Bleeding Disorders Azarm,MD 2007

Normal Hemostasis Primary Hemostasis VascularSub endthel von Willebrand factor(vWF) Platelets SecondaryHemostasis Activation of Fibrinogen to Fibrin ( Intrinsic&Extrinsic Clotting Cascades) Dissolution of Fibrin Clots

XIIa Coagulation cascade IIa Intrinsic system (surface contact) XII XI XIa Tissue factor IX IXa VIIa VII VIIIVIIIa Extrinsic system (tissue damage) X VVa II FibrinogenFibrin (Thrombin) IIa Vitamin K dependant factors Xa

Objectives I. Clinical aspects of bleeding II. Hematologic disorders causing bleeding Coagulation factor disorders Platelet disorders III. Approach to acquired bleeding disorders Hemostasis in liver disease Warfarin toxicity IV. Approach to laboratory abnormalities Diagnosis and management of thrombocytopenia

Objectives - I Clinical aspects of bleeding

Clinical Features of Bleeding Disorders PlateletCoagulation disorders factor disorders Site of bleedingSkinDeep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract) PetechiaeYesNo Ecchymoses (bruises)Small, superficialLarge, deep Hemarthrosis / muscle bleedingExtremely rareCommon Bleeding after cuts & scratchesYesNo Bleeding after surgery or traumaImmediate,Delayed (1-2 days), usually mild often severe

Petechiae Do not blanch with pressure (cf. angiomas) Not palpable (cf. vasculitis) (typical of platelet disorders)

Ecchymoses (typical of coagulation factor disorders)

Objectives - II Hematologic disorders causing bleeding –Coagulation factor disorders –Platelet disorders

Coagulation factor disorders Inherited bleeding disorders –Hemophilia A and B –vonWillebrands disease –Other factor deficiencies Acquired bleeding disorders –Liver disease –Vitamin K deficiency/warfarin overdose –DIC

Hemophilia A and B Hemophilia AHemophilia B Coagulation factor deficiencyFactor VIIIFactor IX InheritanceX -linkedX -linked recessive Incidence1/10,000 males1/50,000 males SeverityRelated to factor level <1% - Severe - spontaneous bleeding 1 - 5% - Moderate - bleeding with mild injury % - Mild - bleeding with surgery or trauma ComplicationsSoft tissue bleeding

Hemophilia Clinical manifestations (hemophilia A & B are indistinguishable) Hemarthrosis (most common) Fixed joints Soft tissue hematomas (e.g., muscle) Muscle atrophy Shortened tendons Other sites of bleeding Urinary tract CNS, neck (may be life-threatening) Prolonged bleeding after surgery or dental extractions

Hemarthrosis (acute)

Hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required. Large amount of vascular synovium removed at surgery from the same knee

Physical Exam. Pseudotumors: are produced by a slow expansion of repeated hemorrhages in bone or soft tissues.,cause resorption of neighboring bone by pressure-induced ischemia, They develop slowly over months to years and often are asymptomatic, unless pressure on the nerves or vascular compromise occurs. Pseudotumors: contain a brownish material and can become infected.

Large pseudocyst involving the left proximal femur

Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.

Lab Data A prolonged aPTT: a normal aPTT does not exclude mild hemophilia A because the aPTT may not be sufficiently sensitive to detect slightly reduced levels of FVIII-C in the approximate 20-30% range Normal PT

Confirmatory tests Mixing test Factor assay

Treatment Avoid aspirating a pseudotumor because of the risk of exacerbation of bleeding. Arthrocentesis must not be performed, either for diagnostic or therapeutic purposes, for a routine joint

FVIII replacement FVIII replacement is used for Acute bleeding Perioperatively for prevention of bleeding Prophylaxis to prevent recurrent bleeding of target joints Childhood prophylactic therapy to preserve long-term joint function Immune tolerance induction (ITI) regimens

Treatment of hemophilia A Intermediate purity plasma products –Virucidally treated –May contain von Willebrand factor High purity (monoclonal) plasma products –Virucidally treated –No functional von Willebrand factor Recombinant factor VIII –Virus free/No apparent risk –No functional von Willebrand factor

Dosing guidelines for hemophilia A Mild bleeding –Target: 30%, dosing q8-12h; 1-2 days (15U/kg) –Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria Major bleeding –Target: %, q8-12h; 7-14 days (50U/kg) –CNS trauma, hemorrhage, lumbar puncture –Surgery –Retroperitoneal hemorrhage –GI bleeding Adjunctive therapy – -aminocaproic acid (Amicar) or DDAVP (for mild disease only)

Complications of therapy Formation of inhibitors (antibodies) –15-20% of severe hemophilia A patients –1-2% of severe hemophilia B patients Viral infections –Hepatitis BHuman parvovirus –Hepatitis CHepatitis A –HIVOther

FVIII inhibitors Approximately 15-20% of individuals with severe hemophilia develop inhibitors to FVIII- C (alloantibodies) Acquired spontaneously developing FVIII inhibitors (autoantibodies): systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, drug reactions pregnancy, solid tumors, lymphoproliferative disorders, infections, skin diseases (Approximately 50% may not have an obvious cause).

The Bethesda inhibitor assay Determination of the specific titer of an inhibitor to FVIII

Bethesda assay Serial dilutions of patient plasma are incubated with pooled normal plasma at 37ºC for two hours; Residual factor VIII activity then is measured using a clotting assay. The reciprocal of the dilution of patient plasma that neutralize 50 percent factor VIII activity is the titer of the inhibitor in Bethesda units (BU). The higher the inhibitor titer, the greater the dilution required to neutralize 50 percent factor VIII activity.

FVIII inhibitors Treatment Human FVIII concentrates ( <5 BU ) Porcine FVIII ( <5 BU ) Recombinant FVIIa ( >5 BU ) Activated prothrombin-complex concentrates ( >5 BU ) IV IgG, plasmapheresis ( >5 BU )

Recombinant human factor VIIa (rhVIIa; Novoseven) Mechanism –Direct activation of common pathway (TF depended) –Plt depended TF independed Use –Factor VIII inhibitors –Bleeding with other clotting disorders –Warfarin overdose with bleeding –CNS bleeding with or without warfarin –Dose –90 µg/kg IV q 2 hr –Adjust as clinically indicated Cost (70 kg person) - $1 per µg –~$5,000/dose or $60,000/day

Treatment of hemophilia B Agent –High purity factor IX –Recombinant human factor IX Dose –Initial dose: 100U/kg –Subsequent: 50U/kg every 24 hours

von Willebrand Disease: Clinical Features von Willebrand factor –Synthesis in endothelium and megakaryocytes –Forms large multimer –Carrier of factor VIII –Anchors platelets to subendothelium –Bridge between platelets Inheritance - autosomal dominant Incidence - 1/5-10,000 Clinical features - mucocutaneous bleeding

von Willebrand Disease vWD is the most common inherited bleeding disorder Males and females are affected equally Deficiency of vWF results in defective platelet adhesion and causes a secondary deficiency in factor VIII The result is that vWF deficiency can cause bleeding that appears similar to that caused by platelet dysfunction or hemophilia

von Willebrand Disease Type I(70-80%) :a mild-to-moderate quantitative deficiency in vWF (ie, ~20-50% of normal levels). Type II(10-15%) : is due to qualitative abnormalities of vWF and is subdivided into types IIA, IIB, IIN. Type III : a severe quantitative deficiency associated with very little or no detectable plasma or platelet vWF, have a profound bleeding disorder.

vWD type IIA 1. type IIA is the most common qualitative abnormality of vWF and is associated with the selective loss of large- and medium-sized multimers.

vWD type IIB vWD type IIB is characterized by the loss of large multimers through binding of vWF to the platelet receptor glycoprotein Ib (GpIb). The large multimers have the highest affinity for GpIb and are rapidly cleared from the plasma along with the bound platelets, resulting in thrombocytopenia and the characteristic loss of large multimers. Platelet type vWD

vWD type IIN vWD type IIN, sometimes referred to as vWD Normandy is characterized by a defect residing within the patient's plasma vWF that interferes with its ability to bind FVIII. This has important implications in the differential diagnosis of mild hemophilia.

