A. Causes [1]

1. True Idiopathic: bone marrow aplasia (megakaryocytopenia) without autoantibodies
2. Autoimmune [2]
   1. ITP (Immune Thrombocytopenic Purpura): normal megakaryocytes
   2. Most cases of ITP are associated with platelets covered with antibodies
   3. Systemic lupus erythematosus (SLE) - usually with increased risk of clots
   4. Anti-phospholipid antibody syndrome - increased risk of clots
   5. Heparin induced thrombocytopenia (HIT)
   6. Antiplatelet antibodies also found in critically ill patients with thrombocytopenia [6]
3. Heparin Induced Thrombocytopenia (HIT) [3,4,5]
   1. Heparin binds platelet factor 4 (PF4) and complex stimulates autoantibody formation
   2. Autoantibodies bind PF4-heparin complex; this trimeric complex aggregates platelets
   3. Leads to reduced platelet counts but increased risk of new and/or extended thromboses
   4. Occurs in 2-5% on standard heparin and <1% on low-molecular weight heparin
   5. Increased risk of clotting due to platelet aggregation (reduced free platelet numbers)
   6. Venous more common (about 3:2) than arterial thrombosis
   7. Increased risk of HIT in patients with anti-phospholipid antibodies
   8. Treatment by discontinuing heparins; use direct thrombin inhibitors
4. Drug Induced Thrombocytopenia [7,15]
   1. Quinidine
   2. Gold - immune mediated, targets platelet glycoprotein V
   3. Trimethoprim / Sulfamethoxazole (TMP/SMX, Bactrim®)
   4. Heparin - through autoimmune mechanisms (HIT; see above)
   5. Interferons - alpha > beta > gamma interferons
   6. Procainamide - related to drug induced lupus syndrome
   7. Quinine
   8. Chemotherapy - mainly bone marrow suppression
   9. Rifampin
   10. Aldomet (alpha-methyldopa)
   11. Vancomycin - immune mediated, rare side effect [25]
   12. Miscellaneous idiopathic reactions
   13. Evidence for thrombocytopenia induced by quinidine, gold, TMP/SMX, heparin is very good [7]
   14. Many of these are immune mediated, inducing antiplatelet antibodies
   15. Drug induced antibodies often against platelet glyproteins IIb/IIIa or Ib/IX
   16. Drugs should ALWAYS be suspected in causing or contributing to thrombocytopenia [8]
5. Viral Infection
   1. Cytomegalovirus (CMV) - bone marrow suppression, especially in neonates [9]
   2. Human Immunodeficiency Virus (HIV) - autoantibodies and marrow suppression
   3. Parvovirus B19 - bone marrow suppression
   4. Neonatal infections - Epstein-Barr Virus, CMV, Parvovirus [13]
   5. Dengue hemorrhagic fever
6. Neoplastic Processes
   1. Myelodysplastic Syndrome
   2. Leukemia (indirect suppression)
   3. Bone Marrow Infiltration by Neoplastic Process: especially Leukemias and Carcinomas
7. Microangiopathic Processes
   1. Thrombotic Thrombocytopenic Purpura (TTP) - may have autoimmune component
   2. Disseminated Intravascular Coagulopathy (DIC)
   3. Severe Preeclampsia (see below)
8. Alloimmune (Isoimmune) [10]
   1. Similar to Rh type disease due to polymorphism of platelet protein IIIa
   2. In humans, two forms of PLA-1 (HPA-1) exist, A and B
   3. Anti-PLA-1A antibodies (Abs) form when mother is PLA-1- and fetus is PLA-1+
   4. These Abs cross placenta and cause destruction of fetal platelets
   5. Neonate delivers with very low platelets and 25-50% risk of cerebral hemorrhage
   6. Intravenous immunoglobulin (IVIg) ± glucocorticoids given to mother is effective
   7. <10% of cases of alloimmune thrombocytopenia have Abs against other platelet proteins
   8. Most common cause of thrombocytopenia in healthy neonates
9. Pregnancy Associated Thrombocytopenia
   1. Immune Thrombocytopenia Purpura (ITP)
   2. TTP and HUS
   3. HELLP Syndrome
   4. Type II von Willebrand Disease
   5. Systemic Lupus Erythematosus and Anti-Phospholipid Syndrome
10. HELLP Syndrome
    1. Complication of pregnancy (severe pre-eclampsia)
    2. Hemorrhage
    3. Elevated Liver enzymes
    4. Low Platelets
    5. This is a form of microangiopathic hemolytic anemia
11. Hyper-IgE (Job) Syndrome
12. Neonatal Thrombocytopenia (Table 2 in Ref [9], Ref [13])
    1. Maternal Antiplatelet antibodies: alloimmune, ITP, systemic lupus, drug-induced antibodies
    2. Congenital Abnormalities: with absent radii, large hemangioma, congenital leukemia
    3. Metabolic Diseases: methylmalonicacidemia, ketotic glycinemia, isovalericacidemia, holocarboxylase synthetase deficiency
    4. Other Genetic Disorders: Fanconi's Anemia, Wiskott-Aldrich Syndrome, trisomy 13, 18, 21
    5. Infections: bacterial sepsis, fungal sepsis, parasites, TORCHS diseases
    6. TORCHS: toxoplasmosis, rubella virus, CMV, HIV, herpes zoster, herpes simplex, syphilis
    7. Hemophagocytic Lymphohistiocytosis - infection, familial, or with rheumatoid arthritis
13. Hereditary Syndromes [11,13]
    1. Epstein's Syndrome - nephritis, deafness, and large platelets with thrombocytopenia
    2. Bernard-Soulier Syndrome - similar to Epstein Syndrome
    3. May-Hegglin Anomaly [12]
    4. Familial hemophagocytic lymphohistiocytosis
14. Familial Hemophagocytic Lymphohistiocytosis [13]
    1. Inherited autosomal recessive disorder
    2. Impaired natural killer and cytotoxic T cell activities
    3. Type 1 due to mutations at chromosome 9q21.3-22 (~10% of cases)
    4. Type 2 due to mutations in perforin gene at chromosome 10q21-22 (~30% of cases)
    5. Unclear genetic causes in remaining cases
    6. Demonstration of impaired perforin mediated natural killer cell activity for diagnosis
    7. Hepatosplenomegaly, pancytopenia, infiltration of histiocytes elsewhere including CNS
    8. Most infants present at age 2-6 months
    9. Allogeneic bone marrow transplantation is only currently effective treatment
15. Thrombocytopenia in Sepsis Syndrome
    1. Hemophagocytosis by macrophages
    2. Macrophage stimulation with increased serum M-CSF in patients with thrombocytopenia
    3. Also associated with DIC and bone marrow suppression (cytokine mediated)
    4. Platelet associated antibodies specific for GPIIb/IIIa, Ib/IX, or others found in 30% of cases of critically ill patients with thrombocytopenia [6,15]
16. Thrombotic Events and Thrombocytopenia
    1. These are conditions where thrombotic events are associated with low platelets
    2. Antiphospholipid Ab Syndrome
    3. HIT (as above) [3,4]
    4. Thrombotic Thrombocytopenic Purpura

B. Symptoms / Signs

1. Purpura: purple colored skin manifestations - leaked blood
2. Ecchymoses (purplish patch on skin), petechiae (minute hemorrhagic spots)
3. Splenomegaly (sequestration) - depends on cause of thrombocytopenia
4. Most patients have no symptoms with platelets >50K/µL
5. Many patients live without symptoms with platelets 30-50K/µL for years
6. Concern for Platelets <30K/µL
   1. Especially with evidence of platelet dysfunction
   2. Intracerebral hemorrhage usually occurs with platelets <10-15K/µL

C. Signs

1. Splenomegaly
2. Cirrhosis (Liver)
3. Bleeding Gums
4. Cerebral hemorrhage
5. Petechiae

D. Evaluation of Platelet Function

1. Peripheral smear - number, size of platelets
2. Bleeding Time
   1. Mainly measures platelet function (clot formation); normal 3-7 minutes
   2. Useful for platelet counts >100K/µL
   3. Normal bleeding time (platelets 10K-100K/µL) = 30.5±(platelet count per µL ÷ 3850)
3. Bleeding Time may be affected by fibrinogen levels, other anti-coagulants
4. Prolonged Bleeding Time: Uremia, Dysglobulinemia, Liver Disease
5. Bone Marrow Biopsy (Aspiration) - number and appearance of megakarycytes
6. Rapid test for antif-heparin/platelet factor 4 antibodies in development [5]

E. Associated Disorders

1. IgA Deficiency (nonsecretory form)
   1. Immune IgA Antibodies ~1% of population has this
   2. Chest syndrome: atypical pneumonia such as mycoplasma, lobar pneumonia (pneumococcus)
   3. Seen also in sickle cell disease
   4. Persons with lower IgA tend to have a more long term/chronic disease.
2. Aplastic Anemia
3. Erythrocytopenia - may be due to antibodies or extrinsic factors
4. Evan's Syndrome
   1. Immune hemolytic anemia
   2. Immune thrombocytopenia (ITP)
   3. Generally more difficult to treat than ITP alone
   4. Often requires splenectomy, intermittant IVIg therapy

