Thrombocytopenia in Pregnancy – Causes, Symptoms, Treatment

Thrombocytopenia in Pregnancy – Causes, Symptoms, Treatment

Thrombocytopenia in Pregnancy/Thrombocytopenia, defined as a platelet count of under 150 x 10^9/L, is the second most common hematological abnormality in pregnancy. The International working group (IWG) adopted a lower threshold of platelets, 100 x 10^9/L, to define immune thrombocytopenia, which is observed in less than 1% of all pregnancies. Thrombocytopenia in pregnancy occurs either due to obstetric conditions (like gestational thrombocytopenia, pre-eclampsia/eclampsia) or secondary to systemic disorders (like thrombocytopenic thrombotic purpura, immune thrombocytopenia). For the present discussion, the approach to thrombocytopenia has its basis on the trimester in which the thrombocytopenia develops and the etiology of the thrombocytopenia. This division will help in understanding the workup and guiding management. Even though thrombocytopenia is a common abnormality in pregnancy, it seldom leads to life-threatening complications by itself. The management of thrombocytopenia focuses on the underlying cause. Platelet transfusion is usually not required to achieve a particular goal and is only for bleeding patients. Local hospital policies govern the goal of platelet counts and are quite variable between institutions. Nevertheless, a hematologist must be involved in the management of thrombocytopenia in pregnancy, especially if the platelet count drops below 70 x 10^9/L, or if a coexistent bleeding disorder is either encountered or suspected.

Types of Thrombocytopenia

Although the rare causes of thrombocytopenias do not constitute more than 1% of pregnant patients with low platelet counts, they often designate severe conditions that contribute significantly to maternal morbidity and mortality.

  • Gestation thrombocytopenia: Overall, gestational thrombocytopenia is the reason for low platelets in nearly 75% of pregnancies presenting with thrombocytopenia. It is the most common cause of low platelets in the third trimester of pregnancy.The mechanism behind gestation thrombocytopenia remains anecdotal. Dilution from expanded plasma volume, formation of autoantibody against platelets, pooling or consumption of platelets in the placenta, changes in the activity of von Willebrand factor and ADAMTS-13, increased macrophage colony-stimulating factors from the placenta and inadequate response to thrombopoietin are some of the proposed as the mechanisms leading to gestational thrombocytopenia. In theory, gestational thrombocytopenia is thought to be a continuum of the dilutional changes of pregnancy, where the affected women are simply producing platelets at the lower end of the normal spectrum. However, the fact that it recurs with subsequent pregnancies; tends to develop late in the pregnancy (with increasing gravidity of uterus and changes in placental blood flow), and resolves soon after parturition (which excludes autoimmunity); reflects a mechanism in maternal physiology which is still not completely understood.
  • Immune thrombocytopenia (ITP): ITP is the most common cause of low platelets in the first trimester of pregnancy. Overall it affects 1 to 4% of all pregnancies and affects 1 to 2 per 1000 pregnancies each year. Approximately two-thirds of women have ITP diagnosed before the start of pregnancy. ITP is a heterogeneous disease that can either be diagnosed during pregnancy or may flare up during pregnancy. Up to 60% of patients have an antibody-mediated disease, but in up to 40% of patients, the driver for ITP may be malfunctioning T-cells or antigen-presenting cells. ITP can present in association with a systemic autoimmune disease like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma, anti-phospholipid antibody syndrome (APLS), etc. which can present as a combination of autoimmune-mediated and TMA induced thrombocytopenia.
  • Thrombotic microangiopathy (TMA):

    1. Pregnancy specific TMA

      • Pre-eclampsia (PEC): Throughout the world, PEC affects 2% to 8% of all pregnancies and accounts for 20% of patients developing thrombocytopenia in pregnancy. Thrombocytopenia in a patient with PEC occurs primarily in the second and third trimester of pregnancy and occurs in up to 50% of pre-eclamptic women. Rarely, pre-eclampsia can also occur within the first week post-partum.
      • HELLP (Hemolysis, elevated liver enzymes, low platelets): HELLP syndrome affects 0.2 to 0.8% of all pregnancies. However, it is one of the rare causes of thrombocytopenia in pregnancy. It is associated with pre-eclampsia in up to 70 to 80% of patients. Up to 20% of cases of HELLP are identified 24 to 48 hours postpartum, where thrombocytopenia may persist for up to 4 days after delivery.
      • Acute fatty liver of pregnancy (AFLP): It is a rare cause of thrombocytopenia in pregnancy, which is estimated to affect 1 in 5000 to 20,000 pregnancies.
    2. TMA not specific to pregnancy: These are amongst the rarest causes of thrombocytopenia in pregnancy.

