemarthrosis

MC symptom and potentially debilitating MC symptom and potentially debilitating manifestationmanifestation

Spontaneous or secondary to trivial traumaSpontaneous or secondary to trivial trauma Accumulation of blood in synovial space Accumulation of blood in synovial space

synovial proliferation synovial proliferation increase in joint increase in joint vascularity which predisposes to further vascularity which predisposes to further bleeding bleeding recurrent bleeding recurrent bleeding chronically chronically deformed and painful jointdeformed and painful joint

Management of Bleeding in Management of Bleeding in HemophiliaHemophilia

Overall principlesOverall principles Depends of severity of bleedingDepends of severity of bleeding Underlying disease severityUnderlying disease severity Availability of replacement productsAvailability of replacement products

Assume during an acute bleeding episode Assume during an acute bleeding episode that factor activity is 0%that factor activity is 0%

Recommended to raise FVIII levels to 50%Recommended to raise FVIII levels to 50%

Management of Bleeding in Management of Bleeding in HemophiliaHemophilia

OptionsOptions Specific factor replacement Specific factor replacement Cryo Cryo FFPFFP Do nothingDo nothing

Factor replacementFactor replacement

1 unit/kg of FVIII will raise plasma FVIII 1 unit/kg of FVIII will raise plasma FVIII activityactivity by 2%by 2%

Goal is to achieve >50% activityGoal is to achieve >50% activity Post-infusion the initial recovery of FVIII is 80% Post-infusion the initial recovery of FVIII is 80% Administer replacement at rate of 3cc/minAdminister replacement at rate of 3cc/min

Peds at 100u/minPeds at 100u/min

15% will develop alloantibodies (IgG) against FVIII which 15% will develop alloantibodies (IgG) against FVIII which neutralize exogenous administration. Pts will require 3-4X the neutralize exogenous administration. Pts will require 3-4X the dose of replacement.dose of replacement.

CryoprecipitateCryoprecipitate

Contains 100U FVIII Contains 100U FVIII (als contains vWF, fibrinogen, (als contains vWF, fibrinogen, FXIII and fibronectin)FXIII and fibronectin)

Considered a second line agent for Hem AConsidered a second line agent for Hem A Dose = 2bags/10kg to raise FVIII to Dose = 2bags/10kg to raise FVIII to

hemostatic levelshemostatic levels T ½ = 8hrsT ½ = 8hrs

FFPFFP

Fluid portion of blood separated at 18C Fluid portion of blood separated at 18C then frozenthen frozen

Contains all coagulation factorsContains all coagulation factors Approx 7% of of all coag factor activity of a Approx 7% of of all coag factor activity of a

70kg person70kg person

Not routinely used as factor replacement Not routinely used as factor replacement in Hem Ain Hem A Could consider if nothing else availableCould consider if nothing else available

Case Case

35 yo with hemophilia35 yo with hemophilia Fell backwards while showing the ladies what Fell backwards while showing the ladies what

a phat boarder he is.a phat boarder he is. No neurologic defecitsNo neurologic defecits No Can CT head criteriaNo Can CT head criteria To the scanner? To the scanner? Factor replacement if normal scan (or before Factor replacement if normal scan (or before

scan)?scan)?

IC bleeds and the HemophiliacIC bleeds and the Hemophiliac

Remain a MC of deathRemain a MC of death mortality rate of 30%mortality rate of 30%

Probably should receive prophylactic Probably should receive prophylactic factor replacementfactor replacement

Dose of replacementDose of replacement 50U/kg q12hrs50U/kg q12hrs Consider cryo at 6bags/10kgConsider cryo at 6bags/10kg

Case Case

70M with likely urosepsis in ICU on 70M with likely urosepsis in ICU on pressors.pressors. Oozing from all IV sitesOozing from all IV sites INR and PTT upINR and PTT up

