Thrombocytopenia in Pregnancy

Thrombocytopenia, or a low blood platelet count, is encountered in 7-12% of all pregnancies. ^[1] Women are more commonly diagnosed with platelet disorders during pregnancy, because screening is done as part of the initial clinical evaluation with automated blood counts. Thrombocytopenia can result from a wide range of conditions, with several of them related to pregnancy. ^[2]

Platelets are nonnucleated cells derived from megakaryocytes in the bone marrow and normally live in the peripheral circulation for as long as 10 days. Platelets play a critical initiating role in the hemostatic system.

Primary hemostasis begins when platelets adhere to the site of endothelial disruption, leading to platelet clumping. This is followed by platelet activation, which is characterized by release of granules containing von Willebrand factor, adenosine 5'-diphosphate (ADP), and serotonin. This serves to recruit other platelets into the growing platelet plug, which acts to stop the bleeding. Simultaneously, the synthesis of thromboxane A₂ and release of serotonin leads to vasoconstriction to reduce blood loss at the site of vascular injury.

The secondary hemostatic phase begins when the coagulation pathway is activated on the surface of the activated platelets to form a fibrin meshwork, which serves to reinforce the platelet plug.

Definition

The normal range of platelets in nonpregnant women is 150,000-400,000/μL

Average platelet count in pregnancy is decreased (213,000/μL vs 250,000/μL), and declines as pregnancy progresses.

Change in platelet count is due to hemodilution, increased platelet consumption, and increased platelet aggregation driven by increased levels of thromboxane A₂.

Thrombocytopenia can be defined as platelet count less than 150,000/μL or platelet count below the 2.5th percentile for pregnant patients (116,000/μL).

Classification

Classification of thrombocytopenia in pregnancy is arbitrary and not necessarily clinically relevant.

Mild thrombocytopenia is 100,000-150,000/μL. Moderate thrombocytopenia is 50,000-100,000/μL. Severe thrombocytopenia is < 50,000/μL.

In normal pregnancies, 7.6% of women present with mild thrombocytopenia during pregnancy, and 65% of them will not be associated with any pathology.

Any pregnant patient with a platelet count of less than 100,000/μL should undergo further clinical and laboratory assessment.

Manifestations

Clinical assessment is the most important factor for the evaluation of a pregnant patient with thrombocytopenia.

Medical history may include the following:

• Current or previous bleeding problems

• Family history of bleeding

• Alcohol or substance abuse history

• Past obstetrical history

• Transfusion history

Examination findings suggestive of thrombocytopenia include the following:

• Petechiae, ecchymoses, and nose and gum bleeding

• Rare - Hematuria, gastrointestinal bleeding, intracranial bleeding

Bleeding associated with surgery is uncommon unless the platelet counts are lower than 50,000/μL.

Clinically significant spontaneous bleeding is rare unless counts fall below 10,000/μL.

A retrospective study by Shin et al indicated that in pregnant women with aplastic anemia, obstetric and disease complications are more prevalent in those with severe thrombocytopenia than in those with nonsevere thrombocytopenia. The study, which included 61 patients with aplastic anemia, found that in women with severe thrombocytopenia, the incidence of transfusion during pregnancy or the postpartum period (72.7% and 45%, respectively) was greater than in those with nonsevere thrombocytopenia (15.4% and 2.7%, respectively). It was also found that 25% of women with severe thrombocytopenia underwent bone marrow transplant after delivery, compared with 0% of those in the nonsevere thrombocytopenia group. ^[3]

Moreover, the odds ratios for composite disease complications and composite obstetric complications were higher in the women with severe thrombocytopenia than in the nonsevere thrombocytopenia patients. In addition, among patients in the severe thrombocytopenia group, gestational age at the platelet count’s nadir and at delivery was lower than in the women with nonsevere thrombocytopenia. ^[3]

The etiologic classification for thrombocytopenia can be divided into 3 broad categories: (1) increased destruction, (2) decreased production, and (3) sequestration.

Platelet destruction is more common in the obstetric practice.

