- 1. What Is Thrombocytopenia?
- 2. Classification Of Thrombocytopenia in Pregnancy
- 3. Miscellaneous Causes Of Thrombocytopenia
Thrombocytopenia, also known as low blood platelet count, is the second most common hematological disorders in pregnancy after anemia. It affects nearly 7-10% of all pregnancies (1).
Platelets are non-nucleated cells, derived from megakaryocytes of the bone marrow. They are usually found in the peripheral circulation for about ten days and play a significant role in the hemostatic system as they stop bleeding.
It is common for the platelets to undergo many physiological changes in pregnancy, but severe pathological changes can cause thrombocytopenia. It, therefore, has a negative impact on both the mother and her baby. MomJunction tells you about the causes, diagnosis, and ways to manage the condition.
What Is Thrombocytopenia?
According to the book Principles of Critical Care in Obstetrics, a normal platelet count ranges from 150,000 to 400,000 platelets per microliter (µl) of blood. A drop in platelet count below 150,000 platelets per µl or platelet count below the 2.5th percentile for pregnant patients (116,000 platelets/ µl) is known as thrombocytopenia.
Women are usually diagnosed with platelet conditions in their pregnancy as they are required to undergo a screening process as part of the clinical evaluation of blood cells. The physiologic reduction in the platelets is multifactorial and is mainly related to:
- Hemodilution (decreased concentration of blood)
- Increased platelet consumption
- Increased platelet aggregation caused by high levels of thromboxane a2.
Platelet count is also lower in women carrying twins compared to those with singleton pregnancies. It may be because of increase in the thrombin generation.
The classification of thrombocytopenia in pregnancy is uncertain and not relevant clinically.
- Mild thrombocytopenia – 100,000 to 150,000 platelets/µl
- Moderate thrombocytopenia – 50,000 to 100,000 platelets/µl
- Severe thrombocytopenia – below 50,000 platelets/µl
About 7.6% of pregnant women have mild thrombocytopenia in pregnancy, and 65% of these will not show any pathological cause.
Etiologic Classification Of Thrombocytopenia in Pregnancy:
The condition can be divided into three broad categories – increased platelet destruction, decreased platelet production, and platelet sequestration (loss within the body). Loss of platelets is more common in the obstetric practice.
Increased destruction of the platelets involves Gestational thrombocytopenia, and immunologic-related thrombocytopenia can be caused by the following:
- Immune thrombocytopenic purpura (ITP)
- Systemic lupus erythematosus (SLE)
- Antiphospholipid syndrome
- Connective tissue disorders
- Viral infections, for instance, Epstein-Barr virus
Non-immunologic-related can be caused by the following:
- Thrombotic thrombocytopenic purpura
- HELLP syndrome
- Acute fatty liver during pregnancy
- Hemolytic uremic syndrome
- Vascular malformation
- Heparin-induced thrombocytopenia
Decreased production of the platelets involves Vitamin B-12 and folate deficiency, and bone marrow suppression, which are caused by the following:
- Paroxysmal nocturnal hemoglobinuria
- Bone marrow infiltration (can be hematologic or non-hematologic malignancy)
Platelet sequestration can be caused by the following:
- Liver disease
- Portal hypertension
- Myeloproliferative disorders
- Portal or hepatic vein thrombosis
- Storage disorders (like Gaucher disease)Lymphoproliferative disorders
- Infections like malaria
Among the above, the most common causes of thrombocytopenia during pregnancy are:
- Gestational thrombocytopenia (70% of all thrombocytopenia cases of pregnancy)
- Preeclampsia (21%)
- Immune thrombocytopenia purpura (3%)
- Others (8%)
1. Gestational Thrombocytopenia (GT):
This is also known as Incidental Thrombocytopenia and develops in 8% of all pregnancies. It accounts for approximately 75% of all thrombocytopenia cases in pregnancy (2).
Although the pathophysiology of gestational thrombocytopenia is not known, it is known to be associated with two factors –
- Increased platelet activation, which is suspected to occur at placental circulation.
