22 - Platelet Disorders

Question 1

Platelets (Thrombocytes) - Redux

Answer 1

• Cytoplasmic fragments derived from megakaryocytes
• Participate in (primary) hemostasis through interactions with von Willebrand factor (GP1b) and fibrinogen (GPIIb/IIIa)
• Normal platelet counts range from 150,000 – 400,000/μL
• Approximately one-third of circulating platelets are
  normally sequestered in the spleen

Question 2

Platelets and Bleeding

Answer 2

• Thrombocytopenia – platelet count below 150,000/μL, but…
• Platelet counts > 50,000/μL not associated with
  clinical bleeding (unless coexistent functional defect)
• Clinically significant “spontaneous” bleeding occurs with platelet counts below 10,000/μL
• Platelet bleeding typically manifests as more superficial skin and mucous bleeding (petechiae, epistaxis, menorrhagia, etc.)

Question 3

Thrombocytopenia

Answer 3

• Mechanisms
• Decreased production (aplastic anemia, marrow infiltration, marrow suppression)
• Ineffective production (megaloblastic anemia, myelodysplasia)
• Increased destruction/consumption (immune versus
  non-immune)
• Increased sequestration (splenomegaly)
• Hemodilution (transfusion)
• Pseudothrombocytopenia (platelet clumping)

Question 4

Pseudothrombocytopenia

Answer 4

• Artifactual decrease in platelet count
• Inadequate anticoagulant/mixing
• EDTA-dependent agglutinins (0.1% of patients)
• Cold platelet agglutinins
• Redraw draw sample in sodium citrate tube
• May appear as platelet clumps or platelet satellitism

Question 5

Idiopathic/Immune Thrombocytopenia (ITP)

Answer 5

• Auto-immune
• IgG auto-antibodies to platelets/megakaryocytes
• Increased destruction by (splenic) macrophages
• T cell-mediated destruction
• Idiopathic or secondary to autoimmune disease
  (lupus), lymphoma, infections (HIV), drugs

Question 6

ITP - Clinical

Answer 6

• Females > males
• Children – self-limited, post viral infection
• Adults – chronic, relapsing
• Isolated thrombocytopenia
• IgG anti-platelet antibodies detected (80% patients)

Question 7

ITP - Morphology

Answer 7

• Thrombocytopenia with large platelets
• Normal to increased megakaryocytes in bone marrow

Question 8

ITP - Management

Answer 8

• Conservative (especially children)
• First-line
• Corticosteroids (80% response)
• Intravenous immunoglobulin (IVIg)
• Second-line – rituximab, romiplostim, eltrombopag,
  fostamatinib, splenectomy
• Third-line – chemotherapy, stem cell transplant

Question 9

Heparin-Induced Thrombocytopenia (HIT) - Non-immune (type I)

Answer 9

• Non-immune (type I)
• Common (10-30% of patients receiving heparin)
• Heparin directly binds to platelets causing mild activation
• Develop within 5 days of starting heparin
• Mild thrombocytopenia (80-100K)
• Spontaneous recovery despite continued heparin
• Usually clinically insignificant

Question 10

Heparin-Induced Thrombocytopenia (HIT) - Immune (type II)

Answer 10

• Immune (type II)
• Heparin binds to platelet factor 4 (PF4)
• IgG antibodies against heparin-PF4 complexes,
  which bind to and activate platelets (thrombosis)
• Destruction of platelets by splenic macrophages
  (thrombocytopenia)

Question 11

Immune HIT – Clinical Features

Answer 11

• Unfractionated heparin > low molecular weight heparin
• Decrease in platelet count by >50% from the highest value after heparin is started
• Develops 5-10 days after starting heparin (can be
  earlier with previous exposure)
• Moderate thrombocytopenia (50-80K)
• Associated with venous thrombosis (50%) or arterial
  thrombosis (less common)

Question 12

Immune HIT - Management

Answer 12

• Discontinue all heparin
• Still a risk for thrombotic events, so…
• Anticoagulation with non-heparin agent
• Direct thrombin inhibitors (argatroban, bivalirudin,
  dabigatran
• Factor Xa inhibitors (apixaban, rivaroxaban,
  fondaparinux)

Question 13

Drug-Induced Thrombocytopenia

Answer 13

• Over 300 drugs have been implicated
• Immune and non-immune mechanisms
• Diagnostic criteria
• Exposure to the drug preceded thrombocytopenia
• Recovery with discontinuation of the drug
• Candidate drug was the only drug used
• Other causes are excluded
• Re-exposure causes recurrent thrombocytopenia

Question 14

Drug-Induced Thrombocytopenia

• Management

Answer 14

• Discontinue the offending drug(s)
• With multiple possible drugs, stop all recently-
  started drugs (especially antibiotics) and restart as needed
• Expect recovery after 4-5 half-lives of the drug

Question 15

Other Immune Thrombocytopenia

Answer 15

• Neonatal allo-immune thrombocytopenia
• Maternal antibodies cross placenta and cause
  destruction of fetal platelets
• Post-transfusion purpura
• Allo-immune antibodies secondary to prior transfusion with platelets
• Most common target is HPA-a1 antigen (glycoprotein
  IIIa/CD61)

Question 16

Thrombotic Thrombocytopenic Purpura (TTP)

Answer 16

• First described in 1924 by Eli Moschcowitz
• Deficiency of ADAMTS13 (vWF cleaving enzyme)
• Ultra-large vWF multimers accumulate and activate platelets
• Systemic microvascular platelet thrombi
• Inherited or acquired
• Gene mutations
• Drug-induced (clopidogrel)
• Auto-immune disease
• Infections
• Pregnancy
• Malignancy

Question 17

TTP – Laboratory Findings

Answer 17

• Thrombocytopenia
• Intravascular hemolysis with red cell fragmentation
• Reticulocytosis
• Schistocytes
• Decreased haptoglobin
• Increased lactate dehydrogenase (LD)
• Low ADAMTS13 activity
• Normal coagulation studies (PT/PTT)

Question 18

TTP - Morphology

Answer 18

Question 19

TTP - Clinical

Answer 19

• Classic “pentad” of findings (<10% of patients)
• Fever
• Neurologic dysfunction (60%)
• Renal dysfunction (proteinuria/hematuria)
• Thrombocytopenia
• Microangiopathic hemolytic anemia
• Management – medical emergency
• Therapeutic plasma exchange (daily until improved)
• Steroids
• Rituximab, Caplacizumab (anti-vWF nanobody)

Question 20

Hemolytic-Uremic Syndrome (HUS)

Answer 20

• Shiga-like toxin (E. coli O157:H7, Shigella)
• Endothelial cell damage
• Platelet activation
• Microvascular platelet thrombi (especially renal)
• Similar morphology to TTP (thrombocytopenia, red
  cell fragmentation, schistocytes)
• Primarily in children, acute renal failure

Question 21

Disseminated Intravascular Coagulation (DIC)

Answer 21

• Systemic activation of coagulation and platelet
• Microvascular platelet-fibrin thrombi
• Consumption of platelets (thrombocytopenia) and
  coagulation factors (prolonged PT/PTT)
• Red cell fragmentation with schistocytes
• Activation of fibrinolytic system (D-dimers)

Question 22

Bernard-Soulier Syndrome

Answer 22

• Autosomal recessive inheritance
• Defective GPIb receptor on platelets
• Abnormal binding to vWF (impaired platelet adhesion)
• Mild thrombocytopenia with large platelets, prolonged bleeding time, abnormal ristocetin-induced platelet aggregation
• Variable clinical severity

Question 23

Glanzmann Thrombasthenia

Answer 23

• Autosomal recessive inheritance
• Defective GPIIb/IIIa receptor on platelets
• Abnormal binding to fibrinogen (impaired platelet
  aggregation), abnormal clot retraction
• Normal platelet count, prolonged bleeding time,
  abnormal platelet aggregation (except ristocetin)
• Variable clinical severity

Question 24

Storage Pool Disorders

Answer 24

• Group of related disorders, variable inheritance
• Abnormal platelet granules/secretion (impaired
  aggregation)
• Normal platelet count, pale/hypogranular platelets,
  prolonged bleeding time, abnormal platelet
  aggregation (primary wave only, disaggregation)
• Variable clinical severity

Question 25

Acquired Platelet Function Disorders

Answer 25

• Drug-related (adverse effects versus therapeutic)
• Renal disease – “uremic” toxins
• Clonal hematologic stem cell disorders