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Introduction:Disseminated intravascular coagulation is aclinical syndrome characterized by systemicactivation of coagulation cascade simul-taneously leads to intravascular thrombusformation (compromising blood supply tovarious organs ) and exhaustion of platelets andcoagulation factors (resulting in hemorrhage).DIC is uncommon but not rare. The incidenceof the syndrome varies in association withdifferent disorders. In obstetrical conditions,such as abruptio placenta and amniotic fluidembolism, DIC occurring in more than 50% ofcases1. In severe preeclampsia DIC occurred

DISSEMINATED INTRAVASCULAR COAGULATION(DIC) IN OBSTETRIC PRACTICESULTANA S1, BEGUM A2, KHAN MA3

Abstract:Disseminated intravascular coagulation (DIC) is an acquired and complex disorder that occursin a wide variety of clinical conditions. This is basically a state of increased propensity for clotformation triggered by a variety of stimuli related to such diverse disorders as sepsis, endothelialcell damage (heat stroke, shock), obstetrical complication (abruptio placenta, amniotic fluidembolism, severe preeclampsia and retained intrauterine dead foetus) and neoplasm. DIC is aclassic complication of obstetric conditions occurring in more than 50 percent of patients withobstetric causes. In DIC, an unregulated thrombin explosion cause release of free thrombininto the circulation that leads to the clinical features of DIC, with thrombin and plasminresponsible for the thrombotic and haemorrhagic manifestations, respectively. The diagnosisand treatment of this syndrome require an understanding of its pathophysiology, awareness ofthe disorders that can trigger it and its early recognition. Acute DIC is usually associated withinfections, the commonest cause, about 10-20% of patients with gram negative sepsis haveevidence of DIC. Chronic DIC is usually associated with retained dead fetus, carcinomatosis.The diagnosis of this syndrome is essentially clinical, with laboratory tests providing confirmatoryevidence. Microvascular thrombosis is the primary mechanism in most cases, and end organfailure is a major cause of death. No single diagnostic test exists for DIC. DIC is initiallysuggested by the following combination; a clinical condition consistent with DIC,thrombocytopenia, prolonged PT, APTT, and presence of FDP/D-dimer. Medical treatmentdepends on the cause of the DIC. Basically it involves removing the cause for example, deliveryof placenta if it is retained or abrupted, delivery of foetus if retained, quick delivery if severeeclampsia and so on, hysterectomy if bleeding can not be controlled from placental site. Afterthen, and/or con-currently treat DIC with blood and plasma transfusions and appropriatesupportive measures. As the sequel of DIC can be devastating, early clinical suspicion andlaboratory diagnosis are essential. This review article provides essential guideline for theappropriate diagnosis and clinical management of DIC in obstetric patients.

Key words: Disseminated intravascular coagulation (DIC), Obstetric, Thrombosis, Fibrin, D-dimer, FDP, Anticoagulant.

J Dhaka Med Coll. 2011; 20(1) : 68-74.

1. Dr. Sufia Sultana, Assistant Professor, Department of Obstetrics and Gynaecology, National Institute of CancerResearch & Hospital (NICRH), Mohakhali, Dhaka.

2. Prof. Anowara Begum, Ex-Professor & Head, Department of Obstetrics and Gynaecology, Dhaka MedicalCollege & Hospital, Dhaka.

3. Prof. MA Khan, Professor & Head, Department of Haematology, Dhaka Medical College & Hospital, Dhaka.Correspondence: Dr. Sufia Sultana, Assistant Professor, Department of Obstetrics and Gynaecology, NationalInstitute of Cancer Research & Hospital (NICRH), Mohakhali, Dhaka. Cell Phone: +8801715867740, E-mail:[email protected]

in 7% of patients, in one study2. Disseminatedintravascular coagulation may be classifiedaccording to its acuteness and clinical severity;i) Acute DIC, ii) Sub-acute DIC or Chronic DIC.Obstetrical causes of DIC can be classified asacute and chronic. DIC may be the result ofsingle or multiple conditions. Acute DIC inplacental abruption, amniotic fluid embolism,severe preeclampsia or eclampsia, Obstetricsepsis, Septic abortion or saline abortion,acute fatty liver of pregnancy, extensivesurgical trauma, massive blood transfusion.sub-acute or chronic DIC in retained dead fetussyndrome, retained products of conception,

degenerating hydatidiform moles, abdominal(ectopic) pregnancy, saline induced abortion,fetomatarnal blood passage, postpartumhaemolytic ureamic syndrom metastaticcarcinoma (e.g; ovary). Hematological changesduring pregnancy are critical. Normalpregnancy is associated with a range ofalterations to haemostatic component, whichcombine to give an increased risk ofhemorrhage, thrombosis and DIC. Pregnancyis associated with a 20-200% increase in levelof fibrinogen and factors II,VII, X, VIII and XII,where as concentrations of factors V and IX areunchanged3. Thus net effect of pregnancyassociated changes in haemostatic andfibrinolytic proteins enhances the risk ofthromboembolism. The normal range for theplatelet count (150- 400 x109/L) does not alterduring pregnancy.

The pathogenesis of DIC is complex4-8:The mechanisms that trigger DIC act onprocesses of platelet adhesion and aggregationand contact activated (intrinsic) and tissuefactor activated (extrinsic) pathway ofcoagulation. The normal compensatory processmay become impaired, creating a selfperpetuating “vicious cycle”. The ultimateoutcome is determined by a dynamic interplaybetween the various pathologic processes andcompensatory mechanisms in other wordsfibrin deposition versus fibrinolysis; depletionversus repletion of coagulation of factors andplatelets; and production versus clearance offibrin, FDP and other products of coagulation.In most forms of DIC, the initiating factors aremultiple and interrelated. Acute DIC onlyresults when the normal compensatorymechanisms of haemostasis have beenovercome. Direct platelet activation insepticemia and viraemic states; plateletactivation will also result from vessel wallendothelial damage and following thrombingeneration by the coagulation cascade. Acombination of coagulation factor deficiency,thrombocytopenia, impaired platelet function,and inhibitory action of raised FDPS, causesthe generalized and continuing widespreadbleeding tendency. Chronic or “compensated”DIC result from a weak or intermittentactivating stimulus. In such patients,

destruction and production of coagulationfactors and platelets are balanced. Thepathophysiology of such chronic, sub-acute or“compensated” DIC is fundamentally the sameas that in the acute case. Nevertheless, thedistinction is valuable because the clinicalpicture and laboratory findings in the chronicform are quite variable and may bediagnostically confusing. Chronic DIC has beendescribed in most patients with intrauterinefoetal death . Other etiologic factors that mayproduce chronic DIC include various forms ofvasculitis, hydatidiform moles, anddegenerating leiomyomas. Chronic DIC hasmany clinical and laboratory features thatresemble an intermediate stage between the“hypercoagulable state” and acute DIC. Indeed,even normal pregnancy has been suggested asa form of low grade “physiologic” DIC which atterm becomes overt for a short time.

The exposure of procoagulent tissue extractsto blood is a major contributory factor in mostforms of DIC and is of major pathogeneticimportance in cases associated with abruptionplacenta, intrauterine fetal death, acutepromyelocytic leukaemia, amniotic fluidembolism, massive trauma, and variousneoplasms.

Abruptio placentae: In about 10 percent ofpatients with abruptio placentae, an overtcoagulopathy develops due to DIC andfibninolysis9. Degree of placental separatoncorrelates with the severity of DIC. DIC mayoccur in placental abruption involving liberationof tissue thromboplastin or possibleintrauterine consumption of fibrinogen andcoagulation factors during the formation ofretro- placental clot. This leads to activation ofthe extrinsic coagulation mechanism.

