1. D ISODERS OF SECONDARY HEMOSTASIS Disorders of plasma clotting factors

2. D ISORDERS OF S ECONDARY H EMOSTASIS 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. 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 D ISORDERS OF P ROTEINS OF F IBRIN F ORMATION

4. C OAGULATION SCREENING TESTS IN CONGENITAL DEFICIENCIES Platlet count PTAPTTPFATTCongenital Deficiency NNNNNXIII, mild deficiency of any factor, plasminogen activator inhibitor-1, α2 anti- plasmin NANNNVII NNANNXII, XI, IX, VIII, prekallikrein, high molecular weight kininogen NAANNX, V, II NAANAFibrinogen NNA or N NVon Willibrands

5. 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 VON W ILLEBRAND D ISEASE

6. 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 VWD

7. 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 VWD – C LINICAL M ANIFESTATIONS

8. 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 VWD – T HERAPY

9. Hemophilia A Factor VIII Deficiency Antihemophilic Factor 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 H EMOPHILIAS

10. C OAGULATION SCREENING TESTS IN CONGENITAL DEFICIENCIES Platlet count PTAPTTPFATTCongenital Deficiency NNNNNXIII, mild deficiency of any factor, plasminogen activator inhibitor-1, α2 anti- plasmin NANNNVII NNANNXII, XI, IX, VIII, prekallikrein, high molecular weight kininogen NAANNX, V, II NAANAFibrinogen NNA or N NVon Willibrands

11. Insufficient generation of thrombin by 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 H EMOPHILIA

12. 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 H EMOPHILIA

13. 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 H EMOPHILIA – C LINICAL P RESENTATION

14. 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 H EMOPHILIA – T REATMENT

15. 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 A CQUIRED D ISORDERS

16. 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 D ISSEMINATED I NTRAVASCULAR C OAGULATION

17. C LINICAL CONDITIONS ASSOCIATED WITH DIC

18. 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 DIC - P ATHOPHYSIOLOGY

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. 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 DIC – L ABORATORY D IAGNOSIS

21. 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 DIC – T HERAPY

22. 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 V ITAMIN K D EFICIENCY

23. 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 A CQUIRED P ATHOLOGIC I NHIBITORS