Disorders of primary haemostatsis
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Transcript of Disorders of primary haemostatsis
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DISORDERS OF PRIMARY HEMOSTASISDisorders of platlets and blood vessels
Dr Anoop.K.R
Asst Prof. Dept of medicine
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DIAGNOSIS OF BLEEDING PROBLEMS
Questions to address: Is a bleeding tendency present? Is the condition familial or acquired? Is the disorder one affecting
Primary hemostasis (platelet or blood vessel wall problems) Secondary hemostasis (coagulation problems)
Is there another disorder present that could be the cause of or might exacerbate any bleeding tendency?
Principal Presentations of bleeding disorders Easy bruising Spontaneous bleeding from mucous membranes Menorrhagia – excessive bleeding during menstruation Excessive bleeding after trauma
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MUCOSAL BLEEDING & MENORRHAGIA
Epistaxis - nosebleed History of recurrence
Gingival bleeding Hematuria, hemoptysis, hematemesis
Relatively uncommon presenting features Menorrhagia
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EXCESSIVE BLEEDING AFTER TRAUMA
Surgical trauma Dental extraction, tonsillectomy Delayed wound healing Postpartum hemorrhage
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JOINT AND MUSCLE BLEEDS
Hemarthroses (bleeding into joints) and spontaneous muscle hematomas Characteristic of severe plasma protein deficiencies
Characteristic of Hemophilias Rarely occur in other bleeding disorders
Except severe von Willebrand disease
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TYPES OF BLEEDING DISORDERS
Disorder of Primary platlet plug formation Fibrin formation Premature clot dissolution - fibrinolysis
Spontaneous skin petechiae Usually severe thrombocytopenia
Spontaneous hemarthrosis Usually coagulation factor deficiency
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SIGNS AND SYMPTOMS OF 1O HEMOSTASIS PROBLEMS
Ecchymoses Petechiae Mucus membrane bleeding Hematoma Prolonged bleeding after minor surgery
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TYPICAL SCREENING TESTS FOR BLEEDING DISORDERS
Prothrombin Time (PT) Activated Partial Thromboplastin Time (APTT) Quantitative platelet count (+/-) Bleeding Time Test (BTT) (+/-) Thrombin Time
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HEREDITARY VASCULAR PROBLEMS
Hereditary (spider) telangiectasis (Osler-Rendu-Weber): dilated superficial capillaries
Ehlers-Danlos: collagen disorder Marfan syndrome: connective tissue Osteogenesis imperfecta
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ACQUIRED VASCULAR PROBLEMS
Senile purpura (Bateman’s): altered connective tissue support
Cushing syndrome: metabolic Scurvy: abnormal collagen Allergy: vascular inflammation Viral infection
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BLEEDING TIME
For vascular and platelet functions Duke (1910) on earlobes Ivy (1941) on arm with 1mm x 3mm incision Mielke (1969) with 1mm x 10mm template 1980’s: disposable devices (e.g., Simplate,
Surgicutt)
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Bleeding Time
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QUANTITATIVE PLATELET DISORDERS
Thrombocytopenia<100,000/µl BT prolonged≈10,000 Bleeding in trauma or OR<10,000 Spontaneous, CNS bleeding
Thrombocytopenia due to destructionITP (acute in children, chronic in young
women) with anti-glycoproteinDrug reactionHeparin induced thrombocytopeniaDIC and TTP
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ABOUT THROMBOTIC THROMBOCYTOPENEIC PURPURA (TTP) Disorder of systemic platelet aggregation
in microvasculature Stimulus: unusually large vWf In children: likely to be deficiency in vWf
metalloproteinase to break down vWf In adults: vWf metalloproteinase inhibited
by autoantibodies Low PLT count, intravascular hemolysis,
RBC fragmentation, high LDH
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IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
Caused by an autoreactive antibody to the patient’s platlets Young children – acute and usually transient for 1-2
weeks with spontaneous remission Adults – chronic and occurs more often in women Treatment
Corticosteroids Splenectomy Rituximab
