Bleeding Disorders Vascular and Platelet Disorders

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)

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

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)

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.

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

Thrombocytopenia Thrombocytosis Thrombocytopathy
Platelet Disorders Classification: Quantitative PLT Disorders Thrombocytopenia Thrombocytosis PLT Reference Range = 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!

Platelet clumping, or aggregation Pseudothrombocytopenia
Do not forget to assure that the case you have is a real thrombocytopenia and not Pseudothrombocytopenia Platelet clumping, or aggregation Platelet 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 31

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 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)

TTPHUS 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

TTPHUS Labs PT, PTT, and fibrinogen are within reference range
Helmet Cells (Shistocytes) are common

TTPHUS 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

TTPHUS 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

TTPHUS 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

TTPHUS 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 Occasional 10 – 30K/ml Always 10K/ml Frequent BT prolongation proportional to PLT count IF no complicating factors. 49

Significant Lab Data in Defects of Primary Hemostasis
Test Vascular Disorder Thrombocytopenia PLT Dysfunction PLT Count N D PT APTT BT N or ABN ABN 50

Hereditary Platelet Function Defects

Petechiae typical of platelet abnormality
Do not blanch with pressure Not palpable

The table provides a classification of congenital disorders of platelet function based on the platelet functions or responses that are abnormal.

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
61

Platelet Aggregation: PRP
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 62

In patients (red tracings) with vWD (type I) or Bernard-Soulier syndrome (BSS), platelet aggregation studies using platelet-rich plasma show diminished aggregation response to ristocetin with normal responses to ADP and epinephrine. The response to thrombin (low concentrations) may be impaired in BSS.

This slide shows the major mechanisms leading to platelet adhesion, involving GPIb and plasma vWF. In patients with defects in platelet-vessel wall interactions, adhesion of platelets to subendothelium is abnormal. The two disorders in this group are von Willebrand disease (vWD), due to a deficiency or abnormality in plasma vWF, and Bernard-Soulier syndrome, where platelets are deficient in GPIb (and GPV and IX) and the binding of vWF to platelets is abnormal.

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 ( ), 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,

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

Usually as a result of IIb gene mutation
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)

DG, diacylglycerol; PIP2, phosphatidylinositol bisphosphate; IP3, inositol 1,4,5 trisphosphate; R, receptor Disorders characterized by abnormal platelet-platelet interactions (aggregation) arise because of a severe deficiency of plasma fibrinogen (congenital afibrinogenemia) or because of a quantitative or qualitative abnormality of the platelet membrane GPIIb-IIIa complex (Glanzmann thrombasthenia). The activated GPIIb-IIIa complexes constitute the platelet binding sites for fibrinogen; this binding is a prerequisite for platelet aggregation. 12

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

Storage Pool Disorders
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 86

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

Storage Pool Disorders
Diagnosis Measure the whole platelet ATP/ADP ratio Normal: 2.5:1 ADP storage pool deficiency increased >3:1 Often associated with disorders affecting granules in other cells Chediak-Higashi Syndrome Hermansky-Pudlak Syndrome Wiskott-Aldrich Syndrome Platelets are small with decreased number of both alpha and dense granules Typical Lab Findings Usually normal platelet count Morphology is variable Platelet aggregation shows primary wave but absence of secondary wave when stimulated with ADP, epinephrine, arrachidonic acid Platelet aggregation with thrombin is usually normal (overrides need for granule release) Ristocetin agglutination is normal 98

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
Differential diagnosis Table. The clinical distinction between disorders of vessels and platelets and disorders of blood coagulation

Clinical Cases

Nail bed - Hematoma Red Blue/Gr Brown

Contusion - Hematoma

Laceration - Trauma

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

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

Coagulation Platelet 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 /10,000 males /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= = 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 = % 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 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 units/kg. body weight Half-life 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 units/kg. body weight Half-life 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 : 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)
Synthetic vasopressin 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 Dosing Every 24-48 hours prn
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 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: mg./kg. q. 6 hours Side effects Contraindications Hematuria

Complications of Treatment
Inhibitors/Antibody development Hepatitis A Hepatitis B Hepatitis C HIV

