Thrombocytopenia – Causes, Symptoms, Diagnosis, Treatment

Thrombocytopenia is a platelet count below the lower limit of normal, i.e., 150000/microliter (for adults). This activity reviews the etiology, evaluation, and management of thrombocytopenia and highlights the role of the interprofessional team in improving care for patients with this condition.

Thrombocytopenia is a condition in which you have a low blood platelet count. Platelets (thrombocytes) are colorless blood cells that help blood clot. Platelets stop bleeding by clumping and forming plugs in blood vessel injuries

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).

Causes of Thrombocytopenia

Common causes of thrombocytopenia

• 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)[rx][rx][rx][rx]][rx]
• 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

• Myelodysplasia
• Malignancy: cancer with chronic DIC, cancer with marrow suppression (leukemia, lymphoma, solid tumors)
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Thrombotic microangiopathy (TMA)[rx]
  • 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

Decreased platelet production

• 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[rx][rx][rx]

Increased platelet destruction

• 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.[rx][rx][rx][rx][rx][rx]
• 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. [rx][rx]

Dilutional thrombocytopenia

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

Redistribution of platelets

• 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 the spleen and a decrease in circulating platelets.

or

Thrombocytopenia can be inherited or acquired.^[rx]

Decreased production

Abnormally low platelet production may be caused by:^[rx]

• Dehydration, Vitamin B₁₂ or folic acid deficiency
• Leukemia, myelodysplastic syndrome, or aplastic anemia
• Decreased production of thrombopoietin by the liver in liver failure
• Sepsis, systemic viral or bacterial infection
• Leptospirosis
• Hereditary syndromes
  • ACTN1-related thrombocytopenia
  • Amegakaryocytic thrombocytopenia with radio-ulnar synostosis
  • ANKRD26 related thrombocytopenia
  • Autosomal dominant thrombocytopenia
  • Bernard–Soulier syndrome (associated with giant platelet disorder)
  • Congenital amegakaryocytic thrombocytopenia
  • Congenital amegakaryocytic thrombocytopenia and radioulnar synostosis
  • CYCS-related thrombocytopenia
  • Epstein syndrome (associated with giant platelet disorder)
  • ETV6 related thrombocytopenia
  • Fanconi anemia
  • Filaminopathies A
  • FYB related thrombocytopenia
  • Glanzmann’s thrombasthenia
  • GNE myopathy with congenital thrombocytopenia
  • Gray platelet syndrome (associated with giant platelet disorder)
  • Harris platelet syndrome (associated with giant platelet disorder)
  • Macrothrombocytopenia and hearing loss
  • May–Hegglin anomaly (associated with giant platelet disorder)
  • MYH9-related disease]] (associated with giant platelet disorder)
  • PRKACG-related thrombocytopenia
  • Paris-Trousseau thrombocytopenia/Jacobsen syndrome
  • Sebastian syndrome
  • SLFN14-related thrombocytopenia
  • Stormorken syndrome
  • TRPM7-related thrombocytopenia
  • Thrombocytopenia absent radius syndrome
  • Tropomyosin 4-related thrombocytopenia
  • TUBB1-related thrombocytopenia
  • Upshaw–Schulman syndrome
  • Wiskott–Aldrich syndrome
  • X-linked thrombocytopenia
  • X-linked thrombocytopenia with thalassemia

Increased destruction

Abnormally high rates of platelet destruction may be due to immune or nonimmune conditions, including

• Immune thrombocytopenic purpura
• Thrombotic thrombocytopenic purpura
• Hemolytic–uremic syndrome
• Disseminated intravascular coagulation
• Paroxysmal nocturnal hemoglobinuria
• Antiphospholipid syndrome
• Systemic lupus erythematosus
• Post-transfusion purpura
• Neonatal alloimmune thrombocytopenia
• Hypersplenism
• Dengue fever
• Gaucher’s disease
• Zika virus

Medication-induced

These medications can induce thrombocytopenia through direct myelosuppression

• Valproic acid
• Methotrexate
• Carboplatin
• Interferon
• Isotretinoin
• Panobinostat
• H₂ blockers and proton-pump inhibitors

Other causes

• Lab error, possibly due to the anticoagulant EDTA in CBC specimen tubes; a citrated platelet count is a useful follow-up study
• Snakebite
• Niacin toxicity
• Lyme disease^[rx]
• Thrombocytapheresis (also called plateletpheresis)
• Niemann–Pick disease^[rx][rx]

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 [rx]. 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% [rx]. 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% [rx] 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) [rx].
• 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 [rx].
• 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.

