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Hemostasis
Blood must be fluid Must coagulate (clot) at appropriate time
Rapid Localized Reversible Thrombosisinappropriate coagulation
Fibrinogen Fibrin
Thrombin
Thrombosis
Thrombomodulin
Anti-thrombotic
mechanisms
Fibrinolysis
Breakdown of fibrin Plasmin (Plasminogen)
tPA
Clotting or thrombosis
Rudolph Virchow
Components of haemostasis
COAGULATION PROTEINS
Endothelium
Platelets
Endothelium
PROCOAGULANT
Plasminogen activator inhibitors
ANTICOAGULANT
Plasminogen activators
Thrombin/Thrombomodulin
Tissue Factor
Inhibition of Fibrinolysis
Thrombin activated fibrinolytic inhibitor Plasminogen activator inhibitor
Platelets
Anucleate sub-cellular fragments Arise from megakaryocytes in the marrow Normal count: 200-400 thousand/l Several surface receptors Activated by contact with extra-cellular matrix Aggregation to form a platelet plug Stabilisation by the formation of a fibrin clot
Platelets-2
Contact with collagen Swelling and pseudopod formation Contractile proteins contract forcefully Release of platelet granules Increased adhesion Adhere to collagen and vWF ADP and Thromboxane production Cascade of events lead to a platelet plug
Haemostasis
Primary
Vasoconstriction Platelet plug formation
Secondary
Coagulation Organisation of clot
www.homepage.montana.edu/~awmsg/Coagulation.ppt
www.homepage.montana.edu/~awmsg/Coagulation.ppt
Fibrinogen
Fibrin
Fibrinogen
Thrombin
Fibrin
Factor 2
Thrombin (IIa)
Fibrinogen Fibrin
Thrombin
Fibrinogen Fibrin
Intrinsic pathway
XIIa
Extrinsic Pathway XIa TF Prothrombin IXa VIIIa VIIa Xa Va
Thrombin
Fibrinogen Fibrin
Intrinsic pathway
XIIa
Extrinsic Pathway XIa TF Prothrombin IXa VIIIa VIIa Xa Va
Thrombin
Fibrinogen Fibrin
Unstable clot
XIIIa
Stable clot
Fibrin
XIIa
Extrinsic Pathway XIa TF Prothrombin IXa VIIIa + Fibrinogen VIIa Xa Va +
Thrombin
Soft clot
Fibrin
XIIIa
Hard clot
Fibrin
Role of vitamin K
Some clotting factors require a post-translational modification
Clot removal
Fibrinolysis
Fibrin
Plasmin
Fibrinolysis
Plasminogen
tPA
Fibrin
Plasmin
Inhibitors of fibrinolysis
1. 2.
Coagulation Disorder
More common in Men
Delayed deep muscle bleeding, hemarthrosis, hematuria More commonly congenital
BLEEDING DISORDERS
Is there another disorder present that could be the cause of or might exacerbate any bleeding tendency?
EASY BRUISING
Bruising with mild trauma Bruising without trauma
Petechiae - a Ecchymoses - b Hematoma - c
Menorrhagia
Characteristic of Hemophilias
Rarely occur in other bleeding disorders
Except severe von Willebrand disease
Spontaneous hemarthrosis
Usually coagulation factor deficiency
VASCULAR DISORDERS
Most vascular diseases
Are not associated with platelet or plasma defects Most common symptom
Abnormal bleeding into or under the skin due to increased permeability to blood
Majority of patients
Hemostatic testing is entirely normal, despite a history or physical examination that suggests substantial bleeding
PLATELET DISORDERS
Quantitative
Thrombocytopenia Thrombocytosis
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
Thrombocytopenia may result from
Abnormal platlet distribution Deficient platlet production Increased platlet destruction
DECREASED PRODUCTION
Failure of BM to deliver adequate platelets to the peripheral blood
Hypoplasia of megakaryocytes
Drug or radiation therapy for malignant disease Acquired aplastic anemia Replacement of normal marrow
Leukemias and lymphomas MDS Other neoplastic diseases Fibrosis or granulomatous inflammation
Ineffective thrombopoiesis
Megaloblastic anemia
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)
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
INCREASED DESTRUCTION
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
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
ALLOIMMUNE THROMBOCYTOPENIAS
Posttransfusion purpura
More common in females
Previously sensitized, pregnancy or transfusion
Thrombocytopenia
Usually occurs 1 week after transfusion
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
THROMBOCYTOSIS
platelet count above reference range
Peripheral blood smear
> 20 platelets per 100 x oil immersion field
