Disorders of Primary Hemostasis (Platelet Plug)


Platelet Adhesion Defect

  • Von Willebrand Disease (see Von Willebrand Disease)
    • Inherited Von Willebrand Disease
      • Type 1: autosomal dominant (with incomplete penetrance)
        • Accounts for 75% of All Von Willebrand Disease Cases
      • Type 2A: autosomal dominant (usually)
        • Accounts for 10-15% of All Von Willebrand Disease Cases
      • Type 2B: autosomal dominant
      • Type 2M: autosomal dominant (usually)
      • Type 2N: autosomal recessive (usually)
      • Type 3: autosomal recessive or dominant
      • Platelet-Type: autosomal dominant
    • Acquired Von Willebrand Disease
      • Autoimmune Disease
      • Drugs
        • Ciprofloxacin (see Ciprofloxacin)
        • Dextran (see Dextran): branched polysaccharides of 40 or 70 kDa which inhibit platelet factor-3 availability, adsorb to platelets, and decrease plasma factor VIII-vWF -> inhibit platelet aggregation + secretion
        • Griseofulvin
        • Hydroxyethyl Starch (Hetastarch) (see Hydroxyethyl Starch)
        • Thrombolytics (see Thrombolytics): hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
        • Valproic Acid (see Valproic Acid)
      • High Intravascular Shear Forces
      • Malignant/Hematologic Disease
      • Other
        • Acute Pancreatitis (see Acute Pancreatitis): hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
        • Cirrhosis/End-Stage Liver Disease (see Cirrhosis): hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
        • Gastrointestinal Angiodysplasia (see Gastrointestinal Angiodysplasia)
        • Heyde’s Syndrome = constellation of aortic stenosis + gastrointestinal angiodysplasia -> high intravascular shear forces across the stenotic aortic valve increase clearance of high MW multimers
        • Hemoglobinopathies
        • Hypothyroidism (see Hypothyroidism): decreased synthesis of VWF
        • Post-Multiple Transfusions: due to development of antibodies against VWF
        • Uremia (see Acute Kidney Injury and Chronic Kidney Disease)
  • Bernard-Soulier Syndrome (see Bernard-Soulier Syndrome): autosomal recessive deficiency in platelet glycoprotein Ib-IX complex -> inability to bind Von Willebrand factor

Platelet Aggregation Defect

  • Afibrinogenemia (see Afibrinogenemia)
  • Dextran (see Dextran): branched polysaccharides of 40 or 70 kDa which inhibit platelet factor-3 availability, adsorb to platelets, and decrease plasma factor VIII-VWF -> inhibit platelet aggregation + secretion
  • Glanzmann’s Thrombasthenia (see Glanzmann’s Thrombasthenia,): autosomal recessive deficiency or defect in IIb-IIIa complex -> platelets cannot bind fibrinogen -> inability of platelets to aggregate
  • Hypophosphatemia (see Hypophosphatemia)
    • Phsyiology: adenosine triphosphate depletion results in decreased platelet aggregation
  • Omega-3 Fatty Acids/Fish Oil (see Omega-3 Fatty Acid): increase PGI3 synthesis (a more potent platelet inhibitor than prostacyclin, PGI2), increase thromboxane A3 (a less potent platelet activator than thromboxane A2)
    • Diets naturally rich in omega 3 fatty acids can result in a prolonged bleeding time and abnormal platelet aggregation studies -> the actual associated bleeding risk is unclear
  • Platelet Glycoprotein IIb IIIa Receptor Antagonists (see Platelet Glycoprotein IIb IIIa Receptor Antagonists)
  • Vitamin E (see Vitamin E): inhibits protein kinase C–mediated platelet aggregation and nitric oxide synthesis

Platelet Secretion Defect

  • Cyclooxygenase Defect
    • Inherited Platelet Secretion Defect: defect of cyclooxygenase-1 activity
  • Cyclooxygenase (COX) Inhibitors
    • Aspirin (see Acetylsalicylic Acid): inrreversible inhibition of cyclooxygenase-1 activity -> inhibited synthesis of TXA2 (an important mediator of platelet secretion and aggregation)
      • Single dose of aspirin can impair hemostasis for 5-7 days
      • Effect on platelet function (as assessed by aggregometry) can persist for up to 7 days (although it has frequently returned to normal by 3 days after the last dose)
    • Other Non-Selective COX-1/COX-2 Inhibitor NSAID’s (see Nonsteroidal Anti-Inflammatory Drug): however, these agents have reversible and less sustained COX inhibition (and anti-platelet effects) than aspirin
      • Note: the selective COX-2 inihibitors, celecoxib (Celebrex) and rofecoxib (Vioxx), do not have anti-platelet effects
  • Dextran (see Dextran): branched polysaccharides of 40 or 70 kDa which inhibit platelet factor-3 availability, adsorb to platelets, and decrease plasma factor VIII-vWF -> inhibit platelet aggregation + secretion
  • Ethanol (see Ethanol): decreases TXA2 release
  • Granule Storage Pool Defect
  • Phosphodiesterase Inhibitors: increase cAMP/cGMP (increases in each vary by agent)
    • Cilostazol (Pletal) (see Cilostazol)
    • Dipyridamole (Persantine) (see Dipyridamole): decreased intracellular cAMP metabolism -> increase intracellular cAMP
    • Methyl Xanthines: increase intracellular cAMP
    • Sildenafil (Viagra, Revatio) (see Sildenafil): inhibition of PDE5/PDE6
    • Tadalafil (Adcirca, Cialis) (see Tadalafil): inhibition of PDE5
    • Vardenafil (Levitra, Staxyn, Vivanza) (see Vardenafil): inhibition of PDE5
  • Platelet Coating
    • Paraproteinemia (see Paraproteinemia)
    • Penicillin (see Penicillins): large doses of penicillin can coat platelets and impair hemostasis
  • Platelet P2Y12 Receptor Antagonists (see Platelet P2Y12 Receptor Antagonists): prevent binding of ADP to platelets
  • Selective Serotonin Reuptake Inhibitors (SSRI’s) (see Selective Serotonin Reuptake Inhibitors)
    • Escitalopram (Lexapro) (see Escitalopram)
    • Fluoxetine (Prozac) (see Fluoxetine): decreased serotonin in dense granules
    • Paroxetine (Paxil) (see Paroxetine): decreased serotonin in dense granules
  • Uremia (see Acute Kidney Injury and Chronic Kidney Disease)
    • May Be Due to Retention of Phenolic and Guanidinosuccinic Acids, Excess Prostacyclin Synthesis, or Impaired Von Willebrand Factor Interaction
    • There is a Correlation Between the Degree of Urea and the Degree of Platelet Dysfunction
    • Treatment
      • Dialysis (see Dialysis)
      • Cryoprecipitate (see Cryoprecipitate): increases Von Willebrand factor levels
      • DDAVP (see Desmopressin): increases Von Willebrand factor levels
      • Conjugated Estrogens
      • Increasing Hematocrit to 27-32%

Platelet Coagulant Activity Defect

Undefined or Potential Anti-Platelet Activity

  • Bilberry (Vaccinium Myrtillus)
  • Dong Quai (Angelica Sinensis)
  • Feverfew (Tanacetum Parthenium) (see Feverfew)
  • Garlic (Allium Sativum) (see Garlic)
  • Ginger (Gingiber Officinale) (see Ginger)
  • Ginkgo Biloba (Ginkgo Biloba) (see Ginkgo Biloba)
  • Ginseng (see Ginseng)
    • Asian Ginseng = Panax Ginseng
    • American Ginseng = Panax Quinquefolius
  • Meadowsweet (Filipendula Ulmaria)
  • Siberian Ginseng/Eleuthero (Eleutherococcus Senticosus)
  • Turmeric (Circuma Longa) (see Turmeric)
  • Willow (Salix species)

Disorders of Secondary Hemostasis




Diagnostic Tests

Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time)

  • Etiology of Prolonged INR
    • Deficiency of Common Pathway Factors
      • Fibrinogen
      • Factor II/Prothrombin
      • Factor V
      • Factor X
    • Factor VII Deficiency/Inhibitor

Partial Thromboplastin Time (PTT) (see Partial Thromboplastin Time)

  • Etiology of Prolonged PTT
    • Deficiency/Inhibitors of factors VIII, IX, XI, XII, as well as common pathway factors
    • However, PTT is less sensitive for deficiency/inhbitors of common pathway factors -> this is why vitamin K deficiency (with decreased factors II, VII, IX, X) prolongs INR more than PTT

Thrombin Time (see Thrombin Time)

  • Rationale: measures how fast given amount of thrombin turns fibrinogen into fibrin -> therefore, is designed to detect quantitative or qualitative problems with fibrin
    • Can be prolonged by high levels of fibrin degradation products
    • Very sensitive to heparin

Reptilase Time

  • Rationale: used to determine if prolonged thrombin time is due to heparin
    • Insensitive to Heparin

1:1 Mix

  • Rationale:
  • Technique: mix control plasma (with 100% activity of each factor) + patient plasma to determine if a factor deficiency vs inhibitor is present
    • As factor levels of 50% or higher are sufficient for a normal INR/PTT, 1:1 mix will correct INR/PTT in presence of a factor deficiences, but not in presence of a factor inhibitor

PTT with Polybrene or Heparinase

  • Rationale: used to neutralize heparin in the sample to determine if prolonged PTT is due to heparin

PTT with Excess Phospholipid

  • Rationale: used to detect presence of anti-phospholipid antibody (lupus anticoagulant, etc)

Bleeding Time (see Bleeding Time)

  • Rationale: assesses for platelets defects (relatively insensitive for factor deficiencies or inhibitors)

Platelet Function Analysis (PFA)

  • Rationale: Essentially an in vitro bleeding time assay which assesses different components of platelet activation (in response to ADP, epinephrine, collagen)

Von Willebrand Factor Antigen

  • Rationale: quantifies the amount of Von Willebrand factor -> decreased in Von Willebrand Disease

Ristocetin Cofactor Test (see Ristocetin Cofactor Test)

  • Rationale: evaluates function of Von Willebrand factor by testing ristocetin-induced platelet aggregation of normal platelets in presence of patient’s plasma
    • Most sensitive and specific test for Von Willebrand disease -> decreased in all types of Von Willebrand disease
    • Assesses the binding of Von Willebrand factor to platelet GP1b

Ristocetin-Induced Platelet Aggregation (RIPA) (see Ristocetin-Induced Platelet Aggregation)

  • Evaluates function of Von Willebrand factor by testing ristocetin-induced platelet aggregation of patient’s platelets in presence of patient’s plasma
    • Less sensitive and specific than ristocetin cofactor test
    • Usually decreased in Von Willebrand disease, but may be normal in some cases
    • In type IIB Von Willebrand disease: platelets are hyperresponive to ristocetin (platelets aggregate in response to abnormally low ristocetin concentration)

Factor VIII Activity/Level

  • Factor VIII activity assay is performed -> level is inferred from activity: decreased in factor VIII deficiency and Von Willebrand disease
    • Von Willebrand factor normally carries factor VIII (this prolongs factor VIII half-life) -> therefore, if Von Willebrand factor binding of factor VIII is impaired or Von Willebrand factor is low, then, factor VIII level is low

Diagnostic Patterns of Prothrombin Time (PT)/International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT) in Various Coagulopathies

Stepwise Evaluation of Coagulopathy

  • Step 1 (assessment for platelet problem): platelet count, PFA
  • Step 2 (assessment for single factor deficiency): INR/PTT, factor assays
  • Step 3 (assessment for multiple factor deficiency): INR/PTT, thrombin time, factor assays
  • Step 4 (assessment for circulating anticoagulant): PTT with polybrene or heparinase, PTT with 1:1 mix, PTT with excess phospholipid, thrombin time


Locations of Hemorrhage

  • Central Nervous System Hemorrhage: central nervous system hemorrhage is the major cause of bleeding-related deaths in patients with severe congenital factor deficiencies
  • Epistaxis (see Epistaxis)
  • Excessive Menstrual Bleeding
    • Menorrhagia (see Menorrhagia): loss of >80 mL of blood per cycle (or >4 super pads or tampons per day) or menses lasting >7 days
  • Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage): gastrointestinal hemorrhage in presence of a bleeding disorder is usually associated with underlying gastrointestinal tract pathology
    • Von Willebrand Disease (Especially Types 2 and 3): has been associated with angiodysplasia of the bowel and gastrointestinal hemorrhage
  • Hemarthrosis (see Hemarthrosis)
  • Hematuria (see Hematuria): hematuria in presence of a bleeding disorder is usually associated with underlying urinary tract pathology
  • Hemoperitoneum (see Hemoperitoneum): has been reported in association with rupture of ovarian cysts in association with a bleeding disorder
  • Mucosal/Gingival Bleeding
    • Platelet Adhesion Defect: may have increased bleeding after dental cleanings or gum manipulation
  • Muscle Hematoma
  • Post-Partum Hemorrhage
    • Common in women with underlying bleeding disorders
    • In women with type 1 Von Willebrand Disease and symptomatic hemophilia carriers in whom levels of Von Willebrand factor and factor VIII usually normalize during pregnancy, the onset of post-partum hemorrhage may be delayed
    • Women with a history of postpartum hemorrhage have a high risk of recurrence with subsequent pregnancies
  • Retroperitoneal Hemorrhage (see Retroperitoneal Hemorrhage)
  • Surgical Bleeding
    • Post-Colonoscopic Polypectomy (see Colonoscopy): delayed bleeding may occur
    • Post-Tonsillectomy (see Tonsillectomy): Bleeding may occur early after surgery or after approximately 7 days postoperatively (with loss of the eschar at the surgical site)

Clinical Patterns of Bleeding