Platelet Disorders

Platelet Disorders

Learning Objectives

• Define thrombocytopenia and thrombocytosis.

• Identify common causes of thrombocytopenia.

• Recognize clinical manifestations of platelet disorders.

• Classify qualitative vs. quantitative platelet defects.

• Distinguish primary vs. secondary thrombocytosis.

Platelet Counts

• Normal range: 150,000 - 450,000/μL.

• Thrombocytopenia: <150,000/μL.

• Thrombocytosis: >450,000/μL.

• Lifespan: 7-10 days; 1/3 sequestered in spleen.

Platelet Production

• Megakaryocytes undergo endomitotic synchronous nuclear replication.

• Platelet production involves cytoplasmic granulation.

• Platelet production occurs primarily in the bone marrow, where megakaryocytes differentiate and release platelets into the bloodstream. This process is regulated by various cytokines, such as thrombopoietin, which stimulate the proliferation and maturation of megakaryocytes.

  

Structure of Platelet

• Electron dense granules: Contain nucleotides (ADP), Ca2+, serotonin.

• Specific α-granules: Contain fibrinogen, factor V, VWF, fibronectin, heparin antagonist (PF4), PDGF, and other proteins.

• Other components: Glycogen, glycocalyx, mitochondrion, dense tubular system, lysosome, plasma membrane, platelet phospholipid, open canalicular system, submembranous filaments (platelet contractile protein).

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Function of Platelet

• Adhesion: Platelets adhere to subendothelial microfibrils via von Willebrand factor (VWF) and GPIb.Aggregation: Upon activation, platelets aggregate through fibrinogen binding to GPIIb/IIIa receptors, leading to the formation of a platelet plug at the site of vascular injury.

• 

• Aggregation: Platelets aggregate via GPIIb/IIIa, fibrinogen, and other factors.

• Vascular endothelium is involved in the process.

• Key components: Collagen, VWF, fibrinogen, TSP, PF4, PDGF, β-TG, factor V, ADP, ATP, calcium ++, serotonin, GPIb/IX/V, GPIa/IIa.

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Manifestations of Platelet Disorders

Quantitative and Qualitative

• Platelet/Vessel Wall Diseases: Mucosal bleeding and petechiae are common; deep hematomas are rare; bleeding from skin cuts is persistent; equal sex distribution.

• Coagulation Diseases: Mucosal bleeding and petechiae are rare; deep hematomas are characteristic; bleeding from skin cuts is minimal; >80% male.

Platelet Disorders

• Platelet disorders are the most common cause of bleeding.

• Disorders can involve:

  • Decreased number (Thrombocytopenia)

  • Increased number (Thrombocytosis)

  • Defective function

Classification of Platelet Disorders

Quantitative Disorders

• Thrombocytopenia

  • Decreased production

  • Increased destruction

  • Abnormal distribution

• Thrombocytosis

Qualitative Disorders

• Inherited disorders (rare)

• Acquired disorders

  • Medications (e.g., ASA)

  • Chronic renal failure

  • Cardiopulmonary bypass

Causes of Thrombocytopenia

Decreased Production

• Selective megakaryocyte depression

  • Congenital

  • Acquired (drug, chemical, viral)

• Part of general bone marrow failure

  • Cytotoxic drugs and radiotherapy

  • Aplastic anemia

  • Marrow infiltration (by malignancy)

  • Megaloblastic anemia

  • HIV infection

Increased Consumption of Platelets

• Immune

  • Autoimmune

    • Idiopathic (ITP; “Idiopathic Thrombocytopenic Purpura” – old name)

    • SLE, Lymphoproliferative disorders (CLL, Lymphoma)

  • Disseminated intravascular coagulation

  • Thrombotic thrombocytopenic purpura

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Distribution

• Pseudothrombocytopenia (Platelet clumps)

• Splenomegaly

• Dilutional (Massive transfusion)

• Splenic pool: 30% normally vs. 60-90% in splenomegaly

• Circulating platelets: 70% normally vs. 10-40% in splenomegaly

Approach to the Thrombocytopenic Patient

• History:

  • Is the patient bleeding?

  • Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease)

  • Is there a history of medications, alcohol use, or recent transfusion?

  • Are there risk factors for HIV infection?