- Increased peripheral consumption of platelets because of their reduced lifespan in pregnancy.
The characteristics of gestational thrombocytopenia are –
- Patients are asymptomatic with no history of bleeding.
- The degree of the condition is mild to moderate, with a platelet count greater than 70,000 per µl.
- It is usually detected on routine prenatal screening.
- Mostly develops in the third trimester.
- No specific diagnosis to differentiate between gestational thrombocytopenia and mild Idiopathic thrombocytopenia purpura (ITP).
The preconception platelet count is important to distinguish the condition from ITP, which is highly confusing. However, women having ITP have a history of abnormal bleeding and low platelet count in the prepregnancy stage.
- No preconception history of thrombocytopenia or abnormal bleeding.
- The preconception or early gestation platelet count is within normal range.
- The platelet count returns to normal within 2 – 12 weeks post pregnancy.
Gestational thrombocytopenia poses no risks either to the mother, fetus, or neonate ( a newborn child). Neither bleeding complications nor fetal hemorrhage is observed.
In a study made by Burrows and Kelton (1993), 756 out of 1027 women (73.6%) diagnosed with gestational thrombocytopenia gave birth to only one infant who was diagnosed with congenital bone marrow dysfunction and a platelet count below 50,000/µl. Therefore, the study concluded that though GT is a frequent type of thrombocytopenia, it poses no risks to both the mother or infant at the time of labor.
Nagey et al studied 730 pregnancies with platelet count below 150,000/µl. The findings showed that no neonate had a platelet count below 100,000/µl, and bleeding complications.
These studies conclude that mild to moderately depressed platelet range from GT is not associated with any risks to the fetus, mother, or neonate. Therefore, it requires no medication besides periodic monitoring.
Note that these are general guidelines only. You should discuss everything with your healthcare provider before taking any decisions about your health.
GT can recur. However, there are no statistics that show its recurrence. If you have had GT a very long time ago, your doctor may certainly check for it once again. If you are diagnosed with ITP, then you are at low risk of developing gestational thrombocytopenia. In most cases, women with ITP tend to notice an improvement in their platelet count after conception.
Antepartum (prenatal period):
Periodic monitoring of platelet count is recommended, with no specific treatment required. Invasive approach to fetal blood sampling is not recommended unless the platelet count falls suddenly.
Labor and Delivery:
Maternal/obstetric indications should determine the decision for delivery. Epidural anesthesia is safe when the platelet range is above 50,000/µl. However, every birth center has different recommendations.
Regional Anesthesia Considerations:
The presence of coagulopathy contradicts the use of regional anesthesia as it can lead to an epidural hematoma (epidural hemorrhage), which can, therefore, result in severe neurological conditions. Two cases of epidural hematoma were reported after receiving epidurals in labor (one patient with GT and the lupus anticoagulant, and the other patient with ependymoma). Historically, anesthesia consultants recommend to not administer epidural anesthesia if the platelet range is below 100,000/µl.
In a study of 105 pregnant women with platelet count less than 150,000/µl, 51 women had less than 100,000/µl. They underwent regional analgesia (epidural or spinal) without being recognized thrombocytopenia at the time of labor. However, no complications of anesthesia were reported. But still, doctors do not advise epidurals for platelet range below 100,000/µl because of the small sample size study.
2. Immune Thrombocytopenic Purpura (ITP):
It is also known as Idiopathic Thrombocytopenic Purpura or Autoimmune Thrombocytopenic Purpura (ATP) (3).
It develops among one 1000-10,000 pregnancies and accounts for approximately 3% of all thrombocytopenia cases in pregnancy. It is the most common factor of thrombocytopenia in first and second trimesters.
ITP is an autoimmune disorder caused by the development of Immunoglobulin G antiplatelet antibodies, which are directed against membrane glycoproteins. These bound antibody platelets are cleared from the maternal circulation once they bind to the receptors on macrophages (white blood cells that digest foreign particles and debris), found in the spleen and also in the liver.
