Platelet Disorders and Primary Hemostasis Quiz

Hemostasis and Related Disorders

• Hemostasis is a crucial process for repairing damaged blood vessels, forming a clot to stop bleeding.
• It's a two-stage process:
  • Primary hemostasis: forms a platelet plug (weak) via platelet-vessel wall interaction.
  • Secondary hemostasis: stabilizes the plug through the coagulation cascade, forming a stable clot.

Primary Hemostasis

• Step 1: Transient vasoconstriction of damaged vessel, mediated by reflexes and endothelin release.
• Step 2: Platelet adhesion to the disrupted vessel.
  • vWF (von Willebrand factor) binds exposed collagen.
  • Platelets bind vWF through GPib receptors.
  • vWF is from endothelial cells and platelet α-granules.
• Step 3: Platelet degranulation.
  • Release of mediators (e.g., ADP, TXA2) from dense granules.
  • ADP promotes GPIIb/IIIa receptor exposure on platelets.
  • TXA2 (from COX) promotes aggregation.
• Step 4: Platelet aggregation.
  • Platelets aggregate via GPIIb/IIIa using fibrinogen as a linking molecule.
  • Forms a weak platelet plug, stabilized by secondary hemostasis.

Disorders of Primary Hemostasis

• Often due to platelet abnormalities (quantitative or qualitative).
• Clinical features: Mucosal and skin bleeding.
  • Mucousal: Epistaxis, hemoptysis, GI bleeding, hematuria, menorrhagia, intracranial bleeding with severe thrombocytopenia.
  • Skin: Petechiae (1-2 mm), ecchymoses (> 3 mm), purpura (> 1 cm), easy bruising.
• Laboratory studies:
  • Platelet count (normal 150-400 x 10^9/L): <50 x 10^9/L leads to symptoms.
  • Bleeding time (normal 2-7 minutes): Prolonged with disorders.
  • Blood smear to assess platelets.
  • Bone marrow biopsy to assess megakaryocytes (platelet producers).

Immune Thrombocytopenic Purpura (ITP)

• Autoimmune disorder: IgG produced against platelet antigens (e.g., GPIIb/IIIa).
• Most common cause of thrombocytopenia in children and adults.
• Plasma cells in spleen produce antibodies.
• Antibody-bound platelets consumed by splenic macrophages causing low platelet counts.
• Two types:
  • Acute (children; weeks after viral infections; self-limiting).
  • Chronic (adults, often women; may be primary or secondary; may affect offspring).
• Laboratory findings:
  • Low platelet count (<50 x 10^9/L).
  • Normal PT/PTT (coagulation cascade unaffected).
  • Normal megakaryocytes on bone marrow biopsy.
• Initial treatment: corticosteroids; IVIG for symptomatic bleeding. Splenectomy in refractory cases.

Microangiopathic Hemolytic Anemia

• Pathologic platelet microthrombi in small vessels cause RBC damage (schistocytes).
• Seen in TTP and HUS.
• TTP: Reduced ADAMTS13 (cleaves vWF multimers).
  • Large multimers cause abnormal platelet adhesion, microthrombi.
  • Acquired autoantibody against ADAMTS13 is common (adult females).
• HUS: Endothelial damage (drugs or infection, e.g., E. coli O157:H7).
  • E. coli verotoxin damages endothelial cells, platelet microthrombi.
• Clinical features (TTP and HUS):
  • Skin and mucosal bleeding.
  • Microangiopathic hemolytic anemia.
  • Fever.
  • Renal insufficiency (HUS more common).
  • CNS abnormalities (TTP more common).
• Laboratory findings:
  • Thrombocytopenia, prolonged bleeding time.
  • Normal PT/PTT.
  • Anemia with schistocytes.
  • Increased megakaryocytes on bone marrow biopsy.
• Treatment: plasmapheresis and corticosteroids, especially in TTP.

Qualitative Platelet Disorders

• Bernard-Soulier syndrome: Genetic GPib deficiency; impaired platelet adhesion.
• Glanzmann thrombasthenia: Genetic GPIIb/IIIa deficiency; impaired aggregation.
• Aspirin: Irreversibly inactivates cyclooxygenase, inhibiting TXA2 and aggregation.
• Uremia: Disrupts platelet function; affects adhesion and aggregation.

Secondary Hemostasis

• Stabilizes platelet plug by activating the coagulation cascade which generates thrombin
• Thrombin converts fibrinogen in the plug to fibrin.
• Fibrin is cross-linked for a stable platelet-fibrin thrombus.
• Coagulation cascade factors are produced by liver in inactive forms, requiring:
  • Exposure to an activating substance (tissue thromboplastin activates factor VII; subendothelial collagen activates factor XII).
  • Phospholipid surface of platelets.
  • Calcium.

Disorders of Secondary Hemostasis

• Usually factor abnormalities.
• Clinical features: Deep tissue bleeding (muscles, joints), rebleeding after procedures.
• Laboratory studies:
  • Prothrombin Time (PT): Measures extrinsic and common pathways.
  • Partial Thromboplastin Time (PTT): Measures intrinsic and common pathways.

Hemophilia A

• Genetic factor VIII deficiency (X-linked recessive).
• Presents with deep tissue, joint, and post-surgical bleeding.
• Severity depends on the degree of deficiency.
• Laboratory findings:
  • Prolonged PTT, normal PT.
  • Low FVIII levels.
  • Normal platelet count and bleeding time.
• Treatment: recombinant FVIII.

Hemophilia B (Christmas Disease)

• Genetic factor IX deficiency.
• Similar to hemophilia A, but FIX levels are decreased.

Coagulation Factor Inhibitor

• Acquired antibody against a coagulation factor.
• Most commonly anti-FVIII.
• Clinical and lab findings similar to hemophilia A.
• Mixing study: PTT does not correct with normal plasma.

Von Willebrand Disease

• Genetic vWF deficiency (most common inherited coagulation disorder).
• Multiple subtypes (quantitative and qualitative defects; most common is decreased vWF levels).
• Presents with mild mucosal and skin bleeding.
• Laboratory findings:
  • Prolonged bleeding time.
  • Prolonged PTT (normal PT - vWF stabilizes FVIII)
  • Abnormal ristocetin test (lack of vWF impairs platelet aggregation).
• Treatment: desmopressin (ADH analog) to increase vWF release.

Vitamin K Deficiency

• Disrupts multiple coagulation factors.
• Vitamin K is activated by epoxide reductase in the liver →gamma-carboxylates factors II, VII, IX, X, and proteins C and S (necessary for function).
• Deficiency is seen in:
  • Newborns (due to lack of GI colonization; prophylaxis).
  • Long-term antibiotic therapy (alters gut bacteria).
  • Malabsorption (fat-soluble vitamin deficiency).

Other Causes of Abnormal Secondary Hemostasis

• Liver failure (Decreased coagulation factor production).
• Large-volume transfusion (dilutes factors).

Other Disorders of Hemostasis

• Heparin-induced thrombocytopenia (HIT): Platelet destruction secondary to heparin therapy.

• Disseminated Intravascular Coagulation (DIC): Pathologic coagulation cascade activation.

  • Results in widespread microthrombi causing ischemic and infarct events.
  • Platelet and factor consumption lead to bleeding (especially from IV sites).
  • Almost always secondary to another disease (obstetric complications, sepsis, adenocarcinoma, acute promyelocytic leukemia, rattlesnake bite).
  • Laboratory findings:
    • Low platelet count.
    • Increased PT/PTT.
    • Low fibrinogen.
    • Microangiopathic hemolytic anemia.
    • Elevated fibrin split products (particularly D-dimer). D-dimer is elevated with DIC and is the best test!
  • Treatment: addressing underlying cause and blood product transfusions (e.g., cryoprecipitate).

Disorders of Fibrinolysis

• Normal fibrinolysis removes thrombi after vessel healing.
• Tissue plasminogen activator (tPA) converts plasminogen to plasmin, cleaving fibrin and blocking aggregation &activating coagulation factors.
• a2-antiplasmin inactivates plasmin.
• Disorders are due to plasmin overactivity.
  • Examples: radical prostatectomy, cirrhosis.
  • Laboratory findings:
    • Elevated PT/PTT.
    • Increased bleeding time (without thrombocytopenia).
    • Elevated fibrinogen split products (without D-dimers).
  • Treatment: Aminocaproic acid (blocks plasminogen activation).

Thrombosis

• Pathologic blood clot formation in blood vessel.
• Common in deep leg veins (DVT).
• Characterized by Lines of Zahn (alternating platelets, fibrin, RBCs) and vessel wall attachment.
• Risk factors (Virchow triad):
  • Disrupted blood flow (stasis/turbulence e.g. immobilization, cardiac dysfunction).
  • Endothelial cell damage (atherosclerosis, vasculitis).
  • Hypercoagulable state (inherited/acquired, e.g. Protein C/S def., factor V Leiden, prothrombin 20210A, ATIII def.)

Embolism

• Intravascular mass occluding downstream vessels.
• Thromboembolus (most common: dislodged thrombus).
• Atherosclerotic embolus (from plaque).
• Fat embolus (bone fractures/trauma: bone marrow elements in vessels).
• Gas embolus (decompression sickness, laparoscopic surgery).
• Amniotic fluid embolus (labor/delivery; squamous cells/keratin debris; DIC).

Pulmonary Embolism (PE)

• Usually thromboembolus (often from DVT).
• Often clinically silent (dual blood supply, small embolus).
• Pulmonary infarction (large/medium embolus, pre-existing compromise).
  • Symptoms: shortness of breath, hemoptysis, pleuritic chest pain, pleural effusion.
  • Diagnosis: V/Q lung scan (abnormal perfusion), spiral CT (filling defect), Doppler ultrasound (DVT), elevated D-dimer.

Systemic Embolism

• Usually thromboembolus from left heart.
• Travel to occlude flow to organs, often lower extremities.

Test your knowledge on the initial steps of primary hemostasis and the role of platelets in the bleeding process. This quiz covers key factors that influence platelet adhesion, aggregation, and clinical manifestations of bleeding disorders. It's essential for understanding hemostatic mechanisms and their clinical implications.