Disorders of Hemostasis 5 th Year Medical Students DR. SALMA AL-HADAD APRIL 18 TH 2016

Objectives  To describe the bleeding manifestation; various clinical presentation, laboratory tests and diagnosis.  To list the causes of thrombocytopenia  To outline the steps of diagnosis of Idiopathic Thrombocytopenic Purpura (ITP)  To describe the clinical manifestation and diagnosis of Hemophilia, Von Willebrand Disease & Henoch- Schonlein Purpura

 It is the active process that clots blood in areas of blood vessel injury, yet simultaneously limits the clot size only to the areas of injury.  As a result of injury to the blood vessel endothelium, three events take place simultaneously: I. Vasoconstriction - (vascular phase) II. Platelet plug formation (primary haemostatic mechanism— (platelet phase) III. Fibrin thrombus formation (secondary haemostatic mechanism — (plasma phase)

Inappropriate and excessive bleeding either spontaneous or in response to injury

 In disorders of hemostasis the bleeding manifestations are commonly present at more than one site. 1.Spontaneous skin bruising or purpura 2.Bleeding from mucous membranes, e.g. nose/mouth, GIT, urinary & genital tract 3.Bleeding from venepuncture sites, IV cannulation, operation sites and from tooth sockets post dental extraction 4.Bleeding into muscles, joints or deep tissues 5.Menorrhagia 6.Cerebral hemorrhage

“80% of correct diagnosis can be made by history taking and physical examination”

 Identify if the bleeding problem is due to Local vs. systemic defect  Location: single vs. multiple sites  Severity: Spontaneous? Appropriate to trauma? Hereditary vs. acquired disorder  Onset  Family history  Underlying disease  Medication Primary vs. secondary hemostatic disorder

Primary Hemostatic defectSecondary Hemostatic defect

I.Mucosal bleeding; easy bruises, epistaxis, menorrhagia, petechae, and oozing from surgical wounds is most consistent with a defect in primary hemostasis. Mostly due to defects in platelets, Von Willebrand Factor, or the vessel wall. II.Deep tissue bleeding; (hematomas, joint and muscle hemorrhages) and “delayed” surgical bleeding are more suggestive of a coagulation factor abnormality, e.g. hemophilia.

Do not blanch with pressure, Not palpable (typical of platelet disorders)

Clinical Manifestations of Hemostasis Clinical characteristicPlatelets defectClotting factor deficiency Site of bleeding Skin, mucous membranes (gingival, nares, GI and genitourinary tracts) Deep in soft tissues (joints, muscles) Bleeding after minor cutsYesUnusual PetechaePresentAbsent EcchymosesSmall, superficialLarge, palpable Hemarthroses, muscle hematomas RareCommon Bleeding after surgeryImmediate, mildDelayed, severe

The history should determine:  Site or sites of bleeding  Duration of hemorrhage  Age at onset  Severity was the bleeding spontaneous, or did it occur after trauma, did the symptoms correlate with the degree of injury or trauma?  Was there a previous personal or family history of similar problems?

 If a child has had surgery affecting the mucosal surfaces, e.g. tonsillectomy or major dental extractions, the absence of bleeding usually rules out a hereditary bleeding disorder  History of Circumcision in males  It is important to take a careful menstrual history  Drugs: e.g. Anticoagulants, NSAID & Cytotoxics

 A reliable laboratory approach, including: First-line (screening) and second-line (specific) testing, Essential to screen, diagnose & monitor patients

First-line (screening) tests: 1. CBC: with peripheral smear 2. Bleeding time: bleeding usually stops within 4–8 min, this test should be done only when platelets count is normal to exclude functional defect 3. Platelet function analyzer(PFA-100): to evaluate the platelet functions and VWF interaction 4. PT is a measure of the extrinsic (FVII) and common pathway (FV, FX, prothrombin, fibrinogen) clotting factors. 5. PTT measures the contact system (prekallikrein, FXII) as well as the intrinsic (FVIII, FIX, FXI) and common pathway clotting factors 6. TT measures fibrinogen deficiency

 Clotting factor assays

IVY method Duke’s test

CBC-complete blood count, F-factor, PFA-platelet function analyzer, PT-prothrombin time, PTT- activated partial thromboplastin time, RIPA-ristocetin-induced platelet aggregation, vWD-von Willebrand disease, vWF-von Willebrand factor, vWF:Rco-ristocetin cofactor activity.

1.Decreased bone marrow production: a- Malignant marrow infiltration b- Drugs c- Severe megaloblastic anemia d- Hypoplastic anemia 2. Decreased platelet survival (peripheral consumption): a- Immune mechanisms: 1. Primary —immune thrombocytopenia (ITP) 2. Secondary—SLE, lymphoma 3. Drugs—Thiazides, Sulfonamides b- Excessive consumption: Disseminated intravascular coagulation (DIC), splenomegaly (hypersplenism)

1. Inherited: e.g. Bernard Soulier syndrome, thrombasthenia 2. Acquired: e.g. myeloproliferative diseases, uremia, Drugs, e.g. aspirin and NSAID.