Diagnosis and Clinical Manifestations:
The diagnostic approach for ITP is the same as in non-pregnant women.
- Women are asymptomatic or present with a history of easy bruising, mucosal bleeding, petechiae (purple spot on the skin caused by minor bleeding) and gingival bleeding. No other test differentiates ITP from other thrombocytopenia causes.
- As primary ITP is a diagnosis of exclusion, the causes of secondary thrombocytopenia like hepatitis C, HIV, and autoimmune disorders are to be clinically ruled out.
- Patients having ITP show a prior history of ITP or other immune-mediated diseases.
- Preconception thrombocytopenia, persistence post delivery, and response to ITP directed therapy are diagnostic characteristics.
Since both GT and ITP are diagnoses of exclusion, they need close follow-up during and post delivery. There have to be no hematologic conditions, microangiopathy (small vessel disease) or a history of disseminated intravascular coagulopathy (DIC) and liver failure.
Severe cases of thrombocytopenia can lead to serious illness or even death of both the mother and fetus.
- Mother is at a high risk of developing spontaneous hemorrhage if the platelet count drops below 20,000/µl).
- The maternal IgG can cross the placenta and could cause fetal thrombocytopenia (below 50,000/µl). It could, therefore, lead to bleeding complications in the newborn child.
- Minor bleeding complications in the neonatal period include purpura (purple-colored spots on skin), melena (dark tarry stools) and ecchymosis (escape of blood from ruptured blood vessels).
- Major bleeding complications include intracranial hemorrhage, which can lead to neurological disorders or even death.
Almost 90% of infants will not show any significant thrombocytopenia born to women with ITP. Only 10% can develop low platelet count below 50,000/µl, and 4% can have platelet count below 20,000/µl. Even if the condition is severe, bleeding problems are very rare and can be treated easily.
Platelet count should be monitored in the neonate (newborn) for several days as platelets continuously drop after delivery between one and two days. You should notify your health care provider or pediatrician about your hematological conditions so that they would take necessary steps for taking care of the baby.
The clinical management requires close consultation of the obstetrician and the hematologist. The treatment is based on the symptoms of the patient and the level of thrombocytopenia. The main aim of the treatment is to stop the bleeding.
- Treatment is not required for those with platelet count more than 20,000 – 30,000/µl.
- Close monitoring is required for those with no symptoms and platelet count more than 20,000/µl.
- Treatment is necessary for those with platelet count below 10,000/µl at any time of pregnancy, or if platelet count is below 30,000/µl in the third trimester.
The frequency of monitoring the platelet counts should be increased as the trimester approaches or the condition worsens.
The first line of therapy are Glucocorticoids like prednisone. They primarily block the antibody production and reduce the phagocytosis of antibody bound platelets by macrophages in the spleen. However, the results show up only after several days to weeks, and the procedure is likely to cause unique toxicities like gestational diabetes, pregnancy-induced hypertension, premature rupture of fetal membranes, and placental abruption.
Intravenous immunoglobulin (IVIg) is another option for first line therapy, but can only be used in steroid-resistant patients. It works by blocking the splenic macrophages and is effective in improving the platelets rapidly. However, these effects just last for one to four weeks.
These treatments may be followed by platelet transfusion that markedly increase the platelet count.
Intravenous anti-D treatment is considered for non-splenectomized Rh positive patients resistant to IVIg and other steroids.
Here’s a list of drugs which can be avoided:
- Rituximab, classified under class C drug of pregnancy, is usually used for treating non-pregnant women. However, it should not be used during pregnancy unless there are no other options.
- Cytotoxic and immunosuppressive agents are also avoided during pregnancy due to their teratogenic effects.
- Thrombopoietin receptor agonists like eltrombopag and romiplostim, which are usually used for chronic ITP treatment in adults, should be avoided during pregnancy.
Regional Anesthesia Considerations:
Regional anesthesia during delivery can cause some complications in the peripartum period, which is why vaginal delivery is the most preferred method. C-section can only be considered for obstetric indications alone.
