Reactive Thrombocytosis – Causes, Symptoms, Treatment

Platelets are a component of blood produced in the bone marrow that plays a vital role in the blood clotting process. The normal platelet? count in adults and children is 150,000/microL to 450,000/microL (150 to 450 x 10/L), but the normal range may vary in different clinical laboratories. Thrombocytosis is a condition where the platelet count exceeds 450,000/μl.[rx] It is also referred to as thrombocythemia. Thrombocytosis can be divided into two groups:  primary thrombocytosis and secondary (or reactive) thrombocytosis.[rx]

This distinction between primary and secondary thrombocytosis is important as it carries implications for evaluation, prognosis?, and treatment. Primary thrombocytosis is due to the unregulated abnormality of platelet? production of bone marrow progenitor cells.[rx] They are usually associated with the myeloproliferative neoplasms group. Primary thrombocytosis, especially essential thrombocythemia and polycythemia vera, has an increased risk of thrombosis? and bleeding compared to secondary thrombocytosis.[rx]

Secondary thrombocytosis, also known as reactive thrombocytosis defined as an abnormally high platelet? count due to underlying events, disease, or the use of certain medications. Secondary thrombocytosis is the more common type and is usually identified in routine laboratory results. Among individuals with thrombocytosis, 80% to 90% are known to have secondary thrombocytosis.[rx] Reactive causes of thrombocytosis include transient processes such as acute? blood loss, acute infection?, or sustained forms of reactive thrombocytosis include iron deficiency, asplenia, cancer, chronic? inflammatory, or infectious diseases. Secondary thrombocytosis (reactive thrombocytosis) is a laboratory anomaly that resolves when the underlying causative condition is addressed.

In most cases, the symptoms are due to an underlying disorder and not the thrombocytosis itself. Extreme thrombocytosis may rarely result in thrombotic events such as acute? myocardial infarction?, mesenteric vein thrombosis?, and pulmonary embolism?.[rx] Even though secondary thrombocytosis is benign?, the underlying etiology of thrombocytosis (e.g., malignancy, connective tissue disorders, chronic? infections) can be associated with an increased risk of adverse outcomes.

Causes of Reactive Thrombocytosis

Common causes of secondary thrombocytosis

• Infections (acute? bacterial? and viral? infections/chronic? infections like tuberculosis)
• infection?, or irritation, often causing pain?, swelling?, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।" data-rx-term="inflammation" data-rx-definition="Inflammation is the body’s response to injury, infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।">Inflammation?
• Functional and surgical asplenia
• Hemorrhage/ iron deficiency
• Drugs- aztreonam, ceftazidime, ibuprofen, epinephrine, glucocorticoids
• swelling?, stiffness?, or reduced movement. সহজ বাংলা: জয়েন্টের প্রদাহ।" data-rx-term="arthritis" data-rx-definition="Arthritis means joint inflammation causing pain, swelling, stiffness, or reduced movement. সহজ বাংলা: জয়েন্টের প্রদাহ।">arthritis?: Rheumatoid arthritis is an autoimmune? joint disease causing infection?, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।" data-rx-term="inflammation" data-rx-definition="Inflammation is the body’s response to injury, infection, or irritation, often causing pain, swelling, heat, or redness. সহজ বাংলা: শরীরের প্রদাহ; ব্যথা, ফোলা বা লালভাব হতে পারে।">inflammation?, pain, and swelling. সহজ বাংলা: রোগপ্রতিরোধ ব্যবস্থার ভুল আক্রমণে জয়েন্টের প্রদাহ।" data-rx-term="rheumatoid arthritis" data-rx-definition="Rheumatoid arthritis is an autoimmune joint disease causing inflammation, pain, and swelling. সহজ বাংলা: রোগপ্রতিরোধ ব্যবস্থার ভুল আক্রমণে জয়েন্টের প্রদাহ।">Rheumatoid arthritis?, IBD (Inflammatory bowel disease), sarcoidosis
• Hemolysis
• Metastatic cancer/lymphoma
• Allergic reactions
• Exercise[rx]

Symptoms Of Reactive Thrombocytosis

• 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 Reactive Thrombocytosis

History and Physical

Most patients are asymptomatic and are usually identified on routine laboratory results. History should evaluate the condition that may have precipitated the thrombocytosis or complications of thrombocytosis:

• Prior trauma or surgery
• History of splenectomy or hemolysis
• Findings suggesting infection or inflammation
• History of bleeding (e.g., menorrhagia, gastrointestinal) or iron deficiency
• History of arterial or venous thrombosis
• Medications
• Smoking and alcohol consumption
• Prior diagnosis of a chronic hematologic disorder
• Unexplained fever, sweats, weight loss, fatigue, or other systemic complaints suggesting malignancy

No distinguishing features of secondary thrombocytosis (reactive thrombocytosis) are found on physical examination but should look for

• Cutaneous or mucosal bleeding/bruising
• Lymphadenopathy
• Hepatosplenomegaly
• Signs of arterial or venous thrombosis

Lab Test And Imaging

The laboratory workup  of secondary thrombocytosis (reactive thrombocytosis) includes the following:

• Complete blood count shows an increased platelet count
• Peripheral Blood Smear
• Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
• Antinuclear antibody (ANA), rheumatoid factor (RF)
• Iron studies (serum iron, serum ferritin)

If the clinical condition does not differentiate between primary and secondary thrombocytosis, further tests like genetic testing and a bone marrow biopsy may be indicated.

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 Reactive Thrombocytosis

Secondary thrombocytosis has no specific treatment, but the identification of reactive conditions and appropriate therapy of the underlying disorder is most relevant.[rx] For example, the normalization of platelet counts can be achieved by iron supplementation in inflammatory bowel patients.[rx][rx]

Treatment with anti-platelets like aspirin is usually not indicated as the risk of thrombosis is very low in secondary thrombocytosis. Still, it can be considered for patients with platelets more than 1,000,000/μL, and complications of thrombocytosis are present, or to be at risk of developing complications.[rx] The platelet-reducing effect of the plateletpheresis is done in patients with evidence of thrombosis and active bleeding. Though plateletpheresis is temporary, it helps in the rapid reduction of the platelet count.

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]

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]

Complications

Physicians need to be familiar with the complications associated with thrombocytosis. However, complications due to secondary thrombocytosis are rare.

• Arterial and venous thrombosis leading to stroke, myocardial infarction, mesenteric ischemia
• Bleeding
• Spontaneous abortion
• IUD- intrauterine death/ intrauterine growth retardation
• Transformation to AML and primary myelofibrosis