1000 JClin Pathol 1994;47:100-108 Investigation and management of haemorrhagic disorders in pregnancy J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from

Isobel D Walker, J J Walker, B T Colvin, E A Letsky, R Rivers, R Stevens, on behalf of the Haemostasis and Thrombosis Task Force

Introduction during pregnancy, but in the third trimester Bleeding and blood loss associated with preg- the PT and the APTT are at the lower nancy and delivery remain important causes (shorter) limits of normal or slightly short- of morbidity. Although catastrophic bleeding ened, and this must be taken into account is fairly rare nowadays, haemorrhage, particu- when assessing coagulation screen results larly after giving birth, is still one of the lead- from pregnant women. ing causes of maternal mortality.' Obstetric haemorrhage may be associated with specific complications of pregnancy or Inherited bleeding disorders labour, or it may be due to an inherited or In general, pregnant women with inherited acquired bleeding diathesis. Obstetricians bleeding disorders and the female partners of confronted with a patient who is bleeding, or men with these defects should be managed by who gives a personal or family history of an obstetric unit allied with a haemophilia bleeding or excessive bruising, should be alert centre and a neonatal intensive care unit. to the possibility of an underlying inherited or The most common inherited bleeding acquired haemostatic defect. Each hospital defects involve factor VIII deficiency (haemo- should have a set of management guidelines philia A), factor IX deficiency (haemophilia for severe haemorrhage and must have 24 B), and von Willebrand factor deficiency (von hour ready access to diagnostic laboratory Willebrand's disease). These will be discussed facilities and advice from a designated haema- at length and the more uncommon inherited tologist. Although there are modern alterna- bleeding disorders mentioned briefly there- tives to blood, rapid access to blood and after. blood products is an absolute requirement for acceptable obstetric practice. Therefore, labo- Haemophilia A and haemophilia B-The ratory facilities for blood grouping and com- prevalences of haemophilia A and haemo- http://jcp.bmj.com/ patibility testing should be on site close to the philia B in the United Kingdom population maternity unit. are 90 per 1 000 000 and 20 per 1 000 000, respectively. Most female carriers of these X linked recessive disorders do not have major Haemostatic changes in normal bleeding problems, but in 10-20% of carriers pregnancy extreme Lyonisation results in a substantial Normal pregnancy is associated with major reduction of factor VIII or factor IX concen- on September 29, 2021 by guest. Protected copyright. changes in the coagulation and fibrinolytic trations respectively (to < 40 units/dl) and, at systems-the concentration of many coagula- the lowermost levels, a significantly increased tion factors increasing and plasma fibrinolytic risk of bleeding. Statistically, 50% of the male activity decreasing as the concentrations of children of carrier females will have haemo- The members of tlhe plasminogen activator inhibitors progressively philia and be at risk of serious bleeding. Working Party were: rise. Fibrinogen increases from early preg- Very rarely, homozygous haemophilia A or I D Walker B T Colvin nancy onwards to almost double its pre- B may occur when a female is the offspring of E A Letsky pregnancy value by term. Both factor VIII a haemophilic father and a carrier mother. R Rivers (FVIII) and von Willebrand factor (vWf) rise These women have the same risk of major R Stevens steadily throughout pregnancy. Factors VII haemorrhage as do affected males. J J Walker and X also increase very significantly during The members ofthe Haemostasis and pregnancy, but the other vitamin K depen- Von Willebrand's disease-Von Willebrand's Thrombosis Task dent clotting factors, factors II and IX and disease (vWD) is the most common clinically Force were: factor XII, show a less significant or no rise important inherited abnormality of coagula- B T Colvin S J Machin and factors XI and XIII may fall slightly. tion affecting women. Because of the very T W Barrowcliffe The platelet count does not normally wide spectrum of clinical presentation, it is M Greaves change significantly during pregnancy, difficult to ascertain precisely the prevalence C A Ludlam I Mackie although some authors have reported a slight of all forms of vWD but it is more common F E Preston drop in the count in the third trimester. The than generally realised and may be as high as P E Rose bleeding time remains normal throughout 1%.2 I D Walker pregnancy. Broadly, vWD falls into three classes J K Wood tests used for the investigation of (table 1). Type 1 vWD-the commonest type Correspondence to: Screening Dr B T Colvin, Department bleeding-the activated partial thrombo- (about 75% of patients)-is characterised by of Haematology, The Royal a in all forms of with the London Hospital, London plastin time (APTT) and the prothrombin reduction vWf, high- El 1BB time (PT)-are within normal adult ranges est molecular weight forms remaining Working Party ofthe Haemostasis and Thrombosis Task Force 101

