Thrombocytopenia


Article Author:
Sruthi Jinna


Article Editor:
Paras Khandhar


Editors In Chief:
Lawrence Lee
Michael Firstenberg
Lawrence Greiten


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
5/25/2019 5:15:40 PM

Introduction

A platelet count that falls below the lower limit of normal, i.e., 150000/microliter (for adults) is defined as thrombocytopenia. Platelets are blood cells that help in blood clotting and wound healing — risks associated with thrombocytopenia range from no risk at all to bleeding risks and thrombosis. The correlation of severity of thrombocytopenia and bleeding risk is uncertain. Spontaneous bleeding can occur with a platelet count under 10000/microliter and surgical bleeding with counts below 50000/microL. Thrombocytopenia is associated with risk of thrombosis in conditions like heparin-induced thrombocytopenia (HIT), antiphospholipid antibody syndrome (APS), disseminated intravascular coagulation (DIC), thrombotic microangiopathy (TMA), paroxysmal nocturnal hemoglobinuria (PNH).

Etiology

Common causes of thrombocytopenia[1][2][3][4][5][6][7][8][9][10]:

  • Primary immune thrombocytopenia (primary ITP). An autoimmune condition where antibodies are produced against platelets resulting in platelet destruction.
  • Drug-induced immune thrombocytopenia:
    • Heparin-induced thrombocytopenia (HIT) - in this condition, anti-platelet antibodies activate platelets resulting in thrombosis (both arterial and venous)
    • Quinine
    • Sulfonamides, ampicillin, vancomycin, piperacillin
    • Acetaminophen, ibuprofen, naproxen
    • Cimetidine
    • Glycoprotein IIb/IIIa inhibitors
    • Other over the counter remedies, supplements, foods like African bean, sesame seeds, walnuts) and beverages (herbal teas and cranberry juice)
  • Drug-induced non-immune thrombocytopenia. Drugs like valproic acid, daptomycin, linezolid cause thrombocytopenia by dose-dependent suppression of platelet production.
  • Infections:
    • Viral: HIV, hepatitis C, Ebstein-Barr virus, parvovirus, mumps, varicella, rubella, Zika viral infections can cause thrombocytopenia.
    • Sepsis causes bone marrow suppression.
    • Helicobacter pylori
    • Leptospirosis, brucellosis, anaplasmosis, and other tick-borne infections are associated with thrombocytopenia.
    • Malaria, babesiosis intracellular parasite infections are associated with thrombocytopenia and hemolytic anemia
  • Hypersplenism due to chronic liver disease
  • Chronic alcohol abuse
  • Nutrient deficiencies (folate, vitamin B12, copper)
  • Autoimmune disorders like systemic lupus erythematosus, rheumatoid arthritis associated with secondary ITP
  • Pregnancy. Mild thrombocytopenia presents in gestational thrombocytopenia; moderate-severe thrombocytopenia can occur in preeclampsia and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome

Other causes[11]:

  • Myelodysplasia
  • Malignancy: cancer with chronic DIC, cancer with marrow suppression (leukemia, lymphoma, solid tumors)
  • Paroxysmal nocturnal hemoglobinuria (PNH)
  • Thrombotic microangiopathy (TMA)
    • Thrombotic thrombocytopenic purpura (TTP), a condition manifested by fever, renal failure, thrombocytopenia, microangiopathic hemolytic anemia with or without neurologic manifestations
    • A hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing organism (E. coli and Shigella), seen in children.
    • Drug-induced TMA: quinine, specific chemotherapy agents
    • Antiphospholipid antibody syndrome
  • Aplastic anemia
  • Inherited thrombocytopenia. Often seen in children, rare in adults
    • Von Willebrand disease type 2
    • Alport syndrome
    • Wiskott-Aldrich syndrome
    • Fanconi syndrome.
    • Thrombocytopenia-absent radius syndrome
    • Bernard–Soulier syndrome
    • May-Hegglin anomaly

Epidemiology

Normal platelet count range varies by different ages, sexes, and ethnicity. Women, young individuals, and non-Hispanic blacks have slightly higher platelet counts.[12]

Pathophysiology

Decreased platelet production[13][14][13]:

  • Bone marrow failure presents in aplastic anemia, PNH
  • Bone marrow suppression is a feature with exposure to certain drugs, such as valproic acid, daptomycin, certain chemotherapy agents, and irradiation
  • Chronic alcohol abuse
  • Inherited thrombocytopenia)
  • Viral infection
  • Systemic conditions like nutrient deficiencies (folate, vitamin B12), sepsis, myelodysplastic syndrome impairs platelet production in the bone marrow - these conditions also associated with decreased production of other cell lines leading to anemia and leukopenia

Increased platelet destruction[15][16][17][18][14][19]:

In normal conditions, platelets get removed by monocytes/macrophages of the reticuloendothelial system. The life span of platelets is 8 to 10 days.

