Bleeding Disorders Vascular and Platelet Disorders Ahmad Shihada Silmi Msc,FIBMS IUG Medical Technology Dept Bleeding Disorder Terms Petechiae-pinpoint size/pinhead size hemorrhagic spots in skin Purpura-hemorrhage under the skin, varying in color and duration Ecchymosis-purplish patch caused by extravasation of blood into skin, larger than petechiae Epistaxis-nosebleed Menorrhagia-excessive menses Hematuria-blood in urine Hemarthrosis-bleeding into joint Hematemesis-vomiting blood Hemoptysis-spitting blood Melena-blood in stool (occult blood) Bleeding disorders Vascular Clotting factor Platelet disorders DIC abnormalities abnormalities Vessel Defects Causing Bleeding Begins with bleeding episode in presence of normal lab tests for coagulation function Types divided into hereditary and acquired Symptoms are usually of the superficial ones. Usually these diseases are diagnosed by exclusion. After ruling out PLT disorders, coagulation or fibrinolytic disorders in a patient who has bleeding symptoms. Vascular Diseases PLT count and screening tests for coagulation factors are usually normal. PLT function tests such as bleeding time and other PLT function tests are also normal, but BT may be prolonged in some vascular diseases. Inherited vascular disorders They are very rare, and while bleeding is a common symptom, hemostasis tests are NOT necessary for diagnosis. Hereditary Connective Tissue Defects Defect affects ability to support vessel walls Examples – Ehlers-Danlos Syndrome Lack of structural tissue support (collagen disorders) Skin elasticity and fragility. Hypermobility of joints Evidenced by bleeding/bruising Recurrent joint problems & scarring of the face. The most serious is deficient of type III collagen (blood vessel type). Which leads to Acute & sever Internal bleeding & sudden death. Hereditary Connective Tissue Defects Pseudoxanthoma Elasticum – Autosomal recessive trait – Lack of skin elasticity – Some connective tissue calcified – Bleeding and bruising evident Hereditary Vessel Disease Hereditary Haemorrhagic telangiectasia (HHT) Inherited as autosomal dominant trait Defect of angiogenesis Involves bleeding from abnormally dilated vessels “telangiectasias” Vessels involved do not contract normally and collapse easily Patient has pinpoint lesions (tiny areas of bleeding) Lesions occur on face, hands and feet May develop at all ages Blood loss may cause anemia Diagnosis based on physical appearance Hereditary Vessel Disease Kasabach-Merritt syndrome (Hemangioma) Benign tumour of vascular tissue Grow rapidly to giant proportion. Threaten the function of neighbouring tissues. Mechanical injury may result in sever bleeding. May trigger a localized DIC with thrombocytopeia & consumption coagulopathy, thereby worsening bleeding. Tumor composed of many blood vessels (blood-filled) Hereditary Vessel Disease HHT or also called Cavernous Hemangioma Lesion may swell and bleed Tumor site may form clots, hemolyzed RBCs and vessel obstruction Present at birth Treatment is by surgical removal, if possible,or localized radiotherapy with injection of fibrinolytic inhibitors. Acquired Vascular Disorders Are seen quite often. Are characterized by bruising and petechiae Acquired Connective Tissue Defects Vitamin C Deficiency (Scurvy) Caused deficient Vitamin C Vitamin C required for vessel collagen integrity Acts as “cement” holding endothelial cells together Lack of Vitamin C prevents proper collagen formation Result: bleed and vessel fragility Symptoms include gum bleeding, petechiae and bleeding into tissues and muscles Treated with Vitamin C Acquired Connective Tissue Defects Senile Purpura Occurs in elderly population Usually benign Collagen degradation/loss affects vessel integrity Bruising on arms/hands No treatment/therapy available Purpura due to Paraproteins Due to abnormal proteins in the vascular system Paraproteins are monoclonal Ig produced by a single clone of plasma cells. Also called M component. These paraproteins occur in MM, WM, and lymphoproliferative disorders. Cont’d Purpura due to Paraproteins Symptoms: purpura, bleeding and thrombosis. The defect is related to multifactors: – Qualitative PLT defects. – Acquired inhibitors. – Deficiency in coagulation factors. – Paraproteins binds Ca, Ca either will not be available for coagulation or the Ca bounded paraproteins will interfere with coagulation. – Thrombocytopenia. Cont’d Purpura due to Paraproteins Bleeding symptoms include: – Epistaxis – Petechiae, – Purpura, and – Retinal bleeding. Purpura due to Paraproteins Amyloidosis Occur as primary disease or is associated with paraproteinemias. Deposition of amyloid on skin and vascular walls. Leads to fragility of vessel walls. Other Vascular Disorders Self-produced “autoantibodies” damage to vessels Caused by drugs resulting in purpura Caused by allergic/immune disturbance Evidenced by swelling, ulcers, purpura and lesions and other symptoms Affects children Other allergic purpura-Hemoch-Schonlein variety Accompanied by joint and abdominal pain Avoidance of allergen aids recovery Other Vascular Disorders Infectious purpura Observe petechiae and purpura Results from Inflammatory response to agent Autoimmune/autoantibody response Bacterial products or toxins Injury caused by agent Low platelets observed and DIC Cure is to treat infection Bleeding disorders Vascular *** Clotting factor DIC abnormalities Platelet disorders abnormalities Platelet Disorders Classification: Quantitative PLT Disorders Thrombocytopenia Thrombocytosis PLT Reference Range = 150 - 450 x109/L Thrombocytopathy Qualitative PLT Disorders Thrombocytosis Thrombocytosis resulting from myeloproliferation – essential thrombocythemia – polycythemia vera – chronic myelogenous leukemia – myeloid metaplasia