The management of anaemia and haematinic deficiencies in pregnancy and post-partum.

Anaemia is one of the most common disorders in the world (24·8% of the world population) (de Benoist 2008) and affects patients of all ages and ethnic origins. Underlying causes and prevalences vary by age group and socioeconomic background, but pregnant women everywhere are at high risk of anaemia, the vast majority of cases being due to iron deficiency. One in four pregnant women in Europe are thought to have iron deficiency anaemia (Daru et al., March 2016), whereas in parts of Africa, where hookworm infestation is common, this has been estimated to be as high as 38% (Stevens et al., 2013) to 50% (Bah et al., June 2017). Women of menstruating age are rarely iron replete (Low et al., 18 April 2016) and then enter pregnancy, which carries a major negative iron balance (Bentley, October 1985). Despite a good understanding of the causes of anaemia in pregnancy, there is still uncertainty about how best this should be investigated, prevented and managed. This reflects the limitations of laboratory tests, as well as the poor understanding of how best to replace iron, given the complex physiological mechanisms of iron absorption and distribution. A strategy for iron replacement in a population of anaemic pregnant women needs to be developed not only based on what is biologically and clinically most appropriate but also in the context of each organisation's delivery of care structure, taking into consideration aspects of cost effectiveness. For this reason, management algorithms must be adapted locally, ensuring they meet basic clinical imperatives.

Severe primary autoimmune thrombocytopenia in pregnancy: a national cohort study.

OBJECTIVE: To quantify the incidence of severe autoimmune thrombocytopenia (ITP) in pregnancy in the UK, determine current treatment strategies, and establish maternal and neonatal morbidity and mortality associated with severe ITP in pregnancy. DESIGN: A prospective national cohort study. SETTING: UK. POPULATION: Women with severe ITP, defined as platelets <50 × 109 /L in pregnancy or antenatal treatment of isolated low platelets. METHODS: Data collected via the UK Obstetric Surveillance System (UKOSS) between 1 June 2013 and 31 January 2015 from all UK consultant-led obstetric units. MAIN OUTCOME MEASURE: Incidence of severe ITP in pregnancy. RESULTS: The estimated incidence of severe ITP in pregnancy is 0.83 per 10 000 maternities (95% CI 0.68-1.00). A total of 22 pregnant women (21%) did not receive any antenatal therapy, and 85 pregnant women (79%) received therapy. There was no difference between asymptomatic treated and untreated cohorts in severity of disease or outcome. Postpartum haemorrhage (51%) and severe postpartum haemorrhage (21%) was reported more frequently than the rate reported in the general pregnant population (5-10%). No neonates required treatment for thrombocytopenia and there were no cases of neonatal intracranial bleeding. CONCLUSIONS: Current UK management of severe ITP in pregnancy results in an exceptionally low morbidity and mortality for the neonate. Mothers with ITP remain at increased risk of severe postpartum haemorrhage, and should be delivered at units that have the capacity to manage severe PPH effectively. Whilst balancing the risks for pregnancy from prophylactic antenatal treatment in asymptomatic women against observed low disease morbidity, we may be over treating asymptomatic patients. TWEETABLE ABSTRACT: UKOSS study of severe ITP in pregnancy shows exceptionally low neonatal morbidity with current UK management.

Thromboelastography and peripartum coagulation profiles associated with caesarean section delivery.

Thromboembolic (TE) disease remains the leading direct cause of maternal death in the UK and caesarean section increases TE risk. Women are assessed for their TE risk and may receive thromboprophylaxis. From a single blood sample thromboelastography(®) (TEG(®)) allows a test of coagulation. Blood samples from women undergoing elective caesarean sections were collected at specific stages: antenatally, following overnight 'nil-by-mouth', immediately after surgery, four hours post-delivery and 24 hours post-delivery. Analyses of the R time (time taken for blood to clot) and maximum amplitude (MA) (overall clot strength) were performed. Analyses of the high and moderate risks cohorts were performed and compared to the low risk group. Fifty-four women were recruited. A reduction in the R time was demonstrated following pre-operative fluid restriction and a further reduction in R time occurred after surgery. The R time increased 24 hours after surgery and became comparable to pre-operative levels. The MA changed similarly due to pre-operative fluid restriction. Analysis also showed that pre-operatively, the combined high and moderate risk groups' R time was shorter than the low risk group. The high and moderate risk group, having received thromboprophylaxis, had similar R times 24 hours postoperatively compared to the low risk group. TEG(®) demonstrates that following pre-operative fluid restriction and surgery women become hypercoagulable but by 24 hours coagulation has returned to third trimester levels. Sub-group analysis suggests the relative pre-operative hypercoagulability of high and moderate risk women compared to low risk women, becoming comparable after 24 hours following thromboprophylaxis.

Recombinant factor VIIa and other pro-haemostatic therapies in primary postpartum haemorrhage.

Blood products are an essential component of the management of postpartum haemorrhage, although there is lack of evidence to guide optimal use. Prospective intervention studies, including randomized trials, are needed to clarify optimal timing and dosage. The new generation of virally inactivated blood products, such as fibrinogen concentrate, might further enhance our knowledge of the value of individual blood components. It seems likely that antifibrinolytic agents will receive less attention in future. However, rFVIIa promises to be a powerful tool in managing massive obstetric haemorrhage, although many questions concerning its efficacy and safety in differing clinical scenarios remain unanswered.

Pregnancy outcome in Factor XI deficiency: incidence of miscarriage, antenatal and postnatal haemorrhage in 33 women with Factor XI deficiency.

Pregnancy complications in women with Factor XI deficiency were assessed in this retrospective analysis. All nonnulliparous women registered with Factor XI deficiency in the East Midlands region were included. Each woman was classified into 'bleeder' or 'nonbleeder'. Rates of antenatal and postnatal bleeding and miscarriage rate were recorded. A total of 33 women had 105 pregnancies. Pregnancy and delivery was uneventful in 70% of the cases. Postpartum haemorrhage (PPH) appears increased in women with a 'bleeding' phenotype with a highly significant difference between 'bleeders' and 'nonbleeders' (relative risk [RR] 7.2; CI 1.99-25.9). Miscarriage rate appeared unchanged. We conclude that PPH is increased in a subgroup with a bleeding phenotype. Larger studies are needed to define the underlying factors.

The obstetric and gynaecological management of women with inherited bleeding disorders--review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors' Organization.

The gynaecological and obstetric management of women with inherited coagulation disorders requires close collaboration between obstetrician/gynaecologists and haematologists. Ideally these women should be managed in a joint disciplinary clinic where expertise and facilities are available to provide comprehensive assessment of the bleeding disorder and a combined plan of management. The haematologist should arrange and interpret laboratory tests and make provision for appropriate replacement therapy. These guidelines have been provided for healthcare professionals for information and guidance and it is also intended that they are readily available for women with bleeding disorders.

Acquired haemophilia heralded by bleeding into the oral mucosa in a patient with bullous pemphigoid, rheumatoid arthritis, and vitiligo.

Acquired haemophilia is rare and potentially fatal, with a mortality of 20% if left untreated. There is a strong association with other autoimmune diseases. This report describes a patient with rheumatoid arthritis, vitiligo, and bullous pemphigoid where the diagnosis of acquired haemophilia was made after an extensive bleed into a bullous lesion in the buccal mucosa. This case highlights some of the potential complications of acquired haemophilia and its treatment.

Thrombotic thrombocytopenic purpura associated with statin treatment.

Thrombotic thrombocytopenic purpura (TTP) is a rare condition but associated with 90% mortality if left untreated. The diagnosis is usually made when there is thrombocytopenia and microangiopathic haemolytic anaemia, although the full pentad also includes fever, renal impairment, and neurological dysfunction. A variety of underlying causes have been implicated in acquired TTP including bacterial and viral infections, bone marrow and organ transplantation, pregnancy, immune disorders, and certain drugs. To date there is just one case report of TTP associated with statin treatment. The clinical course of a patient who presented with TTP after being started on simvastatin, a HMG-CoA inhibitor, is described.

Hermansky-Pudlak syndrome in a pregnant patient.

Hermansky-Pudlak syndrome is a multisystem disorder with albinism, bleeding diathesis and visual impairment as the main features. We report a case of epidural analgesia in a pregnant patient, who was subsequently discovered to have this syndrome. We believe this to be the first such report.

Intrapartum care for women on full anticoagulation.

Women requiring full anticoagulation in pregnancy and labour present their care providers with complex management problems, particularly during the peripartum period. Available guidelines often fail to address the practical issues of balancing the risks of recurrent thrombotic events and haemorrhage during labour. This is especially the case in women at high risk of recurrent thromboembolism, in whom the usually recommended temporary peripartum reduction in the level of anticoagulation may be considered unsafe. In order to achieve a satisfactory outcome without undue intervention, multidisciplinary management involving obstetricians, haematologists and anaesthetists is essential. Intrapartum care plans should be made during pregnancy to address the conduct of labour and delivery, anticoagulation, analgesia in labour and the management of any arising obstetric, anaesthetic or haematological complications. In the following we address the practical issues requiring particular attention, as well as management options, in fully anticoagulated patients using a clinical case for illustration.

Serum-induced platelet procoagulant activity: an assay for the characterization of prothrombotic disorders.

Platelets contribute to hemostasis by forming a platelet plug and by providing a procoagulant surface for the assembly and activation of the coagulation factors. The contribution of platelets to prothrombotic disorders has been difficult to analyze. Recently an assay was reported that measured the procoagulant activity of test platelets by making the platelet lipid surface the limiting factor in the production of thrombin. In this report we describe a novel technique, based on this assay, that we used to study patient serum factors that activate control platelets and in turn initiate measurable procoagulant activity. Using this assay we investigated a group of patients with prothrombotic disorders. The patient test serum was incubated with normal platelets in the presence of activated factor Xa. The resultant thrombin was measured in a chromogenic assay. The rate-limiting step was the presence of any potential platelet-activating factors, such as antibodies in the heat-treated test serum, that would allow the Xa to bind to the platelet phospholipid surface. Serum samples from patients with heparin-induced thrombocytopenia (HIT) and the anti-phospholipid antibody syndrome enhanced platelet procoagulant activity, while samples from patients with idiopathic thrombocytopenic purpura and disseminated intravascular coagulation (DIC) did not. HIT serum samples also induced platelet activation, as measured by platelet microparticle shedding, carbon 14-labeled serotonin release, and platelet aggregation. The measurement of serum-induced platelet procoagulant activity provides a method for the investigation of circulating platelet agonists in prothrombotic disorders.

Cutaneous vascular infarcts secondary to spontaneous platelet aggregation.

We report a 23-year-old woman presenting with multiple cutaneous infarcts who was found to have spontaneous platelet aggregation (SPA). Her skin lesions showed a good response to aspirin therapy and platelet aggregation returned to normal. Subsequently, she was found to have and was treated for pulmonary tuberculosis. The SPA may have been related to this via the formation of immune complexes. Isolated cutaneous infarcts have not previously been described in association with SPA. The role of spontaneous and increased platelet aggregation in skin disorders is discussed.

Proteolytic degradation of high molecular weight kininogen in acute thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a disorder characterized by thrombocytopenia and schistocytic haemolytic anaemia. The majority of patients have normal coagulation parameters including the activated partial thromboplastin time (APTT). An intracellular cysteine protease, calpain, has been found in the plasma of many patients with acute TTP, and we hypothesize that it participates in the pathogenesis of the disorder. However, certain aspects of the disorder remain unresolved. For example, high molecular weight kininogen (HK) is one of the primary plasma inhibitors of calpain, and it also can act as a substrate for calpain. Consequently, one might anticipate that the HK could be defective or altered in TTP. In this report we describe the analysis of HK in plasma from live patients with acute TTP and following recovery. The HK was studied immunogenically and functionally. We observed that the HK in plasma samples from patients with acute TTP was proteolysed. This degradation was not observed in remission samples from the same patients. However, both acute and remission TTP samples had normal HK coagulant activity (acute samples, x = 0.84 +/- 0.26 U/ml; remission samples, x = 0.89 +/- 0.21 U/ml; control samples, x = 0.87 +/- 0.05 U/ml). Although the TTP plasmas were able to inhibit calpain activity, less inhibition activity was found in the acute samples (acute: mean inhibition 71 +/- 2.4%; remission: mean 92 +/- 2.1%; control samples: mean 93 +/- 5.4%; P < 0.001). Normal HK treated with calpain also had reduced calpain inhibition capacity (mean 58%). This study suggests that although HK is proteolysed during acute TTP, the proteolysis occurs without a major loss in the coagulation function or depletion of the protease inhibitory activity of HK.

Cyclical thrombocytopenia as a rare manifestation of myelodysplastic syndrome.

Cyclical thrombocytopenia is a rare condition characterized by regular fluctuations in the platelet count. We report a case of myelodysplastic syndrome who presented with cyclical thrombocytopenia--a previously unreported association.