History The most common symptoms include nosebleeds, skin bruises. Prolonged bleeding from trivial wounds, oral cavity bleeding, and excessive menstrual bleeding are common.

Lab Studies: Screening tests typically include prothrombin time (PT) activated partial thromboplastin time (aPTT), FVIII level ristocetin cofactor (RCoF) activity vWF antigen (vWF:Ag).

Laboratory evaluation of von Willebrand disease Classification –Type 1 Partial quantitative deficiency –Type 2 Qualitative deficiency –Type 3Total quantitative deficiency Diagnostic tests: vonWillebrand type Assay vWF antigen Normal vWF activity Multimer analysisNormalAbnormalAbsent

Treatment of von Willebrand Disease Cryoprecipitate –Source of fibrinogen, factor VIII and VWF –Only plasma fraction that consistently contains VWF multimers DDAVP (deamino-8-arginine vasopressin) – plasma VWF levels by stimulating secretion from endothelium –Duration of response is variable –Not generally used in type 2 disease –Dosage 0.3 µg/kg q 12 hr IV Factor VIII concentrate (Intermediate purity) –Virally inactivated product

TREATMENT Of Type III vWD DDAVP, an agent that causes release of stored vWF, has no effect in patients with vWD type III. The treatment of choice for patients with vWD type III is virus-inactivated, vWF-containing FVIII concentrates.

Vitamin K deficiency Source of vitamin K Green vegetables Synthesized by intestinal flora Required for synthesisFactors II, VII, IX,X Protein C and S Causes of deficiencyMalnutrition Biliary obstruction Malabsorption Antibiotic therapy TreatmentVitamin K Fresh frozen plasma

Definition of DIC DIC is a clinicopathologic syndrome in which widespread intravascular coagulation is induced by procoagulant that are introduce or produce in circulation and overcome the natural anticoagulant mechanisms. DIC may cause tissue ischemia from occlusive microthrombi as well as bleeding from both consumption of platlet and coagulation factor and anticoagulation effect of product of secondary fibrinolysis.

Common clinical conditions associated with Disseminated Intravascular Coagulation Sepsis Trauma –Head injury –Fat embolism Malignancy Obstetrical complications –Amniotic fluid embolism –Abruptio placentae Vascular disorders Reaction to toxin (e.g. snake venom) Immunologic disorders –Severe allergic reaction –Transplant rejection Activation of both coagulation and fibrinolysis Triggered by

Disseminated Intravascular Coagulation (DIC) Mechanism Systemic activation of coagulation Intravascular deposition of fibrin Depletion of platelets and coagulation factors BleedingThrombosis of small and midsize vessels with organ failure

Pathogenesis of DIC CoagulationFibrinolysis Fibrinogen Fibrin Monomers Fibrin Clot (intravascular) Fibrin(ogen) Degradation Products Plasmin Thrombin Plasmin Release of thromboplastic material into circulation Consumption of coagulation factors; aPTT PT TT Fibrinogen Presence of plasmin FDP Intravascular clot Platelets Schistocytes

Disseminated Intravascular Coagulation Treatment approaches Treatment of underlying disorder Platelet transfusion Fresh frozen plasma Anticoagulation with heparin Coagulation inhibitor concentrate (ATIII)

Management of underlying disordes although the pt may benefit from other treatment survival depend on vigorous treatment of underlying disorder : Intensive antibiotic treatment in G- bacteremia Hysterectomy in abruptio placenta Resection of aortic aneurism Debridment of crush tissue Volume replacement, correction of hypotention & oxygenation, restore the function of coagulation inhibitory system.

Replacement therapy For thrombocytopenia : 6-10 U plat (ideally rise to more than ) For hypofibrinogenemia (<100 ) : 8-10 U cryopercipitate For coagulation factor depletion : 1-2 U FFP ( depend on severity of depletion & body weight)

Classification of platelet disorders Quantitative disorders –Abnormal distribution –Dilution effect –Decreased production –Increased destruction Qualitative disorders –Inherited disorders (rare) –Acquired disorders »Medications »Chronic renal failure »Cardiopulmonary bypass

Classification of thrombocytopenia Associated with bleeding –Immune-mediated thrombocytopenia (ITP) –Most others Associated with thrombosis –Thrombotic thrombocytopenic purpura –Heparin-associated thrombocytopenia –Trousseaus syndrome –DIC –AML (m3)

Approach to the thrombocytopenic patient History –Is the patient bleeding? –Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease) –Is there a history of medications, alcohol use, or recent transfusion? –Are there risk factors for HIV infection? –Is there a family history of thrombocytopenia? –Do the sites of bleeding suggest a platelet defect? Assess the number and function of platelets –CBC with peripheral smear –Bleeding time or platelet aggregation study

Thrombocytopenia Immune-mediated Idioapthic Drug-induced Collagen vascular disease Lymphoproliferative disease Non-immune mediated DIC Microangiopathic hemolytic anemia

Features of Acute and Chronic ITP FeaturesAcuteITPChronic ITP Peak ageChildren (2-6 yrs)Adults (20-40 yrs) Female:male1:13:1 Antecedent infectionCommon Rare Onset of symptomsAbruptAbrupt-indolent Platelet count at presentation<20,000<50,000 Duration2-6 weeksLong-term Spontaneous remissionCommonUncommon

Initial Treatment of ITP Platelet countSymptomsTreatment (per µl) >50,000None 20-50,000Not bleedingNone BleedingGlucocorticoids IVIG <20,000Not bleedingGlucocorticoids BleedingGlucocorticoids IVIG Hospitalization

Objectives - III Approach to acquired bleeding disorders –Hemostasis in liver disease –Surgical patients –Warfarin toxicity

Liver Disease and Hemostasis 1. Decreased synthesis of II, VII, IX, X, XI, and fibrinogen 2. Dietary Vitamin K deficiency (Inadequate intake or malabsortion) 3. Dysfibrinogenemia 4. Enhanced fibrinolysis (Decreased alpha-2- antiplasmin) 5. DIC (decreased pro c,s,ATIII)+decreased clearance of activated coagolation factors&fibrinolytic system. 6. Thrombocytoepnia due to hypersplenism

Management of Hemostatic Defects in Liver Disease Treatment for prolonged PT/PTT Vitamin K 10 mg SQ x 3 days - usually ineffective Fresh-frozen plasma infusion 25-30% of plasma volume ( ml) immediate but temporary effect Treatment for low fibrinogen Cryoprecipitate (1 unit/10kg body weight) Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia Replacement therapy

Vitamin K deficiency due to warfarin overdose Managing high INR values Clinical situationGuidelines INR therapeutic-5Lower or omit next dose; Resume therapy when INR is therapeutic INR 5-9; no bleedingLower or omit next dose; Resume therapy when INR is therapeutic OR Omit dose and give vitamin K (1-2.5 mg po) Rapid reversal: vitamin K 2-4 mg po (repeat) INR >9; no bleedingOmit dose; vitamin K 3-5 mg po; repeat as necessary Resume therapy at lower dose when INR therapeutic Chest 2001:119;22-38s (supplement)

Vitamin K deficiency due to warfarin overdose Managing high INR values in bleeding patients Clinical situationGuidelines INR > 20; serious bleedingOmit warfarin Vitamin K 10 mg slow IV infusion FFP or PCC (depending on urgency) Repeat vitamin K injections every 12 hrs as needed Any life-threatening bleedingOmit warfarin Vitamin K 10 mg slow IV infusion PCC ( or recombinant human factor VIIa) Repeat vitamin K injections every 12 hrs as needed Chest 2004:119;22-38s (supplement)

Post-operative bleeding 1. Is the bleeding local or due to a hemostatic failure? 1. Local: Single site of bleeding usually rapid with minimal coagulation test abnormalities 2. Hemostatic failure: Multiple site or unusual pattern with abnormal coagulation tests

Objectives - IV Approach to laboratory abnormalities –Diagnosis and management of thrombocytopenia