Secondary (reactive) thrombocytosis – systemic inflammation – malignancy – iron deficiency – hemorrhage – postsplenectomy Thrombocytopenia Reduced platelet count. The most common cause of excess or abnormal bleeding. As anemia is a symptom of a disease as we have seen in Hematology #1, thrombocytopenia is also a symptom of a disease! Do not forget to assure that the case you have is a real thrombocytopenia and not Pseudothrombocytopenia Platelet clumping, or Platelet aggregation Satelltism Pseudothrombocytopenia Thrombocytopenia Platelet count Symptoms 50-100 X109/L Prolonged bleeding following trauma < 50X109/L Easy bruising Purpura following minor trauma < 20 X109/L Spontaneous bleeding Petechiae May suffer spontaneous internal and intracranial bleeding Hemostatic Level Hemostatic Platelet count level is more than 50 x109/L. This means that normal hemostasis may occur ≥ 50 x109/L Classification: platelet disorders Thrombocytopenia Causes Impaired or Decreased Distribution/Dilution Increased Production Disorders Destruction Megakaryocyte aplasia Immune Non-Immune BM Replacement Ineffective poiesis General characteristics of platelet disorders characterized by variable mucocutaneous bleeding manifestations. excessive hemorrhage may follow surgical procedures or trauma. Platelet counts and morphology are normal. prolonged bleeding time, Abnormal Platelet aggregation and secretion studies Thrombocytopenia Usually mucosal bleeding Epistaxis, menorrhagia, and GI bleeding is common Trauma does not usually cause bleeding Thrombocytopenia Three mechanisms of Thrombocytopenia – Decreased production Usually chemotherapy, myelophthisic disease, or BM effects of alcohol or thiazides – Splenic Sequesteration Rare Results from malignancy, portal hypertension, or increased Splenic RBC destruction ( hereditary spherocytosis, autoimmune hemolytic anemia) – Increased Destruction Thrombocytopenia Immune thrombocytopenia – Multiple causes including drugs, lymphoma, leukemia, collagen vascular disease – Drugs Include Digitoxin, sulfonamindes, phenytoin, heparin, ASA, cocaine, Quinine, quinidine, glycoprotein IIb-IIa antagonists – After stopping drugs platelet counts usually improve over 3 to 7 days – Prednisone (1mg/kg) with rapid taper can shorten course Thrombocytopenia HIT – Important Immunologic Thrombocytopenia – Usually within 5-7 days of Initiation of Heparin Therapy but late onset cases are 14-40 days – Occurrence 1-5% with unfractionated heparin and less than 1% with low molecular-weight heparin – Thrombotic complications in up to 50% of HIT with loss of limb in 20% and mortality up to 30% ITP Diagnosis of exclusion Associated with IgG anti-platelet antibody Platelet count falls to less that 20,000 ITP Acute Form – Most common in children 2 to 6 years – Viral Prodrome common in the 3 weeks prior – Self Limited and > 90% remission rate – Supportive Treatment – Steroids are not helpful ITP Chronic Form – Adult disease primarily – Women more often than men – Insidious onset with no prodrome – Symptoms include: easy bruising, prolonged menses, mucosal bleeding – Bleeding complications are unpredictable – Mortality is 1% – Spontaneous remission is rare ITP Chronic Form – Hospitalization common because of a complex differential diagnosis – Multiple treatments – Platelet transfusions are used only for life threatening bleeding – Life threatening bleeding is treated with IV Immune globulin (1g/kg) TTPHUS Exist on a continuum and are likely the same disease Diagnosed by a common pentad – Microangiopathic Hemolytic Anemia: Schistocytes membranes are sheared passing through microthrombi – Thrombocytopenia: More sever in TTP – Fever – Renal Abnormalities: More prominent in HUS: include Renal insufficiency, azotemia, proteinuria, hematuria, and renal failure – Neurologic Abnormalities: hallmark of TTP 1/3 of HUS: Sx of HA, confusion, CN palsies, seizure,coma TTPHUS Labs – PT, PTT, and fibrinogen are within reference range – Helmet Cells (Shistocytes) are common TTPHUS HUS – Most common in infants and children 6mo - 4 years – Often associated with a prodromal diarrhea – Strongest association to E. coli O157:H7 but also associated with SSYC as well as multiple virus – Prognosis Mortality 5-15% Younger patients do better TTPHUS HUS – Treatment Mostly supportive Plasma exchange reserved for sever cases Treat hyperkalemia Avoid antibiotics with Ecoli – May actually increase verotoxin production. – May be helpful with cases of Shigella dysenteriae TTPHUS TTP – More common in adults – Untreated mortality rate of 80% 1 to 3 months after diagnosis – Aggressive plasma exchange has dropped the mortality to 17% – Splenectomy, immune globulin, vincristine all play a role in therapy TTPHUS AVOID PLATELET TRANSFUSION – May lead to additional microthrombi in circulation – Transfuse only with life threatening bleeding Dilutional Thrombocytopenia PRBC are platelet poor Monitor platelet count with every 10 u PRBC (for each 8-10 units of PRBC, 2 units of FFP & 5 units of platelet concentrate are given) Transfuse when count below 50,000 Get them upstairs before you transfuse 10 units PRBC Bleeding Clinical Correlation - PLT Numbers PLT Count Spontaneous Bleed Post Trauma Bleed >50K/ml No Rare 30 – 50K/ml Rare Occasional 10 – 30K/ml Occasional Always 10K/ml Frequent Always BT prolongation proportional to PLT count IF no complicating factors. Significant Lab Data in Defects of Primary Hemostasis Test Vascular Disorder Thrombocytopenia PLT Dysfunction PLT Count N D N PT N N N APTT N N N BT N or ABN ABN N or ABN Hereditary Platelet Function Defects Petechiae typical of platelet abnormality Do not blanch with pressure Not palpable Bernard-Soulier Syndrome First described in 1948 by Jean Bernard and Jean- Pierre Soulier; French