Case 1  4 yr old boy  URTI 2 weeks ago  Sudden onset bruising/petechiae  Past Hx.: Nil  Family Hx.: Nil  Physical examination:

Investigations  Hb 11g/dl; WBC 8.000/cmm; Plat /cmm.  PTPTTFibrinogen  PT 14 sec ; PTT 33 sec; Fibrinogen 2.0g/l  Treatment options  Treatment options: Nil  Outcome80% recovery; 20% chronic  Outcome: 80% recovery; 20% chronic

Case 2  You are on call for ENT and are asked to see a 14-year old girl with sudden refractory nosebleed.  The nose is packed & bleeding does not stop.  You noticed a few bruises  The lab results showed with a “critical” platelet count of /cmm 1. What is likely diagnosis? 2. What to do? 3. What is needed for diagnosis? 4. Does she require hospitalization ?

ITP (Immune Thromboctopenic Purpura) 1. When isolated and very low--- ITP is most likely diagnosis 2. If mucosal bleeding &/or platelets are less than /cmm, needs action:  Hospitalization  Steroids  IVIG  Anti D 3. Bone marrow examination

 Bleeding disorder characterized by isolated low platelet count (Plts. < x 10 9 /L)  The most common cause of acute onset of thrombocytopenia in an otherwise well child.  1–4 wk after exposure to a common viral infection, an autoantibody directed against the platelet surface develops  Antiplatelet antibody that binds to the platelet surface and enhances its destruction in the spleen and liver

 The classic presentation is that of a previously healthy child who has sudden onset of generalized petechae and purpura  Often there is bleeding from the gums and mucous membranes, particularly with profound thrombocytopenia (platelet count <10 × 10 9 /L).  Physical exam is normal, other than the finding of petechae and purpura.  Absence of HSM or remarkable LAP (which might suggest other diagnoses like leukemia)

 No symptoms  Mild: bruising and petechae, occasional minor epistaxis, very little interference with daily living  Moderate: more severe skin and mucosal lesions, more troublesome epistaxis and menorrhagia  Severe: bleeding episodes—menorrhagia, epistaxis, melena—requiring transfusion or hospitalization, symptoms interfering seriously with the quality of life

Petechae & Ecchymoses Subconjunctival Hemorrhage

Platelet Count (10 9 /L) Signs and Symptoms >100None 50 to 100Minimal (after major trauma & surgery) 20 to 50Mild (cutaneous) 5 to 20Moderate (cutaneous and mucosal) <5Severe (mucosal and CNS)

 Common finding is platelet count <20 × 10 9 /L  Hb, WBC and differential count should be normal  BM examination is normal (normal or increased megakaryocytes).  Indications for BMA include:  An abnormal WBC or differential  Unexplained anemia  Findings suggestive of bone marrow disease on history & physical examination.

 History: careful drug history  Examination: healthy appearing child, no HSM, no LAP, has petechae, purpura and occasionally mucous membrane bleeding.  Blood counts: CBC should be normal except thrombocytopenia  Peripheral smear evaluation: essential to 1. Rule out platelets clumping 2. Evaluate WBC and RBC morphology 3. Evaluate size of platelets

 The goal of all treatment is to achieve an adequate hemostasis (>20 ×10 9 /L) & prevent the rare intracranial hemorrhage, rather than a normal platelet count.  The majority of patients with no bleeding or mild/moderate bleeding can be treated with observation alone regardless of platelet count.  First-line treatment includes:  Observation,  Corticosteroids,  IVIG, or  anti-D immunoglobulin. Platelets transfusions should be reserved to life threatening bleeding and CNS hemorrhage only as their half life is very short in patient with ITP

 In 70–80% of children who present with acute ITP, spontaneous resolution occurs within 6 months  <1% of patients have intracranial hemorrhage.  20% of children go on to have chronic ITP.

Congenital  Usually single factor deficiencies.  Sometimes clinically apparent at birth, but mild deficiencies may not become apparent until adolescence or adult life,  e.g. Hemophilia A (Factor VIII) and B (Factor IX, Christmas disease), Von Willebrand disease, Factor XI deficiency

Acquired  More common, Usually associated with multiple factor deficiencies, secondary to underlying disease or drug treatment. 1. Decreased production: e.g. liver disease, Vitamin K deficiency – neonates, malabsorption 2. Increased consumption: DIC 3. Circulating inhibitors: e.g. antibodies –especially to F. VIII and in SLE 4. Drugs: Heparin and Warfarin. 5. Dilution: massive, rapid blood transfusion

 Deficiencies of factors VIII and IX are the most common severe inherited bleeding disorders.

 Neither factor VIII nor factor IX crosses the placenta; bleeding symptoms may be present from birth.  About 2% of neonates with hemophilia sustain intracranial hemorrhages and 30% of male infants with hemophilia bleed with circumcision.  Obvious symptoms of easy bruising, intramuscular hematomas, and hemarthrosis begin when the child “begins to cruise.”

HEMOPHILIA Non-carrier Mother + Father with Hemophilia

HEMOPHILIA Carrier Mother + