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Queen Victoria, Royal disease, Hemophilia B
- Congenital deficiency of factor IX
- X-dominant
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Hemostasis
- Complex process.
- Hematostatic system maintains a complete balance of the body’s tendency toward clotting and bleeding.
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Constituents of the Hemostatic System
- Coagulation protein
- Platelets
- Endothelium
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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.
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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.
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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
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Vitamin K dependent factors:
Factor II (common, IIa in int), VII (ext), IX (int), X (common), S (common) and C (common)
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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
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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).
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Combined Abnormal high aPTT and PT
- Coumadin
- Heparin
- Liver disease
- Vitamin K deficiency
- DIC - disseminated intravascular coagulation, septic patients
- Dysfibrinogenemia
- Primary fibrinolysis
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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
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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
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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
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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.
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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
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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
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TYPES OF HEMOPHILIA
- Hemophilia A: VIII deficiency; X linked recessive
- Hemophilia B: IX deficiency; X linked recessive
- Hemophilia C: XI deficiency; Autosomal recessive
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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
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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).
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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
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Treatment
- Factor concentrates
- plasma or cryoprecipitate
- DDAVP [desmopressin] or antifibrinolytic therapy - stabilizing small clots
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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
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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
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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
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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.
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Platelet Disorders
- Quantitative and Qualitative
- Quantitative : Thrombocytopenia (decrease) and Thrombocytosis (increase)
- Qualitative Disorders (+/- thrombocytopenia): defective platelet function; Congenital, or Acquired
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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
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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).
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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)
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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.
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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
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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
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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.
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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%
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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)
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