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Haematology Updates 2010

Disseminated Intravascular Coagulation


Gynaecologists Perspective
MCH Centre, Pakistan Institute of Medical Sciences, Islamabad

Prof Syeda Batool Mazhar

Disseminated intravascular coagulation (DIC) is an acquired consumption coagulopathy occurring secondarily in the course of severe diseases. It is a thrombohemorrhagic disorder with simultaneous activation of the coagulation and fibrinolytic paths. DIC can occur in any area of medicine and can have varied clinical manifestations. It should be considered as a hematological emergency and has been described as a critical care clotting catastrophe.1 Among acquired bleeding disorders, more than a quarter is represented by DIC.2 Levi in 2009 reported that in Western hospitals 1-5% of patients with DIC have a peripartum haemostatic emergency as the underlying cause while in the developing countries the frequency is probably much more.3 The obstetric disorders associated with DIC have the placenta playing a major role in the activation of the coagulation system. Moreover peri partum DIC has more severe manifestations due to the large placental site behaving like an open wound .The common obstetric causes of DIC include placental abruption, placenta previa, HELLP syndrome, preeclampsia, eclampsia, intrauterine fetal demise, septic abortion and intrauterine infection. The less frequent though serious conditions in obstetrics associated with DIC are amniotic fluid embolism, acute fatty liver of pregnancy and gestational trophoblastic disease. Worldwide these are the leading direct causes of maternal mortality and DIC can be a complication in all of these conditions. Women with uncorrected obstetric hemorrhage of any cause require massive transfusion and are at risk of DIC both due to the blood loss as well as its treatment. The international Society of Haemostasis and Thrombosis (ISTH) following a previously developed scheme has proposed a scoring algorithm for DIC in a patient already diagnosed with an underlying condition associated with DIC. This score is based on the platelet count,(>100,000=0, <100,000=1, <50,000=2) prolongation of prothrombin time (PT <3 sec=0, 3 to 6 sec=1, >6 sec=2), reduced plasma fibrinogen (>1.0g/L =0, <1.0 g/L =1) and increased fibrin degradation products ( FDP) or D dimers (no increase=0, moderate increase=2, strong increase > 5 times=3). A score > 5 is compatible with DIC.4,5 This scoring algorithm is a simple bedside clinical tool to be repeated daily and can also be used in clinical trial designing and execution thereby improving care of these critically ill patients.

Normal Coagulation and Pregnancy


Haemostasis has been described to occur in four major phases namely, the vascular phase characterized by vasospasm, followed by platelet plug formation. The third phase is the coagulation system activation resulting in a fibrin-rich stable clot followed by a final phase of fibrinolysis. To understand DIC an understanding of coagulation is necessary. Normal plasma in men and non pregnant women contains an excess of clotting factors and needed percentage values of these factors to maintain haemostasis varies from 5-50% of mean normal values.6 Pregnancy has been described as a hypercoaguable state7, as there is a significant rise in the levels of serum fibrinogen and factors VII, VIII, IX and X. Factors V and II remain almost the same while factors XI and XIII are decreased to almost 70% of the non pregnant levels.8 Most of the evidence in literature suggests that in normal pregnancy there is reduced activity of the fibrinolytic system.9

Pathophysiology
The pathophysiology of DIC is very complex. The underlying disease process activates the coagulation cascade as well as the fibrinolytic pathways. Hemorrhage is the most obvious easily recognized manifestation, yet it is easier to manage. It is however the micro vascular thrombosis which contributes far more to end organ damage due to ischemia leading to irreversible morbidity and mortality. Supportive measures and removal of the triggering mechanism are the key to successful management. The fetomaternal outcome depends mainly on proper management of the trigger and not on primary correction of the coagulation deficit. After delivery prevention and treatment of postpartum hemorrhage ensures rapid recovery.

