Disseminated Intravascular Coagulation (DIC) in Pregnancy

A NOVA SCOTIAN PERSPECTIVE

DARRIEN RATTRAY PGY4 DR THOMAS BASKETT SEPT 29, 2010

Obstetrical DIC

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

De Lee 1901
Mrs H, 35 years of age, IV para, German At 2 AM of the 13th she awoke with a pain in the

abdomenshe sent for me about 7 and I arrived at 8:20 The pulse was full and bounding, but the patient was palethe uterusnow very hard, large, symmetrical, and tender. No heart tones Diagnosed premature detachment of the placentathe flow soon became profuse With the help of the husband alone I put her on the table and prepared the parts

De Lee 1901
gave a hypodermic of strychnine and a large,

bloody infiltration of the skin and subcutaneous tissue took place salt solution, one quart, was injectedDeep blue ecchymoses appeared around the puncture and extended up into the axilla, blood oozing persistantly from the hole and not to be stopped with plaster I tried to do a version, but the hands, tired with two hours hard operating, were paralyzed

De Lee 1901
Placenta was loose in the cavity, which was filled

with 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 hours from the time I started and ten hours from the onset of first symptoms

De Lee 1901
Is there such a disease as acquired hemophilia? The causes of this are unknown; consanguinity of

marriage, tuberculosis, gout, maternal mental shock during gestation Does the loss of blood favor further hemorrhage per se?...the blood that is lost is light and watery, not dark I believethere is such an affection as a temporary hemophilia, but the demonstration of the same, I admit, presents no little difficulty

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

Coagulation 101
PRIMARY HAEMOSTASIS

Coagulation

Formation of platelet plug at site of endothelial injury Formation of Fibrin clot

SECONDARY HAEMOSTASIS

Intrinsic pathway Extrinsic pathway Common pathway FIBRINOLYSIS

Primary Haemostasis
Interaction between

platelets, vWF, and the vessel wall

Endothelium important

Platelet plug is unstable Requires formation of organized fibrin clot Important in

pathogenesis of DIC
Sepsis Preeclampsia Hypovolemic shock

Secondary Haemostasis

Scanning Electron Microscopy of a cross-linked fibrin clot

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)

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 (Ddimers)

Many other conditions have D-dimers Trauma Recent surgery Venous thromboembolism Pregnancy

What is DIC?
SYSTEMIC THRO Bleeding MBOHE & M Clotting ORRHAGIC DISORDER SEEN IN ASSOCIATION WITH WELL-DEFINED CLINICAL SITUATIONS AND LABORATORY EVIDENCE OF:
1. 2. 3. 4.

Procoagulant activation Fibrinolytic activation Inhibitor consumption Biochemical evidence of end-organ damage or failure

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

Processes in DIC

Levi et al. Br J Haematology (2009) 145: 24-33.

Objective Approach
Multitude of tests with multiple variables affecting

results makes diagnosis confusing Analysis of 900 pts with DIC (non-pregnant)

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

International Society for Thrombosis and

Haemostasis (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

What is Obstetrical DIC?

PROBLEMS WITH DIC IN PREGNANCY
1. 2. 3.

No universally accepted definition of DIC Great spectrum of manifestations Normal pregnancy state is hypercoagulable

Pathogenesis of DIC in Pregnancy

Three main triggers

Endothelial injury Thromboplastin release Phospholipid exposure

End result = generation

of thrombin with fibrin deposition Many pathologies overlap

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

Diagnosis of Obstetrical DIC

Almost all coagulation factors are elevated in

pregnancy

Marked shortening of PT and aPTT Consumption of coagulation factors may elevate the PT and aPTT 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.

Spectrum of DIC in Obstetrics

Severity of DIC Stage 1: Low-grade compensated In vitro Findings FDPs Platelets Obstetric Conditions Commonly Associated Pre-eclampsia and related syndromes Small Abruptio Severe Pre-eclampsia

Stage 2: Uncompensated As above plus: but no haemostatic Platelets Fibrinogen failure Factors V and VIII Stage 3: Rampant with haemostatic failure As above plus: Platelets Gross depletion of coagulation factors (particularly fibrinogen) FDPs

Abruptio placentae Amniotic Fluid Embolism Eclampsia

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

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

Thrombocytopenia
Feature of ~98% of DIC cases Platelet count <50 x 109 in ~50% Correlates to Thrombin generation

Thrombin-induced platelet aggregation is mainly responsible for platelet consumption

Low or decreasing platelet count not very specific for DIC

as many conditions that are associated w/ DIC have low platelets

Gestational Thrombocytopenia HELLP Sepsis Leukemia

aPTT and PT
Prolonged in 50-75% of cases of DIC at some point in

their illness Several causes

Consumption of coagulation factors Abnormal synthesis in the liver Loss of proteins with massive bleeding

Times may actually be shortened initially (~50%) activated circulating clotting factors

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

FDPnot just a marker

Fibrin degradation products also implicated in the

pathophysiology of obstetrical DIC

Impair fibrin monomer polymerization (i.e. prevent crosslinking of fibrin and formation of new clots) Coat platelet membranes resulting in decreased platelet function Impairs myometrial contractility

Worsens atonic PPH Low cardiac output and blood pressure = organ perfusion

May be cardiotoxic

Induce synthesis of inflammatory cytokines

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

Fibrinogen in Obstetrical DIC

Elevated as part of normal pregnancy Can be used as a predictor of PPH severity (often

linked with DIC)

Data from 128 women with PPH analyzed Analyzed serial coagulation tests Fibrinogen was the only marker associated with the occurrence of severe PPH
NPV of FG > 4g/L = 79% PPV of FG < 2g/L = 100%

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

Treatment of Obstetrical DIC

1. TREAT THE OBSTETRICAL ABNORMALITY!! 2. REPLACE BLOOD PRODUCTS

Massive Transfusion Protocol

3. TREAT ACIDOSIS, HYPOTHERMIA, AND

HYPOCALCEMIA 4. THERAPY HIGHLY INDIVIDUALIZED

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

Blood Products
PRBCs

Improve O2 carrying capacity Transfuse based on physical exam, vitals, and ongoing loss Contains all plasma proteins and clotting factors Transfuse if microvascular bleeding from clotting factor deficiency Contains clotting factors and high concentrations of fibrinogen Use if fibrinogen <1.0 g/L and volume status is a concern 1 adult dose should plt count by 25-30 Use if microvascular bleeding and plt count <50

FFP

Cryoprecipitate

Platelets

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

IWK Massive Transfusion Protocol

Guiding Principles Volume resuscitation with PRBCs as soon as available Little evidence for standardized ratios in pregnant women but ratio of 2:1:1 (PRBC:FFP:Plts) may be beneficial Maintain low-normal BP and prevent hypothermia & acidosis Use PRBCs <14 days old Balance is key (avoid large volumes of crystalloid) Use O- until ABO/Rh type are confirmed Early contact with Blood Bank

IWK Massive Transfusion Protocol

Activate MTP if: Request for emergency PRBCs Expecting to lose one blood volume within first 24 hours (~5L in 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

IWK Massive Transfusion Protocol

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 Meditech Arterial Blood Gases Ionized calcium Lactate Electrolytes BCP (CBC without WBC differential) INR, PTT, fibrinogen Collect every 30-60 min depending on clinical situation

IWK Massive Transfusion Protocol

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 Antifibrinolytics (Cyklokapron)

Consider the use of adjuvant Tx

10mg/kg IV (max 1g/dose) 20 50 g/kg/dose IV 10g/m2 IV (max 20 g)

Recombinant Factor VIIa

Prohemostatic drugs (DDAVP)

IWK Massive Transfusion Protocol

May discontinue MTP if: Hgb > 70 INR < 1.7 Platelet count >50 Fibrinogen > 1.0 Resolution of shock and no evidence of bleeding

The Silver Bullet of PPH?

