Critical Care Obstetrics part 42 pot

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Am J Respir Crit Care Med 2003 ; 168 : 63 – 69 . 24 Reiter CD , Gladwin MT . An emerging role for nitric oxide in sickle cell disease vascular homeostasis and therapy. Erythroid system and its diseases . Curr Opin Haematol 2003 ; 10 ( 2 ): 99 – 107 . 25 Ratto D , Balmes J , Boylen T , Sharma OP . Pregnancy in a woman with severe pulmonary fi brosis secondary to hard metal disease . Chest 1988 ; 93 : 663 – 665 . 26 Sharma CP , Aggarwal AN , Vashisht K , Jindal SK . Successful outcome of pregnancy in idiopathic pulmonary fi brosis . J Assoc Physicians India 2002 ; 50 : 1446 – 1448 . 27 Schmitt F , Martinez F , Brillet G , et al. Early glomerular dysfunction in patients with sickle cell anemia . Am J Kidney Dis 1998 ; 32 : 208 – 214 . 28 Pham PT , Pham PC , Wilkinson AH , Lew SQ . Renal abnormalities in sickle cell disease . Kidney Int 2000 ; 57 : 1 – 8 . 29 Anyaegbunum A , Morel M , Merkatz IR . Antepartum fetal surveil- lance tests during sickle cell crisis . Am J Obstet Gynecol 1991 ; 165 ( 4Pt1 ): 1081 – 1083 . 30 Vichinsky EP , Neumayr LD , Earles AN , et al. Causes and outcomes of the acute chest syndrome in sickle cell disease . N Engl J Med 2000 ; 25 ( 342 ): 1855 – 1865 . 31 Bellet PS , Kalinyak KA , Shukla R , Gelfand JM , Rucknagel DL . Incentive spirometry to prevent acute pulmonary complications in sickle cell disease . N Engl J Med 1995 ; 333 ( 11 ): 699 – 703 . 32 Mallouh AA , Asha MA . Benefi cial effect of blood transfusion in children with sickle cell chest syndrome . Am J Dis Child 1988 ; 142 ( 2 ): 178 – 182 . 33 Davies SC , Win AA , Luce PJ , Riordan JF . Acute chest syndrome in sickle cell disease . Lancet 1984 ; 1 ( 8367 ): 36 – 38 . 34 Atz AM , Wessel DL . Inhaled nitric oxide in sickle cell disease with acute chest syndrome . Anesthesiology 1997 ; 87 ( 4 ): 988 – 990 . 400 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy. © 2010 Blackwell Publishing Ltd. 31 Disseminated Intravascular Coagulopathy Nazli Hossain 1 & Michael J. Paidas 2 1 Department of Obstetrics and Gynaecology Unit - III, Dow University of Health Sciences, Civil Hospital, Karachi, Pakistan 2 Yale Women & Children ’ s Center for Blood Disorders, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA Normal c oagulation d uring p regnancy Pregnancy brings about changes in the circulating levels of coagulation factors. The hemostatic system is dependent upon an intricate balance between platelets, procoagulants and endoge- nous anticoagulant pathways. Table 31.1 indicates the changes, if any, in the coagulation factors during each trimester of pregnancy. Levels of vWF increase as much as 400% near term. Except for factors V and II, the rest of the factors show a 20 – 1000% increase in circulating levels [1] . Serum markers of hypercoagulation in normal pregnancy include increased levels of D - dimer, thrombin – antithrombin (TAT) complexes, and prothrombin fragments 1+2 (F1+2). The anticoagulant pathway includes tissue factor pathway inhibitor (TFPI), activated protein C resistance (APC) and the protein Z - dependent protease inhibitor (ZPI). The ZPI causes inactivation of factor Xa, and this inhibition is enhanced 1000 - fold in the presence of protein Z. There is a fall in the levels of anticoagulant activity, especially protein S, both free and circulating level [2] . Free protein S levels decline signifi cantly as much as 55% during pregnancy. In addi- tion 40% of the women may develop an acquired resistance to activated protein C, unrelated to factor V Leiden mutation. This may be due to increase in factor VIII activity, or a decrease in protein S activity or other as yet undefi ned mechanisms. Fibrinolytic activity is reduced in pregnancy by the secretion of plasminogen activator inhibitor type 2 (PAI - 2) by the placenta, and plasminogen activator inhibitor type 1 (PAI - 1) produced by the liver and endothelium. Levels of both PAI - 1 and PAI - 2 are increased in pregnancy. Plasmin is directly and indirectly inhib- ited by α 2 plasmin inhibitor and by thrombin - activatable fi brinolysis inhibitor (TAFI). Levels of TAFI are increased in the third trimester. Pathophysiology General p rinciples Disseminated intravascular coagulation (DIC) in obstetrics is typically due to one of three etiologies: (i) a release of thromboplastin - like substances that causes activation of both intrinsic and extrinsic pathways; (ii) endothelial damage that may cause activation of intrinsic pathway; or (iii) cytokine release in conditions like Gram - negative sepsis. Any of the above mechanisms may activate both thrombin and plasmin in the circulation. Thrombin causes conversion of fi brinogen into fi brin. During this process, there is formation of fi brin monomers. These monomers then polymerize to form fi brin, which in turn cause occlusion of the microvessels. This may involve multiple organs or peripheral vas- culature. This vessel occlusion results in multiple organ damage seen in DIC. The deposition of fi brin, leads to trapping of platelets, leading to thrombocytopenia. Activation of plasmin also causes release of fi brin degradation products from the fi brinogen, recognized as X, Y, D and E. These degradation products (FDPs) combine with fi brin monomers before polymerization to form soluble fi brin monomer. This further impairs hemostasis and leads to hemorrhage. FDPs also interfere with myometrial and myocardial contraction, thus leading to hemorrhage and hypotension. Thrombin also induces monocyte release of IL - 1, IL - 6 and tumor necrosis factor (TNF), along with endothelial release of thrombomodulin, endothelin and selectin. Endothelin causes intense vasospasm and vasoconstriction, followed by thrombus formation and vascular occlusion. The selectin E (ELAM - 1), binds to monocytes, lymphocytes, and