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QUANTITATIVE PLATELET DISORDERS Thrombocytopenia due to decreased production
Aplastic anemia (e.g., Fanconi’s)FibrosisAcute leukemiaMegaloblastic anemiaHereditary (e.g., May-Hegglin, Wiscott-
Aldrich, Bernard-Soulier) Splenic sequestration HELLP syndrome (hemolysis, elevated liver
enzyme, low PLT) in pre-eclampsia Dilution (massive transfusion)
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Platelet Satellitosis in EDTA
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QUANTITATIVE PLATELET DISORDERS
Thrombocytosis Primary with dysfunctions (e.g., CML, ET) Post splenectomy: also see HJ, etc. Hemolytic anemia Acute hemorrhage and surgery
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PSEUDO THROMBOCYTOSIS
Red cell abnormalitiesHJ bodiesClumped Pappenheimer bodiesnRBCMalariaMicrospherocytes and schistocytes
White cell abnormalitiesUnlysed WBCWBC fragments and necrobiotic cells
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AGGREGATION STUDIES ADP
reversible 1o wave if ADP is released, then 2o waveabnormal with aggregation and release
problems Epinephrin
similar to ADP Collagen
direct release so only one wave of aggregation Ristocetin
antibioticaggregation only with vWF and GP-Ib
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Platelet Aggregometry
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Platelet
Aggregation
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THROMBOCYTOPENIA
Platelet count <150 x 109/L Usually no ↑ risk of bleeding unless <50 x 109/L Risk of severe and spontaneous bleeding when platelet
count is <10 x 109/L Petechiae Bleeding from mucous membranes
GI, GU tract, etc Bleeding into CNS BT is related to the platelet count unless there is also a concurrent
platelet dysfunction Thrombocytopenia may result from
Abnormal platlet distribution Deficient platlet production Increased platlet destruction
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PLATELET SEQUESTRATION (DISTRIBUTION DEFECT)
Normally ~30% of platelets held in spleen Splenomegaly/hypersplenism
Up to 90% sequestered May occur in a wide variety of diseases
Infection Inflammation Hematologic diseases Neoplasias
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DECREASED PRODUCTION
Failure of BM to deliver adequate platlets to the peripheral blood Hypoplasia of megakaryocytes
Drug or radiation therapy for malignant disease Generalized marrow suppression
Acquired aplastic anemia Replacement of normal marrow
Leukemias and lymphomas MDS Other neoplastic diseases Fibrosis or granulomatous inflamm
Ineffective thrombopoiesis Megaloblastic anemia
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DECREASED PRODUCTION
Hereditary thrombocytopenias Congenital aplastic anemia Wiskott-Aldrich Syndrome (WAS) X-Linked Thrombocytopenia (XLT) Bernard-Soulier syndrome (BSS) May-Hegglin anomaly (MHA) Congenital amegakaryocytic thrombocytopenia (CAMT) Congenital thrombocytopenia with radioulnar synostosis
(CTRUS) Thrombocytopenia with absent radii Syndrome (TAR)
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INCREASED DESTRUCTION Immune destruction
Platelets are destroyed by antibodies Platelets with bound antibody are removed by mononuclear
phagocytes in the spleen Anti-platlet antibody tests to identify antibodies on platelets are
available
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ALLOIMMUNE THROMBOCYTOPENIAS
Isoimmune neonatal thrombocytopenia Maternal antibodies produced against paternal
antigens on fetal platelets Similar to erythroblastosis fetalis HPA-1a Most serious risk: bleeding into CNS
Posttransfusion purpura More common in females
Previously sensitized, pregnancy or transfusion Thrombocytopenia
Usually occurs 1 week after transfusion Transfused and recipient’s and antigen-negative
platelets are destroyed
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DRUG-INDUCED THROMBOCYTOPENIAS
Many drugs implicated Same mechanisms as described for drug induced
destruction of RBCs Symptoms of excess bleeding
Usually appear suddenly and can be severe Removal of drug
Usually halts thrombocytopenia and bleeding symptoms
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HEPARIN AND THROMBOCYTOPENIA
Heparin associated thrombocytopenia (HAT) Non-immune mediated mechanism Develops early in treatment and is benign Heparin causes direct platelet activation