3. Preeclampsia/Eclampsia and HELLP Syndrome:
Preeclampsia accounts for 21% of all thrombocytopenia cases in pregnancy. The very low count (below 20,000/µl.) is considered as a sign of worsening condition.
The vascular damage of endothelium increases the platelet activation.
A highly severe form of preeclampsia develops when the vascular endothelial damage causes microangiopathic hemolytic anemia, causing a spike in liver enzymes along with low platelet count. It, therefore, causes a syndrome called HELLP (hemolysis, elevated liver enzymes, low platelets). It is a variant of severe preeclampsia and was first described by Dr. Louis Weinstein in 1982.
Incidence of HELLP Syndrome:
HELLP syndrome accounts for 21% of all thrombocytopenia cases in pregnancy and develops in 10% of women with preeclampsia. This syndrome affects 0.5 – 0.9% of all pregnancies (4).
Diagnosis and Classification of HELLP Syndrome:
Hemolysis (destruction of RBC) is associated with the following characteristics –
- Abnormal results on peripheral blood smear, usually schistocytes (fragmented RBC) are observed
- Total bilirubin count will be greater than 1.2mg/dL.
- Lactic dehydrogenase (LDH) will be higher than 600U/L.
Elevated liver enzymes are associated with –
- Aspartase aminotransferase (AST) greater than 70U/L
- LDH greater than 600U/L
A platelet count below 100,000/µl is also noted.
Almost 50% women have complete HELLP syndrome, where all components are present, and other 50% show incomplete HELLP, like EL, ELLP, HEL, LP.
HELLP syndrome is also classified based on the severity of thrombocytopenia –
- Class 1 – Above 50,000 platelets/µl
- Class 2 – 50,000 to 100,000 platelets/µl
- Class 3 – 100,000 to 150,000 platelets/µl
HELLP syndrome represents advanced preeclampsia, but almost 15-20% with HELLP will not show any antecedent hypertension and proteinuria. It develops around the third trimester in between 28 to 36 weeks of pregnancy, and a small percentage can occur before 27 weeks.
- Clinical manifestations include abdominal pain, soreness in the upper right quadrant, and epigastrium, that are associated with vomiting, nausea, and malaise.
- Proteinuria and hypertension occur in 85% of the cases. Generalized swelling precedes HEELP in more than 50% of the cases.
- No bleeding complications are present.
- Thrombocytopenia is severe in HELLP than in preeclampsia patients.
The perinatal (period starts from 20th to 28th week of gestation and ends one to four weeks after birth) mortality rate is 11%. Perinatal deaths may be due to placental abruption, extreme prematurity, and asphyxia (deficient supply of oxygen from the body).
Restriction in fetal growth may occur before the clinical manifestations of HELLP.
Neonates are at high risk of developing thrombocytopenia.
In a study by Burrows (1993), out of 216 women with preeclampsia and HELLP, four of them gave birth to infants who experienced severe thrombocytopenia. Another study of 1198 women with preeclampsia but no thrombocytopenia had one infant with severe thrombocytopenia. And five infants born preterm with severe thrombocytopenia, all were delivered by C-section. Two of them had intracranial hemorrhages, although born cesarean.
Fetal delivery is the key to management of HELLP syndrome.
If delivery is after 34 weeks of gestation, there are risks of maternal multiorgan failure and fetal distress. Women may need platelet transfusion if there is bleeding.
HELLP syndrome will also occur after pregnancy in 30% of women within 48 hours of delivery, and could last for a week post delivery. Unlike preeclampsia, it is more common in women giving birth to multiple babies. Platelet count will rise around fourth or sixth day post delivery.
If severe abnormalities remain after 72 hours of delivery, your doctor may consider plasma exchange and glucocorticoids.
4. Thrombotic Microangiopathies:
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are together referred as thrombotic microangiopathies. They are characterized by low blood platelet count, multiorgan failure, and hemolytic anemia (5).