Amniotic fluid embolism: Here is someuncertainty about what elements in theamniotic fluid are responsible for the syndromeand whether prior exposure and sensitizationto amniotic fluid are necessary. Cellularelements and other debris, such as lanugo hairand vernix, may be important. Mucin frommeconium in the amniotic fluid causes aparticularly intense reaction in the pulmonaryarterioles10. The manifestation of amniotic

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fluid embolism does not appear to the dependenton the quantity of amniotic fluid that entersthe maternal circulation or reaches thepulmonary circulation and therefore it isbelieved to be an anaphylactic response whichis patient depenent11. The pathophysiology ofamniotic fluid embolism is a biphasic response:the initial phase occurs after the amniotic fluidenters the pulmonary circulation resulting invasoconstriction and pulmonary hypertension;second phase is the stage of hemodynamiccompromise characterized by oedema and rightsided heart failure. Amniotic fluid containshigh concentrations of plasminogenproactivators, but it lacks plasminogenactivator.

Intrauterine foetal death: Retention of a deadfoetus can precipitate abnormal maternalbleeding. Unless the dead foetus is retain forthree weeks or longer, clinically evidentcoagulation disorders are rare12. The DICassociated with the foetal death is a chronicprocess, and the patient may present in eithera compensated or a decompensated state. Inintrauterine foetal death tissue thromboplasticsubstances from the dead foetus are slowly butcontinuously absorbed, producing a picture ofchronic, but progressive DIC.

Preeclampsia & Eclampsia: The exact etiologyand mechanism remain unknown. Thiscondition is associated with chroniccoagulation abnormalities that may lead tothrombocytopenia and elevation of fibrindegradation products. The coagulationabnormalities reflect platelet adherence toexposed collagen at the sites of damageendothelia. It is related to, but clearly distinctfrom DIC. Preeclampsia and eclampsia areunknown and unclear precursors to DIC. Inpreeclampsia and eclampsia, patients havehigher amounts of FDPs in the blood and urinethan others. The thrombocytopenia seen inpreeclampsia and eclampsia is due to theincreased consumption of platelets13.

Saline or septic abortion: Saline inducedabortion has been associated with subclinicalDIC 14. Severe cases of DIC have occurred in1:400-1:1000 cases. Disease may be related tothe release of tissue thromboplastin from the

placenta. Septic abortion may also causerelease of tissue thromboplastin or release ofbacterial endotoxin (phospholipids).Thecommon infections in obstetric practice areseptic abortion and chorioamnionitis inpremature rupture of the membranes. Gram-negative bacteria are responsible for septicshock in more than 95 percent of affectedpatients.

Massive trauma: In massive trauma , majorsurgical procedures such as lacerated injuriesof cervix during delivery, damaged tissueexpressing tissue factor activity presumably isa major initiating factor15.

Infections: DIC often accompanies septicemia(mainly due to Gram-negative) as a result ofseptic abortion, bacteria that possess potentendotoxins.

Shock: It has been suggested that DIC involvedin all forms of shock and that it is the centralfeature in irreversible or refractory forms.

Clinical presentation:The major clinical features of DIC are bleeding,often of serious magnitude and abrupt onset, avariable element of shock that is often out ofproportion to apparent blood loss, and symptomsof hypoperfusion of various vascular beds.Acute renal failure is common, andthromboembolic manifestations often arenoted. Evidence of major organ dysfunction isa common finding in patients with acute DIC,most often including signs, symptoms, andlaboratory evidence of abnormal pulmonary,renal, hepatic, and central nervous systemfunction. Major clinical problem and presentingfeature of acute DIC is bleeding, which can varyfrom mild to severe form, manifesting asgeneralized bruising, ecchimosis, petechiae,especially over dependent areas and pressuresites and or bleeding from previously intactvenipuncture sites or around indwellingintravenous needles. In patients who developDIC after surgical procedures, alarminghaemorrhage may develop around drains andaccumulation of blood may be concealed inserous cavities. In Obstetric cases, post partumbleeding from the vagina may be particularlysevere. Severe haemorrhage and hypovolaemic

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shock can occur extremely rapidly inpregnancy, when it is usually related to labour.In subacute or chronic DIC, there is slowactivation of the haemostatic system, withspontaneous bruising rather than majorclinical bleeding episodes. Such asintrauterine foetal death may produce as slowprogressive form of DIC, in which bleeding is arelatively late manifestation, often foreshadowed by deteriorating renal function.

