Thrombocytopenia

Aka: Thrombocytopenia, Low Platelets, Low Platelet Count

1. Definitions
   1. Thrombocytopenia
      1. Decreased Platelet Count below 100k to 150k
2. See Also
   1. Thrombocytopenia Causes
   2. Platelet Dysfunction
   3. Purpura
3. History
   1. Family History of Thrombocytopenia
      1. Consider congenital Thrombocytopenia Causes
   2. Chronic Liver Disease
      1. Thrombocyteopenia is present in at least two thirds of Chronic Liver Disease patients
      2. Platelet Transfusions or thrombopoetin receptor agonists (e.g. avatrombopag, lusutromobopag) may be used prior to procedures
      3. Causes
         1. Thrombopoetin is synthesized in the liver and is reduced in Chronic Liver Disease (Platelet synthesis, in turn, is reduced)
         2. Splenic Sequestration (Portal Hypertension)
         3. Bone Marrow suppression
   3. Comorbid conditions
      1. Heart Valve Replacement
      2. Rheumatoid Arthritis
      3. Systemic Lupus Erythematosus
      4. Inflammatory Bowel Disease
      5. Sarcoidosis
   4. Pregnancy (Thrombocytopenia occurs in 5 to 10% of pregnancies)
      1. Preeclampsia with HELLP Syndrome
      2. Acute Fatty Liver of Pregnancy
         1. Rare third trimester disorder presenting with Abdominal Pain, Nausea, Vomiting and Altered Mental Status
      3. Gestational Thrombocytopenia
         1. Benign condition in second half of pregnancy
         2. Accounts for 80% of Thrombocytopenia in pregnancy (Platelet Count >80k)
         3. Distinguish from mild immune Thrombocytopenia
   5. Alcohol Use Disorder
      1. Alcohol-Induced Thrombocytopenia
         1. Thrombocytopenia is common in Alcohol Dependence
   6. Recent Viral Infection
      1. Immune Thrombocytopenia (ITP) in children follows acute Viral Infection by days to weeks
      2. Cytomegalovirus (CMV)
      3. Epstein Barr Virus (EBV, Mononucleosis)
      4. Varicella Zoster Virus (VZV, Chicken Pox)
      5. Parvovirus B19
      6. HIV Infection
      7. Hepatitis C
   7. Tick Bite (Tick Borne Illness)
      1. Anaplasmosis
      2. Babesiosis
      3. Rocky Mountain Spotted Fever
      4. Lyme Disease
      5. Colorado Tick Fever
   8. Recent international travel (especially tropical)
      1. Dengue Fever
      2. Malaria
      3. Rickettsial Disease
   9. Malignancy
      1. Acute Leukemia
      2. Lymphoma
      3. Chemotherapy or Irradiation
      4. Malignancy with marrow infiltration
      5. Myelodysplastic Syndrome
      6. Aplastic Anemia
   10. Medications
       1. See Drug-Induced Thrombocytopenia
       2. Heparin-Induced Thrombocytopenia
       3. Chemotherapy
       4. Radiation Therapy
       5. Immunizations (MMR Vaccine, Varicella, H1N1 Influenza Vaccine)
       6. Transfusion
          1. Transfusion Reaction
          2. Infection (Hepatitis C or HIV Infection)
4. Exam
   1. Complete exam to identify underlying cause (see below)
   2. Deep bleeding (e.g. hemarthrosis) suggest clotting disorder, not Thrombocytopenia
   3. Signs of bleeding (mucosal and superficial bleeding)
      1. Petechiae
      2. Purpura
      3. Gingival Bleeding
      4. Gastrointestinal Bleeding
      5. Urinary tract bleeding
   4. Evaluate for findings suggestive lymphoproliferative disorder
      1. Lymphadenopathy
      2. Hepatomegaly
      3. Splenomegaly
   5. Evaluate for findings suggestive of thrombosis (Thrombotic Microangiopathy)
      1. Venous Thromboembolism
      2. Vascular Necrosis
      3. End organ injury (e.g. CVA related findings)
