Thrombocytopenia in Pregnancy

Here’s the RoshReview Question of the Week!

A 23-year-old primigravid woman at 25 weeks gestation presents to the prenatal appointment to follow up on lab results. Her platelet count is noted to be 77,000/μL, decreased from 205,000/μL in the first trimester. She reports no abnormal bruising or bleeding. What is the most likely reason for her thrombocytopenia?

• Autoimmune process

• Consumptive coagulopathy

• Deficient von Willebrand factor-cleaving protease

• Hemodilution

Check your answer and enter the QE Exam Giveaway at the links above!

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Practice Bulletin 207 is our companion reading this week!

Introduction 

• Evaluation of thrombocytopenia in pregnancy can be difficult because there are many things that could cause it - not all of them are related to pregnancy 

• Definition: when platelets are <150,000/microL 

• So what is normal? 

  • Recall in our very first few episodes that pregnancy can lead to increased plasma volume and not necessarily an equal increase in blood components 

  • This can lead to what appears to be some dilutional effects 

  • In the National Health and Nutrition Examination Survey (NHANES), the mean plt count in pregnancy is as follows: 

    • Non pregnant: 273k 

    • 1st trimester: 251k

    • Second trimester 230k

    • Third trimester 225k 

    • Delivery 217 k 

    • Postpartum (7 weeks) 264k  

• Definitely suggests that some decrease in platelet count could be expected in pregnancy

What are the causes of thrombocytopenia in pregnancy?

• Gestational thrombocytopenia - benign and self limited; may even occur in the first trimester, but usually is more common as pregnancy continues; frequency is 5-10% at the time of delivery

  • But remember this is a diagnosis of exclusion! It’s acceptable if there is mild thromboctyopenia, but again, you should look if Plt <100k  

•  Immune Thrombocytopenia (ITP) - 1-3/10,000 pregnancies, but really low plts only affect a small portion of these

  • ITP is more frequent in pregnancy than in the general adult population but may be because of recognition (checking more frequent CBCs in preg) 

  • Autoimmune condition where antiplatelet antibodies interfere with platelet production and causes destruction of circulating platelets

    • Diagnosis based on exclusion of other causes of thrombocytopenia  

• Preeclampsia/HELLP Syndrome

  • Remember that it is very rare <24 weeks, and there are usually other signs and symptoms as well like elevated BP, headache, vision changes, etc. As well as other hematologic abnormalities like anemia due to hemolysis (high LDH), and may have abnormal LFTs 

  • We won’t go too much into preeclampsia since we discuss it elsewhere, but always something to keep in mind 

• Less likely things, but still things to keep in mind 

  • DIC - Disseminated intravascular coagulation

    • There is usually an underlying cause of this such as placental abruption, sepsis, etc 

    • Patients will have bleeding and oozing at IV sites for example 

    • Usually will have low fibrinogen and elevated PT and PTT labs as well  

  • Acute fatty liver of pregnancy 

  • Thrombotic thrombocytopenic purpura (either immune or hereditary)

    • Will usually present with purpura, can have neurological changes, fever, kidney injury, can have elevated BPs and may be confused with PEC 

    • Will have reduced activity of ADMATS13, but this may be a send out lab in most places and will not come back for some time 

    • Will have schistocytes on smear 

  • Lupus 

  • Infection

  • Inherited platelet disorders

So… when should we start to worry?

• When platelets are: 

  • If platelets are between 100k-150k if there are risk factors present (but usually, do not need work up and can be attributed to gestational thrombocytopenia) 

  • At any point <100k (usually this is beyond the lower end of gestational thrombocytopenia)

    • Plts of <100k only occur in 1% of uncomplicated pregnancies 

    • Remember that there is increased risk of spontaneous bleeding if Plt <20k 

    • Some institutions have cut offs for platelets for ability to give neuraxial analgesia - some places are 70-80k, some places are 100k. Please check with your institution and your patients, because this may require treatment or your patient won’t get an epidural! 

Ok, so that’s a lot of causes… how do I go about figuring out what to do? 

• Evaluation of the patient

  • Get a good history and physical - this can sometimes help you determine what it is not

    • If patient is well appearing, with no pain, vaginal bleeding, elevated blood pressure or other complaints, it’s usually not going to be something like AFLP, DIC, TTP, or preeclampsia  

    • Look through the patient’s chart: what were their platelets before? What other medical problems? What about new medications? 

