Coagulation Problem in Pregnancy 4

8/12/2019 Coagulation Problem in Pregnancy 4

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A NOVA SCOTIANPERSPECTIVE

D A R R I E N R A T T R A Y P G Y 4

D R T H O M A S B A S K E T T

S E P T 2 9 , 2 0 1 0

Disseminated Intravascular

Coagulation (DIC) in Pregnancy


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Obstetrical DIC

De Lee JB. Am J Obstet Dis Women Child (1901) 44: 785-92


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De Lee 1901

Mrs H, 35 years of age, IV para, German

At 2 AM of the 13th she awoke with a pain in theabdomenshe sent for me about 7 and I arrived at8:20

The pulse was full and bounding, but the patientwas palethe uterusnow very hard, large,symmetrical, and tender. No heart tones

Diagnosed premature detachment of theplacentathe flow soon became profuse

With the help of the husband alone I put her on thetable and prepared the parts


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De Lee 1901

gave a hypodermic of strychnine and a large,bloody infiltration of the skin and subcutaneoustissue took place

salt solution, one quart, was injectedDeep blueecchymoses appeared around the puncture andextended up into the axilla, blood oozing persistantlyfrom the hole and not to be stopped with plaster

I tried to do a version, but the hands, tired withtwo hours hard operating, were paralyzed


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De Lee 1901

Placenta was loose in the cavity, which was filledwith old, dark, firm, almost black clotsdark, thin,almost lake-coloured blood followed

There was no atony here before we could retampon with gelatin gauze she

became unconscious and died. It was three hoursfrom the time I started and ten hours from the onset

of first symptoms


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De Lee 1901

Is there such a disease as acquired hemophilia?

The causes of this are unknown; consanguinity ofmarriage, tuberculosis, gout, maternal mental shock

during gestation Does the loss of blood favor further hemorrhageper

se?...the blood that is lost is light and watery, notdark

I believethere is such an affection as atemporary hemophilia, but the demonstration of thesame, I admit, presents no little difficulty


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Objectives

Provide an overview of coagulation

Describe the pathophysiology & etiology of DIC in

obstetrics

Discuss approach to treatment of DIC in pregnancy

Review 30 years of obstetrical DIC in the IWK


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PRIMARY HAEMOSTASIS

Formation of platelet plug at siteof endothelial injury

SECONDARY HAEMOSTASIS

Formation of Fibrin clot

Intrinsic pathway

Extrinsic pathway

Common pathway

FIBRINOLYSIS

Coagulation 101

Coagulation


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Primary Haemostasis

Interaction betweenplatelets, vWF, and the

vessel wall Endothelium important

Platelet plug is unstable Requires formation of

organized fibrin clot

Important inpathogenesis of DIC Sepsis Preeclampsia

Hypovolemic shock


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Secondary Haemostasis


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Scanning Electron Microscopy of across-linked fibrin clot


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Haemostasis and the Lab

PT (Prothrombin Time)

Reflection of the extrinsic & common pathway

TF, Factor VII

Prothrombin, Factors V and X, Fibrinogen

Normal 9.0-11.0 sec at IWK

Play Tennis outside (extrinsic)

aPTT (Activated Partial Thromboplastin Time) Reflection of the intrinsic & common pathways

All factors except VII

Normal 24.1 31.6 sec at IWK

Play Table Tennis inside (intrinsic)


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Fibrin Degradation Products & D-Dimers

Measurements of Fibrinolysis

May be measured with Fibrin Degradation Products(FDPs) Do not discriminate between products of cross-linked fibrin

and fibrinogen (limits specificity) Newer assays for cross-linked fibrin degradation products (D-

dimers)

Many other conditions have D-dimers

Trauma Recent surgery

Venous thromboembolism

Pregnancy


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S YS TEMIC THR O MBO HEMOR R HA GIC DIS O R DER

SEEN IN ASSOCIATION WITH WELL-DEFINEDCL INICAL S ITUA TIONS A ND L A B O RA TO R YEVIDENCE OF:

1. Procoagulant activation

2.

Fibrinolytic activation3. Inhibitor consumption

4. Biochemical evidence of end-organ damage or failure

Bick RL. Hematol Oncol Clin N Am (2003) 17: 149-76

What is DIC?

Bleeding & Clotting


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Objective Approach

Multitude of tests with multiple variables affectingresults makes diagnosis confusing

Analysis of 900 pts with DIC (non-pregnant)

Thrombocytopenia > Elevated FDP > prolonged PT >prolonged aPTT > low fibrinogen

International Society for Thrombosis andHaemostasis (ISTH) developed a more objective

scoring system for the diagnosis of DIC Compared to blinded expert assessments for DIC, found to

be 91% sensitive and 97% specific

Bakhtiari et al. Crit Care Med (2004) 32: 2416-21


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What is Obstetrical DIC?

