Critical Care Obstetrics part 42 pot

Pathophysiology General p rinciples Disseminated intravascular coagulation DIC in obstetrics is typically due to one of three etiologies: i a release of thrombo-plastin - like substan

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Critical Care Obstetrics, 5th edition Edited by M Belfort, G Saade,

M Foley, J Phelan and G Dildy © 2010 Blackwell Publishing Ltd.

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

coag-ulation 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

preg-nancy 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

inhib-itor (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

bri-nolysis 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 thrombo-plastin - like substances that causes activation of both intrinsic and extrinsic pathways; (ii) endothelial damage that may cause activa-tion of intrinsic pathway; or (iii) cytokine release in condiactiva-tions 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 plate-lets, 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 hypo-tension 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 endo-thelial 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

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 amni-otic 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 acti-vation 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 comple-ment, and platelet factor III, hence causing platelet - rich fi brin microthrombi [9] Coagulopathy is seen in 83% of cases of amni-otic 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

activa-tion 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

acti-vation by changes in the endothelial protein C receptor and

thrombomodulin [3] Cytokines also cause increased platelet

for-mation, 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

sub-stances 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

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

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 ± 31 < 5

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

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 throm-bomodulin (TM) have been identifi ed in acute phases of abrup-tion [16] TM is not only found in endothelial cells, but is also present in the syncytiotrophoblast Elevated TM has been

identi-fi ed in TTP, pre - eclampsia and SLE The efidenti-fi 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 pla-cental abruption, by the release of thromboplastin into the circu-lation, 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 preg-nancy 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 trimes-ter 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

clini-cally signifi cant Laboratory assessments like prothrombin time,

activated partial thromboplastin time and plasma fi brinogen

levels are usually not affected in hypertensive disorders of

preg-nancy 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

cor-relate 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

tender-ness, non - reassuring FHR

Grade 3: vaginal bleeding, shock, extensive concealed

hemor-rhage, uterine tenderness, fetal death, and sometimes

coagu-lopathy 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

extrin-sic 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

coag-ulopathy 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

The thrombin time is more reliable than either PT or APTT

A fi brin clot not dissolving within 10 minutes signifi es that fi bri-nolysis is an unlikely event If the clot begins to lyse within 10 minutes, it shows signifi cant plasmin activity Prolonged throm-bin 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 con-sumption 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 diges-tion 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

treat-ment 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

throm-botic 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

coag-ulation 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

hemor-rhagic 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

coagula-tion 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

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 brino-gen 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 am-matory 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 coagu-lopathy due to AFLP [27]

While most of the above tests are available in a routine

labora-tory, the last two tests require a specialty laboratory There is no

single defi nitive test for the diagnosis of DIC The practicing

clini-cian 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

transfu-sion 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

combi-nation 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

evi-dence 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

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

coagula-tion Am J Obstet Gynecol 1991 ; 165 ( 5Pt 1 ): 1335 – 1341

7 Villar J , Carroli G , Wojdyla D , et al Preeclampsia, gestational hyper-tension and intrauterine growth restriction, related or independent

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8 Moore J , Baldisseri MR Amniotic fl uid embolism Crit Care Med

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9 Green BT , Umana E Amniotic fl uid embolism South Med J 2000 ;

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10 Letsky EA Disseminated intravascular coagulation Best Pract Res

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12 Levi M , de Jonge E , van der Poll T New treatment strategies for dis-seminated 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

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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

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17 Dempfl 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 diagno-sis, 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 dissemi-nated intravascular coagulation Arch Dermatol 1985 ; 121 ( 8 ):

1057 – 1061

22 Yu M , Nardella A , Pechet L Screening tests of disseminated intravas-cular coagulation: guidelines for rapid and specifi c laboratory

diag-nosis 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

hemor-rhage [29 – 32] The mechanism of action of activated

recombi-nant 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

bleed-ing 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

complica-tions 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

acti-vated 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

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 recombi-nant 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

hemor-rhage 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

Critical Care Obstetrics, 5th edition Edited by M Belfort, G Saade,

M Foley, J Phelan and G Dildy © 2010 Blackwell Publishing Ltd.

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

character-istic 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 hematprotein-uria, 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 develop-ment 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,

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 endothe-lial cells Both endotheendothe-lial cells and platelets produce VWF mul-timers larger than the mulmul-timers 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

func-tion 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),

chemotherapeutic agents in combination, gemcitabine and total

-body irradiation have been associated with the subsequent

development of thrombotic microangiopathy [14 – 23] The

drome often more closely resembles the hemolytic – uremic

syn-drome (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