It is known to occur in one of 25,000 pregnancies. Microangiopathies are usually mistaken for preeclampsia or HELLP syndrome, therefore causing a delay in the diagnosis and treatment. The delay may lead to maternal morbidity and mortality. The incidence of the condition is greater in second and third trimesters.
Though the exact cause is not known, the endothelial damage is suspected to be the initiator.
Abnormal platelet aggravation in the intravascular system leads to microthrombi formation that causes thrombocytopenia. There occurs intravascular hemolysis due to the breakage of RBCs through partially occluded vessels causing organ ischemia (inadequate blood supply).
TTP affects the central nervous system, and HUS affects kidneys. An overlap of these show the clinical manifestations.
Diagnosis and Clinical Manifestations:
Tissue biopsy is not essential. The findings to make a diagnosis include microangiopathic hemolytic anemia like the presence of schistocytes and thrombocytopenia (below 100,000/µl).
TTP shows severe thrombocytopenia, hemolytic anemia, fever, and neurological abnormalities like a headache, altered consciousness, seizures.
- HUS shows thrombocytopenia, hemolytic anemia, and acute renal failure.
- Neurological involvement occurs in almost 50% cases and renal involvement in 80% cases.
- Signs and symptoms of TTP and HUS overlap.
- Fibrinogen levels are within the reference range, and Disseminated intravascular coagulation (DIC) is rare.
- Differentiation between TTP, HUS, and HELLP is difficult when the onset of the condition is in the second or third trimesters. Delivery can resolve preeclampsia, but not TTP and HUS. If the suspected preeclampsia or HELLP doesn’t resolve within 48 to 72 hours of birth, then TTP or HUS should be considered.
- The maternal mortality rate is 15%, and recurrences are almost 50% common.
The perinatal mortality rate is 30%. They may occur due to preterm birth, intrauterine fetal death, and growth restriction.
- Plasmapheresis (plasma exchange) is the first line of treatment. It removes the platelet aggravating substances that cause TTP and HUS. In the case of TTP, treatment is 90% successful, but it is less with HUS.
- Steroids are also used along with plasmapheresis, but are less effective and can increase the risk of complications in women.
- Platelet transfusions are to be avoided as they are risky. They can only be used when there is uncontrolled bleeding or intracranial hemorrhage.
- Other treatment procedures include immunosuppressive agents, hemodialysis for HUS, and splenectomy for TTP.
- Unlike preeclampsia and HELLP syndrome, premature termination of pregnancy is not associated with relapse.
5. Acute Fatty Liver Of Pregnancy:
AFLP is a rare disorder and occurs in one of 10,000-15,000 pregnancies. The maternal mortality rate is 18%, and the fetal mortality rate is 23%. Women are usually nulliparous (who has never given birth), and there is a high incidence of twin births.
It is known to occur because of abnormalities in the intramitochondrial fatty acid beta-oxidation. The mother’s heterozygosity for the long chain 3-hydroxyacyl-CoA dehydrogenase deficiency causes a reduction in the oxidation of fatty acids. This condition, when combined with the dietary factors, aggravates the AFLP.
When a heterozygous pregnant mother carries a fetus which in homozygous, the fetal hepatotoxic fatty acids accumulate. These acids return to the mother’s circulation, leading to liver and vascular damage (6).
Diagnosis and Clinical Manifestations:
- Women in their third trimester suffer from nausea, vomiting, pain in the upper right quadrant, malaise, and cholestatic liver dysfunction (impairment of bile flow).
- Lab findings detect low to normal platelet count, normocytic normochromic anemia, elevated leucocytes, extended prothrombin time, low antithrombin III, and fibrinogen levels with raised transaminases.
- AFLP is associated with liver and renal dysfunction, and concomitant coagulopathy (excessive bleeding).
- 50% of AFLP patients have the feature of preeclampsia and some with features of HELLP.
- Disseminated intravascular coagulation (DIC) occurs with AFLP. Among them, 7% with preeclampsia and 20-40% with HELLP have DIC.
Treatment includes intensive supportive care with blood transfusion for coagulopathy. Your doctor may also recommend immediate termination of pregnancy.