PROBLEMS WITH DIC IN PREGNANCY

1. No universally accepted definition of DIC2. Great spectrum of manifestations

3. Normal pregnancy state is hypercoagulable


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Pathogenesis of DIC in Pregnancy

Three main triggers Endothelial injury

Thromboplastin release

Phospholipid exposure

End result = generationof thrombin with fibrindeposition

Many pathologies

overlap

Letsky EA. Best Pract Res Clin Obs Gynecol (2001) 15: 623-44.


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Diagnosis of Obstetrical DIC

Almost all coagulation factors are elevated inpregnancy Marked shortening of PT and aPTT

Consumption of coagulation factors may elevate the PT andaPTT but be still within normal non-pregnant ranges

Important to assess serial changes in PT and aPTT

Similar problem with platelet count

Fibrinogen levels can double in pregnancy Not all cases of DIC have low fibrinogen

Thachil et al. Blood Reviews 23 (2009) 167-176.


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Spectrum of DIC in Obstetrics

Severity of DIC In vitro Findings Obstetric ConditionsCommonly Associated

Stage 1: Low-gradecompensated

FDPs Platelets

Pre-eclampsia and relatedsyndromes

Stage 2: Uncompensatedbut no haemostaticfailure

As above plus: Platelets Fibrinogen Factors V and VIII

Small AbruptioSevere Pre-eclampsia

Stage 3: Rampant with

haemostatic failure

As above plus:

PlateletsGross depletion ofcoagulation factors(particularly fibrinogen) FDPs

Abruptio placentae

Amniotic Fluid EmbolismEclampsia

***Rapid progression may occur if underlying cause not treated

Adapted from Letsky EA. Best Pract Res Clin Obs Gynecol (2001) 15: 623-44.


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Thrombocytopenia

Feature of ~98% of DIC cases Platelet count


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aPTT and PT

Prolonged in 50-75% of cases of DIC at some point intheir illness

Several causes

Consumption of coagulation factors Abnormal synthesis in the liver

Loss of proteins with massive bleeding

Times may actually be shortenedinitially (~50%)

activated circulating clotting factors


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FDP & D-Dimers

Elevated in 85-100% of patients with DIC Non-specific

Problems in pregnancy

Nishii et al(2009) Examined levels of D-dimers in 1131 pregnancies

1.1 1.0 g/ml in 1st trimester

2.2 1.1 g/ml in 3rd trimester

Nishii et al. J Obstet Gynaecol Res (2009) 35:689-93


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FDPnot just a marker

Fibrin degradation products also implicated in thepathophysiology of obstetrical DIC Impair fibrin monomer polymerization (i.e. prevent cross-

linking of fibrin and formation of new clots)

Coat platelet membranes resulting in decreased plateletfunction

Impairs myometrial contractility

Worsens atonic PPH

May be cardiotoxic Low cardiac output and blood pressure = organ perfusion

Induce synthesis of inflammatory cytokines

Bick RL. Hem Onc Clin North Am (2000) 14: 999-1034.


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Fibrinogen in Obstetrical DIC

Elevated as part of normal pregnancy

Can be used as a predictor of PPH severity (oftenlinked with DIC)

Data from 128 women with PPH analyzed Analyzed serial coagulation tests

Fibrinogen was the only marker associated with the occurrenceof severe PPH

NPV of FG > 4g/L = 79%

PPV of FG < 2g/L = 100%

Charbit et al. J Thromb Haemost (2007) 5: 266-73


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1 . T R E A T T H E O B S T E T R I C A L A B N O R M A L I T Y ! !

2 . R E P L A C E B L O O D P R O D U C T S Massive Transfusion Protocol

3 . T R E A T A C I D O S I S , H Y P O T H E R M I A , A N DH Y P O C A L C E M I A

4 . T H E R A P Y H I G H L Y I N D I V I D U A L I Z E D

Treatment of Obstetrical DIC

Mercier et al. Curr Opin Anaest (2010) 22: 310-16.