granulocytes causing more release of cytokines. These degradation products cause synthesis and release of monocyte - or macrophage - derived interleukins IL - 1 and IL - 6, and PAI - 1. Interleukins induce additional endothelial damage, whereas PAI - 1 inhibits fi brinolysis, causing further thrombosis. Free plasmin in the circulation also causes the activation of complement system. This leads to further destruction of platelets and thrombocytopenia. Complement activation also leads to increased vascular permeability, leading Disseminated Intravascular Coagulopathy 401 been found to be associated with multiple pregnancies, older maternal age, cesarean or instrumental vaginal deliveries, polyh- dramnios, eclampsia, abruption, uterine rupture and fetal distress [7] . Pathophysiologically, AFE results from a simultaneous tear in the fetal membranes and uterine vessel, through which amniotic fl uid can pass into uterine venous circulation, and then into maternal pulmonary arterial circulation [8] . The presence of amniotic fl uid debris in the maternal circulation causes the release of thromboplastin - like material, which in turn causes activation of factor X. Activated factor X is the most potent activator of thrombin. This results in the occlusion of small microvascula- ture with platelet - rich fi brin microthrombi. The end result is fulminant DIC. Amniotic fl uid also causes release of complement, and platelet factor III, hence causing platelet - rich fi brin microthrombi [9] . Coagulopathy is seen in 83% of cases of amniotic fl uid embolism, and may appear as early as within 4 hours of a triggering event [8] . The laboratory diagnosis of DIC is based on levels of ATIII , fi brinopeptide levels, D dimers, and platelet counts. Hemodynamic stabilization, oxygen inhalation, and use of vasopressor drugs are the mainstay of treatment. AFE is the only condition where heparin can be used in DIC to clear the microvascular occlusion [10,11] . to hypotension. The diffuse endothelial damage leads to activation of factor XII. Activated XII induces the conversion of prekal- likrien to kallikrein, which in turn causes activation of kinins. This further increases vascular permeability. In summary, a triggering event leads to activation of thrombin and plasmin in circulation. Once activated a vicious cycle ensues, leading to generation of FDPs, release of IL - 1, IL - 6, TNF - α and complement activation. Subsequent endothelial activation further aggravates the situation. Infl ammatory cytokines such as IL - 6 and TNF - α have been shown to be prothrombotic by increasing endothelial tissue factor production and affecting protein C activation by changes in the endothelial protein C receptor and thrombomodulin [3] . Cytokines also cause increased platelet formation, and these new platelets are more sensitive to thrombin activation and increased procoagulant activity [4] . This cycle is further aggravated by a decrease in the circulating anticoagulants, namely antithrombin (AT), and protein C and S. This decrease is markedly seen in pre - eclampsia and sepsis. The decreased levels correlate directly with the severity of the disease as well [5] . There is consumption of coagulation factors and platelets, leading to hemorrhage. Both coagulation and hemorrhage coexist, but mostly it is the hemorrhage that seeks obstetrician attention. Etiological f actors for DIC There are number of clinical scenarios in obstetrics that can lead to DIC (Table 31.2 ). Amniotic fl uid e mbolism and DIC Mechanism Amniotic fl uid is rich in both procoagulant and fi brinolytic substances. All the procoagulant activity is dependent upon the presence of tissue factor, whose concentration increases with gestational age [6] . Amniotic fl uid embolus syndrome (AFE) has Table 31.1 Normal clotting values in pregnancy. Variables (mean ± SD) First trimester Second trimester Third trimester Normal range Platelets 275 ± 64 256 ± 49 244 ± 52 150 – 400 Fibrinogen (g/L) 3.7 ± 0.6 4.4 ± 1.2 5.4 ± 0.8 2.1 – 4.2 Prothrombin complex (%) 120 ± 27 140 ± 27 130 ± 27 70 – 30 Antithrombin (U/mL) 1.02 ± 0.10 1.07 ± 0.14 1.07 ± 0.11 0.85 – 1.25 Protein C (U/mL) 0.92 ± 0.13 1.06 ± 0.17 .94 ± 0.2 0.68 – 1.25 Protein S, total (U/mL) 0.83 ± 0.11 0.73 ± 0.11 0.77 ± 0.10 0.70 – 1.70 Protein S, free (U/mL) 0.26 ± 0.07 0.17 ± 0.04 0.14 ± 0.04 0.20 – 0.50 Soluble fi brin (nmol/L) 9.2 ± 8.6 11.8 ± 7.7 13.4 ± 5.2 < 15 Thrombin - antithrombin( µ g/L) 3.1 ± 1.4 5.9 ± 2.6 7.1 ± 2.4 < 2.7 D - dimers (ug/L) 91 ± 24 128 ± 49 198 ± 5 9 < 80 Plasminogen activator inhibitor - 1 (AU/mL) 7.4 ± 4.9 14.9 ± 5.2 37.8 ± 19.4 < 15 Plasminogen activator inhibitor - 2 (ug/L) 31 ± 14 84 ± 16 160 ± 3 1 < 5 Protein Z (ug/mL) 2.01 ± 0.76 1.47 ± 0.45 1.55 ± 0.48 Table 31.2 Clinical scenarios in obstetrics associated with disseminated intravascular coagulation ( DIC ). Amniotic fl uid embolus syndrome Placental abruption Gram - positive and Gram - negative septicemia Massive blood loss leading to DIC Massive transfusions secondary to blood loss Severe pre - eclampsia and eclampsia Intrauterine fetal death Acute fatty liver of pregnancy Chapter 31 402 delivery, and the prognosis of fetus as well. In abruption of a lesser degree it is assumed that silent placental infarcts will cause consumption of coagulation factors like factor VIII, along with release of degradation products, whereas in massive abruption, placental thromboplastin and activated coagulation factors enter into the systemic circulation through uterine veins and cause DIC. Clinical features are the same as described below, along with the laboratory evidence. Recently elevated levels of thrombomodulin (TM) have been identifi ed in acute phases of abruption [16] . TM is not only found in endothelial cells, but is also present in the syncytiotrophoblast. Elevated TM has been identifi ed in TTP, pre - eclampsia and SLE. The effi cacy of TM as a marker of DIC in acute phases of abruptio placentae requires confi rmation in larger studies. Intrauterine d eath and DIC Intrauterine death causes release of necrotic tissue material and enzymes into maternal circulation. This happens when the fetus has been dead for more than 5 weeks. In such cases coagulopathy is seen in around 25% of cases. The pathway is same as for placental abruption, by the release of thromboplastin into the circulation, but consumption of coagulation factors take place slowly, over weeks. Serum fi brinogen levels are decreased, and fi brinogen degradation products are increased in circulation. This clinical scenario is also seen in cases of single fetal demise in twin pregnancy. Hemostatic failure is of concern for the surviving fetus and not for the mother. Intrauterine i nfections and DIC Antepartum and postpartum uterine infections and septic abor- tion can trigger DIC. Endothelial injury, caused by TNF - α , results in release of tissue factor. Tissue factor leads to the production of thrombin, which combines with thrombomodulin to activate protein C. This leads to inhibition of factors Va and VIIIa. This procoagulant effect results in fi brin deposition in microvascula- ture. In sepsis there is a decrease in the activity of protein C and S, EPCR expression. TNF - α also leads to increased PAI - 1 levels, and hence decreased fi brinolysis [17] . Thus sepsis leads to altera- tion in procoagulant – anticoagulant balance, with an increase in procoagulant factors and decrease in anticoagulant factors. Evacuation of uterus under antibiotic cover helps in stopping further progression of the disease. The choice of antibiotic depends upon prevalence and susceptibility patterns in the facil- ity. Both laboratory parameters and clinical signs should be taken into account when diagnosing DIC. Acute f atty l iver of p regnancy Acute fatty liver of pregnancy (AFLP) is a rare, potentially fatal complication of pregnancy, usually seen in the third trimester. There are case reports of earlier appearance in the second trimester as well. It has been found associated with DIC, which is seen in a majority of patients ( > 50%). Castro et al. in a series of 28 Eclampsia and DIC Coagulation abnormalities and intravascular coagulation do occur in hypertensive disorders of pregnancy, but are not clinically signifi cant. Laboratory assessments like prothrombin time, activated partial thromboplastin time and plasma fi brinogen levels are usually not affected in hypertensive disorders of pregnancy. Severe pre - eclampsia and eclampsia lead to low - grade DIC in circulation. It is usually seen in 10% of cases of severe pre - eclampsia and eclampsia. The basic mechanism is the damage to the endothelial cells resulting in activation of both extrinsic and intrinsic pathways. This results in the disappearance of procoagulants, the appearance of fi brin degradation products and end - organ damage secondary to the formation of microthrombi. Signifi cantly higher levels of thrombin – antithrombin complex, soluble fi brin, fi brin degradation product and plasmin - α 2 anti- plasmin are found in pre - eclamptic women [12] . This has been established in peripheral as well as in uteroplacental circulation [5] . Platelet counts are decreased, and low platelet counts correlate well with the severity of disease. The occurrence of HELLP syndrome in severe pre - eclampsia is reported at between 13% to 17%. Activation of endothelial cells causes increased release of VWF, which in turn leads to consumptive thrombocytopenia and thrombotic microangiopathy [13] . In severe cases, decrease of procoagulants like fi brinogen and platelets may produce sponta- neous hemorrhage. Placental a bruption and DIC Advanced maternal age, hypertension, cocaine use, trauma and multiparity can be associated with abruptio placentae. Thrombophilic mutations have also identifi ed as a risk factor for abruptio. Factor V Leiden mutation, protein S defi ciency and prothrombin gene mutations have been identifi ed in the etiology of abruptio placentae [14] . Placental abruption has been graded into the following categories, fi rst introduced in 1978 [15] . Grade 0: refers to a retrospective diagnosis of abruptio placentae. Grade 1: vaginal bleeding. Grade 2: vaginal bleeding, concealed hemorrhage, uterine tenderness, non - reassuring FHR. Grade 3: vaginal bleeding, shock, extensive concealed hemorrhage, uterine tenderness, fetal death, and sometimes coagulopathy. Grade 3 is further subdivided based on the presence or absence of a coagulopathy. Coagulopathy as seen in grade 3 placental abruption causes a release of procoagulant substances and thromboplastin - like material into the circulation. This causes the activation of extrinsic coagulation pathway. This, if left unattended for an excessive period of time, will lead to consumption of coagulation factors and fulminant DIC. Only 10% of patients show signifi cant coagulopathy with abruption [10] . In the event of massive separa- tion, coagulopathy is seen in 20 – 30% of cases. The risk of developing DIC in abruptio placentae depends upon the degree of abruption, the time interval between placental abruption and Disseminated Intravascular Coagulopathy 403 The thrombin time is more reliable than either PT or APTT. A fi brin clot not dissolving within 10 minutes signifi es that fi brinolysis is an unlikely event. If the clot begins to lyse within 10 minutes, it shows signifi cant plasmin activity. Prolonged thrombin time is seen with hypofi brinogenemia and also with increased fi brin degradation products. Platelets counts are low in DIC, as explained previously. In cases of thrombocytopenia ( < 100 000) counts should be repeated at 4 - hourly intervals. A repeat low count indicates increased consumption by the generated thrombin. Low