In immune-mediated thrombocytopenia, anti-platelet autoantibodies bind to platelets and megakaryocytes, resulting in increased platelet destruction by the reticuloendothelial system and decreased platelet production.

Anti-platelets antibodies are present in primary ITP, drug-induced ITP, lymphoproliferative disorders, autoimmune conditions like SLE and in chronic infections like HEP C, HIV, and Helicobacter pylori.

Non-immune mediated increased platelet destruction occurs in mechanical valve replacement patients, preeclampsia/HELLP syndrome, DIC, and thrombotic microangiopathy. In conditions like DIC and thrombotic microangiopathy, increased platelet consumption within thrombi takes place. 

Dilutional thrombocytopenia[20][21]:

Dilutional thrombocytopenia presents in massive fluid resuscitation and massive blood transfusion.

Redistribution of platelets[22]:

In normal individuals, one-third of platelet mass is in the spleen. In conditions that cause splenomegaly and increases spleen congestion (cirrhosis) results in increased platelet mass in spleen and a decrease in circulating platelets.

Histopathology

Review of peripheral blood smear. Analysis of platelet size and morphology helps in identifying conditions that are associated with platelet destruction and increased platelet consumption.

  • Clumping of platelets occurs when EDTA is used as anticoagulant causing pseudothrombocytopenia.[23]
  • Adhesion of platelets to polymorphonuclear cells is known as “platelet satellitism” can be identified by review of a peripheral blood smear.[24]

  • Giant platelets present in inherited conditions like Bernard-Soulier syndrome.

A review of WBC and RBC morphology may suggest a specific condition.

  • Schistocytes are a feature in thrombotic microangiopathic conditions.
  • Teardrop cells, nucleated RBCs, leukoerythroblastic findings suggest bone marrow infiltrative process.
  • Immature WBCs suggest leukemia.
  • Megaloblastic process characterized by hypersegmented neutrophils seen in nutritional deficiencies.

History and Physical

History. Obtaining a thorough history helps to identify the etiology of thrombocytopenia. Patients with platelets greater than 50000/mL, rarely have symptoms. Patients with platelets under 20000/mL most likely have spontaneous bleeding.

  • Ask the patient about the prior blood count testing and baseline platelet count. The recent drop in platelet count is concerning.
  • Ask for the history of bleeding (petechiae, hemorrhagic bleeding, gingival bleeding, epistaxis)
  • Ask for any potential exposure and symptoms of infections (viral, bacterial, rickettsial). Assess risk factors for HIV infection. Ask about travel to an area endemic for malaria [25] [26], dengue virus, and Ebola.
  • Obtain a diet history to detect any nutritional deficiencies.
  • Ask about other conditions like SLE, RA, bariatric surgery, and blood transfusion.
  • Review the medication list. Ask whether the patient is taking over the counter medications, quinine-containing beverages, and herbal teas.
  • In the hospitalized patient, look for exposure to heparin products.
  • Check for a family history of thrombocytopenia or bleeding disorders.
  • In pregnant patients ask for headache, visual symptoms, abdominal pain, flu-like symptoms; these patients may have preeclampsia/HELLP syndrome.

Physical Examination includes examining the skin and other sites of bleeding and examination of liver, spleen, and lymph nodes. Bleeding caused by thrombocytopenia characteristically demonstrates petechiae, nonpalpable purpura, and ecchymosis. Dry purpura refers to purpura in the skin; wet purpura refers to purpura in the mucosa. Examine for hepatomegaly and splenomegaly which occur in lymphoma, chronic liver disease, and other hematologic conditions. Enlarged lymph nodes are present in infections, autoimmune disorders, lymphoma, and other malignancies.

Evaluation

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.
  • 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.

Treatment / Management

In asymptomatic, mild thrombocytopenia patients, repeat CBC and routine monitoring is the recommended process.

Thrombocytopenic emergencies that require immediate action includes conditions of suspected HIT, TTP, HUS, drug-induced ITP, pregnancy with severe thrombocytopenia, bleeding with severe thrombocytopenia, urgently needed an invasive procedure in the presence of severe thrombocytopenia, leukopenia, and aplastic anemia.

In patients with bleeding and severe thrombocytopenia, treatment includes platelet transfusion.  

