Quantitative

Overview of Platelet Quantitative Abnormalities

Platelets (Thrombocytes): Small, anucleate cell fragments essential for hemostasis (blood clotting)
Normal Platelet Count: 150,000 - 450,000 /μL (150-450 x 10^9/L)
Quantitative Abnormalities:
- Thrombocytopenia: Decreased platelet count
- Thrombocytosis: Increased platelet count
Clinical Significance: Abnormal platelet counts can lead to bleeding (thrombocytopenia) or thrombosis (thrombocytosis)
Laboratory Evaluation: Accurate platelet counting and peripheral blood smear examination are essential for diagnosis and management

Thrombocytopenia

Definition: A decreased platelet count, defined as a platelet count <150 x 10^9/L
Classification:
- Based on Mechanism:
  - Decreased Platelet Production: The bone marrow is not producing enough platelets
  - Increased Platelet Destruction: Platelets are being destroyed or consumed at an accelerated rate
  - Sequestration: Platelets are trapped in the spleen
  - Dilutional: As a result of blood transfusions or fluid administration.
- Based on Severity:
  - Mild Thrombocytopenia: 100-150 x 10^9/L
  - Moderate Thrombocytopenia: 50-100 x 10^9/L
  - Severe Thrombocytopenia: <50 x 10^9/L
Pseudothrombocytopenia: A falsely low platelet count due to platelet clumping in the presence of EDTA anticoagulant

Causes of Thrombocytopenia

Decreased Platelet Production:
- Bone Marrow Disorders:
  - Aplastic Anemia: Bone marrow failure with decreased production of all blood cell lines
  - Myelodysplastic Syndromes (MDS): Dysplastic changes in megakaryocytes leading to impaired platelet production
  - Leukemia: Infiltration of the bone marrow by leukemic cells, crowding out normal megakaryocytes
  - Myelofibrosis: Scarring of the bone marrow, impairing megakaryopoiesis
- Infections:
  - Viral Infections: Parvovirus B19, HIV, hepatitis C
  - Bacterial Infections: Sepsis
- Nutritional Deficiencies:
  - Vitamin B12 or folate deficiency (megaloblastic anemia)
  - Iron deficiency
- Alcohol Abuse:
  - Direct toxic effect on megakaryocytes
- Medications:
  - Chemotherapy
  - Thiazide diuretics
  - Alcohol abuse
  - Others
Increased Platelet Destruction:
- Immune Thrombocytopenic Purpura (ITP):
  - Autoantibodies (usually IgG) bind to platelet surface antigens, leading to their destruction by the spleen
  - Can be acute (often in children after viral infection) or chronic (more common in adults)
  - Warm Autoimmune Hemolytic Anemia (AIHA):
    - The RBC is also destroyed
    - Evans Syndrome is having an AIHA and Immune Thrombocytopenia Purpura (ITP) at the same time
  - Drug-Induced Thrombocytopenia:
    - Certain drugs (e.g., heparin, quinine, sulfonamides) can induce antibody formation that leads to platelet destruction
  - Heparin-Induced Thrombocytopenia (HIT):
    - Antibodies against heparin-platelet factor 4 (PF4) complex, leading to platelet activation and thrombosis
- Thrombotic Microangiopathies (TMAs):
  - Thrombotic Thrombocytopenic Purpura (TTP):
    - Deficiency of ADAMTS13, a metalloprotease that cleaves von Willebrand factor (vWF)
    - Large vWF multimers accumulate in the microvasculature, leading to platelet activation, microthrombi formation, and organ damage
    - PENTAD: Thrombocytopenia, Microangiopathic Hemolytic Anemia (MAHA), Neurologic Abnormalities, Fever, and Renal abnormalities.
  - Hemolytic Uremic Syndrome (HUS):
    - Primarily caused by Shiga toxin-producing Escherichia coli (STEC-HUS)
    - Shiga toxin damages endothelial cells in the kidneys, leading to platelet activation, microthrombi formation, and renal failure
    - Triad: Thrombocytopenia, MAHA, and acute kidney injury
  - Disseminated Intravascular Coagulation (DIC):
    - Systemic activation of coagulation and fibrinolysis, leading to consumption of platelets and clotting factors
    - Caused by infection, trauma, malignancy, or obstetric complications
- HELLP Syndrome (Hemolysis, Elevated Liver Enzymes, Low Platelet Count):
  - A complication of pregnancy characterized by hemolysis, elevated liver enzymes, and thrombocytopenia
- Post-Transfusion Purpura (PTP):
  - Rare, delayed hemolytic transfusion reaction in which the patient develops antibodies against platelet antigens, leading to thrombocytopenia
Sequestration:
- Hypersplenism: Enlargement of the spleen, leading to increased trapping and destruction of platelets
Dilutional:
- Massive transfusion or fluid resuscitation may cause dilutional thrombocytopenia

Laboratory Findings

Complete Blood Count (CBC):
- Platelet Count: Decreased (<150 x 10^9/L)
- Other Cell Lines: May be normal or abnormal depending on the underlying cause
  - Anemia: May be present in some cases
  - Leukopenia or Leukocytosis: May be present depending on the cause
Peripheral Blood Smear Examination:
- Platelet Estimate: To confirm the accuracy of the automated platelet count
- Platelet Morphology:
  - Large platelets (megathrombocytes): May be seen in ITP and other conditions with increased platelet turnover
  - Schistocytes (fragmented RBCs): Seen in thrombotic microangiopathies (TTP, HUS, DIC)
- Red Blood Cell Morphology:
  - Spherocytes: May be seen in AIHA
  - Schistocytes: Seen in thrombotic microangiopathies
- Presence of Abnormal Cells:
  - Blasts: May be seen in bone marrow disorders
Bone Marrow Aspiration and Biopsy (If Indicated):
- Megakaryocyte Number: To assess platelet production
  - Increased in thrombocytopenia due to increased destruction
  - Decreased in thrombocytopenia due to decreased production
- Megakaryocyte Morphology: To evaluate for dysplasia
Coagulation Studies (PT, aPTT, Fibrinogen, D-dimer):
- To evaluate for DIC
Direct Antiglobulin Test (DAT or Coombs Test):
- To detect antibodies or complement proteins on the surface of RBCs (used to rule out AIHA)
Specific Tests for Immune-Mediated Thrombocytopenia:
- Platelet Antibody Testing: Detects antibodies against platelet surface antigens (e.g., GPIIb/IIIa, GPIb/IX)
- HIT Antibody Testing: Detects antibodies against heparin-platelet factor 4 (PF4) complex
ADAMTS13 Activity Assay:
- Measures the activity of ADAMTS13, which is decreased or absent in TTP
Stool Shiga Toxin Assay:
- Detects Shiga toxin in the stool, which is associated with STEC-HUS

Thrombocytosis

Definition: An increased platelet count, defined as a platelet count >450 x 10^9/L
Classification:
- Reactive (Secondary) Thrombocytosis:
  - Transient elevation in the platelet count due to an underlying condition
- Primary (Essential) Thrombocythemia (ET):
  - A myeloproliferative neoplasm characterized by sustained thrombocytosis and increased risk of thrombosis and bleeding

Causes of Thrombocytosis

Reactive (Secondary) Thrombocytosis:
- Infections:
  - Acute and chronic infections (bacterial, viral, fungal)
- Inflammation:
  - Rheumatoid arthritis
  - Inflammatory bowel disease (IBD)
  - Vasculitis
- Iron Deficiency Anemia:
  - Mechanism is not fully understood but may involve increased thrombopoietin (TPO) levels
- Splenectomy:
  - Loss of splenic sequestration leads to increased circulating platelets
- Surgery or Trauma
- Malignancy:
  - Certain cancers can stimulate thrombocytosis
- Rebound Thrombocytosis:
  - After recovery from thrombocytopenia
- Physiologic:
  - Exercise
  - Stress
  - Pregnancy
  - Postpartum
Essential Thrombocythemia (ET):
- A myeloproliferative neoplasm characterized by sustained thrombocytosis and increased risk of thrombosis and bleeding
- Caused by mutations in JAK2, CALR, or MPL genes

Laboratory Findings

Thrombocytopenia:
- Platelet Count: Decreased (<150 x 10^9/L)
- Peripheral Blood Smear: Decreased number of platelets, may show large platelets (megathrombocytes)
- Bone Marrow Examination:
  - Increased, normal, or decreased megakaryocytes depending on the cause
Thrombocytosis:
- Platelet Count: Increased (>450 x 10^9/L)
- Peripheral Blood Smear:
  - Increased number of platelets
  - May show large platelets or abnormal platelet morphology
- Tests to Evaluate for Underlying Causes (for Reactive Thrombocytosis):
  - Inflammatory markers (ESR, CRP)
  - Iron studies (serum iron, TIBC, ferritin)
  - Complete blood count (CBC) to assess for infection or other hematologic abnormalities
- Molecular Testing (for Suspected ET):
  - JAK2, CALR, and MPL mutation analysis

Key Terms

Thrombocytopenia: Decreased platelet count (<150 x 10^9/L)
Thrombocytosis: Increased platelet count (>450 x 10^9/L)
Reactive Thrombocytosis: Transient increase in platelet count due to an underlying condition
Essential Thrombocythemia (ET): Myeloproliferative neoplasm with sustained thrombocytosis
Megathrombocytes: Large platelets
JAK2, CALR, MPL: Genes mutated in myeloproliferative neoplasms
ADAMTS13: A metalloprotease that cleaves von Willebrand factor (vWF)
Schistocytes: Fragmented red blood cells
Bone Marrow Aspiration and Biopsy: Procedures to collect and examine bone marrow cells

PLT Destruction

Thrombocytopenia