Laboratory Evaluation of Bleeding Overview CBC and smearPlatelet countThrombocytopenia RBC and platelet morphologyTTP, DIC, etc. CoagulationProthrombin timeExtrinsic/common pathways Partial thromboplastin timeIntrinsic/common pathways Coagulation factor assaysSpecific factor deficiencies 50:50 mixInhibitors (e.g., antibodies) Fibrinogen assayDecreased fibrinogen Thrombin timeQualitative/quantitative fibrinogen defects FDPs or D-dimerFibrinolysis (DIC) Platelet functionvon Willebrand factorvWD Bleeding timeIn vivo test (non-specific) Platelet function analyzer (PFA)Qualitative platelet disorders and vWD Platelet function testsQualitative platelet disorders

Laboratory Evaluation of the Coagulation Pathways Partial thromboplastin time (PTT) Prothrombin time (PT) Intrinsic pathwayExtrinsic pathway Common pathway Thrombin time Thrombin Surface activating agent (Ellagic acid, kaolin) Phospholipid Calcium Thromboplastin Tissue factor Phospholipid Calcium Fibrin clot

Initial Evaluation of a Bleeding Patient - 1 Normal PT Normal PTT Consider evaluating for: Mild factor deficiency Monoclonal gammopathy Abnormal fibrinolysisPlatelet disorder ( 2 anti-plasmin def)Vascular disorder Elevated FDPs Urea solubility Normal Abnormal Factor XIII deficiency

Initial Evaluation of a Bleeding Patient - 2 Normal PT Abnormal PTT Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare) Repeat with 50:50 mix 50:50 mix is normal 50:50 mix is abnormal Test for inhibitor activity: Specific factors: VIII,IX, XI Non-specific (anti-phospholipid Ab)

Initial Evaluation of a Bleeding Patient - 3 Abnormal PT Normal PTT Test for factor deficiency: Isolated deficiency of factor VII (rare) Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC) Repeat with 50:50 mix 50:50 mix is normal 50:50 mix is abnormal Test for inhibitor activity: Specific: Factor VII (rare) Non-specific: Anti-phospholipid (rare)

Initial Evaluation of a Bleeding Patient - 4 Abnormal PT Abnormal PTT Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC) Repeat with 50:50 mix 50:50 mix is normal 50:50 mix is abnormal Test for inhibitor activity: Specific : Factors V, X, Prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common)

Coagulation factor deficiencies Summary Sex-linked recessive Factors VIII and IX deficiencies cause bleeding Prolonged PTT; PT normal Autosomal recessive (rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleeding Prolonged PT and/or PTT Factor XIII deficiency is associated with bleeding and impaired wound healing PT/ PTT normal; clot solubility abnormal Factor XII, prekallikrein, HMWK deficiencies do not cause bleeding Prolonged PTT; PT normal

Thrombin Time Bypasses factors II-XII Measures rate of fibrinogen conversion to fibrin Procedure: –Add thrombin with patient plasma –Measure time to clot (18-22s) Variables: –Source and quantity of thrombin

Causes of prolonged Thrombin Time Heparin Hypofibrinogenemia Dysfibrinogenemia Elevated FDPs or paraprotein Thrombin inhibitors (Hirudin) Thrombin antibodies

Bleeding time and bleeding 5-10% of patients have a prolonged bleeding time Most of the prolonged bleeding times are due to aspirin or drug ingestion Prolonged bleeding time does not predict excess surgical blood loss Not recommended for routine testing in preoperative patients

Approach to bleeding disorders Summary Identify and correct any specific defect of hemostasis –Laboratory testing is almost always needed to establish the cause of bleeding –Screening tests (PT,PTT, platelet count) will often allow placement into one of the broad categories –Specialized testing is usually necessary to establish a specific diagnosis Use non-transfusional drugs whenever possible RBC transfusions for surgical procedures or large blood loss

Fibrinolytic system Congenital and acquired abnormalities of the fibrinolytic system, which are less common, can also be responsible for excessive bleeding or thrombosis, and not presented here.

THE END