Laboratory Diagnosis:In acute DIC, it is essential to demonstratethe abnormal laboratory parameters accuratelyand quickly, so that appropriate therapy canbe instigated. The main haemostaticabnormalities are reflected by a prolongedthrombin time, hypofibrinogenaemia andthrombocytopenia. A fibrinogen level below 100x109/L, and a thrombin time of more thandouble the control value are regarded asvirtually diagnostic, especially if associatedwith a generalized bleeding state.

Laboratory investigations(A) Basic blood Examination: Examination ofthe blood smear reveals schistocytosis inapproximately 50% of cases 17. More subtleevidence of intravascular haemolysis often isfound, such as increased serum level of lacticacid dehydrogenase (LDH) and diminishedheptoglobin levels. Thrombocytopenia is anearly and consistent sign of acute DIC Plateletcounts in the range of 50 to 100X109/L areusual findings but thrombocytopenia may besevere.

(B) Coagulation defect: The Activated partialthromboplastin time (APTT), Prothrombin time(PT), Thrombin time (TT) are prolonged in mostpatients with acute DIC. Early in the course ofthe disorder and in chronic DIC, the APTT maybe normal or even shorter than normal. Theplasma levels of fibrinogen and of factor V andXIII usually are significantly depressed;fibrinogen and factor V are the mostconsistently affected 18. In many patientsparticularly those with abruptio placentae,normal prothrombin levels are maintained 9,16

but marked hypoprothrombinaemia often ispresent in those with sepsis 17. In patients withchronic DIC, prothrombin deficiency is

unusual, where as significant deficiencies offactor X are often noted.

(C) Tests for fibrinolysis: Fibrinolytic activitycauses raised level of circulating fibrincomplexes and FDPs. Levels above 100µg/mlare usually found in acute DIC (normal range<10µg/ml) 18. Immunological assays based onmonoclonal antibodies to D-dimer are morespecific than a general screen. Since falsepositive results may be seen with FDPs. FDPstest is not diagnostic of DIC, yet levels areelevated in 85-100% of patients. The D-dimertest may be more specific in diagnosing DIC,especially in distinguishing the coagulopathyof liver disease from DIC 18,19.

Bed side tests: Bed side tests to evaluate theblood coagulation disorders, which can giveuseful information that help in tacking thecrisis. Bed side tests that may be done are: i.Bleeding time ii. Clotting time, iii. Clotobservation (Weiber) test. iv. Serial clot lysistest v. blood film.

Screening tests: Platelet count (decreased),Bleeding time (increased ), Prothrombintime(increased), APTT(increased or variable),Thrombin time (increased), RBC-morphology (schistocytes & microspherocytes)

Differential diagnosis:

DIC with obstetric causes, the clinicalconditions which are most commonly givingsimilar clinical pictures are the followings:

1. HELLP syndrome

2. Acute Liver Failure / Acute fatty liver inpregnancy.

3. Idiopathic/Autoimmune Thrombo-cytopenic Purpura (ITP/ATP).

4. Thrombotic Thrombocytopenic Purpura(TTP)

5. Postpartum Haemolytic UraemicSyndrome (PHUS)

6. Primary Fibrinogenolysis.

7. Acquired Hemophilia (Factor F-VIIIinhibitor).

Essentials of Diagnosis: No single diagnostictest exists for DIC. DIC is initially suggestedby the following combination:


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• History of recent bleeding diathesis, alwayssecondary to some cause.

• Clinical evidence of multiple bleedingpoints associated with purpura petechiaeand ecchymosis on physical examination.