Symptoms: Clues to Thrombocytopenia Causes

Diagnosis of Thrombocytopenia

History

Your doctor may ask about factors that can affect your platelets, such as:

• The medicines you take, including over-the-counter medicines and herbal remedies, and whether you drink beverages that contain quinine. Quinine is a substance often found in tonic water and nutritional health products.
• Your general eating habits, including the amount of alcohol you normally drink.
• Your risk for AIDS, including questions about blood transfusions, sexual partners, intravenous (IV) drugs, and exposure to infectious blood or bodily fluids at work.
• Any family history of low platelet counts.

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 [rx] [rx], 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 headaches, visual symptoms, abdominal pain, flu-like symptoms; these patients may have preeclampsia/HELLP syndrome.

Physical Examination

• Its includes examining the skin and other sites of bleeding and examination of the 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.

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 an anticoagulant causing pseudo thrombocytopenia.[rx]
• Adhesion of platelets to polymorphonuclear cells is known as “platelet satellites” can be identified by a review of a peripheral blood smear.[rx]
• 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.

Lab and Imaging Test

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

Thrombocytopenic emergencies that require immediate action include 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.

Corticosteroids

Dexamethasone or prednisone is typically prescribed to raise your platelet count. You take it once a day in the form of a pill or tablet. An increased or normalized platelet count is generally seen within 2 weeks of therapy, particularly with high-dose dexamethasone. Your doctor will then likely cut your dose gradually over the next 4 to 8 weeks. The treatment may have to be repeated, but once your platelet count is normal, none is needed again.

Blood transfusion

It temporarily increases platelet levels in your blood. Platelets are transfused only if the platelet count is extremely low. (Transfused platelets only last about three days in the circulation.)

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.[rx]

IVIG (intravenous immune globulin)

If you can’t get your platelet count up with prednisone, if you cannot tolerate steroids, or if your count drops after you’re done with your treatment, your doctor may suggest IVIG. You take this medication through an IV, usually for several hours a day for 1 to 5 days.

Rho(D) immune globulin

This treatment, which you also take through an IV, is an alternative to traditional IVIG in people who have Rh+ blood. It generally takes less than half an hour. The side effects are similar to IVIG. If corticosteroids, IVIG, and Rho(D) aren’t improving your platelet count and you’re having bleeding problems, your doctor may switch to a second set of options. There are pros and cons for each. They include:

Thrombopoietin (TPO) receptor agonists

These drugs are also called platelet growth factors. If you have severely low platelets even after treatment with steroids, surgery to remove the spleen, or rituximab, you will likely do well on these medicines, but you may need to take them long-term.

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.[rx][rx][rx]

TTP gets treated with plasma exchange.[rx]

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 the platelet count.[rx][rx]

Platelet transfusions

Platelet transfusions may be suggested for people who have a low platelet count due to thrombocytopenia.^[rx]

Thrombotic thrombocytopenic purpura

Treatment of thrombotic thrombocytopenic purpura (TTP) is a medical emergency since the associated hemolytic anemia and platelet activation can lead to kidney failure and changes in the level of consciousness. Treatment of TTP was revolutionized in the 1980s with the application of plasmapheresis. According to the Furlan-Tsai hypothesis,^[28] this treatment works by removing antibodies against the von Willebrand factor-cleaving protease ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a normal level of von Willebrand factor multimers. Patients with persistent antibodies against ADAMTS-13 do not always manifest TTP, and these antibodies alone are not sufficient to explain how plasmapheresis treats TTP.^[rx]

Immune thrombocytopenic purpura

Many cases of immune thrombocytopenic purpura (ITP) also known as idiopathic thrombocytopenic purpura, can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts under 50,000 are usually monitored with regular blood tests, and those with counts under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such low platelet counts. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although exceptions to this observation have been documented.^[rx][rx]

Thrombopoietin analogs have been tested extensively for the treatment of ITP. These agents had previously shown promise but had been found to stimulate antibodies against endogenous thrombopoietin or lead to thrombosis. Romiplostim (trade name Nplate, formerly AMG 531) was found to be safe and effective for the treatment of ITP in refractory patients, especially those who relapsed following splenectomy.^[rx]

Heparin-induced thrombocytopenia

Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid thrombosis.^[rx] Treatment may include a direct thrombin inhibitor, such as lepirudin or argatroban. Other blood thinners sometimes used in this setting include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem.^[rx] Warfarin is not recommended until platelets have normalized.^[rx]

Congenital amegakaryocytic thrombocytopenia

Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case.^[rx]

Human-induced pluripotent stem cell-derived platelets

Human-induced pluripotent stem cell-derived platelets is a technology currently being researched by the private sector, in association with the Biomedical Advanced Research and Development Authority and the U.S. Department of Health and Human Services, that would create platelets outside the human body.^[rx]

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