hematologists Bernard J, Soulier JP: Sur une nouvelle variete de dystrophie thrombocytaire hemarroagipare congenitale. Sem Hop Paris 24:3217, 1948 AR; characterized by moderate to severe thrombocytopenia, giant platelets, and perfuse/spontaneous bleeding Basis for the disease is deficiency or dysfunction of the GP Ib-V-IX complex Bernard-Soulier Syndrome Decreased GP Ib-V-IX leads to decreased platelet adhesion to the subendothelium via decreased binding of vWF Approximately 20,000 copies of GP Ib-V-IX per platelet GP 1b: heterodimer with an alpha and beta subunit The gene for GP Ib alpha is located on chromosome 17; GP Ib beta: chromosome 22; GPIX and V: chromosome 3 Most mutations are missense or frameshifts resulting in premature stop codons Most mutations involve GP Ib expression (rare GP IX mutations have been described; no mutations in GP V) Diagnosis Prolonged bleeding time, thrombocytopenia (plt<20 K), peripheral smear shows large platelets (mean diameter >3.5 microns) Diagnosis Platelet aggregation studies show normal aggregation in response to all agonists except Ristocetin (opposite pattern than thrombasthenia) Flow cytometry: decreased expression of mAbs to CD 42b (GPIb), CD42a(GPIX), CD42d(GPV) Platelet Aggregometer Light focused on sample cuvette contained PRP PRP stirred and recorder identified baseline – 0% transmittance Agonist added Transmitted light changes proportionally in response to degree PLT shape changes Change in light transmission continuously monitored and recorded As PLT aggregates form, recorder moves towards 100% transmittance Abnormalities – Diminished or absent shape change – Diminished aggregation Platelet-rich plasma in an optical aggregometer. Platelet count is approximately 200 × 109/L, and platelets are maintained in suspension by a magnetic stir bar turning at 1000 rpm. (Courtesy of Kathy Jacobs, Chronolog, Inc., Havertown, Penn.) Graphic accessed URL http://evolvels.elsevier.com/section/default.asp?id=1138_ccalvo7_0001, 2008. Differentiation between vWD & BSD Measuring the platelet aggregation response to ristocetin following the addition of PPP. A normal aggregation response suggests the plasma defect, which is typical of vWD. The persistence of defective response suggests the presence of a platelet defect which is typical of BSD. Glanzmann’s Thrombasthenia Eduard Glanzmann (1887-1959), Swiss pediatrician Reported a case of a bleeding disorder starting immediately after birth W. E. Glanzmann:Hereditäre hämorrhägische Thrombasthenie. Ein Beitrag zur Pathologie der Blutplättchen. Jahrbuch für Kinderheilkunde, 1918; 88: 1- 42, 113-141. Glanzmann’s IIbIIIa most abundant platelet surface receptor (80,000 per platelet) IIbIIIa complex is a Ca++ dependent heterodimer Genes for both subunits are found on Chromosome 17 Disease is caused by mutations (substitution, insertion, deletion, splicing abnormalities) in genes encoding for IIb or IIIa resulting in qualitative or quantitative abnormalities of the proteins Glanzmann’s Fundamental defect of thrombasthenic patients is the inability of the platelets to aggregate Other problems: platelets do not spread normally on the subendothelial matrix (due to lack of IIbIIIa – vWF/fibronectin interaction) Also, alpha granule fibrinogen is decreased to absent Glanzmann’s AR inheritance Patients present with wide spectrum of disease Like thrombocytopenic bleeding: skin, mucous membrane (petichiae, echymoses), recurrent epistaxis, GI hemorrhage, menorrhagia, and immediate bleeding after trauma/surgery ICH, joint, muscle bleeding uncommon Glanzmann’s patients are stratified into three groups based on complex expression: – Type I less than 5 percent GPIIbIIIa, absent alpha granule fibrinogen Usually as a result of IIb gene mutation – Type II <20 percent, fibrinogen present – Type III >50 percent; “variant” thrombasthenia; qualitative disorder Diagnosis Platelet count and morphology are normal Bleeding time prolonged The hallmark of the disease is severely reduced or absent platelet aggregation in response to multiple agonists ie ADP, thrombin, or collagen (except Ristocetin) Flow cytometry: decreased mAb expression of CD41 (GPIIb) and CD61 (GPIIIa) Platelet Aggregation Studies Platelet-rich plasma (PRP) is prepared from citrated whole blood by centrifugation Inactive platelets impart a characteristic turbidity to PRP When platelets aggregate after injection of an agonist, the turbidity falls, and light transmission through the sample increases proportionally The change in light transmission can be recorded on an aggregometer Agonists Different concentrations of each agonist are used ADP: biphasic pattern: First wave: low concentration, reversible Second wave: high concentration, irreversible Other agonists Epinephrine: triphasic (resting platelets, primary aggregation, secondary aggregation) Other agonists Collagen, arachidonic acid, Calcium ionophore, PAF are potent agonists and induce a single wave of irreversible aggregation Ristocetin (antibiotic): aggregation can be reproduced with metabolically inert, formalin- fixed platelets Defective risto-induced aggregation is characteristic of Bernard-Soulier Problems with platelet aggregation studies Numerous variables affect aggregation: Anticoagulant (sodium citrate best) Plt count in PRP Plt size distribution Time of day Temporal relation to meals and physical activity Storage Pool Defects Classified by type of granular deficiency or secretion defect. Dense body deficiency, alpha granule deficiency (gray platelet syndrome), mixed deficiency, Factor V Quebec Defects in secondary aggregation Deficiency of contents of one of granules Inheritance is variable (heterogeneous group) Bleeding is usually mild to moderate but can be exacerbated by aspirin Clinical: easy bruising, menorrhagia, and excessive postpartum or postoperative bleeding Dense body deficiency decreased dense bodies (ADP, ATP, calcium, pyrophosphate, 5HT) Normal platelet contains 3-6, 300 micron dense bodies Described in inherited disorders ie Hermansky-Pudlak syndrome, Wiskott- Aldrich syndrome, Chediak-Higashi syndrome, and Thrombocytopenia with absent radius (TAR) syndrome Wiskott-Aldrich X-linked, genetic defect in WASp (protein responsible for actin cytoskeleton formation in hematopoetic cells) characterized by thrombocytopenia (with platelet storage pool defect), eczema, and recurrent infections Hermansky-Pudlak Described in 1959 by Hermansky and Pudlak AR, tyrosinase-positive oculocutaneous albinism, ceroid-like deposition in lysosomes of the RES and marrow Highest prevalence in Puerto Rico May be associated with pulmonary fibrosis, and recurrent infections quantitative deficiency of dense granules leading to mild-moderate bleeding diathesis Chediak-Higashi described by Beguez Cesar in 1943, Steinbrinck in 1948, Chédiak in 1952, and Higashi in 1954 AR; abnormal microtubule formation and giant lysozomal granules are present in phagocytes and melanocytes No degranulation/chemotaxis = recurrent bacterial infections Partial oculocutaneous albinism Dense-body granules decreased/absent Thrombocytopenia with absent radius (TAR) First described in 1951 AR, characterized by absent radii, thrombocytopenia (with storage pool defect), and other abnormalities of the skeletal, GI, cardiovascular system Etiology unclear Hemorrhage is the major cause of mortality PX is good if survive the two years Typical Lab Findings Diagnosis – Usually normal platelet count – Measure the whole platelet – Morphology is variable ATP/ADP ratio – Platelet aggregation Normal: 2.5:1 shows primary wave but ADP storage pool deficiency absence of secondary wave when stimulated increased >3:1 with ADP, epinephrine, – Often associated with disorders arrachidonic acid affecting granules in other cells – Platelet aggregation with thrombin is usually normal Chediak-Higashi Syndrome (overrides need for Hermansky-Pudlak Syndrome granule release) – Ristocetin agglutination is Wiskott-Aldrich Syndrome normal – Platelets are small with decreased number of both alpha and dense granules Diagnosis Platelet aggregation studies may show diminished response to low concentration collagen ADP and epinephrine show diminished second wave response Ristocetin shows normal aggregation EM: lack of dense bodies Increased ATP:ADP ratio within platelets Alpha granule deficiency Alpha storage pool deficiency, Gray Platelet Syndrome First described by Raccuglia in 1971 Normal platelets contain approximately 50 granules (PF4, beta-thromboglobulin, PDGF, fibrinogen, vWF, Factor V, fibronectin) Patients lack granules, present with lifelong, mild to moderate mucocutaneous bleeding Diagnosis Prolonged bleeding time, mild thrombocytopenia A granular, large “gray” platelets on peripheral smear Aggregation studies: decreased to absent response to collagen Summary Morphology and role of the platelet in primary hemostasis Adhesion: GP1b-V-IX; Bernard-Soulier; aggregates with everything but Ristocetin Activation (Secretion): dense body deficiency (associated syndromes), alpha granule deficiency Aggregation: GPIIb-IIIa; Glanzmann’s; no aggregation except for Ristocetin Differential diagnosis Table. The clinical distinction between disorders of vessels and platelets and disorders of blood coagulation Fingdings Disorders of platelet or Disorders of coagulation vessels Petechiae Characteristic Rare Deep dissecting Rare Characteristic hematomas Superficial ecchymoses Characteristic; usually Common; uaually large small and multiple and solitary Hemarthrosis Rare Characteristic Delayed bleeding Rare Common Bleeding from Persistent; often Minimal superficial cuts and profuse scratches Sex of patient Relatively more 80-90% of hereditary common in females forms occur only in males Positive family history Rare Common Clinical Cases Nail bed - Hematoma •Red •Blue/Gr •Brown Contusion - Hematoma Laceration - Trauma Petechiae & Echymoses -Plt Petechiae & Echymoses -Plt Bleeding-Coagulation disorder •Deep bleeding •Haematoma •Joint bleeds •Haemophilia Leptospirosis - Weil’s disease: Jaundice Sub Conjuctival Haemorrhage Low PLT Dengue – Hemorrhagic fever Plt Bleeding disorders Vascular Clotting factor Platelet disorders DIC abnormalities abnormalities Hereditary Type The genetic defect can either be the failure of synthesis of one of the proteins or the production of a malfunctioning or abnormal molecule. Quantitative vs Qualitative But in both of these genetic defects they will result in slowing down and ineffective production of fibrin. LAB Screening Tests Lab screening tests are based on the length of time that it takes a clot to form in plasma. So screening tests does not differentiate between qualitative or quantitative defects! CRM + Vs CRM- CRM is the abbreviation of Cross-Reacting Material Any protein has a functional activity and an immunologic characteristics. Abnormal protein is functionally ineffective, but is recognized immunologically. Is called CRM + No protein (deficient) has no function and also will not be recognized immunologically. Is called CRM - Types of Bleeding Disorders Hemophilia A (factor VIII deficiency) Hemophilia B (factor IX deficiency) von Willebrand Disease (vWD) Other Platelet Coagulation Petechiae, Purpura Hematoma, Joint bl. What is Hemophilia? Hemophilia is an inherited bleeding disorder in which there is a deficiency or lack of factor VIII (hemophilia A) or factor IX (hemophilia B) Hemophilia A and B Hemophilia A Hemophilia B Coagulation factor deficiency Factor VIII Factor IX Inheritance X-linked X-linked