Table 1 Simplified classification ofvon Willebrand's disease gical delivery and perineal damage. This ten- Bleeding vWf vWf dency is accentuated by the rapid fall in the Type time FVIIIC antigen activity Multimers concentration of FVIII and vWf after deliv- J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from I NorP R RR All present ery.3 Some patients show variable responses HA P NorR NorR R Large and of their FVIII and vWf during pregnancy45 intermediate absent and measurement of bleeding time, FVIIGC HIB P NorR NorR R Large absent activity, vWf antigen, and vWf activity are not Hi P R or ND R ND ND always predictive ofwhich patients will bleed.67 N = normal P = prolonged R = reduced ND = not detectable. In general, patients with type 1 vWD have increased FVIII and vWf concentrations dur- ing pregnancy and do not bleed excessively; on the other hand, patients with type II and type III do have an increased tendency to detectable. Its inheritance can be autosomal bleed. In those with type IIA vWD the large dominant or recessive and its expression very multimers of vWf antigen do not rise in all variable. In non-pregnant patients with type I patients during pregnancy.8 This may explain vWD the vWf concentrations (by antigen and the greater risk of haemorrhage in women by activity assay) are between 10-40 units/dl with type IIA vWD than in those with type as is the FVIIHC. The bleeding time may be I vWD. Patients with type IIB may develop slightly to moderately prolonged but is often worsening thrombocytopenia during preg- normal and the bleeding tendency is generally nancy and those with type III vWD show mild. little or no increase in their FVIII:vWf con- The feature common to all subvariants of centrations. type II vWD is the loss of the highest molecu- lar weight vWf multimers. Inheritance is usu- PRECONCEPTION COUNSELLING ally autosomal dominant. In type II vWD the As far as possible, it is essential that families vWf is functionally impaired, the bleeding with heritable bleeding disorders understand time is usually prolonged, and bleeding the genetic implications of their particular episodes tend to be more severe and more disorder and that young family members common especially in type IIA (the common- come forward for investigation. Haema- est type II subvariant-10% of all patients tologists responsible for providing haemo- with vWD) than in type 1. In subtype IIB philia services need to see these family studies (7% of all patients with vWD) the abnormal and counselling as an important aspect of vWf has enhanced interaction with platelet their remit and they may want to involve an glycoprotein (Gp) lb: these patients often interested obstetrician at this time. Female have mild to moderate thrombocytopenia. carriers of haemophilia A or B and women Infusion of desmopressin (1-desamino-8-D- with vWD or other inherited bleeding disor- arginine vasopressin, DDAVP) may cause a ders should be reviewed at intervals during http://jcp.bmj.com/ further fall in the platelet count in these their reproductive life, even if they remain patients and should therefore be avoided in asymptomatic. type IIB vWD. Pregnancy planning should be encouraged Type III vWD is clinically the most severe. and patients with inherited bleeding disorders The prevalence in the United Kingdom and carriers or potential carriers should seek of type III vWD is about one in 1 000 000. specialist medical advice from their haematol- Patients with type III vWD have no ogist and if possible also an obstetrician on September 29, 2021 by guest. Protected copyright. detectable or only trace amounts of vWf in before conception. This is most evident their circulation. Probably many patients with where the affected patient is female, but cou- type III vWD are homozygous but some may ples in which the potential father has a heri- be compound heterozygotes. The condition is table bleeding defect must also be offered more prevalent in cultures where consanguin- prepregnancy counselling to discuss the pos- ity is common. In general the parents are sibility of antenatal diagnosis and other clinically unaffected or only mildly affected aspects of the management of the planned although their vWf concentrations may be at pregnancy. Women who may require blood or just below the lower limits of normal. product treatment but who are not immune Patients with type III vWD have only should be immunised against hepatitis B. 1-2 units/dl factor VIIIC and therefore have a This should be carried out before their first bleeding tendency which mimics moderately pregnancy, but immunisation during preg- severe haemophilia A with the added mucosal nancy is safe although not ideal and may be and subcutaneous bleeding characteristic of necessary for women not immunised before. vWD. Parents who have had a child with type Because of recent reports of outbreaks of III vWD require follow up and careful coun- hepatitis A in some haemophiliacs, immuni- selling with respect to the management of sation against hepatitis A is now being offered future pregnancies and the availability of pre- to non-immune haemophiliacs and to natal diagnosis. patients with vWD who may require blood Most women with vWD show an increase products. in their FVIII and vWf concentrations during It is important that as far as possible carri- pregnancy and most do not have excessive ers of haemophilia are identified before preg- bleeding. When bleeding does occur, it hap- nancy so that appropriate genetic counselling pens more frequently after birth than during can be offered and women at increased risk of pregnancy and is usually associated with sur- bleeding can be recognised. Considerable 102 Walker, Walker, Colvin, Letsky, Rivers, Stevens, et al

overlap exists between clotting factor values noted that although the diagnosis of a male in normal women and in obligatory carriers of fetus is almost always correct, the diagnosis of

haemophilia A or B, so not all carriers are a female fetus is less accurate. J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from identifiable by phenotype analysis. Details of carrier identification are beyond the scope of Invasive procedures during pregnancy this paper and readers are referred to pub- The potential benefits and risks of invasive lished papers.9 Genetic analysis is becoming procedures during pregnancy, which may more widely available and greatly improves result in accidental maternal, fetal, or placen- the correct assignment of carrier status. tal bleeding, must be carefully considered on Where there is any doubt about a woman's an individual patient basis. Rational decisions carrier status, genetic testing should be about these procedures require input from offered. The possibility of antenatal diagnosis experts experienced in the management of should be discussed with carriers and facilities pregnant women with bleeding disorders. made available when appropriate for those Because of the risk of haemorrhage even CVS who wish it.'0 for prenatal diagnosis may be hazardous and Women who first present with a history should be performed only after careful con- suggestive of an inherited bleeding disorder sideration and full discussion of the risks and when they are already pregnant may need to benefits with the parents. be managed empirically and full investigation Maternal coagulation factor activity and delayed until three to six months after deliv- vWf concentrations do not rise significantly ery-although with increasing identification until the second trimester. CVS and other of genetic defects, it may be possible, in some invasive procedures, such as pregnancy termi- instances, to make a diagnosis in pregnancy nation, spontaneous abortion, or general despite a normal phenotype. A previously surgery during the first trimester, may there- undiagnosed congenital bleeding disorder fore be complicated by serious maternal should be considered in a patient who is oth- haemorrhage unless coagulation factor activ- erwise well but bleeds and bruises excessively ity is raised to 50 units/dl. either spontaneously, or following venepunc- ture, or at delivery. MANAGEMENT OF DELIVERY If there is any concern over coagulation factor MANAGEMENT OF PREGNANCY activity in the mother a planned delivery date Women with vWD and carriers of haemo- is advised. On admission, a maternal blood philia A or B require regular review (at least sample should be sent for a full blood count every eight to 12 weeks) at a haemophilia and platelet count, coagulation screen, and centre throughout pregnancy for monitoring, appropriate coagulation factor or vWf assays, including coagulation factor activity and, if and for blood grouping and antibody screen- appropriate, the concentrations of vWf anti- ing with a request to the blood bank to retain gen, vWf activity, platelet count and bleeding serum for compatibility testing if that should http://jcp.bmj.com/ time (table 2). Monitoring during the third become necessary (table 2). trimester (around 34-36 weeks) is particu- In the absence of any obstetric contraindi- larly important as it permits final planning cation vaginal delivery is usual but caesarean and discussion of the management of the section should be considered if labour fails to forthcoming delivery. progress steadily. An early recourse to cae- The uptake of prenatal diagnosis in most sarean section is recommended for carriers of centres is surprisingly low, with between haemophilia A or B with a known male fetus on September 29, 2021 by guest. Protected copyright. 20% and 30% of known carriers opting for if any problem develops and the chance of an chorionic villous sampling (CVS). Modem easy vaginal delivery is less likely. Operative ultrasound scanning equipment permits visu- or instrumental delivery (if necessary) should alisation of fetal external genitalia and offers be performed by the most experienced mem- non-invasive techniques for identifying most ber of staff available. Ventouse extraction male fetuses by 18 to 20 weeks. Information should be avoided in cases where the fetus is about the sex of the fetus is invaluable in thought to be affected. Scalp electrodes or managing pregnancy and delivery in carriers scalp vein blood sampling can cause massive of haemophilia A or B where prenatal diagno- haematomata and should be avoided if possi- sis has not been performed. It should be ble if the fetus might have vWD, and in hae- mophilia A or B carriers when the fetus is known to be male or its sex is unknown. Every effort must be made to minimise Table 2 Obstetric management ofwomen with inherited bleeding disorders: general maternal genital tract or perineal trauma as ptinciples this greatly increases the risk of postpartum Prepregnancy diagnosis, counselling, hepatitis B immunisation bleeding. After a difficult delivery, particu- Regular clinical and haemostasis monitoring during pregnancy Ultrasound "sexing" offetus larly if instruments have been required, the Avoid unnecessary invasive procedures neonate may need blood product replacement On admission for delivery Full blood and platelet counts coagulation investigations and this should be readily available. blood group and retain serum Minimise maternal and fetal trauma at delivery Access to blood product replacement may be necessary Blood product therapy Avoid intramuscular injections Factor VIII concentrations usually rise during Collect cord blood sample for investigation Give neonate vitamin K, orally pregnancy and in general also in haemophilia Immunisations to infant by intradermal route A carriers. In type I vWD, providing the Consider hepatitis B immunisation for infant FVIIIC activity exceeds 40 units/dl, no blood Working Party ofthe Haemostasis and Thrombosis Task Force 103

product replacement is required to cover complex activities. Some haematologists and uncomplicated vaginal delivery. Coagulation obstetricians recommend, however, that

factor activity should be rechecked between desmopressin is avoided during pregnancy J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from 34-36 weeks gestation in case emergency and intrapartum because of its effect on oxy- admission or caesarean section is required. If tocin. Demospressin infusion may be used caesarean section is planned or becomes nec- after delivery or following abortion or termi- essary FVIHC activity should be in excess of nation when a moderate rise in FVIII activity 50 units/dl and infusion of FVIH concentrate is required for a few days only. Desmopressin may occasionally be necessary to raise a type I infusions after surgery may cause water reten- vWD or a haemophilia A carrier's concentra- tion and hyponatraemia,"2 so blood urea and tion of FVIIIC. electrolytes should be monitored and exces- Normally factor IX activity does not rise as sive fluid input (such as dextrose infusions) much as FVIII during pregnancy and female avoided. Patients with type IIB vWVlD should carriers of haemophilia B with low factor not be given desmopressin, because of the IX activity more frequently require specific risk of causing platelet aggregation and replacement treatment to raise their factor thrombocytopenia due to binding of abnor- IX activity to safe levels for vaginal mal intermediate sized multimers of vWf anti- delivery (40 units/dl) or caesarean section (50 gen to platelets and subsequent platelet units/dl). High purity factor IX concentrate aggregation."3 should be used as factor IX concentrates con- taining factors II, VII, and X are potentially Analgesia thrombogenic. Intramuscular analgesia should be avoided In carriers of haemophilia A or B, follow- and intravenous or subcutaneous analgesia ing delivery, FVIIIC and factor IX concentra- used if necessary. Providing the coagulation tions should be maintained above 40 units/dl screen is normal, the Simplate bleeding time for at least 3-4 days or for 4-5 days if cae- less than 10 minutes, and the platelet count sarean section has been performed. In the greater than 100 x 109/1, there should be no presence of bleeding or wound infection a contraindication to inserting an epidural longer period of treatment may be necessary. catheter.'4 Care must be exercised before Frequently patients with type m and type removing the catheter and in these patients IIA vWD and occasionally type IIB vWD with an inherited bleeding tendency it is sug- require blood product treatment to raise their gested that a further coagulation screen and FVIII and vWf complex concentrations to platelet count is performed before withdrawal cover delivery-even if vaginal delivery is of the epidural catheter. In cases of elective anticipated (table 3). Prophylactic infusion of surgery spinal anaesthesia may be the safer factor concentrates should start at the onset option. of labour aiming to raise FVIIIC and vWf activity to above 40 units/dl. FVIII concen- LESS COMMON INHERITED BLEEDING DEFECTS http://jcp.bmj.com/ trates which contain large amounts of the Fibrinogen abnormalities larger vWf multimers should be used-for Women with hereditary hypofibrinogenaemia example, 8Y; Blood Products Laboratory, or may sustain recurrent pregnancy loss or Haemate P; Hoechst." Caesarean section is excessive bleeding, but successful pregnancy major surgery and vWD patients with outcome has been described with regular reduced FVIII and vWf concentrations must replacement treatment throughout preg- be given appropriate FVIII and vWf replace- nancy."' on September 29, 2021 by guest. Protected copyright. ment (as above) to raise their FVIIIC and vWf activity to above 50 units/dl before Other coagulation factor deficiencies surgery. Factor VIIIC activities are used to There is very limited recorded experience of monitor the response to infusion in patients pregnancy management in women with other with type I vWD and vWf activity in type II coagulation factor deficiencies.'6 As far as patients. Concentrations must be maintained possible women with these defects should be at above 40 units/dl for 3-4 days after vaginal identified and counselled before pregnancy delivery and for 4-5 days after caesarean and should be managed in obstetric units section. allied to a haemophilia centre. Carriers of haemophilia A and a proportion of patients with type 1 or type II A vWD may Congenital platelet disorders respond to an infusion of desmopressin Congenital platelet function disorders are (DDAVP) with a rise in their FVIII and vWf uncommon, although not rare, and are usu- ally associated with a mild bleeding diathesis. Families with disorders such as familial Table 3 Management ofdelivery andpuerperium in vWD thrombocytopenia, Glanzmann's thrombas- vWD tpe Delivery Postpartum thenia, Bernard-Soulier syndrome, storage I Occasionally require blood Treat bleeds with blood pool defects and disorders of platelet secre- product replacement products or desmopressin tion should attend a haemophila centre and Regard caesarean section as major surgery be offered counselling and care similar to that IIA 1 May require blood products Treat bleeds with blood sctonas ajr srgry offered to families with inherited coagu- egadIaesrenRegard caesarean section as major surgery productsDo not use desmopressin in lopathies. type IIB Pregnancy and delivery are documented in III Treat as major surgery and Prophylactic blood products only a few patients with severe platelet func- offer blood products for 3-5 days tion disorders,'7 18 but in general management 104 Walker, Walker, Colvin, Letsky, Rivers, Stevens, et al

involves the strict avoidance of unnecessary a chronic, compensated state to acute life platelet transfusions, the search for platelet threatening haemorrhage. The chronic DIC

antibodies in patients who have previously which occurs in pre-eclampsia or with hyda- J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from received donor platelets, and in some patients tidiform mole is associated with laboratory the use of single donor platelets or platelet evidence of increased platelet turnover and type specific donor platelets. In patients with mildly reduced fibrinogen concentrations but storage pool defects and a history of bleeding, usually with no excessive bleeding. Many DDAVP may be helpful at the time of deliv- obstetric complications-for example, placen- ery. tal abruption, amniotic fluid embolism, septic abortion-are however associated with a POST PARTUM FOLLOW UP more acute release of tissue thromboplastin A cord sample should be collected for investi- into the circulation with the resultant pro- gation. Because some haemostatic factors are nounced depletion of coagulation factors, physiologically relatively reduced in neonates, increased fibrinolytic activity, and consump- it may be difficult to exclude a mild to mod- tion of platelets and subsequent clinical erate inherited defect at birth (in haemophilia bleeding. B, vWD, or factor XI deficiency). In these children repeat investigation at three to six MANAGEMENT OF ACUTE LIFE THREATENING months is necessary. HAEMORRHAGE IN OBSTETRIC PATIENTS Intramuscular injections must be avoided The immediate management of haemorrhage in children of either sex with confirmed or in obstetric patients is essentially the same possible vWD and in male children of carriers whether or not the bleeding is caused or exac- of haemophilia A or B (unless they have been erbated by DIC. There should be a routine proved to be unaffected). In these neonates, planned procedure agreed by obstetricians, therefore, prophylactic vitamin K1 must be midwives, anaesthetists and haematologists to given orally and their general practitioner deal with acute haemorrhage whenever it informed and asked to ensure that routine arises. Agreed protocols should be produced immunisations are given carefully intra- and given to all staff concerned and be avail- dermally or subcutaneously. Immunisation able in the labour ward. Early and continuing against hepatitis B should be offered. reliable communication with laboratory staff Arrangements to review mother and baby at is mandatory, although the urgency of the the haemophilia centre must be made before clinical situation often demands intervention they are discharged from the maternity unit. before full test results are available. Acute obstetric bleeding is usually obvious as blood escapes from the genital tract. It Acquired bleeding disorders may, however, be very difficult to estimate Acquired bleeding disorders developing dur- the volume of blood loss from the circulation ing pregnancy, at delivery, or following deliv- as much of the loss may be concealed behind http://jcp.bmj.com/ ery, present a different set of problems from the placenta and in the myometrium, within those faced in women with an inherited the uterine cavity or the broad ligament, and bleeding tendency. Women with inherited total blood loss is often dangerously underes- bleeding problems are most frequently known timated. In some cases of abruption, there is and otherwise well. With careful counselling, no visible vaginal bleeding with all the haem- and if necessary prophylaxis, they orrhage concealed. The rate of blood loss is planning, on September 29, 2021 by guest. Protected copyright. generally progress through pregnancy and probably more important than volume of delivery in a reasonably predictable way. blood loss, at least initially. Women who develop an acquired bleeding disorder during pregnancy or delivery do so Source of blood loss acutely, are usually unwell, and sometimes Obstetric bleeding occurs most commonly very ill. Their bleeding disorder further com- from the placental bed. Before birth this may plicates their progress and management and be the result of a placenta implanted in the may in some instances dominate their clinical lower uterine segment (placenta praevia) or presentation. the result of abruption of a normally sited placenta. After delivery poor myometrial con- Thrombocytopenia traction due to hypotonia, or to retained The causes of thrombocytopenia in preg- products of conception (placenta or mem- nancy are so numerous and varied that these branes), or blood clot may permit continuing will be the subject of a separate guidelines blood loss from the placental site. document (in preparation). Intrapartum and postpartum bleeding may also be the result of trauma-rupture of the Disseminated intravascular coagulation (DIC) uterine wall, tearing of the cervix or vagina, Disseminated intravascular coagulation or damage to the perineum or vulval varicosi- (DIG) is associated with a wide variety of ties. clinical situations which complicate preg- It is imperative that the source of bleeding nancy. DIC is never a primary event but is is identified and dealt with as soon as possi- always a secondary phenomenon triggered by ble. Shock may trigger DIC which will further the release of procoagulant material into the complicate the bleeding tendency. Active circulation or by damage to the vascular steps to restore blood volume and oxygen car- endothelium. Depending on the triggering rying capacity must be instituted as a matter event, the manifestations of DIC range from of urgency (table 4). Working Party ofthe Haemostasis and Thrombosis Task Force 105

Table 4 Management ofacute obstetric haemorrhage and must be considered as a "first-aid" mea- Secure venous access and insert central venous pressure monitor sure only. If available, a 4-5% solution of Summon additional help human albumin may be used, otherwise other J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from Collect blood samples for cross matching and coagulation screen Contact haematologist and blood bank colloids such as Haemaccel (Hoechst) or Maintain blood volume-with unmatched blood if necessary (same ABO and RhD Gelofusine (Vifor)-up to 1-5 litres-are group as patient) Seek and deal with source of bleeding preferable to dextrans which interfere with Blood product replacement treatment if necessary compatibility testing and with platelet func- tion. Two lines are usually necessary to allow blood and other products to be infused simul- Laboratory investigation taneously. After the initial transfusion fluid A sample of venous blood should be sent for replacement should be monitored with cen- full blood count, coagulation screening, and tral venous pressure monitoring. cross matching. Emergency packs with all necessary samples tubes and forms should be Stopping the bleeding kept available in a labour ward refrigerator. Although the circulation can be maintained in Results of coagulation screening tests must the short term, survival of the patient is always be interpreted, bearing in mind that dependent on stopping the bleeding. How normally in the third trimester the APTT and this is done depends on whether the bleeding PT are at the lower limits of normal. occurs before or after birth. Measurement of products of plasmin diges- tion of fibrinogen or fibrin provides an indi- ANTEPARTUM HAEMORRHAGE rect test for fibrinolysis along with a platelet If the bleeding is severe delivery and the emp- count and a fibrinogen assay (Clauss method) tying of the uterus is the only way to stop it. or thrombin time will quickly distinguish If blood loss is not adequately replaced acute coagulation screen abnormalities caused by renal tubular necrosis may occur. DIC from those attributable to other causes. Placenta praevia Maintenance ofblood volume In the case of placenta praevia, most of the Severe bleeding is an obstetric emergency. bleeding will be apparent. Coagulation The aim of management should be to main- defects are rare and the main problem is tain the circulation and stop the bleeding. blood replacement. Delivery must be by cae- Help from the most senior obstetricians, sarean section. If the placenta is anterior, fur- anaesthetists, and midwives available should ther severe haemorrhage may occur during be sought. The laboratory should be notified delivery. After the placenta is delivered the immediately of the problem. Venous access lower uterine segment does not contract as should be achieved at two sites using large well as the upper segment and bleeding can bore cannulae. Blood pressure and pulse continue. If bleeding is not controlled at should be monitored and a central venous delivery the management is similar to that http://jcp.bmj.com/ line should be inserted. required for postpartum haemorrhage. Blood is the best fluid to replace blood loss. Wherever possible this should have been Placental abruption shown to be compatible with the patient's With placental abruption, the blood loss is blood before issue, but in an emergency it always underestimated and replacement may be necessary to issue unmatched blood. should take account of this. As bleeding may Pregnant women who have been attending largely be retroplacental and several litres of on September 29, 2021 by guest. Protected copyright. for antenatal care will have their blood group blood may be concealed behind the placenta, and antibody status already known. Providing the amount of blood issuing from the vagina this blood group has been confirmed, before delivery is no indicator of the extent of unmatched blood of the patient's own ABO placental detachment or of the subsequent and RhD group is preferable to unmatched blood loss. There is usually a concomitant group 0 RhD negative blood. Immediately coagulation defect and it is the most common on receipt in the laboratory the patient's cause of acute pregnancy related DIC. The blood sample should be ABO and RhD degree of haemostatic disturbance is related grouped by rapid techniques and ABO to the degree ofplacental separation. incompatibility with issued units excluded by The mere suspicion that a patient may a rapid spin crossmatch (a spin agglutination have placental abruption should prompt an test after 2-5 minutes' incubation at room urgent coagulation screen, full blood and temperature). It should usually be possible to platelet counts, and a blood sample for recheck the patient's blood group and immediate blood group and antibody screen exclude major incompatibility before a large with compatibility testing, if and when appro- amount of blood is transfused. Unmatched priate. group 0 RhD negative, Kell negative, Duffy In placental abruption, prevention or cor- negative blood should only be issued in the rection of hypovolaemia is the primary con- very rare event of life threatening haemor- cern with expeditious vaginal delivery rhage in a woman whose blood group is whenever possible. The bleeding and coagu- unknown. lation defects will not be controlled until after Whilst awaiting blood, the blood volume delivery. There should be prompt replace- must be expanded with crystalloids such as ment of blood volume to maintain renal per- Hartmann's solution (up to 2 litres). fusion. Although depleted coagulation factors However, these leave the circulation rapidly should be replaced, the consumption will 106 Walker, Walker, Colvin, Letsky, Rivers, Stevens, et al