Classification of thrombocytopenia in pregnancy

Increased platelet destruction involves gestational thrombocytopenia and immunologic-related thrombocytopenia, including the following:

• Immune thrombocytopenic purpura (ITP)

• Systemic lupus erythematosus (SLE)

• Antiphospholipid syndrome

• Connective tissue disorders

• Drug-induced

• HIV-related

• Viral infections (eg, Epstein-Barr virus)

• Lymphoma

Nonimmunologic-related thrombocytopenia may include the following:

• Preeclampsia/eclampsia

• HELLP syndrome (hemolysis, elevated liver enzyme levels, and low platelet levels)

• Thrombotic thrombocytopenic purpura

• Hemolytic uremic syndrome

• Acute fatty liver of pregnancy

• Heparin-induced thrombocytopenia

• Vascular malformations

• Hypersplenism

Decreased platelet production may also be noted, and includes vitamin B-12 and folate deficiency, as well as bone marrow suppression that can be caused by the following:

• Drug-induced

• Aplastic anemia

• Paroxysmal nocturnal hemoglobinuria

• Infection

• Bone marrow infiltration (hematologic malignancy, nonhematologic malignancy)

Splenic sequestration may be caused by the following:

• Portal hypertension

• Liver disease

• Portal or hepatic vein thrombosis

• Myeloproliferative disorders

• Lymphoproliferative disorders

• Storage disease (eg, Gaucher disease)

• Infection (eg, malaria)

The most common causes of thrombocytopenia in pregnancy are as follows:

• Gestational thrombocytopenia (70%)

• Preeclampsia (21%)

• Immune thrombocytopenic purpura (3%)

• Other (6%)

Overview

Incidence

The incidence of gestational thrombocytopenia is 5-11% of all pregnancies and accounts for more than 70% of cases of thrombocytopenia in pregnancy. ^[1]

Pathophysiology

The pathophysiology of gestational thrombocytopenia is unknown, but 2 main factors are associated with GT.

1. Accelerated platelet activation is suspected to occur at placental circulation.

2. Accelerated consumption of platelets is due to the reduced lifespan of platelets during pregnancy.

Diagnosis

The following may be noted:

• Asymptomatic patient with no history of abnormal bleeding

• Mild thrombocytopenia (counts >70,000/μ L)

• Usually detected incidentally on routine prenatal screening

• No specific diagnostic tests to definitively distinguish gestational thrombocytopenia from mild ITP

• Usually develops in the mid second to third trimester

Lescale et al evaluated 8 different platelet antibodies in 250 gravidas with thrombocytopenia (160 with presumed GT, 90 with ITP) to determine if any antibodies could distinguish the 2 conditions. Platelet-associated IgG was comparably elevated in most women with GT (69.5%) and ITP (64.6%), P =0.24. A significantly higher proportion of patients with ITP had indirect IgG compared with patients with GT (85.9% vs 60.3%, P< 0.001), but significant overlap existed, limiting its clinical value. Antiplatelet antibody tests, either alone or in combination, cannot be used to distinguish ITP from GT. ^[4]

Clinical manifestations

These include the following:

• No prepregnancy history of low platelets or abnormal bleeding is noted.

• No confirmatory test available to diagnose.

• Platelet counts normalize within 1-2 months following delivery. ^[1]

Fetal/neonatal risks

No pathological significance for the mother or fetus is noted. No risk for fetal hemorrhage or bleeding complications is observed. ^[5]

Samuels et al evaluated 162 pregnant women and their infants with thrombocytopenia, 74 with presumed GT. No infant from a GT gravida had a platelet count < 50,000/μ L or intracranial hemorrhage. ^[6]

In Burrows and Kelton's large study, 756 of 1027 women who were thrombocytopenic (73.6%) had GT. Only 1 infant had a platelet count < 50,000/μL, and this infant had trisomy 21 and congenital bone marrow dysfunction. Burrows and Kelton concluded that GT is the most frequent type of thrombocytopenia and poses no apparent risks for either the mother or infant at delivery. ^[7]

Management considerations

Preconceptional

Gestational thrombocytopenia can recur. Risk of recurrence is unknown.

Antepartum

Monitor platelet count periodically. No treatment is necessary for gestational thrombocytopenia. Invasive approaches to fetal monitoring (fetal blood sampling) are not indicated.

Labor and delivery

Mode of delivery is determined by obstetric/maternal indications. Epidural anesthesia is considered safe when platelet count is >80,000/μL if platelet count is stable. ^[1] Antepartum anesthesia consultation should be obtained to discuss availability of regional analgesia. Document return of maternal platelet count to normal levels after delivery.