      • Thrombotic thrombocytopenic purpura (TTP): TTP is estimated to affect 1 in 200,000 pregnancies, but 10 to 30% of all adult-related TTP is obstetric. Up to 25% of patients with congenital TTP (also known as Upshaw-Schulman syndrome), characterized by the congenital absence of ADAMTS-13 (A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), present for the first time during the first pregnancy or immediately postpartum.
      • Atypical hemolytic-uremic syndrome (HUS): Atypical HUS is seen in up to 1 in 25000 pregnancies and presents with MAHA and renal failure, either at near-term or post-partum.
  • Disseminated Intravascular Coagulation (DIC): DIC occurs in up to 0.35% of all pregnancies. Although DIC can occur in any trimester, it most commonly occurs in the third trimester, either as a direct consequence of an obstetric complication (for eg., PPH, amniotic fluid embolism) or secondary to other pregnancy-related complications (PEC/ HELLP/ AFLP, etc.).
  • Hereditary thrombocytopenia: It is a rare cause of thrombocytopenia in pregnancy that is commonly diagnosed in the first trimester of pregnancy, although it can present during any trimester.
  • Thrombotic microangiopathy (TMA): It is an umbrella of disorders that are united by common clinical and pathological features. The clinical presentation includes microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ injury. On a microscopic level, all TMA’s are defined by vascular damage that manifests as arteriolar and capillary thrombosis, which present with characteristic abnormalities in the endothelium and vessel wall.
    • Pregnancy-related TMA occurs secondary to obstetric complications like PEC, HELLP, and AFLP. The pathogenesis of thrombocytopenia in PEC remains unexplained. The belief is that a hypoxic placenta releases antiangiogenic factors that cause endothelial dysfunction, which leads to the clinical manifestations of PEC.
    • The non-pregnancy-related TMA occurs due to absence/inhibition of ADAMTS-13 (leads to TTP) or due to a mutation in the function or expression of proteins controlling the alternative pathway C3 convertase (leads to atypical HUS).
  • Disseminated Intravascular Coagulation (DIC): DIC denotes an imbalance between activated procoagulant pathways and impairment of the internal anticoagulant pathways and fibrinolytic systems. This imbalance in the coagulation system leads to platelet activation and consumption, along with fibrin deposition. It can occur either with a complication of the process of delivery (post-partum hemorrhage (PPH), uterine atony, vaginal lacerations, abruptio placentae, retained dead fetus) or in association with other complications of pregnancy like HELLP, AFLP or other causes of TMA.
  • Others: Bone marrow failure, antiphospholipid antibody syndrome, PNH, autoimmune conditions, and type II VWD are amongst the rare causes of thrombocytopenia in pregnancy. Less than 1% of patients develop thrombocytopenia secondary to ‘other’ causes listed.

Causes of Thrombocytopenia

Thrombocytopenia in pregnancy happens secondary to many etiologies, differing in their pathophysiology and presentation. A summary of possible etiologies is listed here:

  • Gestational thrombocytopenia
  • Immune thrombocytopenia
  • Thrombotic microangiopathy (TMA): TMA in pregnancy divides into pregnancy-specific TMA and non-pregnancy-specific TMA due to differences in management.

    1. Pregnancy specific TMA

      • Pre-eclampsia (PEC):
      • Hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome
      • Acute fatty liver of pregnancy (AFLP)
    2. TMA not specific to pregnancy

      • Thrombotic thrombocytopenic purpura (TTP)
      • Atypical hemolytic-uremic syndrome (HUS)
  • Disseminated intravascular coagulation (DIC)
  • Hereditary thrombocytopenia (HT): Further classify according to the size of the platelet, genetic defect and inheritance pattern (WAS gene, HOXA 11 gene, MYH9 disorders, etc.)
  • Others:

    • Bone marrow failure syndromes

      • Aplastic anemia
      • Myelodysplastic syndrome (MDS),
      • Myeloproliferative neoplasms (MPN),
      • Leukemia/lymphoma
      • Marrow infiltrative disorders
    • Paroxysmal nocturnal hemoglobinuria (PNH),
    • Drug-induced thrombocytopenia,
    • Type IIB von Willebrand disease (VWD).
    • Heparin-induced thrombocytopenia (HIT)

It is also worthwhile to distribute the etiology of thrombocytopenia according to the trimester and the platelet count.