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Blood Products

PRBCs Improve O2 carrying capacity

Transfuse based on physical exam, vitals, and ongoing loss

FFP

Contains all plasma proteins and clotting factors Transfuse if microvascular bleeding from clotting factor deficiency

Cryoprecipitate Contains clotting factors and high concentrations of fibrinogen

Use if fibrinogen


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IWK Massive Transfusion Protocol

Guiding Principles Volume resuscitation with PRBCs as soon as available

Little evidence for standardized ratios in pregnant women butratio of 2:1:1 (PRBC:FFP:Plts) may be beneficial

Maintain low-normal BP and prevent hypothermia & acidosis

Use PRBCs


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Activate MTP if: Request for emergency PRBCs

Expecting to lose one blood volume within first 24 hours (~5Lin 70 kg patient)

Predicting loss of >50% blood volume within a 3 hour period

Ongoing loss of >15ml/kg/hr

Concern by the Medical Lead
http://www.iwk.nshealth.ca/


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Identify MTP co-ordinator Facilitate transfusions and records use of products

Assigns associated tasks

Notifies blood bank and provides patient info

BLEED order set in MeditechArterial Blood Gases

Ionized calcium

Lactate

Electrolytes

BCP (CBC without WBC differential) INR, PTT, fibrinogen

Collect every 30-60 min depending on clinical situation


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Counter the complications of massive transfusion Ionized Calcium >1.13 mmol/L

Urine output >30 cc/hr (>0.5cc/kg/hr)

SBP low-normal for age or stability

Temperature >35 C

pH >7.10

Consider the use of adjuvant Tx Antifibrinolytics (Cyklokapron)

10mg/kg IV (max 1g/dose)

Recombinant Factor VIIa 20 50 g/kg/dose IV

Prohemostatic drugs (DDAVP)

10g/m2 IV (max 20 g)


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May discontinue MTP if: Hgb > 70

INR < 1.7

Platelet count >50

Fibrinogen > 1.0

Resolution of shock and no evidence of bleeding


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Recombinant Factor VIIa

Produced from

hamster kidney cells Involves extrinsic &

intrinsic pathways

Results in a thrombin

burst to form a strongstable clot at the site of

vessel injury

The Silver Bullet of PPH?


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rFVIIa

Approved for use in congenital coagulationdeficiencies and inherited platelet disorders First off-label use in a wounded soldier in 1999 with no

bleeding disorder

First off-label use in obstetrics was in 2001 following PPH afterC-section

Largest meta-analysis in non-OB cases in 2008 22 RCTs; 3184 patients

Reduction in # of blood transfusions (OR 0.54)

Possible reduction in mortality (OR 0.88; CI 0.71-1.09)

No increased risk of VTE (1% in both groups)

Mild increased risk of arterial thrombosis (OR 1.50)

Hsia CC et al. Ann Surg (2008) 248: 61-68.


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Risks of rFVIIa

FDAs Adverse Event Reporting System (AERS)reviewed (1999-2004) 431 AE reports for rFVIIa; 185 thromboembolic events

Used ~9000 times in timeframe studied

35% in unlabeled indications (most with active bleeding)

CVA (39), MI (34), arterial thrombosis (26), PE (32), DVT(42), clotted devices (10)

50 reported deaths (72% due to thromboembolic event)


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Registry Safety Data

Northern Europe Factor VIIa in Obstetric HemorrhageRegistry 9 European countries (2000-2004)

Reported use in 128 patients

4 cases of DVT

One MI (had cardiac arrest prior to rFVIIa)

Australian and New Zealand Registry 27 cases of rFVIIa in obstetrical hemorrhage

No adverse effects reported

Italian Registry on use of rFVIIa in severe PPH 35 cases

No adverse effects reported


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rFVIIa & PPH

Franchini et al(2010) 9 studies; 272 patients; Median age 31; Median dose 81.5

g/kg

Efficacy in stopping or reducing bleeding = 85%

Failures attributed to inadequate dosages, unrecognized surgicalbleeding, and severe metabolic abnormalities

Adverse events in 2.5% of cases (all thrombotic episodes)

Should not be considered a substitute for performing invasive

procedures (embolization, conservative surgery) Could consider use before hysterectomy

Franchini M et al. Clin Obstet Gynecol (2010). 53: 219-27.


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rFVIIa & PPH with DIC

Franchini et al (2007) 32 cases from 15 studies

Median age 33.3 years

Uterine atony #1 cause of PPH

Majority delivered via C/Section (76%)

Hysterectomy in 56%

Single dose of rFVIIa successful in 81%

Cessation or significant reduction in blood loss

No reports on safety

Franchini et al. Blood Coag Fibrin (2007) 18: 589-93.


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ProposedAlgorithm for

rFVIIa in PPHFranchini et al. TheUse of RecombinantActivated FVII inPostpartumHemorrhage. ClinObstet Gynecol. 2010.53: 219-227.


