Destruction

Overview of Thrombocytopenias due to Increased Destruction

Definition of Thrombocytopenia: Abnormally low platelet count, defined as a platelet count less than 150 x 10^9/L (150,000/µL)
Clinical Significance: Increases the risk of bleeding, ranging from minor skin bruising to severe or life-threatening hemorrhages
Major Causes of Thrombocytopenia Due to Increased Destruction (Immune and Non-Immune):
- Immune Thrombocytopenic Purpura (ITP)
- Thrombotic Thrombocytopenic Purpura (TTP)
- Heparin-Induced Thrombocytopenia (HIT)
- Disseminated Intravascular Coagulation (DIC): Consumptive Coagulopathy, may also be due to non-immune consumptive process
- Hemolytic Uremic Syndrome (HUS)
General Laboratory Findings:
- Reduced platelet count.
- Normal or increased megakaryocytes in the bone marrow (in thrombocytopenias due to increased destruction)
- Prolonged bleeding time and/or abnormal platelet function tests
- Other findings specific to each disorder (see below)

Immune Thrombocytopenic Purpura (ITP)

Definition: An acquired autoimmune disorder characterized by isolated thrombocytopenia (low platelet count) with normal bone marrow and no other causes of thrombocytopenia
Also Known As: Idiopathic Thrombocytopenic Purpura
Types:
- Primary ITP: No identifiable underlying cause
- Secondary ITP: Associated with underlying conditions, such as:
  - Autoimmune disorders (e.g., SLE, rheumatoid arthritis)
  - Infections (e.g., HIV, hepatitis C, Helicobacter pylori)
  - Lymphoproliferative disorders (e.g., CLL)
  - Medications
Pathophysiology:
- Autoantibody Production: Autoantibodies (typically IgG) are produced against platelet membrane glycoproteins (e.g., GPIIb/IIIa, GPIb/IX)
- Platelet Destruction: Antibody-coated platelets are recognized and destroyed by macrophages in the spleen (extravascular hemolysis)
- Impaired Platelet Production: Some autoantibodies may also target megakaryocytes, impairing platelet production
Clinical Features:
- Many patients are asymptomatic
- Bleeding Manifestations:
  - Petechiae (small, pinpoint hemorrhages)
  - Purpura (bruising)
  - Nosebleeds (epistaxis)
  - Gum bleeding
  - Menorrhagia (heavy menstrual periods)
  - Gastrointestinal bleeding (less common)
  - Intracranial hemorrhage (rare but life-threatening)
Laboratory Findings:
- Complete Blood Count (CBC):
  - Isolated thrombocytopenia (platelet count <150 x 10^9/L)
  - Normal hemoglobin, white blood cell count, and differential
- Peripheral Blood Smear:
  - Decreased number of platelets
  - May see large platelets (megathrombocytes), reflecting increased platelet production by the bone marrow
  - No other significant abnormalities (e.g., schistocytes, blasts)
- Bone Marrow Aspiration and Biopsy (Not always necessary; usually performed to rule out other causes of thrombocytopenia):
  - Normal or increased megakaryocytes (platelet precursors)
  - Normal cellularity and maturation of other cell lines
- Direct Antibody Test (DAT) for Platelets:
  - Detects the presence of anti-platelet antibodies
  - Not always performed, as the sensitivity and specificity of these tests are limited
- Exclusion of Other Causes of Thrombocytopenia:
  - Rule out drug-induced thrombocytopenia, TTP, HUS, DIC, and other conditions that can cause thrombocytopenia
Diagnosis: Diagnosis of exclusion. ITP is diagnosed when other causes of thrombocytopenia have been ruled out and is supported by normal or increased megakaryocytes in the bone marrow
Treatment:
- Observation: Mild thrombocytopenia in asymptomatic patients may not require immediate treatment
- Corticosteroids: Prednisone or dexamethasone
  - Suppress autoantibody production and decrease platelet destruction
  - First-line treatment for symptomatic ITP
- Intravenous Immunoglobulin (IVIG):
  - Used to rapidly increase the platelet count in patients with significant bleeding or requiring urgent surgery
  - Mechanism: Blocks Fc receptors on macrophages, reducing platelet destruction
- Anti-D Immunoglobulin (WinRho):
  - Used in Rh-positive patients with ITP
  - Mechanism: Antibody-coated RBCs are then cleared by the spleen, “sparing” the platelets from destruction
- Rituximab:
  - Anti-CD20 monoclonal antibody that depletes B cells, reducing autoantibody production
  - Used in patients who are refractory to corticosteroids and IVIG
- Thrombopoietin Receptor Agonists (TPO-RAs):
  - Eltrombopag and romiplostim
  - Stimulate platelet production by binding to and activating the thrombopoietin receptor on megakaryocytes
  - Used in patients who have failed other treatments
- Splenectomy:
  - Surgical removal of the spleen
  - Used in patients with severe, refractory ITP
  - Increases the risk of infection with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis)
  - Patients require vaccination before splenectomy

Thrombotic Thrombocytopenic Purpura (TTP)

Definition: A life-threatening thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia
Hallmark: Pentad of Thrombocytopenia, Microangiopathic Hemolytic Anemia, Neurologic Abnormalities, Fever, and Renal Abnormalities
Types:
- Acquired TTP:
  - Autoimmune: Antibodies against ADAMTS13
  - Idiopathic: No known underlying cause
  - Secondary: Associated with pregnancy, autoimmune disorders, medications, or stem cell transplantation
- Hereditary TTP (Upshaw-Schulman Syndrome):
  - Inherited deficiency of ADAMTS13
Pathophysiology:
- ADAMTS13 Deficiency: Reduced or absent activity of ADAMTS13, a metalloprotease that cleaves von Willebrand factor (vWF)
- vWF Multimer Accumulation: Ultra-large vWF multimers accumulate in the microvasculature
- Platelet Activation and Microthrombi Formation: vWF multimers bind to platelets, leading to platelet activation, aggregation, and the formation of microthrombi in small blood vessels
- Microangiopathic Hemolytic Anemia (MAHA): RBCs are damaged as they pass through the microthrombi, resulting in fragmentation (schistocytes) and hemolysis
- Thrombocytopenia: Platelets are consumed in the formation of microthrombi
- Organ Ischemia: Microthrombi obstruct blood flow to vital organs (brain, kidneys, heart), leading to organ damage
Clinical Features:
- Thrombocytopenia: Bleeding manifestations (petechiae, purpura, etc.)
- Microangiopathic Hemolytic Anemia (MAHA): Fatigue, pallor, jaundice
- Neurologic Abnormalities: Headache, confusion, seizures, stroke
- Fever
- Renal Abnormalities: Elevated creatinine, hematuria, proteinuria
Laboratory Findings:
- CBC:
  - Thrombocytopenia (platelet count <150 x 10^9/L)
  - Anemia (decreased HGB and HCT)
  - Increased reticulocyte count
- Peripheral Blood Smear:
  - Schistocytes (fragmented RBCs)
  - Polychromasia (increased reticulocytes)
  - Decreased platelets
- Coagulation Studies:
  - PT and aPTT: Usually normal
  - Fibrinogen: Normal or slightly increased
  - D-dimer: May be elevated
- Lactate Dehydrogenase (LDH): Elevated (due to hemolysis)
- Indirect Bilirubin: Elevated (due to hemolysis)
- Haptoglobin: Decreased (due to hemolysis)
- Creatinine: Elevated (due to renal involvement)
- ADAMTS13 Activity Assay:
  - Markedly reduced (<10% of normal) in most cases of acquired TTP
  - Absent in hereditary TTP
- ADAMTS13 Inhibitor Assay:
  - Detects the presence of autoantibodies against ADAMTS13
Diagnosis: Diagnosis of TTP requires prompt recognition and treatment
Treatment:
- Plasma Exchange:
  - Mainstay of treatment
  - Removes vWF multimers and replaces ADAMTS13
- Corticosteroids:
  - To suppress autoantibody production
- Rituximab:
  - Anti-CD20 monoclonal antibody that depletes B cells and reduces autoantibody production
- Caplacizumab:
  - A humanized nanobody that binds to vWF and inhibits its interaction with platelets
  - Reduces the risk of thrombotic events and shortens the duration of plasma exchange
- Avoid Platelet Transfusions: Platelet transfusions may exacerbate the thrombotic process and are generally avoided unless life-threatening bleeding occurs

Heparin-Induced Thrombocytopenia (HIT)

Definition: A potentially life-threatening immune-mediated disorder characterized by thrombocytopenia and an increased risk of thrombosis following exposure to heparin
Types:
- Type I HIT (Non-Immune): Mild, transient thrombocytopenia occurring within the first 2 days of heparin exposure. Not clinically significant
- Type II HIT (Immune-Mediated):
  - Antibodies against heparin-platelet factor 4 (PF4) complex, leading to platelet activation and thrombosis
  - Clinically significant and associated with a high risk of venous and arterial thrombosis
Pathophysiology:
- Heparin-PF4 Complex Formation: Heparin binds to platelet factor 4 (PF4), a positively charged protein released from platelets
- Antibody Production: Patients develop IgG antibodies against the heparin-PF4 complex
- Platelet Activation: IgG antibodies bind to the heparin-PF4 complex on platelet surfaces, leading to platelet activation and aggregation via FcγIIa receptors
- Thrombosis: Activated platelets release procoagulant factors, leading to thrombin generation and thrombosis
- Thrombocytopenia: Platelets are consumed in the formation of thrombi and cleared from the circulation
Clinical Features:
- Thrombocytopenia: Typically occurs 5-10 days after starting heparin (but can occur earlier with prior heparin exposure)
- Thrombosis: Venous and arterial thromboembolic events (e.g., DVT, pulmonary embolism, stroke, limb ischemia, skin necrosis)
- Skin Necrosis at Heparin Injection Sites
- Systemic Reactions: Chills, fever, dyspnea (less common)
Laboratory Findings:
- CBC:
  - Thrombocytopenia (platelet count typically <150 x 10^9/L, but can be variable)
- Peripheral Blood Smear:
  - Usually normal; may see large platelets
- HIT Antibody Testing:
  - Screening Assay: ELISA or immunoturbidimetric assay to detect antibodies against heparin-PF4 complex (high sensitivity, but lower specificity)
  - Confirmatory Assay: Serotonin Release Assay (SRA) or Heparin-Induced Platelet Activation (HIPA) assay (high specificity)
- Coagulation Studies:
  - aPTT: May be prolonged, normal, or shortened
- D-dimer: Elevated
Diagnosis: 4Ts Scoring System
- Thrombocytopenia: Degree and timing of platelet count fall
- Timing: When did the thrombocytopenia occur in relation to Heparin use
- Thrombosis: Presence of new thrombosis or skin necrosis
- Other Causes for Thrombocytopenia: Absence of other obvious causes of thrombocytopenia
Treatment:
- Stop Heparin Immediately: This is the most important step
- Administer Alternative Anticoagulant:
  - Direct Thrombin Inhibitors (DTIs): Argatroban, bivalirudin
  - Fondaparinux: A synthetic pentasaccharide that inhibits factor Xa
- Avoid Platelet Transfusions: Platelet transfusions may exacerbate thrombosis in HIT
- Warfarin: Should be avoided acutely due to the risk of venous limb gangrene; can be initiated once the platelet count has recovered and the patient is on a stable dose of a non-heparin anticoagulant

Key Terms

Thrombocytopenia: Decreased platelet count (<150 x 10^9/L)
ITP (Immune Thrombocytopenic Purpura): Autoimmune destruction of platelets
TTP (Thrombotic Thrombocytopenic Purpura): Microangiopathic hemolytic anemia and thrombocytopenia due to ADAMTS13 deficiency
HUS (Hemolytic Uremic Syndrome): Microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury
DIC (Disseminated Intravascular Coagulation): Systemic activation of coagulation and fibrinolysis
Schistocytes: Fragmented red blood cells
ADAMTS13: A metalloprotease that cleaves von Willebrand factor (vWF)
Heparin-Induced Thrombocytopenia (HIT): Immune-mediated thrombocytopenia caused by antibodies against heparin-PF4 complex
Heparin-Platelet Factor 4 (PF4) Complex: Target for antibodies in HIT
Haptoglobin: Protein that binds free hemoglobin released into the plasma
Microangiopathic Hemolytic Anemia (MAHA): Hemolytic anemia caused by mechanical destruction of RBCs in small blood vessels

Thrombocytopenia

Production