5. Symptoms: Clues to Thrombocytopenia Causes
   1. Abdominal Pain
      1. Liver disease
      2. HELLP Syndrome (pregnancy)
      3. Hemolytic Uremic Syndrome (HUS)
      4. Platelet Sequestration (Splenomegaly)
   2. Bloody Diarrhea
      1. Hemolytic Uremic Syndrome (HUS)
   3. Fever
      1. Viral Infections (e.g. CMV, EBV, VZV, HIV, HCV, Parvovirus B19)
      2. Tick Borne Illness (Anaplasmosis, Babesiosis, Rocky Mountain Spotted Fever, Lyme Disease, Colorado Tick Fever)
      3. Fever in the Returning Traveler (Dengue Fever, Malaria, Zika Virus, Rickettsial Disease)
      4. Hemolytic Uremic Syndrome (HUS)
      5. Thrombotic Thrombocytopenic Purpura (TTP)
      6. Drug Induced Thrombotic Microangiopathy
   4. Weight loss or Night Sweats
      1. HIV Infection
      2. Malignancy (e.g. Leukemia)
      3. Myelodysplastic Syndrome
6. Signs: Clues to Thrombocytopenia Causes
   1. Rash
      1. See Purpura (and Petechiae)
      2. Viral Exanthems (VZV, Parvovirus B19)
      3. Rickettsial infections
      4. Systemic Lupus Erythematosus
   2. Generalized Lymphadenopathy
      1. Viral Infections (e.g. CMV, EBV, HIV)
      2. Systemic Lupus Erythematosus
      3. Acute Leukemia, Lymphoma and other hematiologic malignancies
   3. Hepatomegaly
      1. Chronic Liver Disease
      2. Acute Leukemia
      3. Viral Infections (CMV, EBV, HCV)
   4. Splenomegaly
      1. Viral Infections (CMV, EBV)
   5. Neurologic findings
      1. Thrombotic Thrombocytopenic Purpura (TTP)
   6. Renal Failure
      1. Thrombotic Thrombocytopenic Purpura (TTP)
      2. Hemolytic Uremic Syndrome (HUS)
   7. Combined Bleeding AND Thrombosis (immune complex mediated Thrombotic Microangiopathy)
      1. See Thrombotic Microangiopathy
      2. Drug-Induced Thrombotic Microangiopathic Anemia
      3. Antiphospholipid Syndrome
      4. Heparin Induced Thrombocytopenia
      5. Disseminated Intravascular Coagulation
      6. Thrombotic Microangiopathy
         1. Thrombotic Thrombocytopenic Purpura
         2. Hemolytic Uremic Syndrome
7. Causes
   1. See Thrombocytopenia Causes
   2. Categories of Thrombocytopenia
      1. Decreased Platelet production (e.g. Viral Infection, medications, radiation, B12 Deficiency, marrow infiltration)
      2. Increased Platelet destruction (e.g. ITP, TTP, HUS, DIC)
      3. Platelet loss
      4. Splenic Sequestration
8. Labs: Platelet Count Interpretation
   1. Platelet Count 70,000 to 150,000 per uL
      1. Mild Thrombocytopenia
   2. Platelet Count 50,000 to 70,000 per uL
      1. Asymptomatic Moderate Thrombocytopenia
   3. Platelet Count 30,000 to 50,000 per uL
      1. Symptomatic Moderate Thrombocytopenia with excessive bleeding on Traumatic Injury
   4. Platelet Count 10,000 to 30,000 per uL
      1. Severe Thrombocytopenia with excessive bleeding with minimal Skin Trauma
   5. Platelet Count 5,000 to 10,000 per uL
      1. Severe Thrombocytopenia with risk of spontaneous bleeding, Bruising or Petechiae
      2. Spontaneous bleeding requiring intervention (e.g. Nasal Packing for Epistaxis) required in 42% of patients
   6. Platelet Count below 5,000 per uL
      1. Emergent Thrombocytopenia with high risk of major spontaneous bleeding (e.g. Gastrointestinal Tract, genitourinary tract)
9. Labs: Initial Evaluation of Thrombocytopenia
   1. Complete Blood Count (CBC)
   2. Basic chemistry panel (chem8)
      1. Evaluate for associated Renal Failure (e.g. TTP, HUS)
      2. Expand to comprehensive panel in Hemolysis
         1. Indirect Bilirubin increased in Hemolysis
         2. Serum Lactate Dehydrogenase and Haptoglobin increased in HUS and TTP
   3. Coagulation tests (INR, PTT, Fibrinogen)
      1. Normal in isolated Thrombocytopenia, ITP, TTP, HUS
      2. Prolonged in DIC, liver disease, Massive Transfusion and Trauma
      3. Fibrinogen is decreased in DIC and Trauma
   4. Peripheral Blood Smear
      1. See Platelet Morphology
      2. See Peripheral Blood Smear
      3. Schistocytes are present in DIC and Microangiopathic Hemolytic Anemia (TTP, HUS), but not ITP
      4. Giant Platelets are seen in congenital Thrombocytopenia and Immune Thrombocytopenic Purpura
      5. Consider Parasite stains (Tick Borne Illness, Malaria)
      6. Hemolysis will raise Indirect Bilirubin
   5. Platelet Count
      1. Rule-out Pseudothrombocytopenia
         1. Review Peripheral Smear to evaluate for clumping (Pseudothrombocytopenia)
         2. Repeat manual Platelet Count in non-EDTA Anticoagulant (Heparin or Sodium citrate, blue tube)
      2. Repeat Platelet Count timing (adjust based on chronicity, stability and bleeding complications)
         1. Repeat immediately for developing bleeding complications
         2. Repeat in days to 1 week if Platelet Count <50,000 per uL (and refer to hematology)
         3. Repeat in 2 weeks, and then every 3 months if Platelet Count <100,000 per uL
         4. Repeat in 4 weeks, and then every 3-6 months if Platelet Count <150,000 per uL
   6. Other testing to consider
      1. Thyroid Stimulating Hormone (TSH)
      2. Serum Vitamin B12
      3. Serum Folate
      4. Autoimmune Syndrome Testing
      5. Disseminated Intravascular Coagulation panel
         1. Fibrinogen
         2. D-Dimer
         3. INR
         4. PTT
      6. Hemolysis Screening
         1. Lactate Dehydrogenase
         2. Total Bilirubin and Direct Bilirubin
         3. Direct Antiglobulin Test (Coombs test)
         4. Haptoglobin
      7. Viral Serology
         1. Hepatitis C
         2. HIV Test
         3. Monospot (or EBV and CMV specific titers)
         4. Other viral serologies as indicated
10. Management: General Approach
    1. Management precautions
       1. Avoid platalet transfusion in Hemolytic Uremic Syndrome, Thrombotic Thrombocytopenic Purpura
       2. Avoid Corticosteroids in suspected malignancy (until cancer evaluation and staging)
       3. Distinguish acute from chronic Thrombocytopenia (obtain old blood counts for comparison)
          1. Chronic Thrombocytopenia is less likely to result in acute emergent conditions
    2. Hospitalization Indications
       1. Multiple cell lines (e.g. Anemia, Leukopenia) affected in addition to significant Thrombocytopenia
       2. Severe acute illness (e.g. Sepsis)
       3. Platelet Count <10,000/uL
       4. Hemolysis (e.g. fragmented Red Blood Cells) on Peripheral Smear
          1. Microangiopathic Hemolytic Anemia (TTP, HUS)
          2. Disseminated Intravascular Coagulation (DIC)
       5. Thrombotic Microangiopathy (with findings of thrombosis)
          1. Drug-Induced Thrombotic Microangiopathic Anemia
          2. Antiphospholipid Syndrome
          3. Heparin Induced Thrombocytopenia (HIT)
          4. Disseminated Intravascular Coagulation (DIC)
          5. Thrombotic Microangiopathy
             1. Thrombotic Thrombocytopenic Purpura (TTP)
             2. Hemolytic Uremic Syndrome (HUS)
    3. Red Flag Findings accompanying Thrombocytopenia indicating Hematology Referral
       1. Leukopenia or Leukocytosis
       2. Anemia
       3. Peripheral Blood Smear abnormalities