platelet counts are not characteristic of DIC, as they may also be seen in the presence of underlying disorders leading to DIC. Hence a low platelet count is not diagnostic of DIC. Serum fi brinogen levels fall below 100 mg/dL before the clinical manifestation of DIC. Measurement of FDPs will be raised, due to the increased plasmin activity. FDPs are raised in 85 – 100% of cases of DIC, but they do not predict the clinical course of DIC [21] . An elevated FDP acts as an indirect test for fi brinolysis. It signifi es the presence of acute or chronic DIC. In acute situations it only confi rms the presence of DIC, but is not diagnostic. FDP may be found elevated in conditions like pulmonary embolism, myocardial infarction or surgical trauma, in women taking oral contraceptive pills and in patients with arterial or venous thromboembolism. The D - dimer test is specifi c for fi brin degradation products, and is more specifi c for DIC, though elevated levels of D - dimer may also be found in deep venous thrombosis and pulmonary embolism. D - dimer is a neo - antigen formed as a result of digestion of cross - linked fi brin by plasmin. The use of D - dimer along with FDP and AT levels has been found to be more sensitive in the diagnosis of DIC in clinical practice [22] . Antithrombin levels are found to be low in DIC. This is due to the formation of complexes of thrombin and coagulation factors with antithrombin, leading to considerable decrease in the level of circulating antithrombin. Thus antithrombin testing helps not only in diagnosis, but also for monitoring therapy in ongoing DIC. PF 1+2 assay is a reliable molecular marker which shows the generation of factor Xa and thrombin. ELISA assays are now available to quantitate the levels of circulating PF1+2 and TAT complexes in the circulation [23] . patients, found DIC in all of their patients [18] . The coagulation abnormalities include a marked decrease in AT levels, which precede the onset of clinical symptoms, thrombocytopenia and consumptive coagulopathy leading to a decrease in the circulating coagulation factors. These coagulation abnormalities persist for many days after delivery [19] . Maternal and fetal mortality are high in AFLP. Apart from supportive treatment, investigators have looked at the potential role of AT concentrate in the treatment. Empirical therapy with AT did not show any improvement in the clinical outcome [12] . Clinical d iagnosis The clinical presentation of DIC may be hemorrhagic or thrombotic. Commonly, it is the hemorrhagic variety which is seen in obstetric practice. Hemorrhagic DIC denotes an acute condition, whereas thrombotic DIC indicates chronic activation of the coagulation cascade. Hemorrhagic DIC involves skin or mucous membranes, resulting in ecchymosis, petechiae, bleeding from venepuncture sites, bleeding from gums, hematuria and gastro- intestinal bleeding. Thrombotic DIC may involve the neurologic, renal and pulmonary systems. It is usually seen in chronic com- pensated DIC, as in malignancy and intrauterine fetal demise. It usually involves deposition of fi brin microthrombi, resulting in organ dysfunction. Microvascular cerebral thrombosis causes cortical dysfunction, which is manifested clinically as an altered state of conciousness. Similarly, renal involvement results in acute tubular necrosis and renal failure, seen in DIC. Involvement of peripheral veins and arteries may result in phlebitis and peripheral gangrene. Here, DIC is characterized by skin hemorrhagic necrosis and gangrene in the extremities of the digits as a consequence of arterial fi brin microthrombi. This is usually seen in patients with Gram - negative bacterial sepsis [20] and is also seen in patients with protein C and S defi ciencies [21] . Laboratory d iagnosis Laboratory tests in a bleeding obstetric patient are of value, but prompt treatment should not be withheld while awaiting results. Unnecessary delay in starting the treatment further aggravates the situation. Table 31.3 illustrates the common laboratory tests to obtain in suspected DIC. Prothrombin time (PT) tests the extrinsic system of coagulation. This test may be abnormal in 50% of patients and may be normal or short in 50% of cases, thus making it less reliable in establishing a diagnosis of DIC. It may be normal or short because of circulating activated clotting factors like factor Xa, which accel- erates the formation of fi brin, thus giving a normal or short PT time. Partial thromboplastin time (APTT) is less important. It may also be prolonged in 50 – 60% of patients and normal or short in 50% of patients. Table 31.3 The common laboratory tests to obtain in suspected DIC . 1 Prothrombin time 2 Partial thromboplastin time 3 Thrombin time 4 Platelet count 5 Fibrinogen levels 6 FDP 7 D - dimer assay 8 Antithrombin levels Chapter 31 404 whole blood and is readily available. FFP is obtained from fresh whole blood within 6 hours of donation and immediately stored at − 30 ° C, and if stored properly, can be used over a period of 1 year. Though there are no randomized trials on the use of FFP in DIC, it is generally understood that FFP is benefi cial in patients with active DIC and consumptive coagulopathy who are treated for underlying disorders prior to any invasive procedure. Use of FFP in such circumstances is well indicated, compared to patients with low - grade DIC without bleeding. There is no role of FFP as prophylactic agent, in situations where bleeding is anticipated [24] . Cryoprecipitate contain more fi brinogen than FFP, but carries more risk of transmissible infections. It lacks antithrombin which is depleted in bleeding obstetric patients. There is no evidence for the prophylactic use of platelets in patients with DIC who are not bleeding, or are not at high risk for bleeding. The need for platelet transfusion depends upon