Systemic Pathology - Coagulation - Koshy

  1. Queen Victoria, Royal disease, Hemophilia B
    • Congenital deficiency of factor IX
    • X-dominant
  2. Hemostasis
    • Complex process.
    • Hematostatic system maintains a complete balance of the body’s tendency toward clotting and bleeding.
  3. Constituents of the Hemostatic System
    • Coagulation protein
    • Platelets
    • Endothelium
  4. Coagulation Protein Systems
    • Coagulation (clot forming) system: to form thrombin leading to fibrin clot formation.
    • Fibrinolytic (clot lysing) system: to lyse the clot formed by thrombin.
    • Anticoagulant (regulating) system: to regulate all enzymes of the coagulation and fibrinolytic systems so that no inappropriate excess of clotting or bleeding occurs.
  5. Normal stages of coagulation
    • Vasoconstriction at the site of injury: Reflex and in response to released endotheli
    • Primary hemostasis: platelets aggregation and adhere to endothelium; vWF (von Willebrand factor) required.
    • Secondary hemostasis: fibrin formation and deposition, forming and stabilizing the clot.
    • Tertiary hemostasis: crosslinking of fibrin (insoluble) and fibrinolysis. Further extending the clot; counter-regulatory mechanisms (e.g., tissue plasminogen activator, t-PA, thrombomodulin) are set into motion to confine the hemostatic process to the site of injury.
  6. Coagulation Pathways
    • Extrinsic pathway:
    • - most common
    • - injury convert VII to VIIa, w/ the help of Tissue Factor
    • Intrinsic pathway:
    • - XII -> XIIa
    • - XIIa/IIa (thrombin) converts XI to XIa
    • - XIa converts IX to IXa
    • - IIa converts VIII to VIIIa
    • Common pathway:
    • - X is converted to Xa, w/ the help of IXa and VIIIa from intrinsic pathway or VIIa from extrinsic pathway
    • - IIa converts V to Va
    • - Va and Xa convert II (prothrombin) to IIa
    • - IIa converts fibrinogen to fibrin (Ia), and converts XIII to XIIIa
    • - Ia is cross-linked with the help of XIIIa and clots w/ platelet
  7. Vitamin K dependent factors:
    Factor II (common, IIa in int), VII (ext), IX (int), X (common), S (common) and C (common)
  8. Clinical Coagulation Testing
    • PT - Prothrombin Time; measures the extrinsic pathway; starts w/ thromboplastin; increased PT indicates VII and common factors deficiency, vit K deficiency or antagonist, liver disease
    • aPTT - intrinsic pathway; starts w/ kaolin, phospholipid, ca++; increased aPTT indicates Heparin effect, Hereditary factor deficiencies: hemophilias A, B, C, Acquired factor deficiencies: amyloid, etc., Lupus anticoagulant
    • TT - Thrombin Time; test of fibrin generation, part of common pathway; starts w/ thrombin, promoting fibrinogen -> fibrin -> polymerized fibrin clot
  9. International Normalized Ration (INR)
    • ISI - International Sensitivity Index; related to amount of tissue factor in reagent
    • INR - Developed to compensate for reagent differences
    • INR = (patient PT/normal mean PT)^ISI
    • The reference range: 0.9-1.3.
    • high INR (eg. 5) indicates high chance of bleeding, whereas low INR (eg. 0.5) high chance of clotting.
    • Target range of INR in anticoagulant use (e.g. warfarin/coumadin) is 2 to 3, or higher (eg. mechanical heart valve).
  10. Combined Abnormal high aPTT and PT
    • Coumadin
    • Heparin
    • Liver disease
    • Vitamin K deficiency
    • DIC - disseminated intravascular coagulation, septic patients
    • Dysfibrinogenemia
    • Primary fibrinolysis
  11. Increased TT indicates
    • Decreased functional fibrinogen
    • - Congenital disorders: afibrinogenemia, hypofibrinogenemia
    • - Acquired disorders:
    • -- Hypofibrinogenemia: liver disease, consumption (DIC)
    • -- Disfibrinogenemia: Liver disease, hepatic malignancy
    • Other causes:
    • - Heparin
    • - FDPs (Fibrin degradation products, broken-down fibrin)
    • - Thrombin antibodies: may develop following surgical exposure to bovine thrombin
  12. D-dimer and FDPs
    • FDP: Less specific, detect fragment D, E, D-dimers, fragments X, Y.