    • Any history of lupus, TTP, liver disease, anemia

    • You have the CBC - did the lab do a smear? Are there abnormalities on the smear, like schistocytes? 

    • Most of the time, if you have someone who is sitting in the clinic and appears well, you may have some time  

• The asymptomatic patient with Plt >100k

  • Usually, plts between 100-150k without other cytopenis or other major clinical findings can be attributed to gestational thrombocytopenia 

  • The other major cause could be ITP, but minor ITP with plt >100k also does not need treatment 

  • Our practice is to check plts monthly to make sure they do not drop below 100k, or below threshold for neuraxial analgesia 

• The asymptomatic patient with Plt <100k 

  • Review the CBC - make sure there are no other cytopenias; ask for a smear 

  • Evaluate for HIV (usually already done in pregnant patients), as this could also lead to thrombocytopenias 

  • Obtain other coagulation panel like PT, PTT, fibrinogen level 

  • Also obtain CMP - evaluate kidney and liver function 

  • If no obvious signs, it is ok to get hematology involved early

  • More likely to be ITP if <100k, and patients can be treated with steroids or even IVIG in refractory cases if needed 

  • This is to make sure that the platelets do not drop further so that they cannot get neuraxial analgesia or so that they don’t drop too low as to cause issues with bleeding 

• What if they are symptomatic and <100k?

  • A lot of this is going to depend on their history and physical again - we are usually pretty good at evaluating for preeclampsia - get their vital signs and do your exam

    • Do they have fever? Purpura? 

  • Labs: CBC, CMP, coag panel, HIV, LDH, urinalysis, bilirubin 

  • If you are suspicious of TTP (ie. fevers, kidney injury, neurological changes) 

    • Make sure to get CT head to rule out bleed 

    • ADAMTS13 

    • Hematology consult 

  • Ok to get MFM and hematology involved early 

Management 

• Treatment for bleeding or severe thrombocytopenia 

  • If Plt are <10k or <20k, there is increased risk of spontaneous bleed 

  • If Plt <20k and severe bleed (ie. intracranial), you should give platelets regardless of the underlying cause of thrombocytopenia (yes, even in ITP if it will get consume)

• Some platelet thresholds to consider in delivery 

  • Vaginal delivery: 20-30k 

  • C/S: 50k 

  • Neuraxial anesthesia: institution based; ours is 80k; most institutions will have a count between 50-80k 

• Other considerations 

  • Operative vaginal deliveries are relatively contraindicated if there is severe maternal thrombocytopenia 

  • This is because there is concern that there could also be fetal thrombocytopenia (ie. immune mediated or hereditary) 

  • However, if you must perform an operative delivery, forceps is favored over vacuum 

  • Remember: Just because someone has ITP does not mean they can’t have an operative delivery 

• Treatment of specific disorders 

  • ITP - steroids or IVIG 

    • Dosing of steroids: prednisone 1mg/kg/day for two weeks followed by gradual taper; may need 2 weeks to see peak effect (usually 1-4 weeks for peak) 

    • IVIG should be given at least 1 week in advance to allow for maximal efficacy and platelet count retesting if trying to raise platelet counts for epidural 

    • If refractory, other methods in pregnancy are not well studied, and you should have a conversation with your MFM and hematology colleagues 

  • TTP - plasma exchange

  • Preeclampsia or DIC due to abruption: delivery! 

• What about fetal testing of platelets?

  • There isn’t really evidence to suggest we should test fetal platelets (ie. either via PUBS or from fetal scalp during labor

  •  We won’t discuss fetal/neonatal thrombocytopenia here, but just some brief reasons to test neonatal platelets: 

    • Maternal ITP 

    • Neonatal thrombocytopenia in previous pregnancy (concern for NAIT, though this is usually not associated with maternal platelet issues) 

    • Congenital anomalies associated with thrombocytopenia 

    • Bleeding or petechia on the infant 

    • Neonatal infections (ie. CMV, rubella) 

Imitators of Pre-Eclampsia

Each of the conditions we’ll discuss today could be an episode all its own, so this will be way too brief to cover these topics in detail! But it’s important to keep a broad diagnostic mind open, especially if you feel the picture doesn’t totally add up. 

