Blue and Grey

Bleeding Diathesis

Inherited & Acquired Causes of Bleeding Disorders

Harry Kopolovich

1Clinical Vignette #1

24 y/o male with a history of Hemophilia A is playing baseball, when a line drive strikes him in the headHe is immediately brought to your ER, where he has a GCS of 15, and a normal neuro examHe complains of a slight headache and pain from a bruise that is developing on his temple

Imaging?Management?

2Clinical Vignette #265 y/o woman is brought to your emergency room because of epistaxisMedical history reveals that she is taking Coumadin for a DVT/PE INR is 7.9

Treatment?

3Clinical Vignette #355 y/o man is brought to your hospital after sustaining a frontal crash on I-95. The patients abdomen struck the steering wheelHe is complaining of abdominal painMedical history reveals that he is taking Pradaxa (Dabigatran) for non-valvular atrial fibrillationCt-imaging demonstrates a retroperitoneal hematoma with a blushManagement?

4Disorder of HemostasisInheritedGenetic MutationsFamilialDe Novo Mutations

IatrogenicPurposefulHuge Pharmaceutical Market

5Normal HemostasisBalance between pro-coagulant and anti-coagulant factorsCompeting interest between smooth laminar blood flow and maintenance of structural integrity of vasculatureHealthy individuals have this occurring constantlyDiseased states lead to hemorrhage or thromboembolism

6Arterial V.S. VenousArterialHigh flow and high pressureSmall amounts of damage leads to catastrophic lossesPrimarily relies on plateletsVenousSlower flow and lower pressureCoagulation cascade with thrombin generation primary means of hemostasis

Thus, ASA to prevent coronary artery thrombus and heparin/lovenox/coumadin to prevent DVT

7Disorders Of HemostasisFollowing should be considered:1)Thrombocytopenia or Platelet Dysfunction

2)Low levels of multiple coagulation factors resulting from Vitamin K deficiency of hepatic dysfunction

3)Single factor deficiencyInherited or Acquired

4)Consumptive coagulopathiesEg. DIC

5)Circulating inhibitors to coagulation factors

8Vascular Wall PhysiologyEndothelial CellsFunctions as a barrier to contain bloodPrevents contact with thrombogenic sub-endothelial contentsIntact cells posses strong anti-coagulant functionsProstacyclin, NO, ADPase, plasminogen activator

9Endothelial Cell DamageProcoagulant stateActivated endothelial cellsSelectins, -integrins, vWFExposed sub endothelial matrixTissue Factor

End ResultCombination of activated proteins and exposed surfaces result in:Platelet ActivationLeukocyte MigrationInitiation of Coagulation CascadeInitiation of Anti-coagulant systemsThrombin-thrombomodulin cascade, protein C, S, t-PA

10Coagulation Cascade

Critical for understanding normal hemostasis

Huge target for Pharmaceutical Companies

Potential for remediating deficiencies created by acquired or iatrogenic means

Liver is the primary site for synthesis of coagulation factors

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12Extrinsic PathwayVascular injury leads to exposed sub endothelial matrixResults in exposure of highly thrombogenic Tissue FactorCombines with Factor VII--> VIIaResults in conversion X-->XaMonitored using PT/INRDeficiencies in Vitamin K analogues leads to elevations

13Intrinsic PathwayContact Activation PathwayInitiated by collagen contacting HMWKMonitored by aPTT

14Common PathwayBoth pathways converge ultimately result in activated thrombin

Abnormalities of X, V, II result in elevation of PT & PTT

15Platelet PhysiologyPlatelet functions as cellular based platform for hemostasisAdhesion results in transmembrane signalingTranslocation of receptors to membrane surfaceReceptor transformational changesDegranulationPro-coagulant surface of plateletServes as assembly point for coagulation cascadeAmplifies overall procoagulant responseProduces fibrin-->Leading to clot stabilization

16Platelet PhysiologyPlatelets derived from bone marrowSurvival time 7-10 days~7,100 platelets required/day even with no challenge to vascular integrityNormal count is 150,000-450,000Qualitative function measure through bleeding time