F. Treatment

1. Depends on ruling out causes other than Immune Thrombocytopenic Purpura (ITP)
2. Platelet Transfusions
   1. Generally for any person with platelet counts <5K/µL
   2. In chemotherapy induced thrombocytopenia, safe to give only for counts <10K/µL
   3. Platelets should generally be depleted of lymphocytes to reduce alloimmunization [16]
3. Platelet Stimulating Cytokines
   1. Interleukin 11 (IL11)
   2. Thrombopoietin (TPO), related to MGDF, is also under study
   3. Pegylated megakaryocyte growth and development factor (Peg-MDGF) [17]
   4. Eltrombopag - orally active TPO receptor agonist
   5. Additional megakaryocyte (platelet) stimulators are being evaluated
4. Interleukin 11 (IL-11, Neumega®) [18]
   1. FDA approved for chemotherapy induced thrombocytopenia
   2. Derived from bone marrow stromal cells and supports megakaryocytes
   3. Reduces platelet transfusion requirements after chemotherapy
   4. IL11 may have additional efficacy in reducing mucositis; this is being investigated
   5. Adult dose of E. coli derived recombinant human IL11 is 50µg/kg/d sc
   6. Begin dosing 6-24 hours after chemotherapy and continue until platelets >50K/µL
   7. Generalized edema occurs in ~60% of patients
   8. Conjunctival injection also occurs commonly
   9. Tachycardia occurs, and atrial fibrillation has been reported in older persons
   10. Also prevents gut epithelial cell dysintegrity / destruction after chemotherapy [19]
5. Thrombopoietin (TPO) [14,20]
   1. TPO is the ligand for the c-Mpl receptor found on platelets and megakaryocytes
   2. TPO increases bone marrow CD34+ and CD41+ progenitor cells
   3. Single dose of TPO induces platelet increases in 4 days, peaks in 12 days [14]
   4. Serum half life of the well-tolerated drug was 20-30 hours
   5. Multiple doses of recombinant human TPO (rhTPO) are very well tolerated
   6. Multiple doses of rhTPO prevented prolonged carboplatin-induced thrombocytopenia [20]
   7. TPO prior to autologous platelet donation increases harvested platelets 2-4 fold [25]
   8. TPO stimulated, cryopreserved autologous platelets very effective for alleviating chemotherapy induced thrombocytopenia [21]
6. MDGF [26,27]
   1. PEG-conjugated megakaryocyte growth and development factor stimulates platelet counts in ~80% of chronic ITP but can induce anti-MGDF antibodies
   2. These anti-MGDF antibodies can cause severe, persistent thrombocytopenia
   3. Romiplostim (AMG 531) - novel MGDF stimulating domain linked to immunoglobulin Fc protein
   4. Romiplostim given weekly x 6 as subcutaneous injections in chronic ITP patients lead to target platelet levels in 10 of 16 patients without any major adverse events [27]
   5. Romiplostim given weekly x 24 weeks induced durable (>50K/µL) platelet counts in 38% of splenectomized relapsed ITP patients versus 0% in placebo treated patients [30]
   6. Romiplostim given weekly x 24 weeks induced durable (>50K/µL) platelet counts in 88% of non-splenectomized relapsed ITP patients versus 14% in placebo treated patients [30]
   7. Romiplostim did not induce autoantibodies
7. Eltrombopag
   1. Orally active TPO receptor agonist
   2. Stimulates platelet counts, even in chronic disease settings
   3. Good activity in thrombocytopenia associated with hepatitis C viral cirrhosis [28]
   4. Good activity in relapsed or refractory ITP in adults [29]
   5. Side effects after 4-16 weeks similar to placebo
8. HIT [5,22]
   1. Stop heparin, though this is unlikely to be very effective
   2. Thromboembolectomy may be required
   3. Direct thrombin inhibitors lepirudin and argatroban are approved for HIT
   4. Lepirudin (Refludan®) target anticoagulation leads to normalization of platelet counts [23]
   5. Argatroban (Novastan®) - derivative of L-arginine, direct thrombin inhibitor [24]
   6. Glycoprotein IIb/IIIa inhibitors may be used

G. May-Hegglin Anomaly [12]

1. Uncommon hereditary disorder
2. Autosomal dominant inheritance pattern
3. Thrombocytopenia with increased bleeding risk
4. Platelets are increased in size and have various functional abnormalities
   1. No change in shape of platelets after aggregation
   2. Abnormal alpha-tubulin staining
   3. Defective response to epinephrine in some patients
   4. Normal platelet aggregation after ADP, collagen, and ristocetin
5. Platelet transfusions generally required for treatment

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