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Disseminated Intravascular Coagulation DIC in Pregnancy

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Disseminated Intravascular Coagulation DIC in Pregnancy Powered By Docstoc
					  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
  abdomen…she sent for me about 7 and I arrived at
  8:20”
 “The pulse was full and bounding, but the patient
  was pale…the uterus…now very hard, large,
  symmetrical, and tender. No heart tones”
 “Diagnosed premature detachment of the
  placenta…the 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 injected…Deep 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 clots…dark, 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 believe…there 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
              • SECONDARY HAEMOSTASIS
                •   Formation of Fibrin clot
                    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 (D-
     dimers)
 Many other conditions have ↑ D-dimers
   Trauma
   Recent surgery
   Venous thromboembolism
   Pregnancy
                                    What is DIC?

              Bleeding & Clotting
SYSTEMIC THROMBOHEMORRHAGIC DISORDER
SEEN IN ASSOCIATION WITH WELL-DEFINED
CLINICAL SITUATIONS AND LABORATORY
EVIDENCE OF:
    1.    Procoagulant activation
    2.    Fibrinolytic activation
    3.    Inhibitor consumption
    4.    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.   No universally accepted definition of DIC
 2.   Great spectrum of manifestations
 3.   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                         In vitro Findings                    Obstetric Conditions
                                                                             Commonly Associated
Stage 1: Low-grade                      ↑ FDPs                               Pre-eclampsia and related
compensated                             ↓ Platelets                          syndromes

Stage 2: Uncompensated As above plus:                                        Small Abruptio
but no haemostatic     ↓↓ Platelets                                          Severe Pre-eclampsia
failure                ↓ Fibrinogen
                       ↓ Factors V and VIII
Stage 3: Rampant with                   As above plus:                       Abruptio placentae
haemostatic failure                     ↓↓ Platelets                         Amniotic Fluid Embolism
                                        Gross depletion of                   Eclampsia
                                        coagulation factors
                                        (particularly fibrinogen)
                                        ↑↑ FDPs
***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 µg/ml in 1st trimester
         2.2 ± 1.1 µg/ml in 3rd trimester




Nishii et al. J Obstet Gynaecol Res (2009) 35:689-93
                           FDP…not just a marker

 Fibrin degradation products also implicated in the
   pathophysiology 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 platelet
       function
      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.
                   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
 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 <1.0 g/L and volume status is a concern
 Platelets
       1 adult dose should ↑ plt count by 25-30
       Use if microvascular bleeding and plt count <50


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
 Consider the use of adjuvant Tx
    Antifibrinolytics (Cyklokapron)
        10mg/kg IV (max 1g/dose)
    Recombinant Factor VIIa
        20 – 50 µg/kg/dose IV
    Prohemostatic drugs (DDAVP)
        10µg/m2 IV (max 20 µg)
       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

 FDA’s 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)
 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
                                          rFVIIa & PPH

 Franchini et al (2010)
   9 studies; 272 patients; Median age 31; Median dose 81.5
    µg/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 µg/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 µg!...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
 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 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)         Demographics
                      Average age = 28.1 years
• 72 cases
                      Nulliparous = 27
  identified by
                      Multiparous = 21
  Atlee
  Database            Average gestational age = 35.4 weeks
                      Average stay in hospital = 11.7 days
• 62 charts           Average pre-pregnancy wt = 65.6 kg
  reviewed
                    14 cases excluded
• DIC likely in       Miscoded
  48 cases            Other coagulopathies
    •   ISTH and      Other thrombocytopenias with no
        Letsky         coagulation abnormalities
        criteria
                             Mode of Delivery



C/S = 46%                                       SVD
SVD = 40 %               6   1

Operative vaginal                               C/S (labor)
                                        19
delivery = 14%
                    11                          C/S (no labor)


                                                FAVD
                             11

                                                Vacuum
                                         Causes of DIC

                                                         Abruptio
                                                         Placentae
•   #1 = Abruption
                                                         PPH
      •   38%                   3    2
                            4
                                                   18    Preeclampsia
•   #2 = PPH
      •   29%           7
                                                         AFLP
•   #3 = Preeclampsia
          15%                       14
      •
                                                         Sepsis


                                                         AFE
                           PPH Associations



• PPH                                         Atony
  documented in            3
  38 cases        9
                                              Genital Tract
• Causes of PPH                        21     Trauma
  often overlap
                                              RPOC
                      11

                                              Accreta
                                             9              Hysterectomy
PPH                                      3
                                         3
Management           Surgical        1                      Compression
                    Management           4                  sutures
                                                            Vessel Ligation
Note high rate of
emergency                                                   Embolization
hysterectomy
(24%)                                                       Tamponade

                     Medical
                                                            Misoprostol
                    Management
                                             8
                                                  14        Ergot
                                                       19
                                                            Hemabate
                                 0           10        20
                          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)
                  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
Total of 52                        Neonatal Outcomes
infants born to
48 mothers
•   4 sets of twins

•   69% lived                      3
•   25% died in utero         13
                                                  Living
•   6% died as neonates
                                                  Fetal Death
•   28 NICU admissions
                                                  Neonatal Death
                                             36
•   Gestational Ages
       •   < 33 weeks = 15
       •   34-36 weeks = 14
       •   37+ weeks = 23
                                   Birthweights



• VLBW = 500 -
                                                  Normal
  <1500g
                              10
    •   1 infant <500g
• LBW = 1500 -                               25
  <2500g                                          LBW (but not
                                                  VLBW)
• Normal = 2500g         17
  and above
                                                  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


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