    • D-dimer: indicates that fibrin has been formed and degraded.
    • D-dimer and FDP are positive with
    • - DIC
    • - Thrombosis
    • - End stage liver disease: poor clearance, chronic DIC
    • - Certain tumors, e.g mucin-secreting adenocarcinomas
  13. Mixing study
    • Patient plasma is mixed 1:1 with normal plasma of 100% normal factor level results in a level ≥ 50% in the mixture.
    • If clotting times remain prolonged -> inhibitor
    • If clotting times normalize or reduced -> factor deficiency
  14. Factor Activity
    • Expressed as percent activity. Normal: 100% activity (1 U/mL) for each factor; normal adults range: 60-150%.
    • All factors, except VIII, are relatively low in neonates (more susceptible to bleeding), reaching adult levels by 6 months of age.
  15. Excessive Bleeding
    • Vascular defects
    • - Hereditary hemorrhagic telangiectasia
    • - Elhers-Danlos syndrome
    • - Scurvy
    • Coagulation Defects
    • - Congenital: Hemophilia A/B/C; factor XIII deficiency, etc
    • - Acquired: acquired factor deficiencies; DIC
    • Platelet disorders
  16. Coagulation proteins defects
    • Congenital:
    • - Hemophilia A, B, C
    • - Factor II, V, VII, X
    • - Inherited combined factor deficiency
    • - Fibrinogen deficiency
    • - Factor XIII deficiency
    • - TPAI or a2-antiplasmin deficiency
    • Acquired:
    • - Factor X deficiency
    • - Vitamin K deficiency
    • - DIC
    • - Liver disease
  17. TYPES OF HEMOPHILIA
    • Hemophilia A: VIII deficiency; X linked recessive
    • Hemophilia B: IX deficiency; X linked recessive
    • Hemophilia C: XI deficiency; Autosomal recessive
  18. Classification severity of Hemophilia A and B on the basis of plasma factor activity level
    • Severe - 50-70%
    • VIII or IX level <1 U/dL
    • Bleed spontaneously 2-4 times per month
    • Moderate and mild are rare
  19. Female Carriers
    • Usually have > 50% FVIII activity and often fall within the normal range.
    • No history of bleeding
    • Lab: normal PTT, but the ratio of factor VIII to vWF is usually 1:2 (normal ratio is 1:1).
  20. Clinical Manifestations of hemophilia
    • Hematoma/hemarthrosis
    • Large bruises
    • Spontaneous GI or genitourinary tract bleeding
    • Excessive bleeding with surgery, trauma, dental extraction
    • Intracranial hemorrhage following trauma can occur, life
    • threatening
  21. Treatment
    • Factor concentrates
    • plasma or cryoprecipitate
    • DDAVP [desmopressin] or antifibrinolytic therapy - stabilizing small clots
  22. Pathophysiology of DIC
    • widespread microthrombi when triggered
    • affects most microvasculature
    • increased fibrinolysis
    • increased fibrin split products, inhibition of thrombin, increased of D dimers
    • clotting increases the consumption of the factors
    • deficiency of factors, aggregating the bleeding
    • bleeding and ischemic tissue damage are the end products
    • Lab test - nothing normal
  23. Platelet Function Assessment - Clinical History:
    • Bleeding, Duration, pattern and severity
    • Spontaneous or trauma/surgery
    • Mucocutaneous, ecchymosis, petechiae, purpura, gingival
    • bleeding
    • Drug and dietary history
    • Systemic diseases (renal, hepatic, MPD)
    • Albinism, deafness, nephritis for inherited platelet disorders
  24. Platelet Testing
    • Platelet count (in CBC) and peripheral blood smear:
    • - Normal range: 150,000-400,000/uL
    • Bleeding Time [Not dependable]
    • Platelet aggregation/secretion Test
    • Flow cytometry
    • Electron microscopy
  25. Lab Findings
    • Isolated thrombocytopenia, <100K/uL, often large in size
    • Increased megakaryocytes in the bone marrow
    • Splenectomy specimen: spleen histology, trapped platelet
    • Increased platelet associated IgG against platelet membrane antigen, GPllb/llla.