?? DICDIC

DICDIC

CausesCauses InfectionInfection

GNGN Encapsulated GPEncapsulated GP Viruses Viruses varicella esp varicella esp

Massive TraumaMassive Trauma ObstetricalObstetrical

AbruptionAbruption Amniotic fluid embolismAmniotic fluid embolism

MalignanciesMalignancies BurnsBurns Transfusion-relatedTransfusion-related

LabLab pltplt INRINR PTTPTT FDPFDP FibrinogenFibrinogen

five case studies of DIC, five case studies of DIC, combining over combining over 900 patients900 patientsMC lab abnMC lab abn thrombocytopenia, thrombocytopenia, elevated FDPs, elevated FDPs, prolonged INR, prolonged INR, prolonged PTT, prolonged PTT, and a low fibrinogenand a low fibrinogen

DIC SchematicDIC Schematic

Initiation of DIC usually involves one or both of two mechanisms: mechanical tissue injury and endothelial activation and injury. Primary to both initiating pathways is the exposure of blood to huge amounts of tissue factor.

DICDIC

Bleeding is the predominant clinical Bleeding is the predominant clinical manifestation observed in DICmanifestation observed in DIC

thromboembolic manifestations have been less thromboembolic manifestations have been less frequently observed in DIC and have been frequently observed in DIC and have been reported in 10–40% of patients reported in 10–40% of patients

DICDICWhat to do?What to do?

Treat underlying Treat underlying stimulusstimulus

PltsPlts Maintain >30 or higher if OR Maintain >30 or higher if OR

plannedplanned 1U plts contained 5x109 plt1U plts contained 5x109 plt expected to raise plasma by expected to raise plasma by

samesame

FFPFFP If DIC assoc with increased If DIC assoc with increased

INR and PTTINR and PTT

CryoCryo If fibrinogen <2If fibrinogen <2 Give 1-4U/10kgGive 1-4U/10kg

Role for…Role for… Heparin?Heparin?

No established roleNo established role Can worsen the situationCan worsen the situation ?consider if evidence of ?consider if evidence of

embolic complications in embolic complications in setting of DIC eg purpura setting of DIC eg purpura fulminansfulminans

ATIII -- investigationalATIII -- investigational Ptn C -- investigationalPtn C -- investigational

Hypothermic coagulopathyHypothermic coagulopathy

45M found in snow bank ?duration45M found in snow bank ?duration INR 1.6INR 1.6 Plts normalPlts normal No evidence of liver failure, trauma. - EtOHNo evidence of liver failure, trauma. - EtOH ?mechanism of coagulopathy?mechanism of coagulopathy

Likely d/t slowing of enzymatic reaction with Likely d/t slowing of enzymatic reaction with balance favouring anti-coagulation.balance favouring anti-coagulation.

Treatment?Treatment? rewarmingrewarming

CaseCase

60 yo with ACS60 yo with ACS Got ASA, Heparin, bblockerGot ASA, Heparin, bblocker Waiting for CCUWaiting for CCU LGIB in EDLGIB in ED

Mechanism of heparinMechanism of heparin How do you reverse heparin?How do you reverse heparin?

HeparinHeparin

Unfractionated heparinUnfractionated heparin Major sites of activity ATIII, XaMajor sites of activity ATIII, Xa Other sites IIa, IXa, XIaOther sites IIa, IXa, XIa

Anticoagulant effect largely through Anticoagulant effect largely through ATIIIATIII.. Produces a conformational change which Produces a conformational change which

accelerates the ability of ATIII to inactivate accelerates the ability of ATIII to inactivate thrombinthrombin

Reversing Heparin:Reversing Heparin:ProtamineProtamine

T ½ = 60minsT ½ = 60mins 1mg protamine neutralizes 100 circulating 1mg protamine neutralizes 100 circulating

units of UFHunits of UFH Eg 1500U/h (no recent bolus)Eg 1500U/h (no recent bolus)

1500U + 750U + 375 = 2625U1500U + 750U + 375 = 2625U Dose of promatime = 26.25mgDose of promatime = 26.25mg

If received bolus then need to re-calculate If received bolus then need to re-calculate depending on when received and add to total depending on when received and add to total heparin (after 4-5hrs, bolus effectively gone)heparin (after 4-5hrs, bolus effectively gone)