  • Is there a family history of thrombocytopenia?

  • Do the sites of bleeding suggest a platelet defect?

• Assess the number and function of platelets:

  • CBC with peripheral smear

  • Platelet function study (PFA and platelet aggregation studies)

  • vWD screen

ITP (Immune Thrombocytopenia)

• Immune-mediated acquired disease of adults and children

• Characterized by:

  • Low platelet count (<100 x $10^9$/L, transient or persistent)

  • Increased risk of bleeding due to impaired clotting mechanism

• Currently no definitive diagnostic criteria exist for primary ITP

• Considered a diagnosis of exclusion

Diagnostic Approach in Suspected ITP

• To exclude other causes of thrombocytopenia, recent updates recommended basic evaluation should consist of:

  • Patient history – necessary to rule out other causes of thrombocytopenia

  • Physical examination – normal except for signs of thrombocytopenia; no adenopathy or splenomegaly

  • Complete blood count showing isolated thrombocytopenia with large platelets

  • Clinical or laboratory evidence for other causes of thrombocytopenia

Proposed Mechanism of Immune Dysregulation in ITP

• T cells are activated upon recognition of platelet-specific antigens on the APCs and therefore induce antigen-specific expansion of B cells.

Clinical Manifestations of Platelet Disorders

• Skin purpura, superficial bruising, epistaxis, menorrhagia.

• Mucosal hemorrhage is seen in severe cases and intra-cranial hemorrhage is rare.

Thrombotic Thrombocytopenic Purpura (TTP)

Pathogenesis

• Von Willebrand factor (VWF) consists of a series of VWF multimers each of molecular weight (MW) 250 kDa which are covalently linked.

  • Under physiological circumstances a metalloprotease ADAMTS13 cleaves high molecular weight multimers at a Tyr-842-Met-843 bond and the resulting VWF has an MW of 500-20 000 kDa.

  • In non-familial TTP, an antibody develops to the metalloprotease and so blocks cleavage of VWF multimers.

  • In congenital form of TTP, the protease appears to be absent.

  • In both cases, the resultant ultra-large VWF multimers can bind platelets under high shear stress conditions and lead to platelet aggregation.

Disseminated Intravascular Coagulation (DIC)

Pathogenesis

• Widespread activation of coagulation.

• Endothelial damage leads to:

  • Microthrombi in the circulation

  • ↓ Platelets due to generalized platelet aggregation

  • Fibrinolysis + FDPs

Defective Platelets Function

• A defect in platelet function is suspected if there is prolonged bleeding time with or without skin or mucosal hemorrhage in the presence of a normal platelet count.

Clinical and Laboratory Findings in Hemophilia A, Factor IX Deficiency, and von Willebrand Disease

| Feature | Hemophilia A | Factor IX Deficiency | von Willebrand Disease | |---------------------------|--------------|-----------------------|------------------------|
| Inheritance | Sex-linked | Sex-linked | Dominant (incomplete) |
| Main sites of hemorrhage | Muscle, joints, post-trauma or postoperative | Muscle, joints, post-trauma or postoperative | Mucous membranes, skin cuts, post-trauma or postoperative |
| Platelet count | Normal | Normal | Normal |
| PFA-100 | Normal | Normal | Prolonged |
| Prothrombin time | Normal | Normal | Normal |
| Partial thromboplastin time | Prolonged | Prolonged | Prolonged or normal |
| Factor VIII | Low | Normal | Normal |
| Factor IX | Normal | Low | Normal |
| VWF | Normal | Normal | May be moderately reduced |
| Ristocetin-induced platelet aggregation | Normal | Normal | Impaired |

Classification of von Willebrand Disease

Type 2 VWD Subtypes

Thrombocytosis

• Increased platelet counts can be due to a number of disease processes:

  • Essential (primary)

    • Essential thrombocytosis (a form of myeloproliferative disease)

    • Other myeloproliferative disorders such as:

      • chronic myelogenous leukemia,

      • polycythemia vera,

      • myelofibrosis

  • Reactive (secondary)

    • Inflammation

    • Surgery (which leads to an inflammatory state)

    • Hyposplenism (decreased breakdown due to decreased function of the spleen)

    • Hemorrhage and/or iron deficiency