  26. Platelet Disorders
    • Quantitative and Qualitative
    • Quantitative : Thrombocytopenia (decrease) and Thrombocytosis (increase)
    • Qualitative Disorders (+/- thrombocytopenia): defective platelet function; Congenital, or Acquired
  27. Thrombocytopenia
    • Reduced Production, marrow failure in aplastic anemia, injury, drugs or replacement in Carcinoma
    • Increased destruction, ITP, drugs (Heparint), infections
    • Alloimmune as in Transfusions of neonatal immune
    • thrombocytopenia.
    • Sequestration: splenomegaly
    • Pseudothrombocytopenia
  28. Thombophilia and Thromboembolism
    • Thrombophilia is characterized by hypercoagulability and an increased propensity for thrombosis, an increased risk of venous thrombosis
    • Inherited or acquired.
    • Protein S Deficiency (cofactor of protein C)
    • APC (Activated Protein C, factor V Leiden) Resistance is the most common hereditary thrombophilia (50% of the cases).
  29. Thrombotic Thrombocytopenic Purpura (TTP)
    • Clinical Manifestation: abrupt onset, older children/ Focal or generalized CNS deficits. Need urgent treatment.
    • Pentad:
    • 1. Microangiopathic hemolytic anemia [Schistocytes, helmet-like RBCs]
    • 2. Thrombocytopenia
    • 3. Neurological manifestation
    • 4. Acute renal failure
    • 5. Fever
    • Reduced ADAMTS-13 metalloprotease activity level: some due to Ab against ADAMTS13, others not
    • Labs results:
    • - Increased reticulocytes because of hemolysis
    • - Normal PT/PTT/fibrinogen
    • Diagnosis need to exclude: HUS, ITP, sepsis, DIC
    • Treatment: plasmapheresis (plasma exchange); FFP vs Cryoprecipitate poor plasma; steroids (to suppress Ab production)
  30. von Willebrand Disease
    • vWF - Binds to VIII to activate it; binds to platelet, too.
    • Most frequent inherited bleeding disorder; usually find out incidently.
    • Prevalence: approximately 1%
    • Very wide range of clinical manifestations.
    • Clinically significant - 125 persons per million
    • Severe - 0.5-5 persons per million population.
    • Most forms: autosomal inheritance pattern
    • Males and females are affected equally.
  31. vWF Production
    • By Vascular endothelial cells AND Megakaryocytes (platelet)
    • Most vWF is secreted
    • Some vWF is stored
    • - Weibel-Palade bodies in endothelial cells
    • - Alpha granules of platelets
    • Constitutive and stimulus-induced pathways
    • - Release stimuli (EC): thrombin, histamine, fibrin
    • - Release stimuli (platelets): thrombin, ADP, collagen
  32. Function of vWF
    • Adhesion
    • - Mediates the adhesion of platelets to sites of vascular injury (subendothelium) - Links exposed collagen to platelets
    • - Mediates platelet to platelet interaction - Binds GPIb and GPIIb-IIIa on activated platelets; Stabilizes the hemostatic plug against shear forces
    • Carrier protein for Factor VIII (FVIII)
    • - Protects FVIII from proteolytic degradation
    • - Localizes FVIII to the site of vascular injury
  33. vWD Clinical Presentation
    • Few or no symptoms.
    • With symptoms - mild manageable bleeding disorder, severe hemorrhage only with trauma or surgery.
    • Types II and III: bleeding episodes may be severe and
    • potentially life threatening.
    • May be more pronounced in females because of menorrhagia.
    • Bleeding exacerbated by aspirin.
  34. Clinical Manifestations of vWD:
    • (similar to those seen with platelet disorders)
    • Gingival bleeding 35%
    • Dental extractions 50%
    • Epistaxis 60%
    • Easy bruising 40%
    • Menorrhagia 35%
    • GI bleeding 10%
    • Trauma/wounds 35%
    • Post-partum 25%
    • Post-operative 20%
  35. vWD Workup
    • Platelets count
    • PTT
    • Factor VIII activity
    • Ristocetin Induced Platelet Aggregation (RIPA)
    • Ristocetin Co-factor assay (vWF activity)
    • vWF antigen (measured by immunoassays)
    • Multimer analysis (western blot)
  36. Acquired vWD is rare
Author
neopho
ID
324902
Card Set
Systemic Pathology - Coagulation - Koshy
Description
Systemic Pathology - Coagulation - Koshy
Updated