the platelet count. If the platelet count is below 50 000/cu mm, and operative intervention is required, platelet transfusions are required. Platelet transfusions may also be required in bleeding patients with low platelet counts. Thus, the clinical scenario and not the laboratory reports should guide the clinician with regard to further treatment. Use of h eparin Heparin may be required in the thrombotic variety of DIC involving the renal system and peripheral gangrene. Heparin itself has no anticoagulant activity, but combines with AT and enhances the reactivity of AT with serine proteases. Decreased levels of AT in DIC makes heparin ineffective. It is initially given as a loading dose, followed by continuous intravenous infusion at a rate of 500 – 1000 units per hour. Platelet transfusions may be required in the event of thrombocytopenia. Laboratory control of heparin therapy is diffi cult. In obstetrics, heparin is required in cases of AFE and in intrauterine fetal death [10,11] . Heparin in these circumstances blocks the further conversion of fi brinogen and other clotting factors. Heparin should only be used in women with an intact circulation. Active bleeding and vascular disruption are contraindications to treatment with heparin. Use of a ctivated p rotein C Use of recombinant activated protein C (APC) has been shown to have a benefi cial effect in DIC due to sepsis. It has anti - infl ammatory and antithrombotic effects and has also been found to have profi brinolytic properties. Side effects include increased risk of bleeding with its use. A large double - blind, placebo - controlled, multicenter trial, evaluating the use of recombinant activated protein C, found a signifi cant reduction of 6.1% in mortality as compared to the placebo [25] . There are few published case reports of its use in pregnancy. Kobayashi et al. used APC in 16 cases of placental abruption with DIC. They found administra- tion of APC was associated with a decrease in FDP and TAT complexes, and a signifi cant increase in the fi brinogen level [26] . Use of APC has also been found useful in the treatment of coagulopathy due to AFLP [27] . While most of the above tests are available in a routine laboratory, the last two tests require a specialty laboratory. There is no single defi nitive test for the diagnosis of DIC. The practicing clinician may benefi t from routine global tests, AT levels and FDP. In many cases, serial laboratory studies may be clinically necessary. Management of DIC Fluid balance, adequate tissue perfusion, avoidance of tissue hypoxia and removal of underlying etiologic agent are the main- stays of treatment of DIC. The guidelines for management of a bleeding obstetric patient are the same whether bleeding is caused by or is augmented by a coagulation failure. Blood may be drawn for laboratory work, but availability of results should not delay the start of treatment. Identifi cation of etiologic factors and their removal are the cornerstone of treatment for DIC in obstetrics. Delivery of the fetus and placenta should be the fi rst aim in the management of DIC. This results in return of plasma factors to normal levels within 24 hours of cessation of DIC. Platelets return to normal within 7 – 9 days, the time period required for matura- tion and release from bone marrow. Fluid c hoices Initially fl uids may be required to maintain hemodynamic balance until blood and blood products are available for transfusion. Crystalloid solutions like Ringer ’ s lactate and Hartmann ’ s solution are the fi rst choices for intravenous fl uid replacement. The volume infused should be two to three times more than the estimated blood loss. Infusion of crystalloid also helps in main- taining renal function. Plasma substitutes like dextran, gelatin, and starch solution may be used as well. Dextran is associated with allergic reactions, and interferes with subsequent blood grouping and cross - matching tests. Gelatin is also an important substitute, with minimal immunologic reactions, that improves renal function in the presence of hypovolemia [9] . Blood and b lood p roducts Although transfusion support may be needed, there is no consen- sus regarding optimal treatment. In a bleeding patient, a combination of fresh frozen plasma (FFP) and cryoprecipitate is indicated. However, if there is no bleeding, blood products are not indicated, irrespective of laboratory tests. There is no evidence supporting prophylaxis with platelets or plasma. Whole blood may be the treatment of choice for correction of coagulation failure, but is not readily available, because it requires at least 18 – 24 hours for screening. Transfusion of packed red blood cells is necessary to increase the oxygen - carrying capacity. In case the same blood group is not available, non - cross - matched O - negative blood should be available for transfusion. It should be noted that stored bank blood is defi cient in labile clotting factors V, VIII and platelets. It is advisable to transfuse 2 units of FFP for every 4 – 6 units of bank red cells administered. Fresh frozen plasma (FFP) contains all the clotting factors present in Disseminated Intravascular Coagulopathy 405 5 Higgins JR , Walshe JJ , Darling MR , Norris L , Bonnar J . Hemostasis in the uteroplacental and peripheral circulations in normotensive and pre - eclamptic pregnancies . Am J Obstet Gynecol 1998 ; 179 ( 2 ): 520 – 526 . 6 Lockwood CJ , Bach R , Guha A , Zhou XD , Miller WA , Nemerson Y . Amniotic fl uid contains tissue factor, a potent initiator of coagulation . Am J Obstet Gynecol 1991 ; 165 ( 5Pt 1 ): 1335 – 1341 . 7 Villar J , Carroli G , Wojdyla D , et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol 2006 ; 194 ( 4 ): 921 – 931 . 8 Moore J , Baldisseri MR . Amniotic fl uid embolism . Crit Care Med 2005 ; 33 ( 10 Suppl ): S279 – 285 . 