Clinical Presentation
Clinical conditions found to be associated with DIC among obstetrics patients are listed in Table 1. The clinical manifestations, laboratory results and treatment would vary in the acute fulminant variety of DIC as encountered in amniotic fluid embolism when compared to the compensated low grade variety as seen in intrauterine fetal demise. The acute DIC presents characteristically with multiple defects of hemostasis like hematuria, mucosal bleeding, epistaxis, bleeding gums, petechiae, purpura and oozing from venepuncture sites. On the other hand, the low

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Haematology Updates 2010 grade DIC has predominant thrombosis while the bleeding manifestations may be minor with a notable increase in FDPs on laboratory tests. End organ damage occurs due to hypotension and deposition of fibrin platelet clumps in small vessels causing endothelial damage leading to increased vascular permeability. The organs most susceptible to damage in DIC are the kidneys due to glomerular damage and acute tubular necrosis. Pulmonary edema, adult respiratory distress syndrome and systemic inflammatory response syndrome affect the lungs while cerebral edema and infarcts occur in the central nervous system with associated symptoms and signs. Laboratory evidence of procoagulant activation, fibrinolytic activation, inhibitor consumption and biochemical evidence of end-organ damage or failure (table 2) along with association with the conditions listed in table1 assist in confirming the diagnosis.10 The treatment of DIC should however be initiated whenever there is a strong clinical suspicion. A bedside test in the form of the clot assay may be useful in less equipped facilities. The blood sample is placed in a red topped tube. If there is no clot formation or the clot forms and lyses in 30 minutes, it can be deduced that there is a high probability of a coagulation defect and a fibrinogen level less than 150mg/dl.11 The obstetric causes of DIC fall into three broad categories: 1. Release of thrombogenic tissue factors as in placental abruption and amniotic fluid embolism 2. Injury to the vascular endothelium as in preeclampsia and septicemia 3. Production of procoagulant phospholipids as in septicemia and mismatched blood transfusion The common causes of DIC in obstetrics will be discussed briefly along with their relevant management. will determine whether to deliver the fetus. Almost 50% of women with placental abruption present in labor and mode of delivery is determined by the gestation as well as evidence of fetal compromise. At very early gestations vaginal delivery should be attempted as labor is often short and is augmented where required by artificial rupture of membranes, prostaglandins and oxytocin infusion as appropriate. In the presence of fetal compromise at viable gestations, lower segment caesarean section may be performed after alerting the blood bank for need of cross matched blood and blood products as indicated. In a study of hundred women with abruptio placentae from tertiary care teaching government hospital in Karachi, 7% were complicated by DIC. Among these 7 women with DIC, no maternal mortality occurred while fresh still birth occurred in 6 infants (87.6%) and only one woman required LSCS (14.3%).14 In managing acute abruption, emptying the uterus to rapidly remove the source of thromboplastins, maintaining euvolemia with crystalloids, transfusing red cell concentrates for oxygen carrying capacity and blood components for the coagulation deficit are all essential.

Sepsis
In obstetrics, induced abortion and chorioamionitis in association with prolonged rupture of membranes and dai handling are common causes of sepsis. Pyelonephritis is another important etiology. The most frequent agents are the gram negative microorganisms. Less commonly gram positive bacteria, mycobacterium and others may be implicated. The initial insult is by the bacterial endotoxin or exotoxin. The most important mechanism of DIC in sepsis is the activation of the extrinsic pathway through the tissue factor and tumor necrosis factor alpha following diffuse endothelial damage. The endotoxins also activate the intrinsic pathway via factor XII, induce platelet release with endometrial sloughing resulting in liberation of kinins, histamine and serotonin which induce severe hypotension. The best treatment for DIC associated with sepsis is to treat the underlying condition e.g. removal of the retained infected products of conception in septic abortion or expediting the delivery in chorioamnionitis. The coagulopathy resolves with removal of the septic focus and appropriate intravenous antibiotics. Transfusion of red cell concentrates should only be considered if the patient is actively bleeding or a surgical intervention is planned.