• Laboratory findings classically includethrombocytopenia (<100 x109/L), prolongedPT, APTT and TT, and presence of FDP / D-Dimer. Other tests listed here also mayhelp to exclude DIC.

Management:DIC always is the end result of a seriousunderlying disorder. Although the patient maybenefit greatly from measures directed at theDIC or from the replacement of depletedcoagulation factors or platelets, cure of thesyndrome depend on prompt and energetictreatment of the primary disorder. Symptomsof DIC, although sometimes indolent, cancause life threatening haemorrhage and mayrequire emergency management. Thisincludes:

I. Detection and elimination of primarycause: It is the cornerstone of management ofDIC. Determine the underlying cause andattempt to correct it immediately.

II. Supportive measures: Measures to controlthe major symptoms, either bleeding orthrombosis.

III. Replacement and prophylactic regimen:Prevention of recurrence in cases of chronicDIC. Treatment will vary with the clinicalpresentation. In patients with an obstetriccomplication such as abruptio placentae,intrauterine dead foetus or acute bacterialsepsis, the underlying disorder is easy tocorrect, and prompt delivery of the foetus andplacenta or treatment with appropriateantibiotics will reverse the DIC syndrome.Moderate and low grade DIC may not beassociated with clinical evidence of excessivebleeding and often will require close observationbut no further therapy. The condition will notresolve until the triggering factor is removed,and death of patient with DIC are often theresult of the underlying disease.

Supportive therapy should be directed to thecorrection of shock, acidosis, and tissue

ischemia. Cardiopulmonary support, includingionotropic therapy, blood replacement, andassociated ventilation, should be implementedwith the patient in close proximity to a deliverysuite. Tissue perfusion and respiratory functionmust be maintained by replacing intravenousfluid and providing oxygen to correct hypoxia.Parental antibiotic should be administeredwithout delay when bacterial infection issuspected. Foetal monitoring, careful recordingof maternal fluid balance, and serial evaluationof coagulation parameters are extremelyimportant. Patient may be treated with bloodcomponents to replace depleted coagulationfactors, platelet, and natural inhibitors ofthrombin and plasmin in an attempt to reducebleeding while the underlying problem iscorrected. Specific replacement of fibrinogenshould be accomplished by cryoprecipitate.Each unit of cryoprecipitate carriesapproximately 200 mg of fibrinogen. Plateletshould only be administered in the face ofactive bleeding with a platelet count 20-30X109/L or less or following massive bloodtransfusion with stored old blood. Critically illpatients may develop a coagulopathy, becauseof vitamin K deficiency, and 10 mg of vitaminK should be given on two consecutive daysbefore coagulopathy is attributed exclusively toDIC 20. Patients with DIC can also becomevitamin K deficiency because of it’s increaseduse and administration of vitamin K to allpatients with suspected DIC will replenishstores. Some doctors also give folic acid in orderto prevent acute folate deficiency and impairedplatelet production.

Vaginal delivery, without episiotomy if possible,is preferable to cesarean section. Failure ofimprovement in the coagulopathy withinseveral hours after delivery suggests sepsis,liver disease, retained product of conception,or a congenital coagulation defect.

The use of heparin in the treatment of bleedingis still controversial. Although it is a logicalway to reduce thrombin generation and preventfurther consumption of clotting proteins, itshould be reserved for patients with thrombosisor those who continue to bleed despite vigoroustreatment with plasma and platelets. Patientswho initially have mild DIC and may not be


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symptomatic may begin to bleed followingsurgery. For example, mild DIC, without clinicalbleeding, has been documented during salineor prostaglandin-induced midtrimesterabortions. Prophylactic treatment of patientswith heparin may prevent progression of a mildDIC syndrome and in some patients a retaineddead foetus that require surgical extraction.However most patients with low grade DIC canbe managed simply with plasma and plateletreplacement and do not require heparin.

Emergency care:• Monitor vital signs: pulse, blood pressure,

respiration, renal out put and level ofconsciousness.

• Document extent of haemorrhage andthrombosis.

• Determine the underlying cause of the DICand initiate therapy.

• Send blood specimens for appropriatecoagulation studies and other diagnosticlaboratory tests. Screening test for DIC are:BT, PT, APTT, Platelet count, RBCmorphology.

• Obtain appropriate imaging studies ifnecessary.

• Supportive measures are essential. Attendto life threatening issues such as air wayscompromise or severe haemorrhage.Correction of fluid and electrolyte imbalance.

• Replace blood products as indicated: RBCtransfusion (i.e. packed red cells), Plateletconcentrate, Fresh frogen plasma (FFP).Cryoprecipitate.

Consultation:• Consult hematologist for assistance with

diagnosis and management.

• Consult critical care medicine if multipleorgans failure is present.

• Consult transfusion medicine; determinethe availability of general and specializedblood products that may be necessary forthe acute management of fulminant DIC.

Medication:Therapy should be based on etiology and aimedat eliminating the underlying disease. Therapy

should be appropriately aggressive for thepatient’s age, disease, and the severity andlocation of haemorrhage/thrombosis.Treatment for acute DIC includes anti-coagulants, blood components, andantifibrinolytics.

Haemostatic and coagulation parametersshould be monitored continuously duringtreatment. Base therapeutic decisions dependon clinical and laboratory evaluation ofhaemostasis.

(A) Blood components: Blood components areused to correct abnormal haemostaticparameters. These products should beconsidered only after initial supportive andanticoagulant therapy.

i) Packed red blood cells (washed): Preferredto whole blood since they limit volume,immune, and storage complications. One unitPRBCs should raise haemoglobin by 1g/dl orraise haematocrit by 3%.

ii) Platelet concentrates: Patient with DIC,bleeding and platelet counts less than 50X109/L, should be considered for platelet transfusion.DIC patients may require a higher plateletcount for adequate haemostasis then patientswith thrombocytopenia in the absence ofplatelet dysfunction (in other conditions ofthrombocytopenia seldom needed platelettransfusion until platelet count is less than20X109/L).

iii) Fresh Frozen Plasma (FFP): FFP containsall the coagulation factors and inhibitors, AT-III and protein-C. 4 to 5 units of FFP should berapidly infused.

iv) Cryoprecipitate: It contain factor VIIIc, vWF,fibrinogen, fibronectin and some factor XIII.The amount of cryoprecipitate given should besufficient to elevate the plasma fibrinogen levelto at least 100-150 mg/dl. As a general guide,3 g of fibrinogen can be expected to raise theplasma level of an adult patient approximately100 mg/dl.

B) Anticoagulants:These agents are used in the treatment ofclinically evident intravascular thrombosiswhen the patient continues to bleed or clot 4-6


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hours after initiation of primary and supportivetherapy. Take special precaution in obstetricemergencies or massive liver.

i) Heparin: The indications for treatment withheparin and the dose required are notestablished21. There is no conclusive evidencethat heparin treatment reduces mortality ormorbidity in acute DIC. Heparin treatment maybe ineffective because it requiresantithrombin-III for anticoagulant activity, andthis is usually reduced in DIC. There is oneinstance, however, where heparin has beendemonstrated to benefit in pregnancy-relatedDIC. In the case of retained dead foetus withan intact vascular system, heparin may beadministered to interrupt the coagulationprocess and thrombocytopenia for several daysuntil safe delivery may be implemented 22, 23

ii) Low molecular weight-heparin: It isincreasingly used in pregnancy because of itsfavorable dosing regimen and lack of need forroutine monitoring and lowers risks ofhaemorrhage, thrombocytopenia andosteoporosis. Antithrombin III and Protein-Care other promising potion.

(C) Antifibrinolytic agents: These are usedonly after all other therapeutic modalities havebeen tried and deemed unsuccessful. In theory,epsilon-aminocaproic acid (EACA) and otherantifibrinolytics agents (Tranexamic acid)remove the major antagonist of intravascularfibrin formation, and in several welldocumented cases of DIC, their use hasresulted in serious and even fatalthromboembolic complication. Theindiscriminate use of such drugs should bediscouraged.