Miscellaneous Causes Of Thrombocytopenia:
There are some less common causes of thrombocytopenia. They are:
It accounts for 1% out of all thrombocytopenia cases in pregnancy. In all thrombocytopenia cases, a peripheral smear is examined to determine ethylenediaminetetraacetic acid (EDTA)-dependent platelet clumping, which usually causes this condition. The platelet count is checked in citrate tubes, and if the platelets fall within the reference range, it is more accurately diagnosed as Pseudothrombocytopenia (7).
7. Disseminated Intravascular Coagulation (DIC):
It is mainly associated with bleeding and occurs due to various reasons during pregnancy. The most common causes are the placental abruption, uterine rupture, and amniotic fluid embolism. There is an immense activation of the coagulation system because of the quick release of tissue factor-rich material into the mother’s circulation, which leads to the consumption of coagulation factors and hypofibrinogenemia (partial deficiency of fibrinogen).
It is associated with prolonged Prothrombin Time (PT) & Partial Thromboplastin Time (PTT), low fibrinogen, high fibrin split products, and presence of D-dimers (8).
8. Nutritional Deficiencies:
Severe deficiency of vitamin B12 and folic acid will cause low platelet count, associated with low red and white blood cell counts. However, it is rare in pregnancy as women take folic acid supplements to prevent neural tube deformities. Vitamins B12 deficiency is also uncommon in pregnancy due to the subfertile nature of those having a B12 deficiency.
9. Heparin Induced Thrombocytopenia (HIT):
This is a very rare cause in pregnancy, and there has been only one reported case out of three studies made so far. Therefore routine monitoring is not essential for those receiving prophylactic low molecular weight heparin.
HIT is prothrombotic and thus alternative anticoagulation is required to prevent further coagulation. Treatment involves the withdrawal of low molecular weight heparin, which is replaced with alternative anticoagulants like thrombin inhibitors and fondaparinux (anticoagulant medication). A few case reports show that fondaparinux is used in pregnancy, and it is a class B pregnancy drug which is used with caution (9).
10. Type 2B von Willebrand Disease:
It is a rare subtype of vWD, accompanied by increased affinity for platelet receptor glycoprotein 1b. It binds to the platelets thus, inducing spontaneous platelet aggregation and accelerating platelet clearance, therefore leading to thrombocytopenia.
The abnormal vWF (Von Willebrand factor) increases and the low platelet count during pregnancy becomes more pronounced and evident, by falling as low as 20,000 – 30,000/µl.
During the treatment, a hematology consultation is essential. Platelet transfusion is necessary if they fall below 20,000/µl. Epidural anesthesia, prolonged second stage delivery should be avoided. Normal vaginal delivery should be the aim to prevent the risk of trauma to the mother and baby (10).
11. Marrow Infiltrative Disorders:
They are very rare in women of childbearing age. If it is suspected in the diagnosis, bone marrow biopsy is indicated. The managements depends on the right diagnosis, pregnancy stage, and risks by delaying treatment.
12. Autoimmune Diseases:
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are characterized by pregnancy complications, vascular thrombosis, and secondary immune thrombocytopenia. The incidence of this condition is 0.8% of all thrombocytopenic pregnancies. It is less severe than ITP, but treatment is similar to ITP.
13. Other Inherited Thrombocytopenias:
Congenital conditions like Bernard-Soulier syndrome, Glanzmann’s thrombasthenia, and May-Hegglin anomaly are very rare but are identified during pregnancy because of platelet aggregation and identification of abnormal platelet morphology when observing the peripheral blood smear.
Thrombocytopenia during pregnancy is a great challenge to you and your physician. The myriad of causes, either preconception medical conditions or pregnancy induced disorders, make it difficult to diagnose the right reason. Only a thorough history, physical examination, appropriate consultation, and laboratory evaluation can rule out the major causes. It is also very important to remember that majority of pregnancies show benign condition, and only a minority show severe conditions with risks of high morbidity and mortality. Management of thrombocytopenia requires a close association of obstetrician and hematologist.
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