Regional anesthesia considerations

The presence of a coagulopathy is cited as a specific contraindication to the use of regional anesthesia due to concern for an epidural hematoma, which can result in serious neurologic complications. Only 2 cases of epidural hematoma have been reported in gravidas receiving epidurals in labor (1 patient had gestational hypertension and the lupus anticoagulant, and the other patient had an ependymoma). All other cases of nonpregnant epidural hematomas occurred in women receiving anticoagulants. Historically, anesthesia recommendations were that epidurals should be withheld if platelet counts were < 100,000/μ L.

Three series have been published of gravidas undergoing regional analgesia (epidural or spinal) with unexplained, or initially unrecognized, thrombocytopenia at the time of the procedure. ^{[8, 9, 10]} The combined total was 105 women with platelet counts < 150,000/μ L; of these, 51 had platelet counts < 100,000/μL. No anesthesia complications were reported in these series. Nevertheless, some authors are still reluctant to advise epidurals for platelet counts < 100,000/μ L due to the small sample sizes in these studies.

Some anesthesiologists recommend a bleeding time prior to placing an epidural in a thrombocytopenic parturient. Bleeding time is influenced by various factors, has large interobserver variation, and cannot predict bleeding or transfusion requirements. This is not useful in assessing platelet function with ITP or GT, and its use should be discouraged.

Preeclampsia occurs in 3-4% of pregnancies and accounts for 5-21% of cases of maternal thrombocytopenia. ^[1] Thrombocytopenia is usually moderate, and platelet count rarely decreases to < 20,000/μL. Thrombocytopenia in patients with preeclampsia always correlates with the severity of the disease. A platelet count of < 100,000/uL is diagnostic for preeclampsia. It is considered a sign of worsening disease and is an indication for delivery.

Pathophysiology

There is increased platelet consumption and vascular endothelial damage increases platelet activation. The initiating factor for the fall in platelets is not known.

Clinical manifestations

The most severe spectrum of preeclampsia is established when the vascular endothelial damage produces microangiopathic hemolytic anemia, elevating liver enzymes along with thrombocytopenia and establishing a syndrome known as HELLP (hemolysis, elevated liver enzymes, low platelets).

HELLP syndrome accounts for 21% of maternal thrombocytopenia in pregnancy.

HELLP syndrome is a variant of severe preeclampsia, first described by Dr. Louis Weinstein in 1982.

Incidence

Hypertensive disorders occur in 7-10% of all pregnancies; HELLP complicates 10% of all women with preeclampsia.

Diagnosis and classification of HELLP syndrome

Hemolysis is associated with the following:

• Abnormal results on peripheral smear (presence of schistocytes, also called helmet cells)

• Total bilirubin ≥ 1.2 mg/dL

• Platelet count < 100,000/uL

• Low serum haptoglobin ≤ 25 mg/dL ^[11]

Elevated liver enzymes (3 standard deviations above the mean) are as follows:

• Aspartase aminotransferase (AST) >70 U/L or >2 times the upper limit of normal for the reference lab being used.

Approximately 50% of patients have complete HELLP (all components present), and 50% have incomplete HELLP (at least 1 component present: EL, HEL, ELLP, LP).

Clinical manifestations

Clinical manifestations often are nonspecific (nausea/vomiting, headache in 50%, epigastric or right upper quadrant pain in 50-67%).

Early HELLP syndrome is often misdiagnosed as heartburn, with many women prescribed antacids prior to the correct recognition of this potentially life-threatening condition. Having a high index of suspicion for HELLP syndrome in the second half of pregnancy is important.

Not all patients with HELLP syndrome meet the strict criteria for preeclampsia. Approximately 15% have diastolic blood pressure (BP) >90 mm Hg; 15% have minimal or no proteinuria. Major complications can still occur despite normal blood pressure and proteinuria.

The maternal mortality rate with HELLP is 1%, resulting from ruptured subcapsular hematomas, hemorrhage, and stroke.

Thrombocytopenia is usually moderate, with counts rarely < 20,000/μL.

Major hemorrhage is uncommon, but incisional site oozing or subcutaneous hematomas may occur.

Maternal thrombocytopenia reaches a nadir at 24-48 hours postpartum.