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Committee Opinions on rFVIIa

Conservative use is currently endorsed by: The French health safety agency (AFSSAPS)

Several European and Australian-New Zealandmultidisciplinary expert panels

Suggest giving 90 g/kg after all definitive procedures attempted,and 8-12 U PRBCs given but before hysterectomy

May repeat dose after 20 min if still bleeding

If still no response, proceed to hysterectomy

SOGC 2009 PPH guidelines Evidence for the benefit of recombinant activated factor

VII has been gathered from very few cases of massive PPH.Therefore this agent cannot be recommended as part ofroutine practice. (II-3L)

Welsh A et al. (2008) Aust NZ J Obstet Gynaecol. 48: 12-16.


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Practical rFVIIa tips

Produced under trade name Niastase Available in glass vials of 1.2, 2.4, or 4.8 mg

White lyophilized powder needs to be reconstituted insterile water

Store at 2-8 C Administer within 3 hours of reconstitution

Give as IV bolus over 3-5 minutes

Soon coming in vials of 1, 2, & 5 mg at concentration of 1

mg/ml Can store at room temp

***$1 per g!...average dose ~$6300***


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Tranexamic Acid (Cyklokapron)

Cochrane review (2007) for non-OB surgery Reduced risk of blood transfusion (RR 0.61; CI 0.54-0.69) Reduced need for re-operation from bleeding (RR 0.67; CI 0.41-1.09) No increased risk of VTE

3 RCTs on PPH prevention 461 patients Reduction in PPH incidence (RR 0.4; CI 0.32-0.64) No VTE

WHO guidelines state that tranexamic acid may be usedin PPH if other measures fail Acknowledge low quality of evidence

Two large prospective trials of Tranexamic acid and PPHcurrently underway

Mercier et al. Curr Opin Anaest (2010) 23: 310-16.


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The Nova Scotian Experience


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Atlee Database &Chart Review

(1980-2009)

72 casesidentified byAtlee

Database 62 charts

reviewed

DIC likely in

48 cases ISTH and

Letskycriteria

Demographics Average age = 28.1 years

Nulliparous = 27

Multiparous = 21

Average gestational age = 35.4 weeks

Average stay in hospital = 11.7 days

Average pre-pregnancy wt = 65.6 kg

14 cases excluded Miscoded

Other coagulopathies

Other thrombocytopenias with nocoagulation abnormalities


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C/S = 46%

SVD = 40 %

Operative vaginal

delivery = 14%

19

11

11

6 1

Mode of Delivery

SVD

C/S (labor)

C/S (no labor)

FAVD

Vacuum


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#1 = Abruption

38%

#2 = PPH

29%

#3 = Preeclampsia

15%

18

14

7

4

3 2

Causes of DIC

AbruptioPlacentae

PPH

Preeclampsia

AFLP

Sepsis

AFE


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PPHdocumented in38 cases

Causes of PPHoften overlap

21

11

9

3

PPH Associations

Atony

Genital Tract

Trauma

RPOC

Accreta


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PPH

Management

Note high rate ofemergency

hysterectomy(24%)

1914

8

41 3

39

0 10 20

MedicalManagement

SurgicalManagement

Hysterectomy

Compressionsutures

Vessel Ligation

Embolization

Tamponade

Misoprostol

Ergot

Hemabate


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Blood Products

PRBCs 0 23 units (avg 7.5)

FFP 0 5600 cc

Cryoprecipitate 0 20 units (avg 9.5)

Platelets 0 30 units (avg 11.2)

Albumin 0 2000 cc

rFVIIa Used in 1 case (2 units)


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Morbidity & Mortality

ICU stay 18 patients

Range 1-8 days

ATN requiring dialysis

3 patients Emergency Hysterectomy 9 patients (3/9 primiparous)

Maternal mortality 3 patients (6.25%)

1 fulminant DIC w/ uncontrollable hemorrhage

1 fulminant DIC refusing blood products

1 intracerebral hemorrhage


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Total of 52infants born to

48 mothers 4 sets of twins

69% lived

25% died in utero

6% died as neonates

28 NICU admissions

Gestational Ages

< 33 weeks = 15

34-36 weeks = 14 37+ weeks = 23

36

13

3

Neonatal Outcomes

LivingFetal Death

Neonatal Death


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VLBW = 500 -


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Conclusions

DIC is a rare but serious entity in modern obstetrics High morbidity and mortality (6.25%)

DIC is difficult to diagnose and we must have a highindex of suspicion when dealing with pathologiesknown to cause DIC Mild untreated DIC can rapidly progress to fulminant

haemostatic failure

Treatment of DIC is aimed at the underlying causeplus supportive therapy

Proposed role for rFVIIa prior to hysterectomy


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QUESTIONS?

Thank You

Coagulation Problem in Pregnancy 4

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