9 Green BT , Umana E . Amniotic fl uid embolism . South Med J 2000 ; 93 ( 7 ): 721 – 723 . 10 Letsky EA . Disseminated intravascular coagulation . Best Pract Res Clin Obstet Gynaecol 2001 ; 15 ( 4 ): 623 – 644 . 11 Richey ME , Gilstrap LC , Ramin SM . Management of disseminated intravascular coagulation . Clin Obstet Gynecol 1995 ; 38 ( 3 ): 514 – 520 . 12 Levi M , de Jonge E , van der Poll T . New treatment strategies for disseminated intravascular coagulation based on current understanding of the pathophysiology . Ann Med 2004 ; 36 ( 1 ): 41 – 49 . 13 Hulstein JJ , van Runnard Heimel PJ , Franx A , et al. Acute activation of the endothelium results in increased levels of active von Willebrand factor in hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome . J Thromb Haemost 2006 ; 4 ( 12 ): 2569 – 2575 . 14 Facchinetti F , Marozio L , Grandone E , Pizzi C , Volpe A , Benedetto C . Thrombophilic mutations are a main risk factor for placental abruption . Haematologica 2003 ; 88 ( 7 ): 785 – 788 . 15 Sher G . A rational basis for the management of abruptio placentae . J Reprod Med 1978 ; 21 ( 3 ): 123 – 129 . 16 Magriples U , Chan DW , Bruzek D , Copel JA , Hsu CD . Thrombomodulin: a new marker for placental abruption . Thromb Haemost 1999 ; 81 ( 1 ): 32 – 34 . 1 7 D e m p fl e CE . Coagulopathy of sepsis . Thromb Haemost 2004 ; 91 ( 2 ): 213 – 224 . 18 Castro MA , Goodwin TM , Shaw KJ , Ouzounian JG , McGehee WG . Disseminated intravascular coagulation and antithrombin III depres- sion in acute fatty liver of pregnancy . Am J Obstet Gynecol 1996 ; 174 ( 1 Pt 1 ): 211 – 216 . 19 Castro MA , Fassett MJ , Reynolds TB , Shaw KJ , Goodwin TM . Reversible peripartum liver failure: a new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases . Am J Obstet Gynecol 1999 ; 181 ( 2 ): 389 – 395 . 20 Powars DR , Rogers ZR , Patch MJ , McGehee WG , Francis RB Jr . Purpura fulminans in meningococcemia: association with acquired defi ciencies of proteins C and S . N Engl J Med 1987 ; 317 ( 9 ): 571 – 572 . 21 Molos MA , Hall JC . Symmetrical peripheral gangrene and disseminated intravascular coagulation . Arch Dermatol 1985 ; 121 ( 8 ): 1057 – 1061 . 22 Yu M , Nardella A , Pechet L . Screening tests of disseminated intravascular coagulation: guidelines for rapid and specifi c laboratory diagnosis . Crit Care Med 2000 ; 28 ( 6 ): 1777 – 1780 . 23 Wada H , Gabazza E , Nakasaki T , et al. Diagnosis of disseminated intravascular coagulation by hemostatic molecular markers . Semin Thromb Hemost 2000 ; 26 ( 1 ): 17 – 21 . 24 Mueller MM , Bomke B , Seifried E . Fresh frozen plasma in patients with disseminated intravascular coagulation or in patients with liver diseases . Thromb Res 2002 ; 107 ( Suppl 1 ): S9 – 17 . Role of a ntithrombin III in DIC Antithrombin is a major serine protease inhibitor. It inhibits the activities of thrombin and factors Xa, IXa, VIIa, and XIIa. A double - blind, placebo - controlled, multicenter trial in patients with severe sepsis did not fi nd any benefi cial effect on overall survival and mortality with the use of high - dose AT [28] . The investigators did fi nd some benefi cial effect when it was not used concomitantly with heparin in follow - up substudies. There is increased risk of hemorrhage when combined with heparin. It is recommended before surgery or delivery in patients with DIC, as decreased AT levels may induce severe bleeding in a defi cient patient. Use of r VII a in DIC There have been numerous case reports and case series about the successful off - label use of rFVIIa in DIC in postpartum hemorrhage [29 – 32] . The mechanism of action of activated recombinant factor VII is by formation of complexes with exposed tissue factor (TF) in the absence of factors VII and X. This leads to generation of a thrombin burst. In vitro studies have shown that the clots formed in the presence of rVIIa are fi rmer, stronger and more resistant to digestion by fi brinolytic enzymes. Concerns about the use of rVIIa use in DIC are that by raising the levels of factor rFVIIa by more than 1000 - fold by the drug can potentially cause widespread thrombosis. In vitro studies have not supported this idea. Moreover, the reported incidence of thromboembolism in more than 700 000 doses administered to hemophiliac indi- viduals is as low as 1%. In other series covering its use in trauma and massive bleeding, the incidence varied between 5 and 7% [33] . These patients had other comorbid factors such as obesity, diabetes mellitus, malignancy and advanced age. A literature search did not show any link with thromboembolism in pregnant patients who were given the drug. In our series of 18 patients [34] , we also did not fi nd any adverse side effects related to the use of drug. Though it has proved to be a life - saving medicine in bleeding obstetric patients, further studies are needed to defi ne its use. There are anecdotal reports about its use in DIC due to various obstetric conditions [35,36] . References 1 Lockwood CJ . Pregnancy - associated changes in the hemostatic system . Clin Obstet Gynecol 2006 ; 49 ( 4 ): 836 – 843 . 2 Paidas MJ , Ku DH , Lee MJ , et al. Protein Z, protein S levels are lower in patients with thrombophilia and subsequent pregnancy complications . J Thromb Haemost 2005 ; 3 ( 3 ): 497 – 501 . 3 Ku DH , Arkel YS , Paidas MP , Lockwood CJ . Circulating levels of infl ammatory cytokines (IL - 1 beta and TNF - alpha), resistance to activated protein C, thrombin and fi brin generation in uncomplicated pregnancies . Thromb Haemost 2003 ; 90 ( 6 ): 1074 – 1079 . 4 Esmon CT . Possible involvement of cytokines in diffuse intravascular coagulation and thrombosis . Bailli è re ’ s Best Pract Res Clin Haematol 1999 ; 12 ( 3 ): 343 – 359 . Chapter 31 406 31 Michalska - Krzanowska G , Czuprynska M . Recombinant factor VII (activated) for haemorrhagic complications of severe sepsis treated with recombinant protein C (activated) . Acta Haematol 2006 ; 116 ( 2 ): 126 – 130 . 