Management includes identifying the underlying cause and treating it.

Primary immune thrombocytopenia:

This condition is a diagnosis of exclusion. First line treatment includes glucocorticoids and intravenous immune globulins; these agents inhibit autoantibody production and platelet degradation. Second line treatment includes rituximab, immunosuppressive drugs, and splenectomy. Third line agents are thrombopoietin receptor agonists, which stimulate platelet production.[27]

Drug-induced thrombocytopenia:

  • Withholding the causative drug usually results in improvement of platelet counts in cases of drug-induced thrombocytopenia.
  • The mainstay of treatment in HIT is to withdraw all heparin products and to initiate anti-thrombin and anti-Xa activity anticoagulant agents. Dicoumarol agents added once platelet count reaches normal.[28][29][30]

TTP gets treated with plasma exchange.[31]

In patients with secondary ITP managing the underlying condition is recommended, like, in SLE, SLE treatment is with immunosuppressive agents, and in patients with H. pylori-associated thrombocytopenia, eradication of H.pylori increases platelet count.[32][33]

Differential Diagnosis

Psuedothrombocytopenia: Invitro platelet clumping results from ethylenediaminetetracetic acid (EDTA) dependent agglutinins, inadequately anticoagulated specimen, glycoprotein IIb/IIIa inhibitors. Giant platelets are counted as white blood cells rather than platelets by an automated counter.

Prognosis

A prospective study, it was found that patients with mild thrombocytopenia (100000 to 150000/microliter) have a 10-year probability of developing autoimmune disorders of 12 %.[34]

Complications

Severe thrombocytopenia is associated with severe internal bleeding. Bleeding in the brain is fatal.

In heparin-induced thrombosis (HIT), arterial and venous thrombosis is seen leading to deep venous thrombosis, pulmonary embolism, cerebrovascular accident, and myocardial infarction.[35]

Antiphospholipid antibody syndrome associated with arterial and venous thrombosis, and abortions.[36][37]

In TTP microvascular thrombosis involving various organ systems predominantly central nervous system, whereas in HUS kidneys are affected.

Consultations

Newly- diagnosed patients with thrombocytopenia are referred to a hematologist to confirm the diagnosis. In patients with unexplained thrombocytopenia, consulting hematologist is the recommendation. Immediate consultation is necessary for conditions like TTP, HUS, HIT, aplastic anemia, leukemia, and other bone marrow failure conditions.

Pregnant patients with HELLP/preeclampsia require an obstetrician consultation.

Deterrence and Patient Education

Educate patients about activity restrictions. Patients with a platelet count over 50000/mL should be cautious while participating in contact sports. Restriction from contact sports and other potentially traumatic activities is recommended in patients with platelets count under 10000/ mL.[34][38]

Educate patients that certain over the counter medications like aspirin, Non-steroidal anti-inflammatory drugs, and ginkgo biloba interfere with platelet function. Educate patients about quinine-containing beverages and herbal teas, causing the low platelet count.

Enhancing Healthcare Team Outcomes

Due to the complexity of this condition, management of emergent thrombocytopenic conditions requires a multidisciplinary team of health care professionals, including specialty-trained nursing, pharmacists, physicians, and specialists working together collaboratively to achieve optimal patient outcomes.


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Thrombocytopenia - Questions

Take a quiz of the questions on this article.

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A patient is seen in the clinic with general malaise. His blood smear reveals thrombocytopenia. A bone marrow aspirate is obtained and shows an increased number of megakaryocytes, revealing that he may have which of the following?



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An 85-year-old male who lives in a nursing home presented with fatigue, malaise, arthralgias, and petechiae. On physical exam, the patient is noted to be cachectic, has a perifollicular hemorrhage, follicular hyperkeratosis, and bleeding gums. Which of the following lab findings would be expected to be seen in this patient?



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A 38-year-old female presented to her family provider for a routine health check-up. Routine CBC shows hemoglobin of 12.5 gm/dl, white blood cell count of 4.8 bil/L, and platelets 360,000/microL. Urinalysis showed microscopic hematuria. Prothrombin time (PT) is normal and activated partial thromboplastin time (aPTT) is prolonged. This presentation is most consistent with which of the following?



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A 30-year-old female presented to her primary care physician with a non-pruritic rash. Patient reports occasional episodes of nose bleeding and attributes the nosebleeds to low humidity. She also endorses to drinking tonic water daily and also reports a family history of eczema. What is the most likely cause of the patient's rash?



