Disorders of Platelets and Vessel Wall¶

Chapter 120 | Harrison's 22e · Part 4 – Hematologic Disorders & Hemostasis · Chapter 120

Key Clinical Points¶

Platelet count <150,000/μL defines thrombocytopenia; counts <40,000/μL increase risk of spontaneous bleeding.
Pseudothrombocytopenia is an in vitro artifact caused by platelet clumping in EDTA-anticoagulated blood.
Thrombocytopenia results from decreased production (e.g., marrow failure), sequestration (e.g., splenomegaly), or increased destruction (e.g., ITP, HIT).
Heparin-induced thrombocytopenia (HIT) typically develops 5–14 days after heparin exposure; risk of thrombosis persists for ≥ 1 month.
TTP is caused by ADAMTS13 deficiency/inhibition leading to ultra-high-molecular-weight VWF multimers and platelet aggregation.
Endothelial cells regulate homeostasis via nitric oxide (vasodilation), prostacyclin (inhibition of platelet aggregation), and thrombomodulin (activation of protein C).
Clinical risk of bleeding increases at <50,000/μL (petechiae), <20,000/μL (spontaneous bleeding), and <10,000/μL (intracranial hemorrhage).

1. DEFINITION & OVERVIEW¶

• Platelet Physiology: Platelets (150,000–450,000/μL) are produced by megakaryocytes under the influence of thrombopoietin (TPO). • Vessel Wall Function: Endothelial cells regulate vascular homeostasis through: ◦ Nitric oxide (vasodilation) ◦ Prostacyclin (inhibition of platelet aggregation) ◦ Thrombomodulin (activation of protein C)

1.1 Endothelial Dysfunction¶

• Pathophysiological Drivers: ◦ Inflammation → increased endothelial permeability ◦ Oxidative stress → reduced nitric oxide bioavailability ◦ Atherosclerosis → prothrombotic state ◦ Vasospasm → Raynaud's phenomenon

2. THROMBOCYTOPENIA¶

Thrombocytopenia results from three primary mechanisms: decreased production, sequestration, or increased destruction. Evaluation must first rule out pseudothrombocytopenia (an in vitro artifact caused by platelet clumping in EDTA-anticoagulated blood).

2.1 Causes of Thrombocytopenia¶

• Decreased Production: Aplastic anemia, myelodysplasia, chemotherapy, or TPO deficiency. • Sequestration: Splenomegaly (e.g., hepatosplenomegaly in cirrhosis). • Increased Destruction: Immune-mediated (ITP), drug-induced, or heparin-induced (HIT).

2.2 Diagnostic Approach¶

Initial Assessment: Identify thrombocytopenia (Platelet count <150,000/μL).
Systemic Evaluation: Assess Hemoglobin (Hgb) and White Blood Cell (WBC) counts.
If Hgb/WBC are Abnormal → Bone marrow examination.
If Hgb/WBC are Normal → Proceed to Peripheral blood smear analysis.
Peripheral Blood Smear Analysis:
If Platelets clumped → Redraw in sodium citrate or heparin (to rule out pseudothrombocytopenia).
If Fragmented red blood cells or Microangiopathic hemolytic anemias (e.g., DIC, TTP) → Diagnosis of MAHA.
If Normal RBC morphology; platelets normal or increased in size → Consider: ◦ Drug-induced thrombocytopenia ◦ Infection-induced thrombocytopenia ◦ Idiopathic nonimmune thrombocytopenia ◦ Congenital thrombocytopenia

3. CLINICAL MANIFESTATIONS¶

Symptoms and risks correlate with platelet count: • <50,000/μL: Petechiae, ecchymoses • <20,000/μL: Spontaneous bleeding (gum, nose) • <10,000/μL: Intracranial hemorrhage risk • Note: Platelet count <40,000/μL significantly increases the risk of spontaneous bleeding.

4. MANAGEMENT & TREATMENT¶

Treatment is tailored to the underlying etiology: 1. Immune Thrombocytopenia (ITP): IVIG, splenectomy. 2. Heparin-Induced Thrombocytopenia (HIT): - Action: Discontinue heparin; use argatroban. - Warning: Do not switch to warfarin alone → risk of venous gangrene due to lack of anti-platelet effect during transition. 3. Drug-induced Thrombocytopenia: Identify and stop causative agent (e.g., from Table 120-1). 4. Thrombotic Microangiopathies (TMA): Plasma exchange.

5. Pathophysiology of Specific Conditions¶

• Heparin-Induced Thrombocytopenia (HIT): ◦ Timing: Typically develops 5–14 days after heparin exposure. ◦ Mechanism: Formation of immune complexes with PF4 leads to platelet activation and thrombosis. ◦ Risk: Increased risk of thrombosis for ≥ 1 month after diagnosis. • Thrombotic Thrombocytopenic Purpura (TTP): ◦ Mechanism: ADAMTS13 deficiency/inhibition → failure to process ultra-high-molecular-weight VWF multimers → platelet aggregation and thrombosis.

6. KEY PEARLS & HIGH-YIELD POINTS¶

• Pseudothrombocytopenia: An in vitro artifact; identified by platelet clumping on smear → requires redraw in citrate or heparin. • Drug-Induced Thrombocytopenia (Table 120-1): Includes Abciximab, Amiodarone, Ampicillin, Ciprofloxacin, Heparin, and Quinine. - Note: Risk of HIT only if heparin used in last \sim100 days. • von Willebrand Disease (Table 120-2): - Type 1: \downarrow VWF antigen/activity; Normal distribution of multimers. - Type 2A: \downarrow VWF antigen/activity; Loss of high-MW multimers. - Type 2N: \uparrow\uparrow aPTT; Normal or \downarrow VWF antigen/activity; \downarrow\downarrow VWF activity; Normal distribution of multimers.

Reference Tables¶

TABLE 120-1 Drugs Reported as Definitely or Probably Causing Isolated Thrombocytopenia a Abciximab Acetaminophen…¶

Harrison's 22e, p.923

Abciximab Acetaminophen Amiodarone Amlodipine Ampicillin Carbamazepine Ceftriaxone Cephamandole Ciprofloxacin Diazepam Eptifibatide Furosemide Gold Haloperidol Heparin Ibuprofen Lorazepam	Mirtazapine Naproxen Oxaliplatin Penicillin Phenytoin Piperacillin Quinidine Quinine Ranitidine Rosiglitazone Roxifiban Sulfisoxazole Suramin Tirofiban Tranilast Trimethoprim/sulfamethoxazole Vancomycin
	Risk of HIT
HIT only if heparin in last ~100 days		Delayed-onset HIT occurs rarely

TABLE 120-2 Laboratory Diagnosis of von Willebrand Disease¶

Harrison's 22e, p.926

TYPE	aPTT	VWF ANTIGEN	VWF ACTIVITY	FVIII ACTIVITY	MULTIMER
1	Nl or ↑	↓	↓	↓	Normal distribution, decreased in quantity
	Nl or ↑	↓	↓ ↓	↓
2Ba	Nl or ↑	↓	↓ ↓	↓	Loss of high-MW multimers
	Nl or ↑	↓	↓ ↓	↓
2N	↑↑	Nl or ↓b	Nl or ↓b	↓↓	Normal distribution
	↑↑	↓↓	↓↓	↓↓