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Bleeding Disorders: Hemorrhagic Diathesis

Frederick R. Llanera, MD, FPSP, ASCPi, AMT, RMT


Pathologist, Philippine Heart Center Faculty, University of Santo Tomas

Excessive Bleeding
Increased fragility of vessels Platelet deficiency or dysfunction Derangement of coagulation Combination of these

Normal Hemostatic Response


Blood vessel wall Platelets Clotting cascade

Disorders of Primary Hemostasis


I. Platelet Disorders A. Qualitative B. Quantitative Vascular Disorders A. Hereditary B. Acquired

II.

Disorders of Secondary Hemostasis


I. II. Hereditary Hemorrhagic Coagulation Disorders Acquired Hemorrhagic Coagulation Disorders

Hemophilia A
Most common hereditary disease associated with serious bleeding Low Factor VIII amount or activity X-linked recessive males, homozygous females Excessive bleeding in heterozygous females due to lyonization Unusual inversion of X chromosome; point mutations in Factor VIII

Hemophilia A
Normal bleeding time, platelet count, PT Prolonged PTT Fibrin deposition is inadequate to achieve reliable hemostasis

Hemophilia B
Mutations involving Factor IX gene In 14% of patients Factor IX is present but non functional Factor level assay Treatment: Recombinant Factor IX

Structure & Function of Factor VIII von Willebrand factor complex

Type 1 and 3
Reduced quantity of circulating vWF Type 1 autosomal dominant; 70% of cases, mild Type 3 autosomal recessive severe; with deletions and frameshift mutations

Type 2
25 % of all cases; mild to moderate bleeding Qualitative defects in vWF 2A most common; autosomal dominant Missense mutatisons abnormal vWF formed Prolonged bleeding time; normal platelet count; reduced ristocetin cofactor activity; PTT prolonged in types 1 and 3

Disorders of the Fibrinolytic System


I. II. Hemorrhagic Disorders Thrombotic Disorders

Disorders of Primary Hemostasis


I. Platelet Disorders A. Qualitative Platelet Disorders 1. Disorders of Platelet Adhesion a. Bernard Soullier/Giant Plt Syndr. b. von Willebrand Disease 2. Disorders of Platelet Aggregation a. Glanzmanns thrombasthenia b. Acquired von Willebrand Disease 3. Disorders of Platelet Secretion or Release Rxs. a. Storage Pool Diseases 1. Electron dense/delta granules deficiency - Hermansky Pudlak, Wiskott Aldrich, Chediak Higashi, TAR 2. Alpha granules deficiency - Gray Platelet Syndrome, Quebec platelet disorder 3. Primary granules deficiency Hemmeler anomaly b. Thromboxane Pathway Disorders 1. Hereditary aspirin like defects 2. Acquired due to inhibitors of prostaglandin pathway (chronic aspirin intake or inhibitors of thromboxane or cyclooxygenase pathway)

Disorders of Primary Hemostasis


B. Quantitative Platelet Disorders 1. Thrombocytopenia 2. Thrombocytosis

Disorders of Primary Hemostasis


Platelet Disorders
Qualitative
Disorders of Platelet Adhesion
Bernard Soullier von Willebrand

Disorders of Platelet Aggregation


Glanzmanns Thrombasthenia

Disorders of Platelet Secretion/Release Reactions


Storage Pool Disorders Electron Dense/Delta granules HPS,WAS,CHS,TAR Alpha Granules deficiency Gray platelet, Quebec Primary Granules deficiency - Hemmeler Thromboxane Pathway Disorders hereditary/acquired

Disorders of Primary Hemostasis


Platelet Disorders
Quantitative
Thrombocytopenia
Impaired/decreased platelet production BM failure Congenital hypoplasia MHA,WAS, BS, Fanconi, TAR Neonatal hypoplasia drugs, infections Acquired hypoplasia ionizing radiation, drugs Increased platelet desctruction/utilization TTP, drug induced, non immune mechanisms, DIC Disorders related to distribution or dilution / big spleen

Thrombocytosis (primary and reactive)

Disorders of Primary Hemostasis


Vascular Disorders
Hereditary
Hereditary Hemorrhagic Telangiectasia/Rendu-Weber-Osler, Hemangioma-Thrombocytopenia/ Kasabach Merit, Ehler Danlos, Marfan, Osteogenesis Imperfecta, Pseudoxanthoma elasticum

Acquired
Allergic/anaphylactoid purpura, Henoch Schonlein, Senile purpura, scurvy, purpura simplex, infectious purpura, drug induced, purpuras associated with paraproteinemias, amyloidosis, idiopathic purpuras

Laboratory Tests for Primary Hemostasis


1. Bleeding Time 2. Capillary Resistance / Fragility/ Tourniquet /Rumpel Leedes or Hess Test 3. Clot Retraction Time 4. Platelet Adhesiveness Test 5. Platelet Aggregation Test 6. Platelet Count 7. Platelet Morphology and MPV

Disorders of Secondary Hemostasis


Hereditary
individual coagulation factor deficiencies

Acquired
DIC Liver disease Vitamin K deficiency Acquired pathologic inhibitors or the circulating anticoagulants

Secondary Hemostasis Tests


Clotting Time Plasma Recalcification Time Activated clotting time PTT/APTT PT Stypven time Thrombin Time / Thrombin Clotting Time Reptilase Time

Secondary Hemostasis Tests


Substitutiion Test / Mixing Studiest Prothrombin Consumption / Serum PT Thromboplastin Generation Test Specific Factor Assay Assay of vWR:Ag, vWR:Reo Duckers or Clot solubility Test Tests to evaluate circulating inhibitors of coagualtion

Laboratory Tests for Secondary Hemostasis


1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Clotting Time slide, Dale-Laidlaw, Lee-White, Howell Plasma Recalcification Time Activated Clotting Time PTT / APTT / DAPTT PT Stypven Time Thrombin Time / Thrombin Clotting Time Reptilase Time Substitution Test (Mixing Studies) Prothrombin Consumption/Serum Prothrombin Test Thromboplastin Generation Test Specific Factor Assay Assay of vWR:Ag and vWR:Reo Rockett/Laurel Duckerts or Clot Solubility Test Tests for Circulating Inhibitors of Coagulation

Disorders of the Fibrinolytic System


Hemorrhagic Disorder Thrombotic Disorder
Hereditary
Deficiency in plasminogen and in the activators of plasminogen or plasmin

Acquired
Primary fibrinolysis Secondary fibrinolysis

Thrombosis
Hereditary
deficiencies of natural inhibitors of coagulation deficiency of plasminogen Deficiency of Factor XII Dysfibrinogenemia Homocystinuria Deficiency in heparin co-factor II Defects in fibrinolysis

Thrombosis
Acquired
Malignancy Pregnancy Nephrotic syndrome DM Polycythemia vera, sickle cell anemia

Anticoagulant therapy
Prevention of initiation or extension of venous thrombosis
Heparin, oral anticoagulant, coumarin or warfarin

Antiplatelet drugs arterial thromboembolic disease


Aspirin, phenothiazine, antihistamine

Thrombolytic agents
Streptokinase, urokinase

Laboratory Tests for Fibrinolysis


Determination of: 1. Fibrinolytic Products 2. Lysis Time 3. Proteins involved in Fibrinolysis

DIC
Formation of microthrombi in microcirculation Trigger mechanisms:
Release of tissue factor or thromboplastic substances into the circulation Widespread injury to endothelial cells