recessive recessive Incidence 1/10,000 males 1/50,000 males Severity Related to factor level <1% - Severe - spontaneous bleeding 1-5% - Moderate - bleeding with mild injury 5-25% - Mild - bleeding with surgery or trauma Complications Soft tissue bleeding Inheritance of Hemophilia Hemophilia A and B are X-linked recessive disorders Hemophilia is typically expressed in males and carried by females Severity level is consistent between family members ~30 % of cases of hemophilia are new mutations Genetics of Hemophilia A The gene F8 is located in the X chromosome, at Xq28, near telomeric region. It consists of 26 exons, and 25 introns. The F8 gene spans 186 Kb. Mature RNA is 8.8 Kb. The F8 protein is 2351 amino acid. The leader sequence is 19 a.a. So the real protein= 2351-19= 2332 aa. Genetics of Hemophilia A Half of hemophilia A patients have no detectable factor VIII; about 5% have normal levels of dysfunctional factor VIII as protein and are termed CRM+ whereas the rest (45%) have plasma factor VIII Ag protein reduced to an extent roughly comparable to the level of factor VIII:C activity and are designated CRM-. Detection of Hemophilia Family history Symptoms – Bruising – Bleeding with circumcision – Muscle, joint, or soft tissue bleeding Hemostatic challenges – Surgery – Dental work – Trauma, accidents Laboratory testing Screening Tests in Secondary Hemostasis Defects PT is prolonged or (test extrinsic pathway) APTT is prolonged or (test intrinsic pathway) Both are prolonged. Platelets are normal in count and function. TT (thrombin time): prolonged in disorders of fibrinogen. If any test is abnormal of these screening tests, additional testing may resolve the disorder>>>> Additional Testing Specific Factor Assays. Fibrinogen Level D-Dimer FDP’s Antithrombin Level The list continues to expand…………. Degrees of Severity of Hemophilia Normal factor VIII or IX level = 50-150% Mild hemophilia – factor VIII or IX level = 6-50% Moderate hemophilia – factor VIII or IX level = 1-5% Severe hemophilia – factor VIII or IX level = <1% Hemophilia Prevalence Hemophilia A; 1 in 5000 population – coagulation factor VIII deficiency Hemophilia B; 1 in 30000 population – coagulation factor IX deficiency Hemophilia A is six-fold more prevalent than hemophilia B. Types of Bleeds Joint bleeding - hemarthrosis Muscle hemorrhage Soft tissue Life threatening-bleeding Other Hemarthrosis Joint or Muscle Bleeding Symptoms – Tingling or bubbling sensation – Stiffness – Warmth – Pain – Unusual limb position Life-Threatening Bleeding Head / Intracranial – Nausea, vomiting, headache, drowsiness, confusion, visual changes, loss of consciousness Neck and Throat – Pain, swelling, difficulty breathing/swallowing Abdominal / GI – Pain, tenderness, swelling, blood in the stools Iliopsoas Muscle – Back pain, abdominal pain, thigh tingling/numbness, decreased hip range of motion Other Bleeding Episodes Mouth bleeding Nose bleeding Scrapes and/or minor cuts Menorrhagia Complications of Bleeding Flexion contractures Joint arthritis / arthropathy Chronic pain Muscle atrophy Compartment syndrome Neurologic impairment Hemophilia “General Consideration” There is a strong correlation between residual clotting factor level and severity of bleeding symptoms. Spontaneous bleeding is only seen in severe disease. Affected males with severe disease are generally diagnosed by the age of one year. Even where there is no prior family history of hemophilia, sporadic cases caused by new mutations, which are responsible for 1/3 of cases. In males with mild hemophilia, it is not unusual for the disorder to not be diagnosed until middle age, possibly following prolonged bleeding at surgery. Treatment of Hemophilia Replacement of missing clotting protein – On demand – Prophylaxis DDAVP / Stimate Antifibrinolytic Agents – Amicar Supportive measures – Icing – Immobilization – Rest Factor VIII Concentrate Intravenous infusion – IV push – Continuous infusion Dose varies depending on type of bleeding – Ranges from 20-50+ units/kg. body weight Half-life 8-12 hours Each unit infused raises serum factor VIII level by 2 % Factor IX Concentrate Intravenous infusion – IV push – Continuous infusion Dose varies depending on type of bleeding – Ranges from 20-100+ units/kg. body weight Half-life 12-24 hours Each unit infused raises serum factor IX level by 1% History of Clotting Factor Concentrates Prior to 1950: whole blood 1952: Hemophilia A distinguished from B 1950-1960: FFP and Cryoprecipitate Early 1970s: Commercial plasma-derived factor concentrates Mid-late 1970’s: Home infusion practices 1981: First AIDS death in the Hemophilia community History of Clotting Factor Concentrates (cont’d) Mid-1983: Factor concentrates heat treated for hepatitis 1985: All products heat treated for viral inactivation 1987: Monoclonal factor concentrates 1992: Recombinant factor VIII 1994: Recombinant factor IX-albumin free 2001: 2nd generation recombinant factor VIII Infusions of Factor Concentrates Verify product with physician order. Dose may be +/- 10% ordered. Do not waste factor even if the dose is not exactly what is ordered. Reconstitute factor per package insert. Infusion rate per package insert or pharmacy instructions. Document lot number, expiration date, time of infusion, and exact dose given in units. Prophylaxis Scheduled infusions of factor concentrates to prevent most bleeding Frequency: 2 to 3 times weekly to keep trough factor VIII or IX levels at 2-3% Types – primary prophylaxis – secondary prophylaxis Use of IVAD necessary in some patients DDAVP (Desmopressin acetate) Syntheticvasopressin Method of action - – release of stores from endothelial cells raising factor VIII and vWD serum levels Administration - – Intravenous – Subcutaneously – Nasally (Stimate) Side effects Stimate How supplied – 1.5 mg./ ml (NOT to be confused with DDAVP nasal spray for nocturnal enuresis) – 2.5 ml bottle - delivers 25 doses of 150 mcg. Dosing – Every 24-48 hours prn – <50 kg. body weight - 1 spray (150 mcg.) – >50 kg. body weight - 2 sprays (300 mcg.) Amicar (epsilon amino caproic acid) Antifibrinolytic Uses – Mucocutaneous bleeding Dosing: 50 - 100 mg./kg. q. 6 hours Side effects Contraindications – Hematuria Complications of Treatment Inhibitors/Antibody development Hepatitis A Hepatitis B Hepatitis C HIV Inhibitors Definition – IgG antibody to infused factor VIII or IX concentrates, which occurs after exposure to the extraneous VIII or IX protein. Prevalence – 20-30% of patients with severe hemophilia A – 1-4% of patients with severe hemophilia B Hepatitis Hepatitis A- small risk of transmission – Vaccination recommended Hepatitis B - no transmissions since 1985 – Vaccination recommended Hepatitis C - no transmissions since 1990 – ~90% of patients receiving factor concentrates prior to 1985 are HCV antibody positive Human Immunodeficiency Virus No transmissions of HIV through factor concentrates since 1985 due to viral inactivation procedures HIV seropositive rate - – 69.6% of patients with severe hemophilia A receiving factor concentrates prior to 1985 – 48.6% of patients with severe hemophilia B receiving factor concentrates prior to 1985 Nursing Considerations Factor replacement to be given on time Laboratory monitoring Increase metabolic states will increase factor requirements Factor coverage for invasive procedures Document - infusions, response to treatment Avoid NSAIDS Utilize Hemophilia Center staff for questions / problems Psychosocial Issues Guilt Challenge of hospitalizations Control issues Financial / insurance challenges Feeling different / unable to do certain activities Counseling needs Hemophilia Treatment Center Team Members Patient / Family Primary Care Hematologist Infectious Disease Nurse Genetics Social Worker Pharmacy Physical Therapist Dental Orthopedist Hepatology Role of Hemophilia Treatment Centers State-of-the-art medical treatment for persons with hemophilia through the life span Education Research Outreach Model of comprehensive care for chronic disease von Willebrand’s Disease Outline vWF – Structure – Location – Function vWD – History – Clinical manifestations – Categories – Diagnosis – Treatment vWD Family of bleeding disorders Caused by a deficiency or an abnormality of von Willebrand Factor vWF VWF gene : short arm of chromosome 12 – VWF gene is expressed in endothelial cells and megakaryocytes vWF is produced as a propeptide which is extensively modified to produce mature vWF – Two vWF monomers bind through disulfide bonds to form dimers – Multiple dimers combine to form vWF multimers vWF Production Vascular endothelial cells Release stimuli (EC) Megakaryocytes – Thrombin Most vWF is secreted – Histamine Some vWF is stored – Fibrin – Weibel-Palade bodies – C5b-9 (complement in endothelial cells membrane attack – Alpha granules of complex) platelets Release stimuli (platelets) Constitutive and stimulus- – Thrombin induced pathways – ADP – Collagen vWF Function Adhesion – Mediates the adhesion of platelets to sites of vascular injury (subendothelium) Links exposed collagen to platelets – Mediates platelet to platelet interaction Binds GPIb and GPIIb-IIIa on activated platelets Stabilizes the hemostatic plug against shear forces vW Factor Functions in Hemostasis Carrier protein for Factor VIII (FVIII) – Protects FVIII from proteolytic degradation – Localizes FVIII to the site of vascular injury – Hemophilia A: absence of FVIII vWD History 1931: Erik von Willebrand described novel bleeding disorder – Hereditary pseudohemophilia – Prolonged BT and normal platelet count 1950s: Prolonged BT – Mucosal bleeding associated with reduced FVIII – Both sexes affected 1970s: Discovery of vWF 1980s: vWF gene cloned Frequency Most frequent inherited bleeding disorder – Estimated that 1% of the population has vWD – Very wide range of clinical manifestations – Clinically significant vWD : 125 persons per million population – Severe disease is found in approximately 0.5-5 persons per million population Autosomal inheritance pattern – Males and females are affected equally vWD Classification Disease is due to either a quantitative deficiency of vWF or to functional deficiencies of vWF – Due to vWF role as carrier protein for FVIII, inadequate amount of vWF or improperly functioning vWF can lead to a resultant decrease in the available amount of FVIII vWD Classification 3 major subclasses – Type I: Partial quantitative deficiency of vWF Mild-moderate disease 70% – Type II: Qualitative deficiency of vWF Mild to moderate disease 25% – Type III: Total or near total deficiency of vWF Severe disease 5% Additional subclass – Acquired vWD Clinical Manifestations Most with the disease Types II and III: Bleeding have few or no symptoms episodes may be severe and potentially life For most with symptoms, threatening it is a mild manageable Disease may be more bleeding disorder with pronounced in females clinically severe hemorrhage only with because of menorrhagia trauma or surgery Bleeding often exacerbated by the ingestion of aspirin Severity of symptoms tends to decrease with age due to increasing amounts of vWF Clinical Manifestations Epistaxis 60% Easy bruising / hematomas 40% Menorrhagia 35% Gingival bleeding 35% GI bleeding 10% Dental extractions 50% Trauma/wounds 35% Post-partum 25% Post-operative 20% vWD Type I Mild to moderate disease Mild quantitative deficiency of vWF – vWF is functionally normal Usually autosomal dominant – Penetrance may vary dramatically in a single family vWD Type 2 Usually autosomal dominant Type 