Recombinant Factor VIIa

Produced from

hamster kidney cells Involves extrinsic & intrinsic pathways Results in a thrombin burst to form a strong stable clot at the site of vessel injury

rFVIIa
Approved for use in congenital coagulation

deficiencies 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 after C-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.

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)

Registry Safety Data

Northern Europe Factor VIIa in Obstetric Hemorrhage

Registry

9 European countries (2000-2004) Reported use in 128 patients 4 cases of DVT One MI (had cardiac arrest prior to rFVIIa) 27 cases of rFVIIa in obstetrical hemorrhage No adverse effects reported 35 cases No adverse effects reported

Australian and New Zealand Registry

Italian Registry on use of rFVIIa in severe PPH

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 surgical bleeding, 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.

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.

Proposed Algorithm for rFVIIa in PPH

Franchini et al. The Use of Recombinant Activated FVII in Postpartum Hemorrhage. Clin Obstet Gynecol. 2010. 53: 219-227.

Committee Opinions on rFVIIa

Conservative use is currently endorsed by: The French health safety agency (AFSSAPS) Several European and Australian-New Zealand multidisciplinary 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 of routine practice. (II-3L)
Welsh A et al. (2008) Aust NZ J Obstet Gynaecol. 48: 12-16.

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 in

sterile 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***

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

3 RCTs on PPH prevention

WHO guidelines state that tranexamic acid may be used

in PPH if other measures fail

Acknowledge low quality of evidence

Two large prospective trials of Tranexamic acid and PPH

currently underway

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

The Nova Scotian Experience

Atlee Database & Chart Review (1980-2009)

72 cases

identified by Atlee Database reviewed 48 cases

62 charts DIC likely in

ISTH and Letsky criteria

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 no coagulation abnormalities

Mode of Delivery

C/S = 46% SVD = 40 % Operative vaginal delivery = 14%

SVD 6 1 19 11 C/S (labor) C/S (no labor) FAVD Vacuum

11

Causes of DIC
Abruptio Placentae

#1 = Abruption

38%

3 4

2 18

PPH Preeclampsia AFLP

#2 = PPH

29%

#3 = Preeclampsia

15%

14

Sepsis AFE

PPH Associations

PPH

Atony 3 9 21 Genital Tract Trauma RPOC 11 Accreta

documented in 38 cases
Causes of PPH

often overlap

PPH Management
Note high rate of emergency hysterectomy (24%)

Surgical Management

3 3 4

Hysterectomy Compression sutures Vessel Ligation Embolization Tamponade

Medical Management

Misoprostol 8 14 Ergot Hemabate

19 20

10

Blood Products
PRBCs

0 23 units (avg 7.5) 0 5600 cc 0 20 units (avg 9.5) 0 30 units (avg 11.2) 0 2000 cc Used in 1 case (2 units)

FFP

Cryoprecipitate

Platelets

Albumin

rFVIIa

Morbidity & Mortality

ICU stay

18 patients Range 1-8 days 3 patients 9 patients (3/9 primiparous) 3 patients (6.25%)
1 fulminant DIC w/ uncontrollable hemorrhage 1 fulminant DIC refusing blood products 1 intracerebral hemorrhage

ATN requiring dialysis

Emergency Hysterectomy

Maternal mortality

Total of 52 infants born to 48 mothers

Neonatal Outcomes

4 sets of twins 69% lived 25% died in utero 6% died as neonates 28 NICU admissions Gestational Ages

3 13 Living Fetal Death Neonatal Death

36

< 33 weeks = 15 34-36 weeks = 14 37+ weeks = 23

Birthweights

VLBW = 500 -

<1500g

Normal 10 25 LBW (but not VLBW)

1 infant <500g

LBW = 1500 -

<2500g
Normal = 2500g

and above

17

VLBW

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 high

index of suspicion when dealing with pathologies known to cause DIC

Mild untreated DIC can rapidly progress to fulminant haemostatic failure

Treatment of DIC is aimed at the underlying cause

plus supportive therapy

Proposed role for rFVIIa prior to hysterectomy

Thank You
QUESTIONS?