Coagulopathy


Etiology

Disorders of Primary Hemostasis (Platelet Plug)

Thrombocytopenia

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

Inherited

Acquired


Diagnosis

Diagnostic Tests

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

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

Thrombin Time (see Thrombin Time)

Reptilase Time

1:1 Mix

PTT with Polybrene or Heparinase

PTT with Excess Phospholipid

Bleeding Time (see Bleeding Time)

Platelet Function Analysis (PFA)

Von Willebrand Factor Antigen

Ristocetin Cofactor Test (see Ristocetin Cofactor Test)

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

Factor VIII Activity/Level

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

Stepwise Evaluation of Coagulopathy

Clinical

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)

Patterns of Bleeding

COAGULOPATHY1

References