Etiology
Disorders of Primary Hemostasis (Platelet Plug)
Thrombocytopenia
Platelet Adhesion Defect
- Von Willebrand Disease (see Von Willebrand Disease, [[Von Willebrand Disease]])
- Inherited Von Willebrand Disease
- Type 1 (75% of all von Willebrand Disease cases): autosomal dominant (with incomplete penetrance)
- Type 2A (10-15% of all von Willebrand Disease cases): autosomal dominant (usually)
- 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
- Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome, [[Anti-Phospholipid Antibody Syndrome]]): antibodies against VWF
- Scleroderma (see Scleroderma, [[Scleroderma]]): antibodies against VWF
- Systemic Lupus Erythematosus (see Systemic Lupus Erythematosus, [[Systemic Lupus Erythematosus]]): antibodies against VWF (higher MW multimers appear to be more susceptible to degradation by this mechanism)
- Drugs
- Ciprofloxacin (see Ciprofloxacin, [[Ciprofloxacin]])
- Dextran (see Dextran, [[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, [[Hydroxyethyl Starch]])
- Thrombolytics (see Thrombolytics, [[Thrombolytics]]): hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
- Valproic Acid (see Valproic Acid, [[Valproic Acid]])
- High Intravascular Shear Forces
- Aortic Stenosis (see Aortic Stenosis, [[Aortic Stenosis]]): high intravascular shear forces -> increased clearance of high MW multimers (possibly due to increased susceptibility to serum proteases)
- Extracorporeal Membrane Oxygenation (ECMO) (see Extracorporeal Membrane Oxygenation, [[Extracorporeal Membrane Oxygenation]])
- Hypertrophic Obstructive Cardiomyopathy (HOCM) (see Hypertrophic Obstructive Cardiomyopathy, [[Hypertrophic Obstructive Cardiomyopathy]]): high intravascular shear forces -> increased clearance of high MW multimers
- Mitral Valve Replacement: high intravascular shear forces (due to paravalvular leak) -> increased clearance of high MW multimers
- Mitral Valve Prolapse (see Mitral Valve Prolapse, [[Mitral Valve Prolapse]]): high intravascular shear forces -> increased clearance of high MW multimers
- Ventricular Assist Device (VAD) (see Cardiac Assist Devices, [[Cardiac Assist Devices]]): high intravascular shear forces -> increased clearance of high MW multimers
- Ventricular Septal Defect (VSD) (see Ventricular Septal Defect, [[Ventricular Septal Defect]]): high intravascular shear forces -> increased clearance of high MW multimers
- Malignant/Hematologic Disease
- Chronic Lymphocytic Leukemia (CLL) (see Chronic Lymphocytic Leukemia, [[Chronic Lymphocytic Leukemia]])
- Chronic Myeloid Leukemia (CML) (see Chronic Myeloid Leukemia, [[Chronic Myeloid Leukemia]])
- Disseminated Intravascular Coagulation (DIC) (see Disseminated Intravascular Coagulation, [[Disseminated Intravascular Coagulation]]): hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
- Essential Thrombocytosis (see Essential Thrombocytosis, [[Essential Thrombocytosis]]): increased numbers of platelets may result in increased VWF binding -> increased VWF clearance
- Lymphoma (see Lymphoma, [[Lymphoma]]): adsorption of VWF to lymphoma cells
- Monoclonal Gammopathy of Unclear Significance (MGUS) (see Monoclonal Gammopathy of Unclear Significance, [[Monoclonal Gammopathy of Unclear Significance]])
- Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]]): adsorption of VWF to malignant cells
- Polycythemia Vera (see Polycythemia Vera, [[Polycythemia Vera]]): increased numbers of platelets may result in increased VWF binding -> increased VWF clearance
- Waldenstrom’s Macroglobulinemia (see Waldenstrom’s Macroglobulinemia, [[Waldenstroms Macroglobulinemia]]): adsorption of VWF to malignant cells
- Wilm’s Tumor (see Wilm’s Tumor, [[Wilms Tumor]]): adsorption of VWF to malignant cells