First Trimester

  • Immune thrombocytopenia (ITP) (most common)
  • Hereditary thrombocytopenia (HT)
  • Others (Please see above for a detailed list)
  • Thrombotic microangiopathy (TMA)

Second Trimester

  • Platelet count greater than 100 x 10/L

    • Gestational thrombocytopenia
    • ITP
    • Pre-eclampsia/ HELLP
    • HT/Others/TMA
  • Platelet count under 100 x 10/L

    • ITP (most common)
    • HT
    • Pre-eclampsia/HELLP
    • Others
    • Gestational thrombocytopenia
    • TMA

Third Trimester

  • Platelet count more than 100 x 10/L

    • Gestational Thrombocytopenia (most common)
    • Pre-eclampsia/ HELLP (second most common)
    • Others/TMA/ITP/HT
  • Platelet count less than 50 x 10/L

    • Pre-eclampsia/ HELLP (most common)
    • ITP
    • Others
    • TMA
    • Gestational thrombocytopenia/HT

Symptoms Of Thrombocytopenia

  • Limb anomalies can affect both upper and lower limbs, although upper limb involvement tends to be more severe than lower limb involvement. Individuals with thrombocytopenia absent radius (TAR) syndrome almost always have a bilateral absence of the radius. The thumbs are always present. The thumbs in individuals with TAR syndrome are of near-normal size but are somewhat wider and flatter than usual. They are also held in flexion against the palm and tend to have limited function, particularly in terms of grasp and pinch activities []. The upper limbs may also have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth finger clinodactyly is common. Lower limbs are affected in almost half of those with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is tetraphocomelia.
  • Thrombocytopenia may be congenital or may develop within the first few weeks to months of life. In one review, it was noted that thrombocytopenia developed during the first week of life in only 59% []. In general, thrombocytopenic episodes decrease with age, with most children with TAR syndrome having normal platelet counts by school age. However, cow’s milk allergy is common and can be associated with the exacerbation of thrombocytopenia.
  • Bleeding, most often from the gums or nose. Women with thrombocytopenia may have heavier or longer periods or breakthrough bleeding. You may also see blood in your pee or poop.
  • Red, flat spots on your skin, about the size of a pinhead. You see these mostly on your legs and feet, and they may appear in clumps. Your doctor may call them petechiae.
  • Blotches and bruises. You might have large areas of bleeding under the skin that don’t turn white when you press on them. You also might see what look like the bruises you get from a bump or being hit. They could be blue or purple and change to yellow or green over time. These are caused from the inside, by the sudden leaking from tiny blood vessels. The medical name for these is purpura.
  • Cardiac anomalies affect 15%-22% [] and usually include septal defects rather than complex cardiac malformations.
  • Gastrointestinal involvement includes cow’s milk allergy and gastroenteritis. Both tend to improve with age.
  • Genitourinary anomalies include renal anomalies (both structural and functional) and rarely, Mayer-Rokitansky-Kuster-Hauser syndrome (agenesis of uterus, cervix, and upper part of the vagina) [].
  • Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm3. These leukemoid reactions are generally transient [].
  • Cognitive development is usually normal in individuals with TAR syndrome.
  • Growth. Most have height on or below the 50th centile.
  • Other skeletal manifestations, including rib and cervical vertebral anomalies (e.g., cervical rib, fused cervical vertebrae), tend to be relatively rare.
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Symptoms: Clues To Thrombocytopenia Causes

  • Abdominal Pain
    • HELLP Syndrome (pregnancy)
    • Hemolytic Uremic Syndrome (HUS)
    • Platelet Sequestration (Splenomegaly)
  • Bloody Diarrhea
    1. Hemolytic Uremic Syndrome (HUS)
  • Fever
    • Viral Infections (e.g. CMV, EBV, VZV, HIV, HCV, Parvovirus B19)
    • Tick-Borne Illness ()
    • Dengue Fever
    • Malaria
    • Rickettsial Disease
    • Hemolytic Uremic Syndrome (HUS)
    • Thrombotic Thrombocytopenic Purpura (TTP)
  • Weight loss or Night Sweats
    • HIV Infection
    • Leukemia
    • Myelodysplastic Syndrome

Diagnosis of Thrombocytopenia

In any patient with thrombocytopenia, a thorough history and physical exam help in establishing the etiology behind the low platelet count. Usually, the signs and symptoms of thrombocytopenia do not occur unless the platelet count drops to a very low level or the patient presents with symptoms of the underlying disorder. A temporal profile of thrombocytopenia or its bleeding manifestations (acute, chronic, or relapsing-remitting) does not help in determining the etiology of thrombocytopenia but helps in determining the clinical phenotype. The past medical history of other diseases such as existing autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis, etc.), infections (rickettsiosis, malaria, etc.), malignancies, and transplant recipients is essential to establish the diagnosis. Likewise, a history of medications (quinine, antibiotics, heparin, etc.), recent vaccinations, travel history, dietary practices, high-risk behaviors (sexual practices, illicit drug use, smoking, alcohol consumption) also helps in guiding the evaluation of thrombocytopenia. Thorough family history is vital in delineating congenital thrombocytopenia, which can present for the first time well into adulthood.

A physical exam provides clues to determining the etiology of thrombocytopenia. Patients with gestational thrombocytopenia are often healthy, asymptomatic women who are found to have low platelets on lab investigations. On the contrary, a pregnant woman with TMA is usually a gravely ill patient often presenting to the emergency room or admitted to high-risk obstetric units. Patients with low platelet count usually present with mucocutaneous bleeding. However, joint bleed or severe bleeding should prompt a workup towards severe coagulopathies like DIC. Physical exam should also evaluate for hepatomegaly and/or splenomegaly (cirrhosis, lymphoproliferative disorders, etc.), skeletal deformities (like absent radius, humeral abnormality, and sometimes phocomelia seen in thrombocytopenia absent radii syndrome), and skin exam (like petechiae or purpura seen commonly with ITP, or, eczema seen in Wiskott-Aldrich Syndrome).

Specific clues in the history and physical exam can point a clinician towards an underlying etiology.

  • Gestational thrombocytopenia: It is diagnosed based on the following criteria.

    • onset in mid-second to the third trimester
    • no symptoms in the mother and no history of bleeding
    • no effect on the outcome of the pregnancy
    • no thrombocytopenia in the neonate
    • self-limited course and resolution in 4 to 8 weeks
    • A tendency to recur with the same degree in subsequent pregnancies
  • Pre-eclampsia: Patients present with severe hypertension after 20 weeks of gestation (defined as systolic pressure more than 160mmHg and diastolic pressure more than 110 mmHg on two separate occasions, at least 4 hours apart) or with severe persistent right upper quadrant epigastric pain which is unresponsive to medications. Eclampsia can present as a sequel to pre-eclampsia with seizures.
  • HELLP syndrome: It correlates with generalized edema in more than 50% of patients who demonstrate hepatic and renal insufficiency in labs.
  • AFLP: Clinically, it is quite challenging to distinguish between AFLP and HELLP syndrome. However, encephalopathy, hypoglycemia, severe coagulopathy, along TMA-like hemolysis, are more frequently present in patients with AFLP.
  • PNH: Patients usually present with hemolytic anemia, pancytopenia, and thrombosis; however, the characteristic finding of hemoglobinuria is almost never seen. Although thrombosis is a rare presenting feature, it usually occurs in atypical sites, like the portal vein or the cerebral vein.
  • HIT: A history of recent exposure to heparin is quintessential to the diagnosis of HIT. The thrombocytopenia usually develops within 5 to 10 days of exposure to heparin but can occur sooner if the previous exposure was relatively recent. The presence of skin necrosis and/or venous thromboembolism should prompt a workup towards HIT. The clinical 4-T score also aids in the diagnosis of HIT.

Lab Test And Imaging

Laboratory evaluation of thrombocytopenia starts with a review of peripheral smear. Pseudothrombocytopenia, defined as clumping of platelets on peripheral smear, can happen in up to 1% of all pregnancies. This ‘fictitious’ thrombocytopenia occurs due to the collection of blood in ethylenediaminetetraacetic acid (EDTA) anticoagulated tubes. The EDTA-dependent platelet auto-antibodies lead to artifactual clumping on the peripheral smear. It can be corrected by collecting the blood in a heparin tube and then performing a manual count on the peripheral smear. A review of a peripheral blood smear helps to determine the morphology of all three cell lines and the detection of red cell fragments (schistocytes) and atypical white cells like myeloblasts; this is particularly important in a critically ill pregnant patient with thrombocytopenia, where a review of peripheral smear must be done to look for schistocytes and rule out TMA.

A complete blood count with differential helps in realizing the degree of thrombocytopenia and provides a clue about the etiology. Evaluation of thrombocytopenia in pregnancy starts by differentiating between isolated thrombocytopenia and thrombocytopenia, which occurs along with changes in red cell and white cell lines.

  • Thrombocytopenia along with changes in other cell lines

    • Thrombocytopenia, along with hemolytic anemia: TMA should be the first consideration in a pregnant woman presenting with anemia and thrombocytopenia.

      • Hemolysis labs include lactate dehydrogenase, haptoglobin levels, total and direct bilirubin, and reticulocyte count, and the clinician should obtain an index in patients suspected of hemolytic anemia.
      • The diagnosis of TMA usually involves the triad of thrombocytopenia, along with hemolysis and renal failure/injury. The lab evaluation for pregnancy-related TMA and non-pregnancy related TMA is similar; however, certain specific tests are needed to differentiate between PEC/HELLP, TTP, and atypical HUS In patients suspected of TMA, Shiga-toxin must be tested to rule out typical HUS.
      • Specific test to rule out TTP includes testing for ADAMTS-13. A level of ADAMTS-13 above 5 to 10% usually rules out TTP.
      • In patients suspected of atypical HUS, a genetic test must be pursued to identify mutations that prevent the expression or function of proteins involved in the regulation of the alternate C3 pathway.
    • Thrombocytopenia associated with bleeding: A coagulation panel should always be done to identify any coagulopathy which may complicate thrombocytopenia with bleeding. As mentioned above, DIC can occur in association with TMA or secondary to obstetric causes. There is no single test to identify DIC, but a score developed by the international society of thrombosis and hemostasis (ISTH) helps in predicting DIC with a sensitivity of 93% and a specificity of 98%. The components of the ISTH score include fibrinogen level, partial thromboplastin time, platelet count, and fibrin markers (D-dimer is a reasonable marker).
    • Paroxysmal nocturnal hemoglobinuria (PNH): The diagnosis of PNH is via flow cytometric analysis of glycosyl-phosphatidylinositol-anchored proteins (GPI-AP) along with a decreased expression of both CD55 and CD59. CD55 and CD59 are still tested to exclude rare, inherited deficiency of single GPI-AP.
  • Isolated thrombocytopenia:

    • Immune thrombocytopenia: ITP usually presents as isolated thrombocytopenia with petechiae or bleeding manifestations. The workup for ITP follows the American society of hematology guidelines (2011) and the international working group (2010). The mandatory tests include a lab evaluation for hepatitis B and C, human immunodeficiency virus, quantitative immunoglobulins, direct antiglobulin test, and blood group (Rh). Tests that can be of potential utility in such patients include antiphospholipid antibodies, anti-nuclear antibodies, anti-thyroid antibodies along with thyroid function tests, and viral studies for cytomegalovirus. Helicobacter Pylori testing should take place in areas with high prevalence.
    • Heparin-induced thrombocytopenia (HIT): Although rare, HIT can cause thrombocytopenia in pregnancy. HIT is diagnosed based on clinical and pathological features. The 4T score helps in determining the clinical probability of HIT and the anti-platelet Factor-4 (PF-4)/heparin antibodies to help in making a pathological diagnosis. The PF-4 dependent enzyme immunoassays (EIA) have a high sensitivity and specificity for HIT antibodies, especially if the cut-off for optical density is raised (in comparison to serotonin-release assay (SRA)]. However, all positive EIA should be tested with washed platelet assays (like carbon-14-SRA) to confirm the diagnosis.

Gestational thrombocytopenia is a diagnosis of exclusion that is based on a thorough history and physical exam and ruling out of conflicting diagnosis with lab support. With sufficient exclusion of other etiologies, then no further laboratory evaluation is needed to confirm a diagnosis of gestational thrombocytopenia. Rarely, the platelet count drops below 70 x 10^9/L in patients with gestational thrombocytopenia. If the platelet count goes below 70 x 10^9/L, then the patient should be evaluated for a secondary cause like ITP. 

  • Complete Blood Count (CBC)
  • Basic chemistry panel (chem8)
    • Evaluate for associated Renal Failure (e.g. TTP, HUS)
    • Expand to the comprehensive panel in Hemolysis
      1. Indirect Bilirubin increased in Hemolysis
      2. Serum Lactate Dehydrogenase and Haptoglobin increased in HUS and TTP
  • Coagulation tests (INR, PTT, Fibrinogen)
    • Normal in isolated Thrombocytopenia, ITP, TTP, HUS
    • Prolonged in DIC, liver disease, Massive Transfusion and Trauma
    • Fibrinogen is decreased in DIC and Trauma
  • Peripheral Blood Smear
    • See Platelet Morphology
    • See Peripheral Blood Smear
    • Schistocytes are present in DIC and Microangiopathic Hemolytic Anemia (TTP, HUS), but not ITP
    • Consider Parasite stains (Tick-Borne Illness, Malaria)
    • Hemolysis will raise Indirect Bilirubin
  • Platelet Count
    • Rule-out Pseudothrombocytopenia
      • Review Peripheral Smear to evaluate for clumping (Pseudothrombocytopenia)
      • Repeat Platelet Count in non-EDTA Anticoagulant (citrate, blue tube)
    • Repeat Platelet Count timing (adjust based on chronicity, stability and bleeding complications)
      • Repeat immediately for developing bleeding complications
      • Repeat in days to 1 week if Platelet Count <50,000 per uL
      • Repeat in 2 weeks if Platelet Count <100,000 per uL
      • Repeat in 4 weeks if Platelet Count <150,000 per uL
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Evaluation of patients with isolated thrombocytopenia includes obtaining a CBC, peripheral blood smear, HIV, and HCV tests.