32 Moscardo F , Perez F , de la Rubia J , et al. Successful treatment of severe intra - abdominal bleeding associated with disseminated intravascular coagulation using recombinant activated factor VII . Br J Haematol 2001 ; 114 ( 1 ): 174 – 176 . 33 Scarpelini S , Rizoli S . Recombinant factor VIIa and the surgical patient . Curr Opin Crit Care 2006 ; 12 ( 4 ): 351 – 356 . 34 Hossain N , Shamsi T , Haider S , Paidas M . Use of activated recombinant factor VII for massive postpartum hemorrhage . Acta Obstet Gynecol Scand 2007 ; 86 ( 10 ): 1200 – 1206 . 35 Gowers CJ , Parr MJ . Recombinant activated factor VIIa use in massive transfusion and coagulopathy unresponsive to conventional therapy . Anaesth Intens Care 2005 ; 33 ( 2 ): 196 – 200 . 36 Baudo F , Caimi TM , Mostarda G , de Cataldo F , Morra E . Critical bleeding in pregnancy: a novel therapeutic approach to bleeding . Minerva Anestesiol 2006 ; 72 ( 6 ): 389 – 393 . 25 Bernard GR , Vincent JL , Laterre PF , et al. Effi cacy and safety of recombinant human activated protein C for severe sepsis . N Engl J Med 2001 ; 344 ( 10 ): 699 – 709 . 26 Kobayashi T , Terao T , Maki M , Ikenoue T . Activated protein C is effective for disseminated intravascular coagulation associated with placental abruption . Thromb Haemost 1999 ; 82 ( 4 ): 1363 . 27 MacLean AA , Almeida Z , Lopez P . Complications of acute fatty liver of pregnancy treated with activated protein C . Arch Gynecol Obstet 2005 ; 273 ( 2 ): 119 – 121 . 28 Hoffmann JN , Wiedermann CJ , Juers M , et al. Benefi t/risk profi le of high - dose antithrombin in patients with severe sepsis treated with and without concomitant heparin . Thromb Haemost 2006 ; 95 ( 5 ): 850 – 856 . 29 Pepas LP , Arif - Adib M , Kadir RA . Factor VIIa in puerperal hemorrhage with disseminated intravascular coagulation . Obstet Gynecol 2006 ; 108 ( 3 Pt 2 ): 757 – 761 . 30 Shamsi TS , Hossain N , Soomro N , et al. Use of recombinant factor VIIa for massive postpartum haemhorrage: case series and review of literature . J Pak Med Assoc 2005 ; 55 ( 11 ): 512 – 515 . 407 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy. © 2010 Blackwell Publishing Ltd. 32 Thrombotic Thrombocytopenic Purpura, Hemolytic – Uremic Syndrome, and HELLP Joel Moake 1 & Kelty R. Baker 2 1 Rice University, Houston, TX, USA 2 Department of Internal Medicine, Hematology - Oncology Section and Baylor College of Medicine, Houston, TX, USA Thrombotic t hrombocytopenic p urpura ( TTP ) Dr Eli Moschcowitz of New York City initially recognized and reported the fi rst patient with thrombotic thrombocytopenic purpura (TTP) in 1923 [1,2] . Terminal arterioles and capillaries were occluded by hyaline thrombi, later determined to be com- posed mostly of platelets, without perivascular infl ammation or endothelial desquamation. TTP is now considered to be the most extensive and dangerous microvascular (arteriolar/capillary) platelet clumping disorder. From about 1970 – 80 on, for unknown reasons, the incidence of this once rare disease has increased considerably. Clinical f eatures Severe thrombocytopenia and hemolytic anemia with one to several fragmented red cells (schistocytes) in many oil fi elds of the blood smear (i.e. more than 1% of total red cells) [3] , along with neurological symptoms and signs, constitute the characteristic clinical triad. Neurological disorders may range in severity from transient bizarre thought and behavior to sensory motor defi cits, aphasia, seizures, or coma. The peripheral blood smear typically shows increased reticulocytes (polychromatic large erythrocytes) and often nucleated red blood cells, in response to the intense hemolysis. Fever and/or renal dysfunction occur in a minority of patients. Renal abnormalities may include protein- uria and hematuria, as well as azotemia. Symptoms and signs of ischemia in the retinal (visual defects), coronary (conduction abnormalities), and abdominal circulation (abdominal pain) may be present. Microvascular occlusions that cause ischemia of the sinoatrial or atrioventricular node, or of the bundle of His or Purkinje conduction system, may cause sudden death [4 – 6] . Abdominal presentations, sometimes resembling pancreatitis, have become more commonly recognized during the past few years (about 5 – 10% of TTP episodes may present with abdominal symptoms) [7] . Laboratory fi ndings The degree of thrombocytopenia in TTP refl ects the extent of intravascular platelet clumping. Platelet counts are often less than 20 000/mL during acute episodes of TTP. Erythrocyte fragmenta- tion occurs as red cells attempt to bypass, at high fl ow rates, the partially occlusive microvascular platelet aggregates, producing the characteristic schistocytes on peripheral blood fi lms (Figure 32.1 ). Hemolysis is predominantly intravascular and, along with tissue damage, contributes to the increased serum levels of lactate dehydrogenase (LDH) [7] . Coagulation studies are characteristically normal in the early stages of a TTP episode [7] . If there is considerable tissue necrosis, however, secondary disseminated intravascular coagulation (DIC) may occur as a result of overactivation of the coagulation pathway that follows the binding of factor VIIa to exposed tissue factor molecules on injured tissue cells. The ominous development of secondary DIC is indicated by the appearance of elevated levels of D - dimers (or fi brin degradation products), prolongation of the prothrombin or activated partial thromboplastin times, and a decreasing fi brinogen level. Types Since the general application of plasma therapy, many patients have survived episodes of TTP. It has become apparent that there are several conditions associated with the disorder, and more than one etiology [7] (Table 32.1 ). About two - thirds of adult patients with the relatively common acquired idiopathic TTP ( ‘ out - of - the - blue ’ TTP) have a single episode that never recurs (presuming successful treatment). About one - third of adult patients who recover from an initial TTP episode will have recur- rences at irregular intervals, often commencing within the fi rst year after the initial episode. In the rarest type of the disease, familial (or congenital) TTP, frequent episodes may occur at regular (approximately 3 – 4 week) intervals. This entity has also been called chronic relapsing TTP, Chapter 32 408 stem cell transplantation make up a relatively large subgroup [20] . Thrombotic microangiopathy has also been reported after solid organ transplantation (kidney, liver, heart, and lung) [22] . (Transplantation of all types is often managed with immunosup- pression using cyclosporine and/or tacrolimus.) Although TTP may occur at any stage of pregnancy, episodes most frequently occur during the last trimester [24 – 26] . In con- trast, if HUS occurs it is usually during the postpartum period [27 – 31] . HUS during pregnancy is likely to be associated with diarrhea [32] caused by Shiga toxin - producing enterohemor- rhagic E. coli [33] . Causes and p athophysiology Early vascular lesions in TTP consist almost exclusively of platelet thrombi without evidence of perivascular infl ammation or other overt vessel wall pathology [34,35] . Microvascular occlusions are seen in most organs. Most frequently involved are the brain, heart, spleen, kidneys, pancreas, and adrenals; however, even the lungs and eyes are affected in some patients. The histopathological and clinical fi ndings in TTP suggest that organ ischemia and thrombocytopenia are caused by potentially reversible platelet adhesion/aggregation in the microcirculation of multiple organs concurrently. Immunohistochemical studies of TTP thrombi reported in 1985 by Asada and coworkers [34] revealed an abundance of von Willebrand factor (VWF) with little fi brinogen/fi brin, supporting the initial 1982 sugges- tion [9] that VWF is involved in the microvascular platelet adhesion/aggregation that characterizes some types of the disorder. von Willebrand f actor and ADAMTS - 13 Monomers of VWF (280 000 daltons) are linked by disulfi de bonds into multimers with varying molecular masses that range into the millions of daltons [36] . Multimers of VWF are con- structed within megakaryocytes and endothelial cells, and stored within platelet α - granules and endothelial cell Weibel – Palade bodies. Most plasma VWF multimers are derived from endothelial cells. Both endothelial cells and platelets produce VWF multimers larger than the multimers in normal plasma [36] . These ULVWF (ultralarge VWF) multimers bind more effi ciently than the largest plasma VWF multimers to the glycoprotein (GP) Iba components of platelet GPIb - IX - V receptors [37,38] . The initial attachment of ULVWF multimers to GPIba receptors [37] , and subsequently to activated platelet integrin aIIbb3 (GPIIb - IIIa complexes), induces platelet adhesion and aggregation in vitro in the presence of elevated levels of fl uid shear stress [38,39] . After retrograde secretion by endothelial cells, ULVWF multimers become entangled in subendothelial collagen, thereby maximiz- ing the VWF - mediated adhesion of blood platelets to any suben- dothelium exposed by vascular damage and endothelial cell desquamation. An effi cient “ processing activity ” [9,40] in normal plasma prevents the highly adhesive, ULVWF multimers, that are also secreted antegrade into the vessel lumen, from persisting in the bloodstream. and is usually seen initially in infants and children [8 – 10] . A subgroup of familial TTP patients have only occasional episodes, beginning later in life. During the past few years, the structurally similar platelet function inhibitors ticlopidine (Ticlid) [11,12] and clopidogrel (Plavix) [13] have been associated with the induction of TTP in a fraction of exposed patients. These two drugs, which differ only by a single carboxymethyl group, inhibit a platelet adenosine diphosphate (ADP) receptor site and are used to suppress arterial platelet thrombosis. A fraction of patients with human immuno- defi ciency virus - 1 (HIV - 1) infection also develop TTP. Mitomycin C, quinine, cyclosporine, FK506 (tacrolimus), che- motherapeutic agents in combination, gemcitabine and total - body irradiation have been associated with the subsequent development of thrombotic microangiopathy [14 – 23] . The syndrome often more closely resembles the hemolytic – uremic syndrome (HUS, discussed later in this chapter) than TTP, and usually develops weeks to months after exposure [20] . Patients who have been treated for various illnesses with bone marrow/ Figure 32.1 Schistocytes or “ split ” red blood cells, are inevitably present on the peripheral blood smear of patients with TTP. Table 32.1 Clinical types of TTP . Familial (congenital; recurrent) Acquired idiopathic (recurrent in ∼ 1/3) Drugs: thienopyridine - associated ticlopidine (Ticlid) clopidogrel (Plavix) Thrombotic microangiopathies that resemble TTP (or HUS) Drugs: mitomycin cyclosporine; tacrolimus quinine combination chemotherapy; gemcitamine Total - body irradiation Bone marrow/stem cell tansplantation Solid organ transplantation . recombinant factor VIIa for massive postpartum haemhorrage: case series and review of literature . J Pak Med Assoc 2005 ; 55 ( 11 ): 512 – 515 . 407 Critical Care Obstetrics, 5th edition. Edited by. Department of Obstetrics and Gynaecology Unit - III, Dow University of Health Sciences, Civil Hospital, Karachi, Pakistan 2 Yale Women & Children ’ s Center for Blood Disorders, Department. cell disease with acute chest syndrome . Anesthesiology 1997 ; 87 ( 4 ): 988 – 990 . 400 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy.