Excessive platelet activation and consumption are common features of pre-eclampsia [28] and may occur several weeks prior to development of maternal symptoms [29]. It has been reported that plasma β-thromboglobulin levels correlate with urinary protein and serum creatinine [30], suggesting a link between platelet activation and renal damage. Platelets from women with pre-eclampsia are more responsive to in vitro agonist stimulation than those from women with a normotensive pregnancy [31]. The platelets from women with pre-eclampsia also form more platelet-leucocyte aggregates [32, 33], with this contributing to the inflammatory and procoagulant processes. Increased thromboxane A2 [34] and decreased platelet nitric oxide synthase (NOS) [35] offer further evidence for platelet mediated endothelial dysfunction in pre-eclampsia. Although platelet counts in women with pre-eclampsia are highly variable, longitudinal studies have shown that the mean platelet count falls during pre-eclamptic pregnancies with a concomitant increase in platelet volume [36–38]. A falling platelet count is associated with worsening disease, and is a maternal risk in its own right. The Royal College of Obstetricians and Gynaecologists (RCOG) recommends that consultant obstetric staff should document in the woman’s notes the maternal (biochemical, hematological and clinical) and fetal thresholds for elective birth before 34 weeks in women with pre-eclampsia. The levels of biochemical and hematological markers (including proteinuria) correlate poorly with maternal and fetal outcomes, such that the National Institute for Health and Clinical Excellence (NICE) in the UK felt that recommending absolute thresholds for delivery was not warranted. In general, the decision on when to expedite delivery will be made taking into account several factors, including the severity of hypertension, biochemical and hematological disturbance, proteinuria, availability of appropriate neonatal facilities, the presence of fetal growth restriction, and the gestation [39].

The association between coagulation activation and pre-eclampsia has been recognised since the early 1950s [40]. The shift in the hemostatic balance towards a procoagulant/hyperfibrinolytic picture observed in normal pregnancy (described in Chap. 1) is exaggerated in pre-eclampsia as evidenced by perivillous fibrin deposition and placental infarcts [41–43]. Global tests of coagulation show procoagulant changes proportional to the severity of pre-eclampsia: PT and APTT may be shortened; fibrinogen and FVIIIc are elevated [44]; D-dimer and markers of in vivo thrombin generation are raised [45, 46]; and endogenous thrombin potential is increased [32, 47]. As would be expected, a decrease in the natural anticoagulants is observed over and above that of normally pregnancy, with decreases reported in antithrombin [44, 48], protein C [45] and sensitivity to protein C resistance [47, 49, 50]. A decrease in antithrombin plasma levels is indicative of deterioration of the condition [48]. It is notable that activated protein C resistance (APCR) persists long after pregnancy in women with a history of pre-eclampsia [51, 52]. However, the most striking changes are in those proteins associated with endothelial dysfunction; tissue plasminogen activator [53], PAI-1 [54], soluble thrombomodulin [55, 56], soluble endothelial APC receptor [57] and von Willebrand factor [58, 59] are all increased, while a reduction in ADAMTS13 levels appears to be linked to the degree of inflammation [60]. Decreased circulating PAI-2 reflects decreased placental function and/or intrauterine growth restriction [54, 61].

There may be a tendency to over-test in pre-eclampsia. While the gravity of pre-eclampsia and HELLP cannot be overstated, it is not until the platelet count is less than 100 × 10⁹/L that there is likely to be an associated coagulopathy. Consequently, the NICE recommendation is that coagulation studies are not required if the platelet count is above this level. In pregnant women with platelet counts of less than 100 × 10⁹/L, a coagulation screen and fibrinogen level should be performed as initial screening tests, with D-dimer testing in the event of an abnormal clotting screen or if HELLP is suspected [67]. Lumbar epidural may be used for labor analgesia in women with pre-eclampsia if the mothers opt for it. Early epidural should be considered as it helps to diminish the hypertensive responses to pain. A platelet count of 75 × 10⁹/L or more in the absence of coagulation abnormalities is not associated with an increased likelihood of regional anesthetic complications in the setting of pre-eclampsia [68–70].

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) (see Chap. 17) are rarely encountered during pregnancy. The differential diagnosis of thrombotic microangiopathy (TMA) – HELLP and HUS or TTP – during pregnancy may be difficult as there is considerable overlap in the symptoms and laboratory findings [71, 72]. Thrombocytopenia, hemolysis with red cell fragmentation, jaundice, raised lactate dehydrogenase (LDH) and renal impairment are common to all three. The more common form of HUS, Shiga-like toxin-producing Eschericia coli HUS (STEC-HUS), is triggered by the infectious agent Escherishia coli O157:H7. Atypical HUS (aHUS) represents 5–10 % of HUS cases and is largely due to one or several genetic mutations that cause chronic, uncontrolled, and excessive activation of complement. Delivery is the only cure for HELLP and prophylactic platelet transfusion may be necessary for the severely thrombocytopenic patient. However, delivery will not ameliorate the condition of a woman with TTP and platelet transfusion is contraindicated. In the absence of timely and aggressive plasma exchange therapy, the pregnant patient with TTP will deteriorate and may die. The laboratory may help in the differential diagnosis of these conditions. A high LDH to AST ratio (>22.12) has been reported to suggest that TTP may be a more likely diagnosis than HELLP in a woman presenting in the third trimester with findings that could be compatible with either diagnosis [73]. If a TMA cannot be fully explained by a non-TTP pregnancy-related TMA, then the diagnosis of TTP must be considered and plasma exchange (PEX) should be started (2B) [71].

Thromboelastography is a technique currently underutilised in obstetrics and, while it may be of limited diagnostic value in mild pre-eclampsia, it can demonstrate hemostatic defects in severe pre-eclampsia and HELLP, and could fulfil a role in the rapid assessment and subsequent treatment of coagulopathy, platelet dysfunction and hyperfibrinolysis seen in these conditions [74].

As mentioned above, during pre-eclampsia PAI-1 is markedly increased, over and above the level seen in normal pregnancy, but PAI-2 levels are lower than in normal pregnancy, most probably due to placental insufficiency. It has been suggested that the PAI-1/PAI-2 ratio may have prognostic value in determining pregnancy outcome when used in conjunction with uterine artery Doppler ultrasound [75]. TFPI activity measured during the 20th week of pregnancy has also been suggested as a predictor of pre-eclampsia later in pregnancy [76], as have soluble thrombomodulin and soluble endothelial protein C receptor [77]. While these reports are of interest, large prospective studies are necessary to ascertain whether these tests have any clinical utility.

There has been a great deal of speculation about the usefulness of thrombophilia testing to predict the likelihood of pre-eclampsia. To date, studies of thrombophilia and risk for pre-eclampsia in future pregnancy have not identified any strong risk factors. Antiphospholipid antibodies, hyprehomocysteinemia, the factor V Leiden and G20210A prothrombin gene mutations, and homozygosity of the methyltetrahydrofolate reductate (MTHFR) C667T polymorphism have all been linked with an increased incidence of pre-eclampsia. However, most studies have been underpowered and there is a paucity of data from prospective studies. It has been reported that only 13 % of cases of placental infarction are associated with a positive maternal thrombophilia test, suggesting that thrombophilia is not the major cause of infarction [78]. The Guideline Development Group of the National Collaborating Centre for Women’s and Children’s Health in the UK considers that the evidence on the association between thrombophilias and hypertensive disorders remains unclear and is of variable quality. Even with an association, the value of routine screening for these disorders would be unclear as there is no good evidence that treatment (thromboprophylaxis or increased folate intake) improves outcomes related to hypertensive disorders in the next pregnancy or prevents disease occurrence. Their recommendation is to not routinely perform screening for thrombophilia in women who have had pre-eclampsia [39]. The British Committee for Standards in Haematology state that therapeutic decisions should be based on clinical circumstances and not on the results of thrombophilia testing [79]. It is clear that further studies are required in this field.