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A 5-year-old male child followed up with his provider for an itchy rash. Past medical history reveals a history of prolonged bleeding after circumcision, 2 ear infections within the last 1 year and recent hospitalization for pneumonia 6 months ago. Mom also reports that his uncle had a history of prolonged bleeding. On exam, the patient has a dry, scaly erythematous papular rash all over the body and non-blanchable and non-palpable pinpoint macules on both ankles. Given the likely underlying diagnosis, which laboratory value would be most likely in this patient?



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A 16-year-old patient presents status post blunt abdominal trauma with active bleeding necessitating multiple packed red blood cell transfusions. The condition that is expected in this patient is characterized by which of the following?



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A 50-year-old male presented with gingival bleeding. Labs showed thrombocytopenia. On peripheral smear review, there are no megakaryocytes seen, indicating which of the following diseases as the likely scenario?



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A patient notices that her gums bleed whenever she brushes her teeth. This has been going on for at least 5 months. Over the past few weeks, she has also noticed tiny bruises on her ankles and lower leg. She denies any illness, use of medications, or trauma. Which of the following is the next best step in management?



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A 17-year-old male patient presents with a history of severe acute diarrhea for two days. He had a past medical history of pharyngitis two weeks ago with a rash, which is now resolved. On physical examination, he shows signs of dehydration and small petechial patches over the trunk and in the buccal mucosa. A nurse tries to insert a peripheral line for intravenous hydration, but the peripheral veins are very difficult to identify, so the nurse decides to insert a central venous line. As soon as the provider inserts a central line, there is uncontrolled bleeding at the site of insertion. Which clotting parameter must be determined before insertion of a central line and what is the minimum value of the test that the patient should have before a central line is inserted?



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A 31-year-old male patient presented with bleeding gums. Review of systems is positive for blurry vision. Physical examination revealed bilateral cataracts. On laboratory evaluation, CBC shows hemoglobin of 12.5 gm/dl, white blood cell count of 4800 per microliter, platelets 45,000/microL, blood urea nitrogen 42 mg/dl, and serum creatinine 1.5 mg/dl. The peripheral blood smear shows giant platelets. Based on the physical examination and laboratory values, which of the following is the most likely diagnosis?

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    Contributed by David Lynch, MD
Attributed To: Contributed by David Lynch, MD



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A 67-year-old male presents to the clinic with a chief complaint of bleeding gums while brushing teeth for the last 3 months. He reports that he moved to the United States from Japan 10 years ago. He also reports occasional heartburn and a rash on his legs. On physical exam, he is noted to have petechiae on bilateral ankles. Laboratory workup shows a hemoglobin of 14.5 gm/dL, a white blood cell count of 4500/microL, and a platelet count of 50,000/microL. The coagulation profile and peripheral blood smear are normal. Which of the following is the next best step in the management of this patient?



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A 50-year-old female presents to the clinic for an annual health check-up. She denies any complaints. A complete review of systems is unremarkable. A physical exam is within normal limits. Routine blood work is without any abnormalities except for a platelet count of 20,000/microL. Which of the following is the next best step in the management of this patient?



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A 21-year-old male presents to the clinic with complaints of epistaxis and easy bruising. A review of systems is otherwise negative except for decreased hearing. His blood pressure is 148/88 mmHg, heart rate is 80/min, the temperature is 36.4 degrees Celcius, the respiratory rate is 12/min, and oxygen saturation is 98% on room air. A complete blood count is significant only for a platelet count of 21,000/microL. Urinalysis showed 4+ proteinuria. Other lab values include a blood urea nitrogen (BUN) of 14 mg/dl, serum creatinine of 1.3 mg/dL, and serum albumin of 2.6 g/dL. Which of the following is most likely to be seen on the patient's peripheral blood smear?



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A 30-year-old female is seen in the clinic for an annual health maintenance visit. She denies any complaints and reports eating healthy along with exercising five days a week. She reports taking over-the-counter multi-vitamins and several other mineral supplements to stay healthy. Routine bloodwork shows a hemoglobin of 13.5 mg/dL, a white blood cell count of 4800/microL, and a platelet count of 90,000/microL. Which of the following mineral deficiency has most likely resulted in thrombocytopenia for this patient?



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A 28-year-old female presents for follow up of her seizure disorder. Her last seizure episode more than one year ago. Patient reports taking all prescribed medications daily. Recently, the patient had a urinary tract infection that was treated with antibiotics. Complete blood count shows a hemoglobin of 13.0 g/dL, white blood cell count of 4200/microL, and platelets 100,000/microL. Which of the following drugs is most likely to cause thrombocytopenia by decreasing platelet production?



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Thrombocytopenia - References

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