Fetal/neonatal risks

The perinatal mortality rate is 11%. Perinatal deaths may occur from placental abruption, asphyxia, and extreme prematurity.

Fetal growth restriction is common, sometimes occurring before maternal manifestations of HELLP.

Neonates may be at increased risk for thrombocytopenia.

In Burrows and Kelton's study of women with thrombocytopenia, 216 had preeclampsia and HELLP and 4 gave birth to infants with severe thrombocytopenia. Among 1198 women with preeclampsia but no thrombocytopenia, 1 infant had severe thrombocytopenia. Of the 5 infants with severe thrombocytopenia, all were preterm, 3 were small-for-gestational age, and all were delivered by cesarean delivery. Two infants experienced intracranial hemorrhages, despite being born by cesarean delivery. ^[7]

Treatment

Delivery is the ultimate cure. Delivery may be delayed for 24-48 hours between 23 and 34 weeks' gestation to administer corticosteroids if the patient is stable and the fetus has reassuring testing, but delay beyond 48 hours is not recommended.

Magnesium sulfate (MgSO₄) should be administered intravenously to prevent seizures and for neuroprotection between 24 and 32 weeks.

HELLP syndrome with thrombocytopenia does not by itself require a cesarean delivery, although cesarean delivery may be acceptable prior to 32 weeks' gestation with an unfavorable cervix due to an anticipated long induction time in a clinically deteriorating gravida.

Maintain platelet counts >20,000/μL for vaginal delivery and 40,000 to 50,000/μL for cesarean delivery; however, the minimum count is controversial and the decision should be made based on the overall clinical picture if platelets fall below 50,000/μL prior to cesarean delivery.

If thrombocytopenia is severe, regional anesthesia and pudendal blocks may be contraindicated. In this situation, intravenous narcotics can still be administered for analgesia during labor.

Pfannenstiel incision with primary closure is acceptable for cesarean delivery. Briggs et al compared Pfannenstiel to midline incisions, as well as primary versus delayed (48-72 h) closure in 104 women with HELLP syndrome. No significant differences occurred in wound hematoma/infection by incision type (17.3% vs 17.2%, P = 0.78) or closure type (26% vs 24% [NS]). Placement of a subcutaneous drain did not significantly reduce wound complications (18.1% vs 26.4%, P = 0.64). ^[12]

Thrombocytopenia and elevated liver function tests commonly worsen postpartum. Platelets should start normalizing by the third postpartum day.

Dexamethasone for maternal benefit is not recommended by the American College of Obstetricians and Gynecologists task force. ^[11]  

ITP is also known as immune or idiopathic thrombocytopenic purpura in patients with impaired platelet production.

Incidence

Incidence is 1 per 1000-10,000 pregnancies, and it accounts for 3% of all thrombocytopenic gravidas.

Pathophysiology

Immunoglobulin G (IgG) antiplatelet antibodies recognize membrane glycoproteins and coat the platelets, which then are destroyed by the reticuloendothelial system, predominantly in the spleen.

Antiplatelet antibodies may cross the placenta and cause significant fetal thrombocytopenia (< 50,000/μL), which could result in bleeding complications in the neonate.

Minor bleeding complications include purpura, ecchymoses, and melena.

Major bleeding complications include intracranial hemorrhage leading to neurologic impairment or death.

Diagnosis

ITP is a diagnosis of exclusion as there are no diagnostic tests or signs and symptoms. The following may be noted:

• Persistent thrombocytopenia (< 100,000/μL), increased number of megakaryocytes in the bone marrow, exclusion of systemic disorders or medications/drugs, absence of splenomegaly

• Approximately 80% of cases are associated with antiplatelet antibodies, although these are not required for the diagnosis.

• Classified by duration: newly diagnosed, persistent (3 to 12 months duration), and chronic (12 months or more).

Clinical manifestations

The following may be noted:

• Easy bruising, petechiae, epistaxis, and gingival bleeding, although some women are asymptomatic

• Significant hemorrhage is rare, even when counts fall to less than 20,000/μL.

History

In 1977, a case of neonatal intracranial hemorrhage was reported (due to perceived birth trauma) after vaginal delivery of a thrombocytopenic infant to a mother with ITP. This led to the recommendation that women with ITP be delivered by elective cesarean delivery. By the late 1980s, cesarean deliveries were restricted for fetuses with known or suspected thrombocytopenia (counts < 50,000/μL).