Inhibitors Definition Prevalence
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 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 Hematologist Nurse Social Worker Physical Therapist Orthopedist Primary Care Infectious Disease Genetics Pharmacy Dental 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 Megakaryocytes
Most vWF is secreted Some vWF is stored Weibel-Palade bodies in endothelial cells Alpha granules of platelets Constitutive and stimulus-induced pathways Release stimuli (EC) Thrombin Histamine Fibrin C5b-9 (complement membrane attack complex) Release stimuli (platelets) ADP Collagen In plasma, the predominant MW is b/w 500,000-20,000,000 The bigger the multimer: more platelet and collagen binding sites more hemostatically competent

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 Mucosal bleeding Both sexes affected 1950s: Prolonged BT associated with reduced FVIII 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 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 have few or no symptoms For most with symptoms, it is a mild manageable bleeding disorder with clinically severe hemorrhage only with trauma or surgery Types II and III: Bleeding episodes may be severe and potentially life threatening Disease may be more pronounced in females because of menorrhagia 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 2A
Lack high and intermediate molecular weight multimers Type 2B Multimers bind platelets excessively Increased clearance of platelets from the circulation Lack high molecular weight multimers Type 2C Recessive High molecular weight vWF multimers is reduced Individual multimers are qualitatively abnormal Type 2M Decreased vWF activity vWF antigen, FVIII, and multimer analysis are found to be within reference range Type 2N Markedly decreased affinity of vWF for FVIII Results in FVIII levels 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 vWF multimeric distribution

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 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
1

DIC An acquired syndrome characterized by systemic intravascular coagulation Coagulation is always the initial event. Most morbidity and mortality depends on extent of intravascular thrombosis Multiple causes WWW. Coumadin.com

DIC SYSTEMIC ACTIVATION OF COAGULATION An acquired syndrome characterized by systemic intravascular coagulation Coagulation is always the initial event Intravascular deposition of fibrin Depletion of platelets and coagulation factors Thrombosis of small and midsize vessels Bleeding DEATH Organ failure

Pathophysiology of DIC
Activation of Blood Coagulation Suppression of Physiologic Anticoagulant Pathways Impaired Fibrinolysis Cytokines

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

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

Impaired Fibrinolysis relatively suppressed at time of maximal activation of coagulation due to increased plasminogen activator inhibitor type 1

Pathophysiology of DIC - 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 Coagulation Inflamation

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
Pulmonary ARDS/RDS Pulmonary embolism Severe acidosis Severe anoxia Collagen vascular disease Anaphylaxis Malignancy Leukemia Metastatic disease Cardiovascular Post cardiac arrest Acute MI Prosthetic devices Hypothermia/Hyperthermia

Conditions Associated With DIC
Infectious/Septicemia Bacterial Gm - / Gm + Viral CMV Varicella Hepatitis Fungal Intravascular hemolysis Acute Liver Disease Tissue Injury trauma extensive surgery tissue necrosis head trauma Obstetric Amniotic fluid emboli Placental abruption Eclampsia Missed abortion

Clinical Manifestations of DIC
Ischemic Findings are earliest! Bleeding is the most obvious clinical finding

Clinical Manifestations of DIC

Microscopic findings in DIC
Fragments Schistocytes Paucity of platelets

Laboratory Tests Used in DIC
D-dimer* Antithrombin III* F. 1+2* Fibrinopeptide A* Platelet factor 4* Fibrin Degradation Prod Platelet count Protamine test Thrombin time Fibrinogen Prothrombin time Activated PTT Protamine test Reptilase time Coagulation factor levels *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 . Supportive therapy
The only proven treatment! Supportive therapy No specific treatments Plasma and platelet substitution therapy Anticoagulants Physiologic coagulation inhibitors

Plasma therapy Indications Prophylactic therapy has no proven benefit.
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 ml/kg

Platelet therapy Indications Platelets 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 (> %). 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. 24

Bleeding Disorders Vascular and Platelet Disorders

Similar presentations

Presentation on theme: "Bleeding Disorders Vascular and Platelet Disorders"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Bleeding Disorders Vascular and Platelet Disorders

Similar presentations

Presentation on theme: "Bleeding Disorders Vascular and Platelet Disorders"— Presentation transcript:

Similar presentations

About project

Feedback