Abruptio Placentae
This is the most common cause of DIC among the pregnant population. The main mechanism is thromboplastin release and activation of the extrinsic pathway (factor VII) due to ante partum placental separation. The consumption of clotting factors by the extravascular clot makes a minor contribution to the coagulopathy. Placental abruption can affect up to 5% of gestations although the vast majority of these are minor. The severity of abruption is graded from 0 to 3, with almost 30% of women with grade 3 abruption developing DIC.12 Marked derangement of laboratory tests, abruption grade, longer time interval from onset of separation to delivery and its occurrence in second trimester are all associated with increased severity of DIC, greater end organ damage as well as mortality.13 The clinical picture and gestation at presentation

Preeclampsia and Eclampsia


Majority of women with preeclampsia have subclinical consumptive coagulopathy. The placenta is central to pathophysiology of preeclampsia. Placental hypoperfusion produces oxidative stress and releases circulating factors which cause activation of the vascular endothelium. Endothelial cell activation leads to liberation

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Haematology Updates 2010 of vasoactive substances, decreased activity of prostacyclin and activation of clotting cascade. The levels of D-dimers are elevated in women with preeclampsia and fibrin deposition has been found on biopsies in kidneys, lungs, liver and placentae of these women. Frank DIC in hypertensive disorders occurs in association with superadded placental abruption or HELLP syndrome.13 In preeclampsia with laboratory reports suggesting DIC, immediate delivery is recommended to avoid clinically evident DIC.15 If expeditious delivery of baby is affected, specific treatment of DIC is often unnecessary. earliest abnormalities to become evident. The risk of DIC in the mother after the demise of one fetus in a multiple pregnancy is negligible. A baseline coagulation profile will suffice and subsequent laboratory surveillance is probably unnecessary. However in monochorionic twin gestations there is a 12% risk of neurological deficit in the surviving fetus.16 Low dose subcutaneous heparin is the treatment of choice for chronic low grade DIC associated with IUFD. After correction of hypofibrinogenemia to 200-300 mg/dl and platelet levels > 50,000/mm3, delivery can be planned. In women presenting in labor, heparin is inadvisable and fibrinogen replacement may best be achieved by cryoprecipitate.13

Intrauterine Fetal Demise


The mechanism of coagulopathy is the activation of factor VII of extrinsic pathway by the release of tissue thromboplastin from the fetoplacental unit. The association of prolonged retention of dead fetus and coagulation disorder is uncommon in modern obstetrics largely due to early aggressive treatment of intrauterine fetal demise (IUFD). Table 1: Conditions complicated by DIC in Obstetrics Placental Abruption Placenta Previa Preeclampsia / Eclampsia / HELLP syndrome Intrauterine fetal demise Induced / Septic abortion Intrauterine infection Massive transfusion Amniotic fluid embolism Acute fatty liver of pregnancy Gestational trophoblastic disease Table 2: Abnormal Laboratory Tests in DIC Decreased platelet count Decreased Serum fibrinogen Decreased Antithrombin III Elevated D dimers Elevated Fibrin Degradation Products

Massive Obstetric Hemorrhage and Massive Transfusion


Dilution coagulopathy is the mechanism of DIC in these women. Massive transfusion means transfusion within 24 hours of a volume of whole blood, its components or replacement fluids greater than the total blood volume of the patient receiving transfusion.17 Majority of healthy pregnant women can tolerate massive transfusion without developing dilutional coagulopathy or dilutional thrombocytopenia. Women receiving massive transfusion should have periodical screening laboratory tests including platelet count, PT, APTT and serum fibrinogen. Bleeding after massive transfusion is likely if PT and APTT are prolonged 1.5 times and platelet values are below 50,000/mm.3 Platelet transfusions followed by FFP administration is recommended.17

Amniotic Fluid Embolism


Amniotic Fluid Embolism (AFE) also called anaphylactoid syndrome of pregnancy, although uncommon, has become the leading cause of maternal mortality in the developed countries. The mortality rate of this condition was reported to be 60-70%18 whereas the recent UK data19 quotes it around 24%. An anaphylactic reaction to the passage of amniotic fluid and particulate matter in the lungs results in pulmonary hypertension and hypoxia. About half of all women who survive the initial insult develop DIC. The mechanism leading to DIC in AFE is similar to that in placental abruption with the activation of factor VII of extrinsic pathway by thromboplastin like effects of fetal antigens in maternal circulation.19 The hemorrhage of AFE is treated by volume and component replacement often in massive quantities till the correction of laboratory parameters.

Prolonged PT and APTT


The haemostatic derangements become evident after 4 to 5 weeks of IUFD. It is recommended that a complete blood count, PT, APTT, D-Dimers, fibrinogen and FDP's should be done with the latter two being the

Acute Fatty Liver of Pregnancy


This is a very rare, pregnancy specific, potentially fatal disorder of third trimester with a prevalence of 5 per 100,000.20 It is characterized by severe liver failure. It is associated with renal impairment, markedly raised uric acid,

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Haematology Updates 2010 elevated white blood cell count, diabetes insipidus, hypoglycemia and marked deficiency of clotting factors is the result. Profound decrease in antithrombin III (ATIII) levels helps in differentiating it from HELLP syndrome. Treatment comprises of resuscitation with aggressive fluid and blood products replacement13, intravenous vitamin K followed by delivery. The use of ATIII concentrates is useful in women with active bleeding.21 Multidisciplinary approach and intensive care unit admission is recommended.
7. 8. Elby C.S. A review of a hypercoagulable state. Hematol Oncol Clin North Am 1993;7 1121-1142. Hobisch-Hagen P, Mortl M, Schobersberger W. Haemostatic disorders in pregnancy and peripartum period. Acta Anesthesiol Scand1997; 111:2167. Ostlund E, Bremme K, Wiman B. Soluble fibrin in plasma as a sign of activated coagulation in patients with pregnancy complications. Acta Obstet Gynecol Scand1998; 77:165-169. Bick RL, Frenkel EP, Baker WF, Sarode R. Hematological complications in obstetrics, pregnancy and gynecology. Cambridge University Press. May 2006. Gabbe S, Niebyl J, Simpson JL. Obstetrics, Normal and Problem Pregnancies; 4th edn. New York: Churchill Livingstone. 2002. Luesley DM, Baker PN. Obstetrics and Gyneccology. An evidence based text for MRCOG: 2nd edn. Edward Arnold Ltd. 2010. Dildy III GA. Critical care obstetrics: 4th Edn. Blackwell Science. 2004. Khooharo Y, Memon FA, Noorani KJ. Disseminated intravascular coagulation in Abruptio Placentae. Pak J of Med Sci.2009; Vol 25(4): 660-664 Rath W, Faridi A, Dudenhausen JW. HELLP syndrome. J Perinat Med 2000; 28: 249-260. Creasy R, Resnik R, eds. Maternal Fetal Medicine, 4th edn. Philadephia: WB Saunders, 1999. Reiss RF. Hemostatic defects in massive transfusion: rapid diagnosis and management. Am J Crit Care 2000;9: 158165. Morgan M. Amniotic fluid embolism. Anaesthesia 1979;34:29. Waterstone M, Bewley S, Charles Wolfe C. Incidence and predictors of severe obstetric morbidity: case control study. BMJ 2001;322:1089-94. Knight M, Nelson-Piercy C. Kurinczuk JJ et al. A prospective national study of acute fatty liver of pregnancy in the UK. Gut 2008; 57: 951-6. Castro MA, Goodwin TM Shaw KJ, et al. Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy. Am J Obstet Gynecol 1996; 174: 211-216.

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Conclusion
In obstetrics DIC contributes significantly to maternal morbidity and mortality. All obstetricians should recognize this state early on to prevent the serious consequences of DIC. A multidisciplinary approach including the intensivist, haematologist and physician is necessary to ensure better maternal outcome in the difficult cases.

References
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DeLoughery TG. Critical care clotting catastrophies. Critical care Clinics 2005; 21:531-62. Asthana B, Sharma P, Ranjan R, Jain P, Aravindan A, Chandra Mishra P. et al. Patterns of acquired bleeding disorders in a tertiary care hospital. Clinical and Applied Thrombosis / Haemostasis 2009; 15: 448-53. Levi M. Disseminated intravascular coagulation (DIC) in pregnancy and peri-partum period. Thrombosis Research 2009; 123 (Suppl2): 63-4. Taylor FBJ, Toh CH, Hoots WK, Wada H, Levi M. Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001; 86: 1327-30. Levi M. Settling the score for disseminated intravascular coagulation. Critical Care Medicine 2005; 33: 2417-8. American Association of Blood Banks. 13th edn. Bethesda, M.D: American Association of Blood Banks 1999.

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