Unfortunately, fetal platelet counts do not correlate with maternal platelet counts, history of splenectomy, or presence of platelet-associated antibody. The only certain method of determining fetal platelet count is by direct fetal blood sampling. By assessing platelet counts in utero, most cesarean deliveries could be avoided because most fetuses of ITP mothers (about 90%) have normal platelet counts.

Fetal scalp sampling was the first direct fetal blood sampling technique. It requires ruptured membranes and a cervix dilated at least 3 cm. Falsely low fetal platelet counts are encountered often. Due to procoagulants in amniotic fluid, fetal platelets start to clump immediately after scalp puncture, resulting in falsely low platelet counts. Additionally, the capillary tube into which the fetal blood is drawn is lined with heparin, which can cause platelet clumping and a spuriously low count. Clumping observed on the smear from scalp sampling usually indicates a platelet count of at least 20,000/μL.

Percutaneous umbilical blood sampling (PUBS) is more accurate than scalp sampling, but it is associated with a higher complication rate (2-3%).

Studies of ITP in pregnancy

Cook et al reviewed a 10-year experience (1980-90) with treatment of ITP, which included 25 women and 32 infants. Platelet counts were obtained in 23 of 32 newborns. Of 8 infants with low platelets at birth, 3 were mild, 3 were moderate, and 2 were severe. A total of 6 infants had severe thrombocytopenia at birth or during the neonatal period. Median platelet nadir occurred 4 days following delivery. Eighteen cesarean deliveries were performed, 6 with complications (infection, hematoma, transfusion). ^[13]

The authors reviewed the literature over 20 years, which included 474 women with ITP. Approximately 15% of infants were found to have severe thrombocytopenia (counts < 50,000/μL). The incidence of intracranial hemorrhage among infants with severe thrombocytopenia was 4% after cesarean delivery, compared with 5% after vaginal delivery

Burrows and Kelton reported on a large series of maternal platelet counts collected on all women admitted to labor and delivery over a 6-year period at McMaster University (15,607 samples), as well as cord blood platelet counts at the time of delivery (15,932 samples). Of 46 women with ITP, 4 infants were born with severe thrombocytopenia. Three of these 4 infants were delivered vaginally, and 1 was delivered by cesarean delivery. No infant experienced an intracranial hemorrhage. ^[7]

Payne et al reviewed a 10-year experience with 55 newborns born to 41 women who had ITP. A total of 16 scalp samplings were performed (platelet count range was 0-150,000/μL). Three PUBS were performed. Two were associated with complications—one case of fetal bradycardia and one case of an umbilical cord hematoma with fetal distress resulting in an infant with anoxic encephalopathy and cerebral palsy (and a platelet count of 209,000/μL). ^[14]

Of 24 (44%) cesarean deliveries reported, half were performed solely for ITP. Five of the cesarean deliveries were associated with postpartum hemorrhage, and 3 were associated with blood transfusions. Four (8%) infants had severe thrombocytopenia (counts < 50,000/μL) at birth. Two of the 4 infants were delivered vaginally, 2 were delivered by cesarean delivery, and all had normal results on head ultrasonography. Three additional neonates developed severe thrombocytopenia during the first week of life. One experienced an intracranial hemorrhage on the fourth day of life. Scalp platelet counts did not correlate with neonatal platelet counts.

Their literature review of 18 studies on maternal ITP involved 601 neonates. Severe thrombocytopenia occurred in 72 of 601 neonates (12%). Intracranial hemorrhage occurred in 6 out of 601 neonates (1%) and was unrelated to mode of delivery. PUBS complication rate was 4.6%.

Conclusions from the above studies/reviews, including Silver's 1995 review of 15 studies of ITP in pregnancy are as follows:

• The rate of severe neonatal thrombocytopenia is approximately 12%.

• Intracranial hemorrhage is rare (approximately 1%) and appears to be unrelated to the mode of delivery.

• Vaginal delivery has never been proven to cause intracranial hemorrhage.

• Cesarean delivery should be reserved for obstetrical indications only.

• Scalp sampling is unreliable, and the risks of PUBS appear to outweigh the risk of a vaginal delivery of an infant with thrombocytopenia.