2C – Recessive Type 2A – High molecular weight vWF – Lack high and multimers is reduced intermediate molecular – Individual multimers are weight multimers qualitatively abnormal Type 2B Type 2M – Decreased vWF activity – Multimers bind platelets – vWF antigen, FVIII, and excessively multimer analysis are found Increased clearance to be within reference range of platelets from the Type 2N circulation – Markedly decreased affinity of vWF for FVIII – Lack high molecular Results in FVIII levels weight multimers reduced to usually around 5% of the reference range. vWD Type III Recessive disorder vWF protein is virtually undetectable – Absence of vWF causes a secondary deficiency of FVIII and a subsequent severe combined defect in blood clotting and platelet adhesion Acquired vWD First described in 1970's fewer than 300 cases reported Usually encountered in adults with no personal or family bleeding history Laboratory work-up most consistent with Type II vWD Mechanisms – Autoantibodies to vWF – Absorption of HMW vWF multimers to tumors and activated cells – Increased proteolysis of vWF – Defective synthesis and release of vWF from cellular compartments Myeloproliferative disorders, lymphoproliferative disorders, monoclonal gammopathies, CVD, and following certain infections vWD Screening PT aPTT (Bleeding time) vWD: aPTT and PT aPTT – Mildly prolonged in approximately 50% of patients with vWD Normal PTT does not rule out vWD – Prolongation is secondary to low levels of FVIII PT – Usually within reference ranges Prolongations of both the PT and the aPTT signal a problem with acquisition of a proper specimen or a disorder other than or in addition to vWD vWD and Bleeding Time Historically, bleeding time is a test used to help diagnose vWD – Lacks sensitivity and specificity – Subject to wide variation – Not currently recommended for making the diagnosis of vWD vWD Diagnostic Difficulties vWF levels vary greatly – Physiologic stress – Estrogens – Vasopressin – Growth hormone – Adrenergic stimuli vWF levels may be normal intermittently in patients with vWD – Measurements should be repeated to confirm abnormal results – Repeating tests at intervals of more than 2 weeks is advisable to confirm or definitively exclude the diagnosis, optimally at a time remote from hemorrhagic events, pregnancy, infections, and strenuous exercise vWF levels vary with blood type vWD Diagnosis Ristocetin – Good for evaluating vWF function, – Results are difficult to standardize – Method Induces vWF binding to GP1b on platelets Ristocetin co-factor activity: measures agglutination of metabolically inactive platelets RIPA: metabolically active platelets Aggregometer is used to measure the rate of aggregation vWF Antigen – Quantitative immunoassay or an ELISA using an antibody to vWF Discrepancy between the vWF:Ag value and RCoF activity suggests a qualitative defect – Should be further investigated by characterization of the Additional Assays Multimer analysis PFA-100 closure time – Screens platelet function in whole blood – Prolonged in vWD, except Type 2N FVIII activity assay vWD Treatment DDAVP Cryoprecipitate FVIII concentrate vWD and DDAVP Treatment of choice for vWD type I – Synthetic analogue of the antidiuretic hormone vasopressin – Maximal rise of vWF and FVIII is observed in 30-60 minutes – Typical maximal rise is 2- to 4-fold for vWF and 3- to 6-fold for FVIII – Hemostatic levels of both factors are usually maintained for at least 6 hours – Effective for some forms of Type 2 vWD May cause thrombocytopenia in Type 2b – Ineffective for vWD Type 3 Factor VIII Concentrates Alphanate and Humate P Concentrates are purified to reduce the risk of blood-borne disease Contain a near-normal complement of high molecular weight vWF multimers vWD Treatment Platelet transfusions – May be helpful with vWD refractory to other therapies Cryoprecipitate – Fraction of human plasma – Contains both FVIII and vWF – Medical and Scientific Advisory council of the National Hemophilia Foundation no longer recommends this treatment method due to its associated risks of infection FFP – An additional drawback of fresh frozen plasma is the large infusion volume required Disseminated Intravascular Coagulation DIC An acquired syndrome 6 characterized by Thrombosis systemic intravascular Platelet coagulation Red Blood Cell Coagulation is always the initial event. Fibrin Most morbidity and mortality depends on extent of intravascular thrombosis WWW. Coumadin.com Multiple causes SYSTEMIC DIC ACTIVATION OF COAGULATION An acquired syndrome characterized by Intravascular Depletion of systemic deposition of platelets and fibrin coagulation intravascular factors coagulation Coagulation is always the initial event Thrombosis of small and Bleeding midsize vessels Organ failure DEATH Pathophysiology of DIC Activation of Blood Coagulation Suppression of Physiologic Anticoagulant Pathways Impaired Fibrinolysis Cytokines Pathophysiology of DIC Activation of Blood Coagulation – Tissue factor/factor VIIa mediated thrombin generation via the extrinsic pathway complex activates factor IX and X – TF endothelial cells monocytes Extravascular: – lung – kidney – epithelial cells Pathophysiology of DIC Suppression of Physiologic Anticoagulant Pathways – reduced antithrombin III levels – reduced activity of the protein C-protein S system – Insufficient regulation of tissue factor activity by tissue factor pathway inhibitor (TFPI) inhibits TF/FVIIa/Fxa complex activity Pathophysiology of DIC Impaired Fibrinolysis – relatively suppressed at time of maximal activation of coagulation due to increased plasminogen activator inhibitor type 1 Pathophysiology of DIC - Cytokines Cytokines – IL-6, and IL-1 mediates coagulation activation in DIC – TNF- mediates