       4. Symptomatic Thrombocytopenia with Bleeding Diathesis, Petechiae, Purpura or Ecchymosis
       5. Platelet Count <50,000 per uL (or persistently below 100,000 per uL on repeat testing)
    4. Platelet Findings regarding no further evaluation
       1. Pseudothrombocytopenia (clumped Platelets on Peripheral Smear)
       2. Gestational Thrombocytopenia without findings of Preeclampsia or HELLP Syndrome
    5. Empiric Management and Other Considerations
       1. Eliminate Drug-Induced Thrombocytopenia Causes
       2. Consider acute infectious causes (Rickettsia, CMV, EBV, VZV, Zika Virus, Parvovirus B19, Tick Borne Illness, HIV, Hepatitis C)
    6. Findings most suggestive of Immune Thrombocytopenic Purpura
       1. Isolated Thrombocytopenia without systemic findings, obvious triggers (e.g. medications, infections, pregnancy)
       2. Platelet Count >50,000
       3. Giant Platelets on Peripheral Smear
    7. Disposition home Indications
       1. Isolated Thrombocytopenia >30,000/mm3 without signs of bleeding in children
       2. Isolated Thrombocytopenia >30,000 to 50,000/mm3 without signs of bleeding in adults
       3. No serious cause suspected of Thrombocytopenia (i.e. not HUS, TTP, HIT, DIC)
          1. Less severe causes include ITP and Drug induced Thrombocytopenia
       4. Reliable patient or family
          1. No NSAIDS
          2. Follow activity restrictions as below
    8. Follow-up
       1. Hematology Consultation for Platelet Count <50,000 or other indications as above
       2. Platelet Count at intervals
          1. Repeat in days to 1 week if Platelet Count <50,000 per uL (and refer to hematology)
          2. Repeat in 2 weeks, and then every 3 months if Platelet Count <100,000 per uL
          3. Repeat in 4 weeks, and then every 3-6 months if Platelet Count <150,000 per uL
11. Management: Activity and Procedure Limitations
    1. Platelet Count >50,000 per uL
       1. No limitations to activity or procedures
       2. Use caution in Collision Sports with Thrombocytopenia
       3. Most surgical procedures can be perfromed safely at this Platelet Count (preoperative Platelet Transfusion targets 50k/uL)
       4. Epidural Anesthesia is safe at 50,000 per uL, but >100,000 per uL is preferred
    2. Platelet Count >20,000 per uL
       1. Bone Marrow Biopsy, bronchoscopy, Central Lines and endoscopy can be performed
       2. LImit Exercise to walking, range of motion, stationary cycling, elastic band Resistance Training
    3. Platelet Count <10,000 per uL
       1. Indication for emergent Platelet Transfusion
       2. Risk of spontaneous bleeding
       3. Avoid Collision Sports and other activities with risk of Traumatic Injury
12. Prognosis
    1. Isolated mild Thrombocytopenia (100k to 150k/uL)
       1. Over 10 years, nearly two thirds of patients in one study normalized or remained with stable mild Thrombocytopenia
       2. Only 7% developed Immune Thrombocytopenia, and 12% developed another autoimmune disorder
       3. Myelodysplastic Syndrome developed in only 2% of the patients
       4. Stasi (2006) PLoS Med 3(3): e24 [PubMed]
13. References
    1. Merrill and Gillen (2016) Crit Dec Emerg Med 30(3): 3-8
    2. Gauer (2012) Am Fam Physician 85(6): 612-22 [PubMed]
    3. Gauer (2022) Am Fam Physician 106(3): 288-98 [PubMed]
    4. George (2000) Lancet 355(9214):1531-9 [PubMed]
    5. Goldstein (1996) Am Fam Physician 53(3):915-20 [PubMed]
    6. Rizvi (1999) Curr Opin Hematol 6(5):349-53 [PubMed]