Reading: Sibai: Imitators of Severe Pre-Eclampsia (2007)

Previous podcasts: Hypertension and Pregnancy Trio (3/2019)

Diagnosing Pre-Eclampsia:

• Pre-eclampsia is a syndrome - a recognizable complex of symptoms and physical findings that indicate a specific condition, but for which a cause isn’t necessarily understood. 

• We need to think about the symptoms and signs of pre-eclampsia and determine how they overlap with other diseases!

  • What else might tie together: 

    • Hypertension

    • Neurologic changes

    • Pulmonary edema

    • LFT abnormalities and RUQ pain

    • Thrombocytopenia

    • Acute kidney injury

• Some potential examples:

  • Acute hepatitis or cirrhotic liver disease

  • Lupus

  • Meningitis

  • TTP / HUS

  • Drug reactions or overdoses

  • Malignant hypertension (i.e., pheochromocytoma, renal artery stenosis)

  • Heart failure or heart attack

    • You can probably think of more if you try!

• Let’s focus this broad differential on three primary significant culprits today: Acute Fatty Liver of Pregnancy (AFLP); Thrombotic Thrombocytopenic Purpura (TTP) / Hemolytic Uremic Syndrome (HUS); and a Lupus (SLE) Flare

Acute Fatty Liver of Pregnancy

• Exactly what it sounds like -- acute fatty infiltration of the liver, typically in the 3rd trimester, leading to fulminant hepatic failure.

  • Appears to be related to defects in fatty acid metabolism -- 20% of AFLP associated with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency of the fetus. 

• Incidence: 1 in 7k-20k pregnancies.

• Risk factors:

  • Fetal LCHAD deficiency: fetal homozygosity renders it incapable of processing fatty acids, and mother (typically heterozygous) has decreased function to keep up -- thus the infiltration.

  • Prior history of AFLP

  • Multiple gestation

  • Preeclampsia / HELLP syndrome (so they can even be co-existent!)

  • Male fetal sex

  • Low BMI (<20)

  • Nulliparity

• Typical presentation:

  • 3rd trimester: most common after 30 weeks

  • Often nonspecific symptoms: nausea/vomiting, abdominal pain, malaise, headache, anorexia

  • Frequently with hypertension +/- proteinuria 

    • Reported co-existent HELLP in 20-40% of cases

  • Hypoglycemia is frequent on laboratories - from impaired hepatic gluconeogenesis

    • Additionally can see signs of acute liver failure -- jaundice, ascites, encephalopathy, DIC. 

  • Renal failure upwards of 90% of cases.

• Diagnosis:

  • Typically a clinical diagnosis -- biopsy can be performed to demonstrate fatty infiltration, but rarely performed.

  • Swansea criteria:

    • Ranges pending on reading from 6-9 positive signs. 

      • Most typically need 6 (in my experience)

    • Supposed to be done in patients without HELLP syndrome/preeclampsia, limiting utility.

  • Imaging can be performed, but is also of limited utility in diagnosis

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Swansea Criteria (UpToDate)

• Treatment of AFLP:

• Supportive with critical care expertise! 

• Have ongoing monitoring for:

  • MELD score (Model for End-Stage Liver Disease) - high MELD > 30 associated with increased risk of maternal complications

  • Hypoglycemia: typically need infusion of dextrose-containing fluids

  • Coagulopathy

• Delivery!

  • Labor induction is reasonable if can be reasonable accomplished within 24 hours, and disease not rapidly progressing.

  • Cesarean delivery outright should be considered otherwise.

  • Betamethasone administration for FLM given, but shouldn’t delay delivery.

  • Magnesium as indicated for suspected preeclampsia and/or for CP prophylaxis. 

• Postpartum:

  • Mortality in AFLP is attributable to hemorrhage, liver failure, and kidney injury.

  • AFLP will often resolve within 7-10 days after delivery

  • Hemorrhagic pancreatitis is a potential and fatal complication known to be associated with AFLP - follow lipase

  • Liver transplantation may need to be considered in those with persistent fulminant hepatic failure (though this is rare). 

  • LCHAD deficiency testing should be pursued in infants.

    • LCHAD deficiency in newborns can be life-threatening!

Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)

• Related but different diseases characterized by microangiopathic hemolysis, thrombocytopenia, acute renal failure, neurologic abnormalities, and fever.

• TTP - caused by deficiency in ADAMST13, a protein involved in regulating blood-clotting by cleaving von Willebrand factor from endothelial surfaces, and at the sites of vascular injury.

  • Can be familial or acquired

  • Characterized by marked thrombocytopenia - platelets frequently <20k

• HUS - can be caused by a variety of insults, but commonly Shiga-toxin from certain bacterial organisms as well as with abnormalities in complement system regulation. 

  • Renal failure is the dominating feature of HUS and tends to be particularly severe. 

• Presentation:

  • Also tends to be vague: abdominal pain, nausea/vomiting, headache, vision changes, confusion, fever

  • May also include bleeding: epistaxis, GI bleeding, petechia/purpura, hematuria (particularly in HUS)

  • Can present with or without hypertension

• Diagnosis:

  • Involve your hematology colleagues if there’s suspicion!

  • Early-onset preeclampsia may raise suspicion: 20-26ish week range, but can occur at any point

• Treatment:

  • Plasma exchange: helps to remove large multimers of von Willebrand factor and autoantibodies against ADAMST13. 

  • Steroids - help to calm autoimmune response

  • Splenectomy - helps to avoid sequestration of platelets 

  • Platelet transfusion should be avoided - may contribute to increased microvascular thrombus formation

• Delivery:

  • Not indicated immediately! PLEX and other therapies can be given opportunity to work

  • However, serial / frequent therapy is often indicated to continue pregnancy and prevent relapse

Systemic Lupus Erythematosus / Antiphospholipid Antibody Syndrome

• SLE is an autoimmune disorder with varying symptomatology but can result in significant end-organ damage

  • 30-40% of SLE patients have antiphospholipid antibodies

  • Only 1% of patients will have antiphospholipid antibody syndrome - a disorder that is characterized by microangiopathy affecting multiple organ systems, and with particularly high pregnancy risks

• Diagnosis:

  • Classically SLE diagnosis requires at least 4 / 11 American College of Rheumatology criteria;

  • However, in 2019 the ACR and European League Against Rheumatism came up with a combined criteria based on a points system:

ACR / ELAR Combined Diagnostic Criteria for SLE (2019)

• APLAS diagnostic criteria we’ve previously reviewed in our RPL episode:

• One of two clinical criteria:

  • a) Vascular thrombosis 

  • b) Pregnancy morbidity, defined as:

    • One or more unexplained deaths of morphologically normal fetus after 10 weeks of gestation by ultrasound or direct examination of fetus.

    • One or more premature births of morphologically normal neonate before 34 weeks because eclampsia or severe pre-eclampsia or recognized features of placental insufficiency.

    • Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic or hormonal abnormlaities and paternal and maternal chromosomal causes excluded.

• And one of the following laboratory criteria 

  • a) Lupus anticoagulant present in plasma on 2 or more occasions at least 12 weeks apart or 

  • b) Anticardiolipin antibody IgG or IgM isotype in serum or plasma present in medium or high titer on 2 or more occasions at least 12 weeks apart, or  

  • c) Anti-B2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th%ile), present on two or more occasions at least 12 weeks apart 

• Fortunately, many patients with SLE will come into pregnancy with an established diagnosis.

  • To determine if they’re having a flare to distinguish from preeclampsia, you’ll often use a serum marker for rheumatologic disease, such as:

    • Hypocomplementemia (C3 / C4 levels)

    • Anti ds-DNA antibody levels

• Symptoms are vague, as previously described with the clinical criteria for SLE diagnosis, and have overlap with preeclampsia! 

• Treatment:

  • If known from outset of pregnancy -- these patients should definitely be on aspirin for preeclampsia prevention!

  • Steroids are often used in acute flares - prednisone

  • DMARDs - safe medications for pregnancy can include azathioprine, hydroxychloroquine, and encouraging data exists for immunomodulating antibodies (i.e., adalimumab / Humira)

  • APLAS - low molecular weight heparin for prevention of VTE and pregnancy morbidity

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SIBAI 2009 (ref above)

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SIBAI 2009 (ref above)