• Neonatal platelet counts normally decrease and typically reach a nadir during the first two weeks of life. ^[1] This result may be due in part to the passage of IgG antiplatelet antibody in the breast milk, although breastfeeding is not contraindicated. Neonatal thrombocytopenia may lead to delayed postnatal intracranial hemorrhage. Notifying pediatrics of any parturient with maternal ITP is important so that neonatal platelet counts can be monitored closely.

Maternal treatment for ITP

Initiate treatment if the patient has symptomatic bleeding, platelet counts fall below 30,000/uL, and/or prior to invasive procedures. ^[1]

Below are recommended treatments for maternal thrombopenia due to ITP. While they all improve maternal platelet counts, none have been shown to adequately prevent or treat fetal/neonatal thrombocytopenia.

With steroids (eg, prednisone), the following is noted:

• Standard initial treatment according to expert opinion. ^[1]

• Response time is 4 to 14 days; maximum effect occurs by 1 to 4 weeks. ^[1]

• Give for 21 days, then taper.

• Approximately 70% of patients will respond, and 25% will enter complete remission.

• Risks include hyperglycemia, fluid retention, and bone calcium loss.

With intravenous immune globulin (IVIG), the following is noted:

• IVIG works by binding to platelets, blocking the attachment of antiplatelet antibodies.

• IVIG is ideal when time is inadequate for steroids to take effect (prior to surgery or low platelet counts with bleeding).

• Response time is 1 to 3 days, peak effect within 2 to 7 days.

• Approximately 70% of patients will return to pretreatment levels within 30 days.

• This treatment is very expensive.

With anti-D immunoglobulin in Rh-positive, nonsplenectomized women, the following is noted:

• Anti-D immunoglobulin binds to maternal red blood cells and results in Fc receptor blockade. The spleen directs its phagocytotic activity to the coated red cells rather than to antibody-coated platelets.

• It is not useful in Rh-negative or splenectomized women.

• Response time of anti-D immunoglobulin is 1-2 days, peak effect in 7–14 days, average duration 30 days.

• Little data are available on the use of anti-D immunoglobulin in pregnant women; risk-benefit ratios need to be considered prior to its usage.

• Although anti-D immunoglobulin appears to be well tolerated and effective in Rh-positive, nonsplenectomized women based on results from a small pilot study, this treatment may potentially cause maternal or fetal hemolysis. ^[15]

With splenectomy, the following is noted:

• Splenectomy removes the organ responsible for the destruction of IgG-coated platelets.

• In nonpregnant women, splenectomy is used for patients who are unresponsive to IVIG.

• Splenectomy usually is avoided during pregnancy for technical reasons, although it remains an option in the first and second trimesters when ITP is severe (counts < 10,000/μL) and the patient does not respond to steroids or IVIG.

• Complete remission occurs in two thirds of cases.

• Splenectomy does not have an impact on circulating antibodies that may still cross the placenta and cause neonatal thrombocytopenia.

• Patients should receive immunizations for meningococcus, pneumococcus, and Haemophilus influenzae.

With platelet transfusion, the following is noted:

• This is a temporary measure, which should be administered for life-threatening hemorrhage and should be available prior to surgery for patients with severe thrombocytopenia.

• Six to 10 units of platelets are usually administered at one time.

• Platelet counts normally rise by 10,000/μL for each unit of platelets transfused, but in ITP the rise is less pronounced due to destruction of donor platelets.

Pseudothrombocytopenia

Pseudothrombocytopenia is a spuriously low platelet count due to laboratory artifact.

Incidence

Incidence is 0.1% of all CBC specimens, and it accounts for 1% of all thrombocytopenic gravidas.

Pathophysiology

A laboratory artifact is most often due to platelet clumping. It is often associated with the anticoagulant (ethylenediaminetetraacetic acid [EDTA]) in purple or lavender top tubes.

Clinical manifestations

No clinical manifestations exist.

Diagnosis

Look for a description of platelet clumping on the peripheral smear.

Recheck platelet count in a citrate tube. If the platelet count falls within the reference range in the citrate tube, pseudothrombocytopenia is diagnosed. If clumping occurs in citrate tube as well, it may indicate type 2B von Willebrand disease, in which abnormal von Willebrand factor spontaneously binds to and aggregates platelets.

Treatment

No treatment of pseudothrombocytopenia exists.