Thrombocytopenia Immune mediated destruction of platelets Antibody develops against a platlet factor 4-heparin
complex Attaches to platelet surface ↑ platelet clearance
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MISCELLANEOUS IMMUNE THROMBOCYTOPENIA
Secondary feature in many diseases Collagen diseases Other autoimmune disorders (SLE, RA) Lymphoproliferative disorders (HD, CLL) Infections
EBV, HIV, CMV, bacterial septicemia
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NON-IMMUNE MECHANISMS OF DESTRUCTION
Disseminated intravascular coagulation (DIC) Thrombotic thrombocytopenic purpura (TTP) Hemolytic Uremic Syndrome (HUS) PNH Mechanical destruction – artificial heart valves
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THROMBOCYTOSIS
↑ platelet count above reference range Peripheral blood smear
> 20 platelets per 100 x oil immersion field Result of ↑ production by BM (not prolonged lifespan) ↑ BM megakaryocytes Primary
Occurs in chronic myeloproliferative disorders and myelodysplasia Secondary thrombocytosis
Reactive thrombocytosis ↑ platelets caused by another disease or condition
Transient thrombocytosis
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QUALITATIVE PLATELET DISORDERS
Clinical symptoms vary Asymptomatic → mild, easy bruisability → severe, life-
threatening hemorrhaging Type of bleeding
Petechiae Easy & spontaneous bruising Bleeding from mucous membranes Prolonged bleeding from trauma
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INHERITED QUALITATIVE PLATELET DISORDERS
Defects in platelet-vessel wall interaction Disorders of adhesion
von Willebrand disease Deficiency or defect in plasma VWF
Bernard-Soulier syndrome Deficiency or defect in GPIb/IX/V
Defects in collagen receptors GP-IcIIa; GPVI
Defects in platelet-platelet interaction Disorders of aggregation
Congenital afibrinogenemia - Deficiency of plasma fibrinogen Glanzmann thrombasthenia
Deficiency or defect in GPIIb/IIIa
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QUALITATIVE PLATELET DISORDERS
Berhard-Soulier: GP-Ib deficiency, adhesion problem
Von Willebrand’s: vWF deficiency, adhesion problem
Glanzmann’s thrombasthenia: GP-IIb/IIIa deficiency, aggregation problem -- cannot bind vWF and Fib
Storage pool disease: dense body defect, secretion problem
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QUALITATIVE PLATELET PROBLEMS Aspirin: inhibits cyclo-oxygenase (COX),
secretion problem, no TxA2
Plavix (Clopidogrel) inhibits ADP receptor Other medications affect GPIIa/IIIb interaction
with Fib Uremia, secretion problem Gray platelet syndrome: α-granule defect Hypofibrinogenemia
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INHERITED QUALITATIVE PLATELET DISORDERS
Defects of platelet secretion and signal transduction Diverse group of disorders with impaired secretion of
granule contents Results in abnormal aggregation during platelet activation
Abnormalities of platelet granules Storage pool deficiency
αSPD (grey platlet syndrome) δSPD αδSPD
Defects in platlet coagulant activity Decreased Va-Xa binding and VIIIa-IXa binding slows
normal coagulant response
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INHERITED DISORDERS OF PLATLET FUNCTION
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VON WILLEBRAND DISESE
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ACQUIRED QUALITATIVE PLATLET DISORDERS
Chronic renal failure Platelet defects associated with uremic plasma
Dialysis corrects abnormal test results Cardiopulmonary bypass surgery
Thrombocytopenia Abnormal platelet function
Correlates with duration of the bypass procedure Platelet defect likely due to
Effects of platelet activation Fragmentation in extracorporeal circulation
Liver disease Thrombocytopenis due to splenomegaly from portal hypertension
Paraproteinemias Clinical bleeding and platlet dysfunction are often seen
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HEMATOLOGIC DISORDERS THAT AFFECT PLATELET FUNCTION
Chronic Myeloproliferative Disorders Can see either bleeding or thrombosis Abnormal platelet function
Leukemias & Myelodysplastic Syndromes Bleeding usually due to thrombocytopenia Abnormal platelet function
Dysproteinemias MM and Waldenstrom’s macroglobulinemia Thrombocytopenia most likely cause of bleeding
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