Secondary thrombocytosis
Reactive thrombocytosis platelets caused by another disease or condition
Transient thrombocytosis
Type of bleeding
Petechiae Easy & spontaneous bruising Bleeding from mucous membranes Prolonged bleeding from trauma
Liver disease
Thrombocytopenia due to splenomegaly from portal hypertension
Paraproteinemias
Clinical bleeding and platelet dysfunction are often seen
Dysproteinemias
MM and Waldenstroms macroglobulinemia Thrombocytopenia most likely cause of bleeding
Activity assays
Essential when screening for deficiencies
PT
APTT
TT
Congenital Deficiency
XIII, mild deficiency of any factor, plasminogen activator inhibitor-1, 2 anti-plasmin VII
Fibrinogen
A or N
Von Willebrands
VWF
Multimeric blood protein Performs two major roles in hemostasis
Mediates adhesion of platelets to sites of vascular injury Is a carrier protein for F-VIII
Inherited defects in VWF may cause bleeding by impairing either platelet adhesion or blood clotting
VWD
Three major categories of VWD Type 1 VWD partial quantitative deficiency of VWF Type 2 VWD qualitative deficiency of VWF Divided into 4 variants Type 2A platelet-dependent function Absence of high-molecular weight VWF multimers Type 2B affinity for platelet GPIb Type 2M platelet-dependent function Not caused by the absence of HMW multimers Type 2N Markedly affinity for F-VIII
VWD
Type 3 VWD total deficiency of VWF Types 1 and 2 autosomal dominant inheritance Type 3 autosomal recessive inheritance
Diagnosis Specific tests Quantify VWF and F-VIII activity
VWD Therapy
Goal
Correct both bleeding time and coagulation abnormalities
Raise both F-VIII and VWF to normal levels
Desmopressin acetate (DDAVP) stimulates release of vWF from endothelial cells Intermediate purity factor VIII which contains intact vWF
Hemophilias
Hemophilia A
Factor VIII Deficiency
Antihemophilic Factor X-linked recessive disorder Most common type of hemophilia
Hemophilias
Hemophilia B
Factor IX Deficiency
Christmas Factor (from family of first patients diagnosed with the disorder) X-linked recessive disorder
Hemophilias
Hemophilia C
Factor XI Deficiency Autosomal recessive disorder seen primarily in the Ashkenazi Jewish population Symptoms range from mild to severe
Hemophilia
Insufficient generation of thrombin by
F-IXa/VIIIa complex through the intrinsic pathway of coagulation cascade
Hemophilia
Moderate hemophilia
Factor coagulant activity 1-5% of normal Occasional spontaneous bleeding Excessive bleeding with surgery or trauma
Mild hemophilia
Factor coagulant activity >5% of normal Usually no spontaneous bleeding Excessive bleeding with surgery or trauma
Diagnosis based on
Unusual bleeding symptoms early in life Age of first bleeding varies with severity of disease Family history Physical exam Laboratory evaluation
Hemophilia Treatment
Replacement of clotting factor to achieve hemostasis Various products available
Plasma-derived low, intermediate and high purity products Plasma-derived ultrapure products Ultrapure recombinant products
Hepatitis A, B, C, G; HIV, Parvovirus B-19 Thrombotic complications with some F-IX concentrations Development of alloantibody inhibitors
Acquired Disorders
More common than hereditary disorders
Usually involve defects of multiple hemostatic factors Bleeding often simultaneously from >1 site May occur in response to another disease process Can be produced by a variety of mechanisms
DIC - Pathophysiology
Fibrin strands within small vessels result in
Traumatic destruction of RBC
Microangiopathic hemolytic anemia Formation of schistocytes
DIC Therapy
Eliminate underlying cause, if possible
Acute DIC is often self-limited
Will disappear when fibrin is lysed
Replacement therapy
Platelets, RBC, Cryoprecipitate or fresh frozen plasma
Vitamin K Deficiency
Precursor proteins synthesized by hepatocytes Not -carboxylated Ca++-binding sites are nonfunctional Induced functional deficiencies of all vitamin-K dependent proteins Causes of vitamin K deficiency in adults Malabsorptive syndromes Biliary tract obstruction Prolonged broad-spectrum antibiotics Most often seen in newborns Hemorrhagic disease of the newborn Due to newborn hepatic immaturity