continue until the uterus is emptied. Fresh The placenta and membranes should be frozen plasma (1 litre) is often sufficient to re-examined to check for any evidence of

correct the coagulation defect, but severe retained products. The fundus should be J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from depletion of fibrinogen (to less than 0-8 g/l) examined to make sure that the uterus is requires the infusion of 10-15 units of cryo- contracted. If the uterus is atonic, an intra- precipitate. Thrombocytopenia (platelet venous injection of 10 units of oxytocin or 0 5 count of less than 50 x 109/l) may require mg of ergometrine should be given. After this correction by transfusion of platelet concen- an infusion of oxytocin should be started to trates. Further coagulation investigation and keep the uterus contracted. If the haemor- platelet counts are required to monitor rhage continues, Hemabate (Upjohn), a response to replacement treatment and the prostaglandin F analogue, should be given ongoing clinical condition to judge the either intramuscularly or, in extreme circum- requirement for further replacement. stances, directly into the myometrium. These Having initiated management of hypo- actions should be accompanied by bimanual volaemia and taken samples for coagulation compression of the uterus. screening and for blood group, measures to If there is continual bleeding from the gen- expedite delivery must be addressed. Vaginal ital tract, the patient should be examined examination should be carried out to assess under the appropriate anaesthesia. If the the state of the cervix. In parous women, bleeding is coming through the cervix, the amniotomy may be enough to stimulate cavity should be explored and any retained labour and lead to prompt delivery, but oth- products removed followed by the use of oxy- ers may, in addition, require oxytocin infu- tocics. If the bleeding is coming from lower sion. If the mother is relatively stable, the in the genital tract, the cervix and vagina fetus can tolerate the delay and, providing should be examined for tears and promptly damage to the birth canal and perineum can repaired. be avoided, vaginal delivery is preferable. If If there are persistent problems senior help there is any sign of fetal distress or if vaginal should be summoned promptly. If bleeding delivery is not imminent or seems likely to be continues from the uterus laparotomy should difficult caesarean section may be necessary. be carried out to exclude the possibility of In this case, blood volume and coagulation uterine rupture. If there is persistent bleeding factor replacement before surgery is essential from the placental site oversewing of the as far as it is possible. Delivery should not be bleeding points should be considered. Early delayed to achieve this, however, as emptying recourse to hysterectomy may be life saving, the uterus will stop the consumption and help with tying of the internal iliac arteries a fur- in the correction of the factor deficiency. ther option. Although the urinary tract is at Fresh frozen plasma and platelet infusion can risk in this situation, most damage can be be given as the operation is started. If the repaired at a later date and haemostasis is the fetus is already dead, caesarean section is sel- primary aim. In the acute situation aortic http://jcp.bmj.com/ dom indicated except where, despite ade- compression, either at laparotomy or by quate oxytocin stimulation, cervical dilation abdominal compression, may control bleed- does not occur. ing, enough to visualise the bleeding points or Once the fetus and placenta are delivered, for senior support to arrive. myometrial retraction will usually dramati- In the presence of persisting severe haem- reduce or stop site cally placental bleeding, orrhage, coagulation factors may need to be on September 29, 2021 by guest. Protected copyright. but measures to stimulate myometrial func- replaced rapidly. A litre of fresh frozen tion may be essential and care must be taken plasma and 10 units of cryoprecipitate may to ensure that the uterus remains well con- be thawed and issued empirically before tracted. Abdominal or perineal wound heal- coagulation screening tests are completed. ing may be difficult or slow. Fresh frozen plasma contains all of the coagu- Epidural analgesia is potentially hazardous lation factors normally present in plasma. in patients with DIC and should be avoided. Cryoprecipitate has the advantage of a higher Although heparin has been used in DIC,'9 in concentration of fibrinogen per volume. If the general its use is not recommended in DIC platelet count has fallen below 50 x 109/l associated with pregnancy where the cir- platelet concentrates may be suggested, but culation is not intact because of the placental often haemostasis and control of bleeding can bed. be achieved without platelet transfusion. The risks and disadvantages of fibrinolytic POST PARTUM BLEEDING inhibitors (tranexamic acid, aprotinin) out- Excessive bleeding after delivery can result weigh their potential benefits in most obstet- from one of the above pre-existing antenatal ric haemorrhages. In a very few cases where problems or be caused by retained products persisting postpartum bleeding can clearly be of conception or trauma to the genital tract. shown to be associated with excessive fibri- Immediate intravenous access should be nolytic activity (a shortened euglobulin clot obtained as outlined above and blood drawn lysis time) and no trauma, antifibrinolytic for a full blood count, platelet count, a coagu- agents may be tried with caution. lation screen and cross matching. The blood loss should be replaced and coagulation Management ofless severe obstetric bleeding defects, where identified, should be corrected In patients who are bleeding less severely with appropriate blood product replacement management can be tailored on an individual treatment as outlined above. basis but the broad principles remain the Working Party ofthe Haemostasis and Thrombosis Task Force 107

same as for life threatening haemorrhage. or selective fetocide where the dead fetus may Extra help, including laboratory staff and remain in utero for a number of weeks, a

anaesthetic staff, must be alerted early on; coagulation defect may occur. In this situa- J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from blood samples for full blood count, coagula- tion low dose heparin may be of benefit but it tion screening, and compatibility testing is not without risk to the mother and her sur- should be dispatched urgently; and infusion viving fetus. These pregnancies require close lines should be in place and a careful search management and advice from centres with to identify and deal with the source of bleed- previous experience. ing made. If transfusion is necessary cross- matched blood is always preferable to Acquired inhibitors ofcoagulation unmatched blood. Rarely, a bleeding tendency similar to that If time permits the results of the coagula- observed in haemophilia A may occur sec- tion screening tests may provide a scientific ondary to the development of an inhibitor to basis on which to prescribe blood product factor VIII. Most cases present two to three replacement. In practice, though, this will months after delivery but the inhibitor may usually be fresh frozen plasma in patients develop during pregnancy20 or cause severe without evidence of severe fibrinogen deple- bleeding in the early puerperium.21 The tion or a combination of fresh frozen plasma inhibitor is usually an IgG antibody. It may and cryoprecipitate in patients with fibrino- disappear spontaneously or after immunosup- gen concentrations of less than 0-8 gA. pressive treatment with steroids. In at least 50% of women the inhibitor will be unde- OTHER CAUSES OF ACQUIRED OBSTETRIC tectable a year after initial detection22 and it BLEEDING rarely recurs with subsequent pregnancies.23 Aminoticfluid embolism Frequent monitoring of the inhibitor activity Amniotic fluid embolism is an uncommon is essential to aid planning of treatment if generally fatal complication of pregnancy. It bleeding should occur. A trial of prednisolone may occur during or shortly after labour or at or intravenous immunoglobulin may be con- caesarean section. If the patient survives the sidered. initial event, rapid and virtually total con- Management of bleeding in these patients sumption of clotting factors and platelets is very difficult, involving the use of human or ensues, leading to catastrophic exsanguinat- porcine factor VIII, or activated prothrombin ing uterine haemorrhage. Typically the complex concentrates. It is very much the patient is in or has just completed a strenuous province of haematologists with experience labour with an intact amniotic sac when she in managing patients with pathological suddenly collapses profoundly shocked, coagulation inhibitors. cyanosed with respiratory distress, and bleed- ing from venepuncture sites and from the Acute hepaticfailure genital tract. Acute fatty liver of pregnancy is acute liver http://jcp.bmj.com/ Cardiopulmonary resuscitation may be failure occurring during pregnancy unrelated necessary and preparation made for immedi- to infection, hepatotoxic drugs, or chemicals ate delivery if this has not occurred. Blood or haemolytic uraemic syndrome.24 It can also products, including fresh frozen plasma, occur in association with pre-eclampsia. cryoprecipitate, and platelets are urgently Characteristically the patient rapidly develops required and must be used empirically. If clinical and biochemical evidence of liver fail- occurring after delivery 10 000 units of ure in association with a severe coagulopathy, on September 29, 2021 by guest. Protected copyright. heparin given intravenously may help to reduced platelet count, raised concentrations arrest this cycle of coagulation and haemoly- of fibrin and fibrinogen degradation products sis. (FDPs), reduced fibrinogen, and extremely low antithrombin (AT). The biochemical Retained deadfetus findings are those of liver function impair- This is now a rare occurrence. To cause ment with low plasma albumin and vitamin K detectable consumption of coagulation fac- dependent coagulation factors. The liver tors, the fetus has to be retained in utero for enzymes are often not substantially increased. three to four weeks after its demise. It is important to realise the seriousness of Spontaneous labour usually supervenes this situation. The perinatal mortality is within two weeks of fetal death and current approaching 50% with the maternal mortality obstetric practice would be to induce labour at 30%. If delivery is not expedited the fetus if it did not occur spontaneously shortly after will die in utero followed by the death of the fetal death. Although significant consumptive mother. After delivery the mother will hope- coagulopathy is a rare complication of a fully recover with supportive management. retained dead fetus, it is recommended that a Some benefits from correction of the coagu- coagulation screen and platelet count are per- lopathy after administration of AT have been formed on all mothers with a dead fetus in suggested.25 Infusion of material containing utero before inducing labour, or as early as AT may be worth considering in this dire possible in a spontaneous labour. Replace- clinical condition. ment therapy is rarely necessary. If a coagula- tion defect is found the presence of antiphospholipid antibodies should be sought We acknowledge the advice and help received from a number as they could have contributed to fetal death. of others including Dr G D 0 Lowe and Professor I Peake, who generously gave us their time and expertise during the In the unusual circumstances of a dead twin preparation of this document. 108 Walker, Walker, Colvin, Letsky, Rivers, Stevens, et al

The advice contained in these guidelines is believed to rep- the treatment of patients with haemophilia A, haemo- resent the state of the art at the time of going to press. It is philia B and von Willebrand's disease. Blood Coagul policy to revise the guidelines as new developments occur, but Fibrinolysis 1992;3:205-14.

it may not be possible to do this at the time of such changes 12 Lowe GDO, Pettigrew A, Middleton S, Forbes CD, J Clin Pathol: first published as 10.1136/jcp.47.2.100 on 1 February 1994. Downloaded from and the guidelines should always be used with due regard to Prentice CRM. DDAVP in haemophilia. Lancet 1977; current acceptable practice. ii:614-5. Comments are invited to assist the review process. All cor- 13 Rick ME, Williams SB, McKeown LP. Thrombo- respondence regarding the guidelines should be addressed to: cytopenia associated with pregnancy in a patient with BCSH Secretary, British Society for Haematology, 2 Carlton type 1 lB von Willebrand's disease. Blood 1987;11: House Terrace, London SW1Y 5AF 786-9. 14 Letsky EA. Haemostasis and epidural anaesthesia. Int Y ObstetAnaesth 1991;1:51-4. 1 Department of Health, Welsh Office, Scottish Home and 15 Grech H, Majumdar G, Lawrie AS, Savidge GF. Health Department, Department of Health and Social Pregnancy in congenital afibrinogenaemia: report of Services, Northern Ireland. Report on Confidential a successful case and review of the literature. Br J Enquiries into Maternal Deaths in the United Kingdom Haematol 1991;78:571-2. 1985-1987: London: HMSO, 1991. 16 Bern MM. Acquired and congenital coagulation defects 2 Rodeghiero F, Castaman G, Dini E. Epidemiological encountered during pregnancy and in the fetus. In: investigation of the prevalence of von Willebrand's dis- Haematologic disordes in maternal fetal medicine. Bern ease. Blood 1987;69:454-9. MM, Frigoletto FD, eds. New York: Wiley-Liss, 3 Krishnamurthy M, Miotti AB. von Willebrand's disease 1990:395-448. and pregnancy. Obstet Gynecol 1977;49:244-7. 17 Michalas S, Malamitsi-Puchner A, Tsevrenis H. Preg- 4 Hill FGH, George J, Enayat MS. Changes in VIII:C, nancy and delivery in Bernard-Soulier syndrome. Acta VIHR AG, WF and ristocetin-induced platelet aggrega- Obstet Gynecol Scand 1984;63:185-6. tion during pregnancy in women with von Willebrand's 18 Sundqvist SB, Nilsson IM, Svanberg L, Cronberg S. disease. BrJHaematol 1982;50:691. Pregnancy and parturition in a patient with severe 5 Adashi EY. Lack of improvement in von Willebrand's dis- Glanzmann's thrombasthenia. Scand Y Haematol 1981; ease during pregnancy. N EnglY Med 1980;303:1 178. 27:159-64. 6 Lipton RA, Ayromlooi J, Coller BS. Severe von 19 Thiagarajah S, Wheby MS, Jain RK May H V, Bourgeois J, Willebrand's disease during labor and delivery. JAMA Kitchin JD. Disseminated intravascular coagulation in 1982;248:1355-7. pregnancy: The role of heparin therapy. Y Reprod Med 7 Greer IA, Lowe GDO, Walker JJ, Forbes CD. 1981;26:17-20. Haemorrhagic problems in obstetrics and gynaecology 20 Voke J, Letsky E. Pregnancy and antibody to factor Vm. Y in patients with congenital coagulopathies. Br J Obstet Clin Pathol 1977;30:928-32. Gynaecol 1991;98:909-18. 21 Reece EA, Romero R, Hobbins J. Coagulopathy associ- 8 Takahashi N. Studies on the pathophysiology and treat- ated with factor Vm inhibitor. A literature review. Y ment of von Willebrand's disease VI. Variant von Reprod Med 1984;29:53-8. Willebrand's disease complicating placenta previa. 22 Green D, Lechner K. A survey on 215 non-hemophilic Thromb Res 1983;31:285-96. patients with inhibitors to factor Vm. Thromb Haemostas 9 Peake IR Lillicrap DP, Boulyjenkov V, et al. Report on 1981;45:200-3. Joint WHO/WFH Meeting on the control of haemo- 23 Vincente V, Alberca I, Gonzales R, Alegre A. Normal philia: carrier detection and prenatal diagnosis. Blood pregnancy in a patient with a postpartum factor VIII Coagulation and Fibninolysis 1993;4:313-44. inhibitor. Am J Hematol 1987;24: 107-9. 10 Old JM, Ludlam CA. Antenatal diagnosis in paediatric 24 Kaplan MM. Acute fatty liver of pregnancy. N EnglJ Med haematology. In: Hann IM, Gibson BES, eds. Clinical 1985;313:367-70. haematology: International practice and research 4-2. 25 Liebman HA, McGehee WG, Patch MJ, Feinstein DI. London: Bailliere Tindall, 1991:429-58. Severe depression of antithrombin Im associated with 11 UK Haemophilia Centre Directors Committee. Rec- disseminated intravascular coagulation in women with ommendations on the choice of therapeutic products for fatty liver of pregnancy. Ann Intern Med 1983;98:330-3. http://jcp.bmj.com/ on September 29, 2021 by guest. Protected copyright.