References:1. Weiner C P. The obstetric patient and

disseminated intravascular coagulation. ClinPerinatal 1986; 13: 705.

2. Sibai BM, Spinnato JA, Watson DI, Hill GA,Anderson GD. Pregnancy outcome in 303 caseswith severe preeclampsia. Obstet Gynecol 1984;64: 319-25.

3. Delorme MA, Burrows RF, Ofosu FA, et al. Thrombinregulation in mother and fetus during pregnancy.Semin Thromb Hemost 1992; 18: 81-90.

4. Bick RL, Adams T. Disseminated intravascularcoagulation: etiology, pathophysiology, diagnosisand management. Med Counterpoint 1974; 6: 38.

5. Plow EF. Leukcyte elastase release during bloodcoagulation: a potential mechanism for activation

of the alternative fibrinolytic pathway. J ClinInvest 1982; 69: 564-72.

6. Mekay DG. Trauma and disseminated intra-vascular coagulation. J Trauma. 1969; 9: 646-60.

7. van Glinket CJ, van Aken WG, Oh JIH, VreckenJ. Stimulation of monocyte progualent activity byadherence to different surfaces. Br J Haematol1977; 37: 35-45.

8. McGrath JM, Stewart GJ. The effects of endotoxinon vascular endothelium. 1969; 129: 833-48.

9. Sher G. Pathogenesis and management ofuterineinertia complicating abruption placentaewith consumptive coagulopathy. Am. J. ObstetGynecol 1977; 129: 164-70.

10. Chatelain SM, Qilirk JG. Amniotic fluid andthromboembolism. Clin Obstet Gynecol 1990; 33:478.

11. Clark SL, Montz FJ, Phelan JP. Hemodynamicalterations associated with amniotic fluidembolism: a reappraisal. Am J Obstet Gynecol1985; 151: 617-21.

12. Tricomi V, Hohl SG. Fetal death in utero. Am JObstet Gynecol 1957; 74: 1092.

13. Kleckner HB, Gites HR, Corrgan JJ. Theassociation of maternal and neonatalthrombocytopenia in high risk pregnancies. AmJ Obstet Gynecol 1977; 128: 235-8.

14. Cohen E, Ballard CA. Consumption coagulopathyassociated with intra-amniotic saline instillationand the effect of oxytocin. Obstet Gynecol 1974;43: 300.

15. Attar S, Boyd D, Layne E, et al. Alterations incoagulation and fibrinolisis mechanisms in acutetrauma. J Trauma 1969; 9: 939-65.

16. Merskey C, Johnson AJ, Kleiner GJ, Wohl H.The defibrination syndrome: Clinical fearures andlaboratory diagnosis. Br J Haematol 1967; 13: 528-49.

17. Corrigan JJ, Jordan CM. Heparin therapy insepticemia with disseminated intravascularcoagulation. N Engl J Med 1970; 283: 778-82.

18. Carr J M, McKinney M, Mc Donagh J. Diagnosisof disseminated intravascular coagulation: Roleof D- dimmer. Am J Clin Pathol 1989; 91: 280-7.

19. Alperin J. Coagulopathy caused by vitamen Kdeficiency in critically ill, hospitalized patients.JAMA 1987; 258: 1916-9.

20. Fenstein D. Diagnosis and management ofdisseminated intravascular coagulation: the roleof heparin therapy. Blood 1982; 60: 284-7.

21. Wessler S. Gitel SN. Heparin: new conceptsrelevant to clinical use. Blood 1979; 53: 525-44.

22. Glinsberg J, Kowalchuk G, Hirch J, et al. Heparintherapy during pregnancy: risk to the fetus andmother. Arch Intern Med 1989; 149: 2233-6.

23. Feigin MD, Lounwood DL. Low molecular weightheparin and their use in obstetrics and gynecology.Obstet Gynecol Surv 1994; 49: 424-31.


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