dysregulation of physiologic anticoagulant pathways and fibrinolysis modulates IL-6 activity – IL-10 may modulate the activation of coagulation Inflamation Coagulation Diagnosis of DIC Presence of disease associated with DIC Appropriate clinical setting – Clinical evidence of thrombosis, hemorrhage or both. Laboratory studies – no single test is accurate – serial test are more helpful than single test Conditions Associated With DIC Malignancy Pulmonary – Leukemia – ARDS/RDS – Metastatic disease – Pulmonary embolism Cardiovascular Severe acidosis – Post cardiac arrest Severe anoxia – Acute MI Collagen vascular – Prosthetic devices disease Hypothermia/Hyperthermia Anaphylaxis Conditions Associated With DIC Infectious/Septicemia Tissue Injury – Bacterial – trauma Gm - / Gm + – extensive surgery – Viral – tissue necrosis CMV – head trauma Varicella Obstetric Hepatitis – Amniotic fluid emboli – Fungal – Placental abruption Intravascular hemolysis – Eclampsia Acute Liver Disease – Missed abortion Clinical Manifestations of DIC Ischemic FindingsORGAN ISCHEMIC HEMOR. are earliest! Pur. Fulminans Petechiae Skin Gangrene Echymosis Acral cyanosis Oozing CNS Delirium/Coma Intracranial Infarcts bleeding Renal Oliguria/Azotemia Hematuria Cortical Necrosis Cardiovascular Myocardial Dysfxn Bleeding is the most Pulmonary Dyspnea/Hypoxia Hemorrhagic Infarct lung obvious GI Ulcers, Infarcts Massive clinical finding Endocrine Adrenal infarcts hemorrhage. Clinical Manifestations of DIC Microscopic findings in DIC Fragments Schistocytes Paucity of platelets Laboratory Tests Used in DIC D-dimer* Thrombin time Antithrombin III* Fibrinogen F. 1+2* Prothrombin time Fibrinopeptide A* Activated PTT Platelet factor 4* Protamine test Fibrin Degradation Reptilase time Prod Coagulation factor Platelet count levels Protamine test *Most reliable test Laboratory diagnosis Thrombocytopenia – plat count <100,000 or rapidly declining Prolonged clotting times (PT, APTT) Presence of Fibrin degradation products or positive D-dimer Low levels of coagulation inhibitors – AT III, protein C Low levels of coagulation factors – Factors V,VIII,X,XIII Fibrinogen levels not useful diagnostically Differential Diagnosis Severe liver failure Vitamin K deficiency Liver disease Thrombotic thrombocytopenic purpura Congenital abnormalities of fibrinogen HELLP syndrome Treatment of DIC Stop the triggering process . – The only proven treatment! Supportive therapy No specific treatments – Plasma and platelet substitution therapy – Anticoagulants – Physiologic coagulation inhibitors Plasma therapy Indications – Active bleeding – Patient requiring invasive procedures – Patient at high risk for bleeding complications Prophylactic therapy has no proven benefit. Cons: Fresh frozen plasma(FFP): – provides clotting factors, fibrinogen, inhibitors, and platelets in balanced amounts. – Usual dose is 10-15 ml/kg Platelet therapy Indications – Active bleeding – Patient requiring invasive procedures – Patient at high risk for bleeding complications Platelets – approximate dose 1 unit/10kg Blood Replaced as needed to maintain adequate oxygen delivery. – Blood loss due to bleeding – RBC destruction (hemolysis) Coagulation Inhibitor Therapy Antithrombin III Protein C concentrate Tissue Factor Pathway Inhibitor (TFPI) Heparin Antithrombin III The major inhibitor of the coagulation cascade – Levels are decreased in DIC. – Anticoagulant and antiinflammatory properties Therapeutic goal is to achieve supranormal levels of ATIII (>125-150%). – Experimental data indicated a beneficial effect in preventing or attenuating DIC in septic shock reduced DIC scores, DIC duration, and some improvement in organ function – Clinical trials have shown laboratory evidence of attenuation of DIC and trends toward improved outcomes. – A clear benefit has not been established in clinical trials. Protein C Concentrates Inhibits Factor Va, VIIa and PAI-1 in conjunction with thrombomodulin. Protein S is a cofactor Therapeutic use in DIC is experimental and is based on studies that show: – Patients with congenital deficiency are prone to thromboembolic disease. – Protein C levels are low in DIC due to sepsis. – Levels correlate with outcome. – Clinical trials show significantly decreased morbidity and mortality in DIC due to sepsis. Tissue Factor Pathway Inhibitor Tissue factor is expressed on endothelial cells and macrophages TFPI complexes with TF, Factor VIIa,and Factor Xa to inhibit generation of thrombin from prothrombin TF inhibition may also have antiinflammatory effects Clinical studies using recombinant TFPI are promising. Heparin Use is very controversial. Data is mixed. May be indicated in patients with clinical evidence of fibrin deposition or significant thrombosis. Generally contraindicated in patients with significant bleeding and CNS insults. Dosing and route of administration varies. Requires normal levels of ATIII. Antifibrinolytic Therapy Rarely indicated in DIC – Fibrinolysis is needed to clear thrombi from the micro circulation. – Use can lead to fatal disseminated thrombosis. May be indicated for life threatening bleeding under the following conditions: – bleeding has not responded to other therapies and: – laboratory evidence of overwhelming fibrinolysis. – evidence that the intravascular coagulation has ceased. Agents: tranexamic acid, EACA Summary DIC is a syndrome characterized systemic intravascular coagulation. Coagulation is the initial event and the extent of intravascular thrombosis has the greatest impact on morbidity and mortality. Important link between inflammation and coagulation. Morbidity and mortality remain high. The only proven treatment is reversal or control of the underlying cause.
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