Microangiopathies

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are characterized by thrombocytopenia, hemolytic anemia, and multiorgan failure.

Incidence

Incidence is 1 in 25,000 births. Microangiopathies are often mistaken for preeclampsia/HELLP, often leading to delay in diagnosis and treatment. Delay in diagnosis may result in significant maternal morbidity and mortality.

Pathophysiology

Etiology is unknown, but endothelial damage is suspected as the initiator. Abnormal intravascular platelet aggregation leads to microthrombi formation, which results in thrombocytopenia, intravascular hemolysis from the breakage of red blood cells through partially occluded vessels, and end organ ischemia.

TTP is known for central nervous system involvement, while HUS predominantly affects the kidneys. Significant overlap exists in the clinical manifestations of TTP and HUS.

Diagnosis

Both TTP and HUS are clinical diagnoses. Tissue biopsy is not required.

Obligate findings for either TTP or HUS include hemolytic anemia (hematocrit < 30% with schistocytes on peripheral smear) and thrombocytopenia under 100,000/μ L (50% of patients will have counts < 20,000/μ L). The following are clinical features of TTP and HUS:

• TTP - Severe thrombocytopenia, hemolytic anemia, neurologic abnormalities (headache, altered consciousness, seizures, hemiparesis), fever

• HUS - Thrombocytopenia, hemolytic anemia, acute renal failure (rising blood urea nitrogen [BUN] and creatinine with proteinuria, hematuria, or oliguria/anuria)

Signs and symptoms of TTP and HUS may overlap. Renal involvement occurs in 80% of cases of TTP; neurologic involvement occurs in 50% of cases of HUS

Differentiation between TTP, HUS, and HELLP can be difficult or even impossible, especially when the onset is in the second or third trimester. Delivery leads to resolution with preeclampsia, but the condition may continue or worsen after delivery with TTP/HUS. If suspected preeclampsia/HELLP does not improve within 48-72 hours after delivery, consider TTP/HUS.

Table 1. Clinical and Laboratory Features of TTP, HUS, and HELLP (Open Table in a new window)

Clinical manifestations

Presenting symptoms are often nonspecific (eg, lethargy, nausea, vomiting, headaches, weakness, fever, shortness of breath), although 67% present with bleeding.

Hypertension may be observed in as many as 75% of cases.

Hemolysis and anemia may be absent at presentation in 50% of cases.

Fibrinogen levels are within the reference range, and DIC is rare.

Long-term sequelae, such as hypertension and chronic renal failure, are observed in 44% of patients with TTP or HUS.

The maternal mortality rate is 15%.

Recurrences are common (50%).

Fetal/neonatal risks

The perinatal mortality rate is as high as 30% because of preterm delivery, growth restriction, and intrauterine fetal demise.

Treatment

Plasmapheresis is the first-line therapy. Plasmapheresis removes platelet-aggregating substances causing TTP and HUS. Treatment is 90% successful with TTP but is less successful with HUS.

Steroids have been used, often in conjunction with plasmapheresis. However, steroids are less effective than plasmapheresis (25% response rate).

Platelet transfusions should be avoided when possible because they can cause a clinical deterioration. Use platelet transfusions only for uncontrolled bleeding or intracranial hemorrhage.

Other therapies include immunosuppressive agents (vincristine, azathioprine, cyclosporine), splenectomy for TTP, and hemodialysis for HUS.

Premature termination of pregnancy has been associated with relapse. Delivery should be considered only when no response to other therapies occurs.

Other immunologic conditions

Systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS)

In Burrows' study of thrombocytopenia in pregnancy, 8 mothers had SLE, accounting for 0.8% of all thrombocytopenic gravidas. None of their infants had thrombocytopenia.

Although both SLE and APS can cause fetal/neonatal complications (eg, heart block, second and third trimester fetal demise), thrombocytopenia plays no significant perinatal role.

Hypersplenism

Congestion of the spleen results in sequestration of platelets.

Hypersplenism often is observed in association with cirrhosis of the liver.

The spleen usually is palpable and enlarged.

The thrombocytopenia from hypersplenism usually is not associated with bleeding disorders.

Medications

Well-known agents that cause thrombocytopenia include heparin, zidovudine (ZDV), and sulfonamides.

Almost all medications can result in transient thrombocytopenia.