  • Repeat CBC to confirm that thrombocytopenia is real.
  • Anemia and thrombocytopenia occur with infections, DIC, sepsis, thrombotic microangiopathy, autoimmune disorders like Felty syndrome.
  • Leucocytosis and thrombocytopenia can present in infection, malignancy, chronic inflammatory conditions.
  • Pancytopenia occurs in myelodysplastic syndromes.
  • In patients with symptoms or signs of autoimmune disorders like SLE, antiphospholipid antibody syndrome (APS), obtain anti-nuclear antibodies and antiphospholipid antibodies, respectively.
  • In patients with thrombosis, one should consider heparin-induced thrombocytopenia (obtain platelet factor 4 antibodies), APS (check antiphospholipid antibodies ), DIC and PNH (check PT,aPTT, fibrinogen, LDH)
  • Check liver enzymes and coagulation tests in patients with liver disease.
  • A blood smear is used to check the appearance of your platelets under a microscope. For this test, a small amount of blood is drawn from a blood vessel, usually in your arm.
  • Blood clot test a blood clot test measures the time it takes blood to clot. These tests include partial thromboplastin time (PTT) and prothrombin time (PT).
  • Bone marrow biopsy is indicated in conditions when the cause of thrombocytopenia is unclear, and when a hematologic disorder is suspected.

    • A normal number or rise in megakaryocytes in bone marrow is a presenting feature in conditions with increased platelet destruction.
    • The decrease in megakaryocytes, along with an overall reduction in other cells, is seen in aplastic anemia.
    • In SLE, severe reduction or absence of megakaryocytes is seen due to an autoantibody directed against the thrombopoietin receptor.
    • Megaloblastic changes in RBC and granulocytes occur in vitamin B12, folate, and copper deficiency. In myelodysplasia, cells are dysplastic.
  • Single-gene testing – Gene-targeted deletion/duplication analysis of RBM8A is performed first, followed by sequence analysis of RBM8A if no deletion is found. Although the diagnosis of TAR syndrome can be established by identification of a heterozygous minimally deleted 200-kb region at chromosome band 1q21.1, sequence analysis of RBM8A can be done subsequently in individuals with the deletion to confirm the presence of a second pathogenic variant (hypomorphic allele) and allow family studies. Homozygous RBM8A null alleles (e.g., deletions) are thought to be lethal.
  • More comprehensive genomic testing – (when available) including exome sequencing and genome sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes RBM8A) fails to confirm a diagnosis in an individual with features of TAR syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

Treatment of Thrombocytopenia

In pregnancy, thrombocytopenia usually does not lead to an increased risk of bleeding. Even in patients with ITP, where thrombocytopenia is often quite severe, the risk of bleeding remains low. The obstetric indication decides the mode of delivery. Vaginal delivery is preferable from a hematologic standpoint due to the lower risk of bleeding; however, this is not a deciding factor. Administration of neuraxial anesthesia (epidural anesthesia) is a challenge. The American College of Obstetrics and Gynecology recommend a platelet count of 80 x 10^9/L (level C recommendation) as the goal of administering epidural anesthesia. The platelet goal for delivery is more than 50 x 10^9/L, especially if planning a cesarean section. Here we will briefly discuss the management of pregnant patients with thrombocytopenia according to the etiology of the disease.