- Other
- Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]]): hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
- End-Stage Liver Disease (see End-Stage Liver Disease, [[End-Stage Liver Disease]]): hyperfibrinolytic state -> VWF degradation by proteolytic enzymes (such as plasmin)
- Gastrointestinal Angiodyplasia (Heyde’s Syndrome = constellation of aortic stenosis + gastrointestinal angiodysplasia -> high intravascular shear forces across the stenotic aortice valve increase clearance of high MW multimers)
- Hemoglobinopathies
- Hypothyroidism (see Hypothyroidism, [[Hypothyroidism]]): decreased synthesis of VWF
- Post-Multiple Transfusions: due to development of antibodies against VWF
- Uremia (see Acute Kidney Injury, [[Acute Kidney Injury]] and Chronic Kidney Disease, [[Chronic Kidney Disease]])
- Bernard-Soulier Syndrome (see Bernard-Soulier Syndrome, [[Bernard-Soulier Syndrome]]): autosomal recessive deficiency in platelet glycoprotein Ib-IX complex -> inability to bind Von Willebrand factor
Platelet Aggregation Defect
- Afibrinogenemia (see Afibrinogenemia, [[Afibrinogenemia]])
- Dextran (see Dextran, [[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, [[Glanzmanns Thrombasthenia]]): autosomal recessive deficiency or defect in IIb-IIIa complex -> platelets cannot bind fibrinogen -> inability of platelets to aggregate
- Hypophosphatemia (see Hypophosphatemia, [[Hypophosphatemia]])
- IIb-IIIa Inhibitors (see IIb IIIa Inhibitors, [[IIb IIIa Inhibitors]])
- Abciximab (ReoPro) (see see Abciximab, [[Abciximab]])
- Eptifibatide (Integrilin) (see see Eptifibatide, [[Eptifibatide]])
- Tirofiban (Aggrastat) (see Tirofiban, [[Tirofiban]])
- Omega-3 Fatty Acids/Fish Oil (see Omega-3 Fatty Acid, [[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
- Vitamin E (see Vitamin E, [[Vitamin E]]): inhibits protein kinase C–mediated platelet aggregation and nitric oxide synthesis
Platelet Secretion Defect
- ADP Receptor Antagonists
- Clopidogrel (Plavix) (see Clopidogrel, [[Clopidogrel]]): thienopyridine drug which inhibits binding of ADP to P2Y12 receptor -> inhibition of ADP-mediated platelet aggregation
- Prasugrel (Effient): thienopyridine drug which inhibits binding of ADP to P2Y12 receptor -> inhibition of ADP-mediated platelet aggregation
- Ticlopidine (Ticlid): thienopyridine drug which inhibits binding of ADP to P2Y12 receptor -> inhibition of ADP-mediated platelet aggregation
- Cyclooxygenase Defect
- Inherited Platelet Secretion Defect: defect of cyclooxygenase-1 activity
- Cyclooxygenase (COX) Inhibitors
- Aspirin (see Acetylsalicylic Acid, [[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 Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal 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, [[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, [[Ethanol]]): decreases TXA2 release
- Granule Storage Pool Defect
- Inherited
- Acquired
- Cardiopulmonary Bypass (see Cardiopulmonary Bypass, [[Cardiopulmonary Bypass]]): platelet activation in bypass circuit (due to artificial membrane) -> prolonged bypass may result in platelet degranulation with a transient platelet storage pool disorder
- Treatment: platelet transfusion
- End-Stage Liver Disease (ESLD) (see End-Stage Liver Disease, [[End-Stage Liver Disease]]): some patients manifest permanent platelet degranulation
- Leukemia (see Acute Myeloid Leukemia, [[Acute Myeloid Leukemia]] and Acute Lymphocytic Leukemia, [[Acute Lymphocytic Leukemia]])
- Myeloproliferative Disorder: abnormal platelet membrane receptors, signal transduction, and/or granule release
- Systemic Lupus Erythematosus (see Systemic Lupus Erythematosus, [[Systemic Lupus Erythematosus]]): some patients manifest permanent platelet degranulation
