Disoders of secondary hemostasis

1. Disoders of secondary hemostasis Disorders of plasma clotting factors

2. Disorders of Secondary Hemostasis • Disorders of the proteins of fibrin formation • Disorders of proteins associated with fibrinolysis • Symptoms of secondary hemostatic disorders • Delayed bleeding • Deep muscular bleeding • Spontaneous joint bleeding • Symptoms common to primary and secondary hemostatic disorders • Ecchymoses • GI bleeding • Hematuria • Hypermenorrhea • Gingival bleeding • Increased bleeding after tooth extraction • Intracranial bleeding • Epistaxis

3. Disorders of Proteins of Fibrin Formation • Hereditary vs acquired • Quantitative vs qualitative deficiencies • Laboratory screening tests (PT, APTT) • Does not differentiate quantitative vs qualitative disorders • Qualitative abnormal proteins will • Prolong clotting test • Be recognized by immunologically-based procedures • Activity assays • Essential when screening for deficiencies

4. Coagulation screening tests in congenital deficiencies

5. von Willebrand Disease • Inherited hemorrhagic disorder • Genetically and clinically heterogeneous • Caused by a deficiency/dysfunction of VWF • Most common hereditary bleeding disorder • 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 • Interfere with biosynthetic processing or disrupt specific ligand binding sites • Cause bleeding by impairing either platelet adhesion or blood clotting

6. 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 platlet GPIb • Type 2M – ↓ platelet-dependent function • Not caused by the absence of HMW multimers • Type 2N – Markedly ↓ affinity for F-VIII • 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

7. VWD – Clinical Manifestations • Hemorrhagic tendency is highly variable • Depends on the type and severity of disease • Patients with Type 1 and 2 disease • May have mild bleeding symptoms • Characterized by hemorrhage from delicate mucocutaneous tissues • Epistaxis, easy bruising, GI bleeding, menorrhagia • Hematoma and hemarthroses, characteristic of hemophilia A, are not prominent • Patients with severe type 3 VWD • Severe hemorrhagic tendency • Spontaneous hemorrhage • Mucous membranes, GI tract • Can be frequent and may be life threatening • Low F-VIII level • Deep hematomas • Joint hemorrhages – similar to hemophilia

8. 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 – won’t work for type 3 • Intermediate purity factor VIII which contains intact vWF

9. Hemophilias • Hemophilia A • Factor VIII Deficiency • AntihemophilicFactor • X-linked recessive disorder • Most common type of hemophilia • Hemophilia B • Factor IX Deficiency • Christmas Factor (from family of first patients diagnosed with the disorder) • X-linked recessive disorder • Hemophilia C • Factor XI Deficiency • Autosomal recessive disorder seen primarily in the Ashkenazi Jewish population • Symptoms range from mild to severe

10. Coagulation screening tests in congenital deficiencies

11. Hemophilia • Insufficient generation of thrombinby • F-IXa/VIIIa complex through the intrinsic pathway of coagulation cascade • Bleeding severity complicated by excessive fibrinolysis • Clinical severity corresponds with level of factor activity • Severe hemophilia • Factor coagulant activity <1% of normal • Frequent spontaneous bleeding into joints and soft tissues • Prolonged bleeding with trauma or surgery

12. 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

13. Hemophilia – Clinical Presentation • Readily diagnosed • In severe disease and patients with prior family history • Diagnosis based on • Unusual bleeding symptoms early in life • Age of first bleeding varies with severity of disease • Family history • Physical exam • Laboratory evaluation

14. Hemophilia – Treatment • Replacement of clotting factor to achieve hemostasis • Annual cost for patient with severe hemophilia • $20,000-100,000 • Various products available • Plasma-derived low, intermediate and high purity products • Plasma-derived ultrapure products • Ultrapure recombinant products • Replacement products – benefits vs risks • Blood-born pathogens • Hepatitis A, B, C, G; HIV, Parvovirus B-19 • Thrombotic complications with some F-IX concentrations • Development of alloantibody inhibitors • Neutralize coagulant effects of replacement therapy

15. 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

16. Disseminated Intravascular Coagulation • Normal balance of hemostasis is altered • Results in the uncontrolled inappropriate formation and lysis of fibrin within the blood vessels • Activation of coagulation occurs systemically • Rather than locally at site of injury • Fibrin is deposited diffusely within capillaries, arterioles and venules • Clotting proteins, inhibitors and platelets are consumed faster than they are synthesized • Acquired deficiency of multiple hemostatic components • Fibrinolysis follows fibrin formation • Patient generally bleeds spontaneously at the same time that disseminated clotting is occurring

17. Clinical conditions associated with DIC

18. DIC - Pathophysiology • Fibrin strands within small vessels result in • Traumatic destruction of RBC • Microangiopathic hemolytic anemia • Formation of schistocytes • Fibrin deposition in and obstruction of microvasculature • Tissue anoxia/microinfarcts • Renal failure, liver failure, respiratory failure, shock and death

19. DIC • HELLP syndrome • High blood pressure • Elevated liver enzymes • Low platlets • Occurs in pregnancy and is life-threatening • If the CBC of a woman in labor shows schistocytes and low platlets alert the physician immediately – the baby must be delivered immediately to save the mom!

20. DIC – Laboratory Diagnosis • Laboratory diagnosis is difficult • Available tests are nonspecific • No single test can establish the definitive diagnosis of DIC • PT, APTT, TT prolonged • Fibrin degradation products are (+) • Platelet count ↓; platelet function tests abnormal • Schistocytes, thrombocytopenia on peripheral blood smear

21. 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

22. Vitamin K Deficiency • Precursor proteins synthesized by hepatocytes • Not γ-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

23. Acquired Pathologic Inhibitors • Circulating anticoagulants • Usually IgG or IgM immunoglobulins • Inhibitors of single factors • Patients with inherited factor deficiencies • After treatment with replacement concentrates • Associated with other conditions • Diseases, drugs • Occasionally seen in otherwise healthy individuals • Interfere with or neutralize clotting factor activity • Prolonged screening test not corrected by 1:1 mixture with normal plasma