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 (Ddimers)  Many other conditions have ↑ D-dimers  Trauma  Recent surgery  Venous thromboembolism  Pregnancy What is DIC? S Y S T E M I C T H R OBleeding M B O H E&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 In vitro Findings Obstetric Conditions Commonly Associated Stage 1: Low-grade compensated ↑ FDPs ↓ Platelets Pre-eclampsia and related syndromes Stage 2: Uncompensated As above plus: but no haemostatic ↓↓ Platelets ↓ Fibrinogen failure ↓ Factors V and VIII Small Abruptio Severe Pre-eclampsia Stage 3: Rampant with haemostatic failure Abruptio placentae Amniotic Fluid Embolism Eclampsia As above plus: ↓↓ Platelets Gross depletion of 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 crosslinking of fibrin and formation of new clots) Coat platelet membranes resulting in decreased platelet function Impairs myometrial contractility   May be cardiotoxic   Worsens atonic PPH 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)   Recombinant Factor VIIa   10mg/kg IV (max 1g/dose) 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) • 72 cases identified by Atlee Database • 62 charts reviewed • DIC likely in 48 cases • 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 SVD = 40 % 6 1 Operative vaginal delivery = 14% 19 C/S (labor) C/S (no labor) 11 11 FAVD Vacuum Causes of DIC Abruptio Placentae • #1 = Abruption • 3 38% 4 • • 18 #2 = PPH • 29% 7 15% Preeclampsia AFLP #3 = Preeclampsia • PPH 2 14 Sepsis AFE PPH Associations Atony • PPH documented in 38 cases 3 9 21 • Causes of PPH often overlap Genital Tract Trauma RPOC 11 Accreta PPH Management Surgical Management 1 3 3 9 Hysterectomy Compression sutures 4 Vessel Ligation Note high rate of emergency hysterectomy (24%) Embolization Tamponade Medical Management Misoprostol 8 0 10 14 19 20 Ergot Hemabate 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  Neonatal Outcomes Total of 52 infants 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 3 13 36 Living Fetal Death Neonatal Death Birthweights • VLBW = 500 - Normal <1500g • 10 1 infant <500g • LBW = 1500 - 25 <2500g • Normal = 2500g and above 17 LBW (but not VLBW) 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?