  • Gestational Thrombocytopenia: The platelet count rarely goes below 70 x 10^9/L in patients with gestational thrombocytopenia. No intervention is required in such patients as the condition resolves spontaneously 4 to 8 weeks after delivery. In patients whose platelet counts drop below 70 x 10^9/L, a component of ITP merits consideration. The use of steroids and intravenous immunoglobulins does not benefit patients with gestational thrombocytopenia. However, it may help those who have ITP superimposed on gestational thrombocytopenia. The neonatal outcomes are excellent, and neonates of mothers with gestational thrombocytopenia never develop thrombocytopenia.
  • Immune thrombocytopenia (ITP): ITP is a very complex and heterogeneous disease. Although many treatment options exist for adult patients with ITP, pregnancy offers a unique challenge in terms of minimizing the fetal-maternal risk. Usually, an intervention is not necessary unless the platelet counts drop below 20 to 30 x 10^9/L in the first two trimesters or if thrombocytopenia is complicated with bleeding, regardless of the platelet count. Treatment in the third trimester depends on the mode of delivery and candidacy for epidural anesthesia. Corticosteroids are usually the first line of treatment in pregnant patients with a response time of 3 to 7 days. They are associated with minimal risk of fetal orofacial cleft palate if started in the first trimester and may lead to maternal diabetes, weight gain, and hypertension if started in the third trimester. A single dose of intravenous immunoglobulins (IVIG) at 1000mg/kg, can lead to a rapid rise in platelets within 24 hours. However, the response lasts only for 2 to 3 weeks. One more dose can be repeated either alone or in combination with steroids if unable to achieve the desired response. It is associated with a small risk of renal tubular acidosis and thrombosis. Anti-D, rituximab, and thrombopoietin receptor agonists have been classified as category C by the FDA. Rituximab has been used safely during pregnancy, with minimal complications to the mother. There are reports of transient neonatal B-cell lymphopenia with the use of rituximab, which resolves by six months of age. Splenectomy can be done safely via a laparoscopic approach in the second and third trimester of pregnancy. However, it is rarely pursued in the modern era and is reserved for patients refractory to medical management. Other medical options include azathioprine and cyclosporine. The use of chemotherapeutic agents like cyclophosphamide, vincristine, etc is usually discouraged in pregnant patients. Mycophenolate mofetil is contraindicated in pregnancy due to teratogenic effects on the fetus.
  • Thrombotic Microangiopathy: The management of TMA in pregnancy focuses on the antecedent cause. The thrombocytopenia is a consequence of the TMA and hence improves with the resolution of the underlying condition. It is critical to differentiate between the pregnancy-specific TMA (PEC/HELLP/AFLP), and non-pregnancy-specific TMA as the management of the two conditions is very different.
    • PEC/HELLP syndrome/AFLP: The goal of treatment is the delivery of the fetus, with supportive care provided for the management of the underlying condition.
    • TTP: prompt initiation of plasma exchange helps remove the inhibitor to ADAMTS-13 and supply the patients with fresh plasma to restore the function of ADAMTS-13, resolve hemolysis. Eventually, anti-inhibitor therapy is initiated to reduce the inhibitor activity. Up to 25% of patients presenting with TTP in adulthood have congenital absence of ADAMTS-13 (Upshaw-Schulman syndrome). In such patients, anti-inhibitor therapy has no role. Such patients should receive periodic infusions of plasma. Trials regarding a recombinant ADAMTS-13 are underway to circumvent the need for plasma infusions. Caplacizumab (CABLIVI) was approved by the FDA in 2019 for the treatment of adult patients with acquired TTP, in combination with plasma exchange and immunosuppressive therapy. It is a von Willebrand factor (vWF)-directed antibody fragment that targets the A1-domain of vWF, and inhibits the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption. Its safety in pregnancy has not been established and increases the risk of hemorrhage in both mother and fetus.
    • Atypical HUS: Plasma exchange is not useful in patients with atypical HUS. The FDA has approved eculizumab for patients diagnosed with atypical HUS. Despite being labeled category C by the FDA, several reports have shown that eculizumab can be safely administered during pregnancy.
  • PNH: Eculizumab is a humanized monoclonal IgG antibody that prevents cleavage of C5 into C5a and C5b, eventually blocking the formation of membrane attack complex. It leads to a reduction in complement-mediated hemolysis and improvement in platelet count. As stated above, several reports demonstrate the safety of eculizumab.
  • Disseminated intravascular coagulation: DIC is a consumptive coagulopathy where the primary goal is to treat the underlying cause. However, patients in severe DIC may require supportive measures. Patients in DIC present either with a bleeding phenotype or overt thromboembolism. In a bleeding patient, the goal for platelet transfusion is 30 to 50 x 10^9/L. Plasma/ cryoprecipitate is given to keep prothrombin time less than 3 seconds prolonged and fibrinogen above 1.5 gm/L. In a patient with overt thromboembolism, the clinician should initiate full-dose anticoagulation.
  • Heparin-induced thrombocytopenia: HIT rarely complicates pregnancy, unless the patient receives heparin products. After confirming the diagnosis via platelet activation assays (serotonin release assay is the most commonly used assay), patients should not receive heparin products anymore. In such patients, direct thrombin inhibitors (argatroban and bivalirudin) serve for immediate management. For the follow-up anticoagulation, fondaparinux is an option for anticoagulation in pregnant patients.