Viral illnesses

Cytomegalovirus (CMV) and human immunodeficiency virus (HIV) are well-known causes, although almost all viruses can result in thrombocytopenia.

Pathophysiology

Transient bone marrow suppression occurs.

Fetal/neonatal risks

No significant thrombocytopenia occurs.

Treatment

The condition is usually self-limited and requires no treatment.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is usually associated with bleeding.

DIC is observed obstetrically with abruption and postpartum hemorrhage.

DIC is associated with low fibrinogen, elevated fibrin split products, and the presence of D-dimers.

Fetal-neonatal alloimmune thrombocytopenia

Although not a maternal thrombocytopenia, alloimmune thrombocytopenia represents the most common cause for profound fetal/neonatal thrombocytopenia and intracranial hemorrhage in the infant.

Alloimmune thrombocytopenia has no effect on maternal platelet counts.

Incidence

Incidence is 1 per 1,000-3,000 live births. ^[1]

Pathophysiology

Maternal sensitization to antigens on the surface of the fetal platelets results in alloantibodies, which can cross the placenta and bind to fetal platelets, resulting in their destruction.

Involved human platelet antigens (HPA) now uniformly described with numbers that identify a specific antigen group with alleles marked as "a" or "b." There are currently >15 recognized platelet-specific antigens. ^[1] The most common is HPA-1a (formerly known as P1A1 and Zwa).

Unlike Rh disease, alloimmune thrombocytopenia can affect the first pregnancy. Half of all cases occur in the first pregnancy and are not preventable.

Maternal clinical manifestations

No maternal clinical manifestations occur because the platelet count is within the reference range.

Fetal/neonatal risks

Risks include petechiae, ecchymosis, and intracranial hemorrhage (10-20%). Intracranial hemorrhage can occur in utero, resulting in parenchymal damage, porencephalic cysts, and obstructive hydrocephalus. About 52% can be detected by ultrasound before labor starts. ^[1]

In Burrows' study, 19 pregnancies were complicated by alloimmune thrombocytopenia. Nine infants were born with severe thrombocytopenia. Intracranial hemorrhage was observed in 3 fetuses, one with a fetal demise; no new cases occurred in neonates. Alloimmune thrombocytopenia accounted for all the thrombocytopenia-related fetal morbidity and mortality in this large study.

Treatment

Therapies have included maternal IVIG administration, steroids, weekly fetal platelet transfusions of irradiated P|^A1 –negative platelets (often from the mother), with IVIG emerging as the first-line therapy.

PUBS is used to assess the response to medical therapy; however, a significantly higher risk of fetal exsanguination exists with PUBS and fetal thrombocytopenia.

Randomized clinical trials are ongoing to determine the optimal antenatal therapy for this potentially devastating condition.

Prevention

The key to prevention is the recognition of a previously affected infant with alloimmune thrombocytopenia, because recurrence is close to 100% and subsequent pregnancies can be more severely affected than the first.

Gestational thrombocytopenia is the most common cause of thrombocytopenia during pregnancy (70%), but other underlying causes must be considered as well.

A thorough history and physical examination is important to rule out most other causes.

Look at the remainder of CBC and smear to rule out pancytopenia and platelet clumping associated with pseudothrombocytopenia.

If no antecedent history of thrombocytopenia is present and platelet counts are >70,000/μL, the condition is more likely to be GT.

If platelet counts fall to < 50,000/μL or if a preexisting history of thrombocytopenia is present, the condition is more likely to be ITP.

Direct or circulating antiplatelet antibodies has no value in the workup of thrombocytopenia in pregnancy because they usually are nonspecific and will not distinguish GT from ITP.

Cesarean deliveries for ITP or GT should be reserved for obstetrical indications only because vaginal delivery itself has not been demonstrated to be a cause for intracranial hemorrhage.

Invasive procedures to determine fetal platelet counts (scalp sampling, PUBS) are no longer considered necessary for ITP, because an infant who is thrombocytopenic may be delivered vaginally. However, PUBS may still be of value in alloimmune thrombocytopenia to assess the severity of the condition and therapeutic response.

With ITP, obtain cord blood at delivery (if possible) for platelet count and notify the pediatricians to assess neonatal platelet counts due to the risk for continued quantitative platelet decline and postnatal hemorrhage.

For GT, document normalization of maternal platelet counts after delivery.