- Fluoxetine (Prozac) (see Fluoxetine, [[Fluoxetine]]): decreased serotonin in dense granules
- Paroxetine (Paxil) (see Paroxetine, [[Paroxetine]]): decreased serotonin in dense granules
- Phosphodiesterase Inhibitors: increase cAMP/cGMP (increases in each vary by agent)
- Cilostazol (Pletal) (see Cilostazol, [[Cilostazol]])
- Dipyridamole (Persantine) (see Dipyridamole, [[Dipyridamole]]): decreased intracellular cAMP metabolism -> increase intracellular cAMP
- Methyl Xanthines: increase intracellular cAMP
- Sildenafil (Viagra, Revatio) (see Sildenafil, [[Sildenafil]]): inhibition of PDE5/PDE6
- Tadalafil (Adcirca, Cialis) (see Tadalafil, [[Tadalafil]]): inhibition of PDE5
- Vardenafil (Levitra, Staxyn, Vivanza) (see Vardenafil, [[Vardenafil]]): inhibition of PDE5
- Platelet Coating
- Paraproteinemia (see Paraproteinemia, [[Paraproteinemia]])
- Penicillin (see Penicillins, [[Penicillins]]): large doses of penicillin can coat platelets and impair hemostasis
- Uremia (see Acute Kidney Injury, [[Acute Kidney Injury]] and Chronic Kidney Disease, [[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 degree of urea and degree of platelet dysfunction
- Treatment: dialysis, cryoprecipitate or DDAVP (both increase Von Willebrand factor levels), conjugated estrogens, increasing Hct 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, [[Feverfew]])
- Garlic (Allium Sativum) (see Garlic, [[Garlic]])
- Ginger (Gingiber Officinale) (see Ginger, [[Ginger]])
- Ginkgo Biloba (Ginkgo Biloba) (see Ginkgo Biloba, [[Ginkgo Biloba]])
- Ginseng (see Ginseng, [[Ginseng]])
- Asian Ginseng = Panax Ginseng
- American Ginseng = Panax Quinquefolius
- Meadowsweet (Filipendula Ulmaria)
- Siberian Ginseng/Eleuthero (Eleutherococcus Senticosus)
- Turmeric (Circuma Longa) (see Turmeric, [[Turmeric]])
- Willow (Salix species)
Disorders of Secondary Hemostasis
Inherited
- Afibrinogenemia (see Afibrinogenemia, [[Afibrinogenemia]])
- Dysfibrinogenemia (see Dysfibrinogenemia, [[Dysfibrinogenemia]])
- Factor II/Prothrombin Deficiency (see Prothrombin Deficiency, [[Prothrombin Deficiency]])
- Factor V Deficiency (see Factor V Deficiency, [[Factor V Deficiency]])
- Factor VII Deficiency (see Factor VII Deficiency, [[Factor VII Deficiency]])
- Factor VIII Deficiency (Hemophilia A) (see Hemophilia A, [[Hemophilia A]])
- Factor IX Deficiency (Hemophilia B) (see Hemophilia B, [[Hemophilia B]])
- Factor X Deficiency (see Factor X Deficiency, [[Factor X Deficiency]])
- Factor XI Deficiency (see Factor XI Deficiency, [[Factor XI Deficiency]])
- Factor XII Deficiency (see Factor XII Deficiency, [[Factor XII Deficiency]])
- Factor XIII Deficiency (see Factor XIII Deficiency, [[Factor XIII Deficiency]])
- HK Deficiency (see HK Deficiency, [[HK Deficiency]])
- Prekallikrein Deficiency (see Prekallikrein Deficiency, [[Prekallikrein Deficiency]])
Acquired
- Factor IIa (Thrombin) Inhibitors (see Factor IIa Inhibitors, [[Factor IIa Inhibitors]])
- Argatroban (Acova) (see Argatroban, [[Argatroban]]): intravenous
- Bivalirudin (Angiomax, Angiox) (see Bivalirudin, [[Bivalirudin]])
- Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): oral
- Desirudin (Iprivask, Revasc) (see Desirudin, [[Desirudin]])
- Lepirudin (Refludan) (see Lepirudin, [[Lepirudin]])
- Factor VIII Inhibitor (see Anti-Factor VIII Antibody, [[Anti-Factor VIII Antibody]])
- Factor Xa Inhibitors (see Factor Xa Inhibitors, [[Factor Xa Inhibitors]])
- Apixaban (Eliquis) (see Apixaban, [[Apixaban]]): oral
- Betrixaban: oral
- Danaparoid (Orgaran) (see Danaparoid, [[Danaparoid]]): intravenous and subcutaneous
- Edoxaban (Lixiana) (see Edoxaban, [[Edoxaban]]): oral
- Fondaparinux (Arixtra) (see Fondaparinux, [[Fondaparinux]]): subcutaneous
- Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]]): oral
- Heparins
- Heparin (Unfractionated) (see Heparin, [[Heparin]])
- Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]])
- Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
- Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]])
- Vitamin K Antagonism (see Vitamin K, [[Vitamin K]])
- Vitamin K Deficiency (see Vitamin K, [[Vitamin K]])
Diagnosis
Diagnostic Tests
- INR: prolonged with deficiency of factor VII and common pathway factors (fibrinogen, II, V, and X)
- PTT: prolonged with deficiency/inhbitors 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: 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: used to determine if prolonged thrombin time is due to heparin
- 1:1 Mix: 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:used to neutralize heparin in the sample to determine if prolonged PTT is due to heparin
- PTT with Excess Phospholipid: used to detect presence of anti-phospholipid antibody (lupus anticoagulant, etc)
- Bleeding Time: assesses for platelets defects (relatively insensitive for factor deficiencies or inhibitors)
- Platelet Function Analysis (PFA): essentially an in vitro bleeding time assay which assesses different components of platelet activation (in response to ADP, epinephrine, collagen)
- Von Willebrand Factor Antigen: quanitifies the amount of Von Willebrand factor -> decreased in Von Willebrand Disease
- Ristocetin Cofactor Test: 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): 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 INR/PTT
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
Clinical Locations of Bleeding
- Central Nervous System Hemorrhage: CNS bleeding is the major cause of bleeding-related deaths in patients with severe congenital factor deficiencies
- Epistaxis (see Epistaxis, [[Epistaxis]]): most common symptom in hereditary hemorrhagic telangiectasia and in young males with Von Willebrand Disease
- Excessive Menstrual Bleeding
- Menorrhagia (see Menorrhagia, [[Menorrhagia]]): loss of >80 mL of blood per cycle (or >4 super pads or tampons per day) or menses lasting >7 days
- Gastrointestinal Bleeding (see Gastrointestinal Bleed, [[Gastrointestinal Bleed]]): GI bleeding in presence of a bleeding disorder is usually associated with underlying GI tract pathology
- Von Willebrand Disease (especially types 2 and 3) has been associated with angiodysplasia of the bowel and GI bleeding
- Hemarthrosis (see Hemarthrosis, [[Hemarthrosis]]):
- Usually associated with moderate-severe congenital factor VIII or factor IX deficiency, moderate-severe fibrinogen/prothrombin/factor V/factor VII/factor X deficiency
- May occur in severe Von Willebrand Disease with factor VIII levels <5%
- Hematuria (see Hematuria, [[Hematuria]]): hematuria in presence of a bleeding disorder is usually associated with underlying urinary tract pathology
- Hemoperitoneum (see Hemoperitoneum, [[Hemoperitoneum]]): has been reported in association with rupture of ovarian cysts in association with a bleeding disorder
- Mucosal/Gingival Bleeding
- Patients with platelet adhesion defects may have increased bleeding after dental cleanings or gum manipulation
- Muscle Hematoma
- Usually associated with moderate-severe congenital factor VIII or factor IX deficiency, moderate-severe fibrinogen/prothrombin/factor V/factor VII/factor X deficiency
- Common in acquired factor VIII deficiency
- 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 Hematoma (see Retroperitoneal Hemorrhage, [[Retroperitoneal Hemorrhage]])
- Surgical Bleeding
- Post-Colonoscopic Polypectomy: delayed bleeding may occur
- Post-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
References