Prognosis

The prognosis depends on the underlying etiology for thrombocytopenia. While thrombocytopenia does not lead to complications in pregnancy, the etiology behind the thrombocytopenia can pose significant challenges. The mode of delivery is chosen based on the obstetric indication.

  • Gestational thrombocytopenia: It is a self-limiting condition that usually resolves within 4 to 8 weeks of delivery of the fetus. Although there is a high risk of recurrence with subsequent pregnancies, it is often a benign condition that seldom causes any complications in the mother.
  • Immune thrombocytopenia: ITP can lead to significant bleeding issues in the mother. ITP in the mother can also affect the neonate and lead to neonatal thrombocytopenia. Despite low platelets, the risk of bleeding is quite low in the mother. In the neonates who have thrombocytopenia secondary to maternal ITP, catastrophic bleeding events (like intracranial hemorrhage) occur in less than 1% of patients.
  • TMA: Both pregnancy-related TMA (PEC/HELLP/AFLP) and TMA not specific to pregnancy (TTP/ATypical HUS) are associated with high rates of maternal and neonatal morbidity and mortality. Thrombocytopenia related to these conditions seldom poses any issues in the mother or the neonate. The goal of treatment is the delivery of the baby. Recovery of platelet count may lag behind the delivery of the fetus but eventually resolves once the underlying condition improves.
  • Clinicians should manage other causes of thrombocytopenia (bone marrow failure syndrome, PNH, etc.) according to primary etiology, and the prognosis depends on the underlying etiology.

Neonatal outcome in women with thrombocytopenia

  • The neonatal outcome is excellent in neonates born to mothers with gestational thrombocytopenia. They never develop thrombocytopenia or are at risk of bleeding.
  • Neonates born to mothers with ITP may develop transient thrombocytopenia. Although the passive transfer of antibodies from the mother causing transient thrombocytopenia in the neonate is the most popular theory behind neonates developing thrombocytopenia, it is not entirely proven. The nadir of platelets appears within 24 to 48 hours. Reports of intracranial hemorrhage appear in less than 1% of neonates who develop thrombocytopenia secondary to maternal ITP.

Other Issues

Thrombocytopenia in pregnancy is a benign condition in the majority of patients. However, it may be associated with more severe etiologies in a few patients. A few noteworthy points are listed here.

  • Less than 1% of patients with thrombocytopenia in pregnancy have a platelet count of less than 100 x 10^9/L.
  • A thorough history and complete physical is the initial step in the evaluation of thrombocytopenia in pregnancy.
  • A review of the peripheral smear is the first step in the lab evaluation of thrombocytopenia. It helps in ruling out pseudo-thrombocytopenia and schistocytes.
  • Gestational thrombocytopenia, which is the most common cause of thrombocytopenia in pregnancy, is a diagnosis of exclusion.
  • Despite being the most common cause of thrombocytopenia in pregnancy, gestational thrombocytopenia does not require any intervention as it resolves spontaneously.
  • ITP is the most frequent cause of thrombocytopenia in the first trimester of pregnancy. However, it is also a diagnosis of exclusion.
  • Corticosteroids and IVIG are the first-line treatment for ITP in pregnancy.
  • Rituximab is safe in pregnancy for the treatment of ITP, although it may cause transient B-cell lymphopenia in the neonate, which resolves spontaneously.
  • Pregnancy-related TMA management is by the delivery of the fetus. Thrombocytopenia and other abnormalities may take longer to recover after the delivery of the fetus.
  • TTP is rare during pregnancy, but 10 to 30% of all patients with TTP are obstetric. Up to 25% of TTP in pregnancy is due to a congenital lack of ADAMTS-13 (Upshaw-Schulman syndrome).
  • Eculizumab is designated category C by the FDA, but several reports show that it is safe for the management of atypical HUS and PNH in pregnancy.

Important points to remember for both physicians and patients

  • The mode of delivery depends on the obstetric indication, rather than the platelet count.
  • A platelet count of more than 50 x 10^9/L is safe for delivery.
  • The goal of platelets for administering neuraxial anesthesia is at 80 x 10^9/L.
  • In a patient with gestational thrombocytopenia, if the platelet count drops below 70 x 10^9/L, then a secondary cause, like ITP, should be considered.
  • Platelet transfusions are not required for low platelet counts unless the patient is bleeding.
  • The neonatal outcome is excellent in neonates born to mothers with gestational thrombocytopenia.
  • Transient thrombocytopenia can present in neonates born to mothers with ITP. In less than 1% of neonates, it can lead to intracranial hemorrhage. A pediatrician consult is necessary for such a scenario.
  • Maternal and neonatal morbidity and mortality are high in patients with TMA. The primary goal of treatment is the delivery of the fetus.

References

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