LMWH LMWH

Inhibitor of XaInhibitor of Xa Activity 14-16hrsActivity 14-16hrs T ½ is 4hrsT ½ is 4hrs Reversal is more difficultReversal is more difficult <8hrs post-dose<8hrs post-dose

1mg protamine/1mg heparin1mg protamine/1mg heparin >8hrs>8hrs

0.5/1mg0.5/1mg

Case Case

60 with STEMI that you’ve thrombolyzed60 with STEMI that you’ve thrombolyzed

Reversing lyticsReversing lytics MechanismMechanism

inducing plasmin action on inducing plasmin action on fibrin contained within a fibrin contained within a thrombusthrombus

T ½ 15minsT ½ 15mins Fibrinogen remains low for Fibrinogen remains low for

24hrs24hrs ReversalReversal

Stop lyticStop lytic Replenish fibrinogenReplenish fibrinogen

CryoCryo FFP to correct prolonged FFP to correct prolonged

bleeding timebleeding time ?aminocarproic acid?aminocarproic acid Reverse heparinReverse heparin

Absolute lytic Absolute lytic contraindicationscontraindications Hemorrhagic cerebrovascular Hemorrhagic cerebrovascular

accident, intracranial accident, intracranial neoplasm, recent cranial neoplasm, recent cranial surgery or trauma (10 days), surgery or trauma (10 days), uncontrolled severe uncontrolled severe hypertension hypertension

Major surgery of thorax or Major surgery of thorax or abdomen (10 days), prolonged abdomen (10 days), prolonged cardiopulmonary resuscitation, cardiopulmonary resuscitation, current severe bleeding (e.g., current severe bleeding (e.g., gastrointestinalgastrointestinal) )

CaseCase

50M with known EtOH cirrhosis50M with known EtOH cirrhosis Presents with abnormal coagsPresents with abnormal coags

Pathophysiology of coagulopathyPathophysiology of coagulopathy Multiple points of insult to hemostasis:Multiple points of insult to hemostasis:

Dec coag factor synthesisDec coag factor synthesis Malabsorption/nutritional deficiency of vit. KMalabsorption/nutritional deficiency of vit. K Portal HTN Portal HTN splenomegaly splenomegaly sequestration sequestration Decreased synthesis of fibrinogenDecreased synthesis of fibrinogen

Anticoagulant ODAnticoagulant OD

3 yo presents after father witnessed kid 3 yo presents after father witnessed kid licking his lips after a mouthful of licking his lips after a mouthful of bacon bacon and cheeseand cheese rat poison 4 hrs ago. rat poison 4 hrs ago.

Brings in box Brings in box bromodialone 0.05% bromodialone 0.05%

INR normalINR normal When would you expect it to be abnormal?When would you expect it to be abnormal?

Vit. K and CoumadinVit. K and Coumadin

Vit K dependent coag factors?Vit K dependent coag factors? II, VII, IX, XII, VII, IX, X Ptn C and SPtn C and S Cofactor in carboxylation of enzymes which Cofactor in carboxylation of enzymes which

activate factorsactivate factors

CoumadinCoumadin T ½ = 2.5dT ½ = 2.5d

Vit K pathwayVit K pathway

SuperSupercoumadinscoumadins

inhibition of the complete synthesis of the vitamin K-inhibition of the complete synthesis of the vitamin K-dependent proteins may continue for months after initial dependent proteins may continue for months after initial exposure, even in the absence of re-exposure. exposure, even in the absence of re-exposure.

Very high fat solubilityVery high fat solubility Can lead to prolonged INR >1yr Can lead to prolonged INR >1yr vitamin K1 at normal doses of administration is vitamin K1 at normal doses of administration is

ineffective. ineffective. Will require daily doses of 100–150 mg of vitamin K1 Will require daily doses of 100–150 mg of vitamin K1

administered orally have been effective in normalizing administered orally have been effective in normalizing the PT. Over time, the dose of vitamin K1 needed to the PT. Over time, the dose of vitamin K1 needed to correct the PT can be adjusted downward, so that only correct the PT can be adjusted downward, so that only the required amounts of vitamin K are employed.the required amounts of vitamin K are employed.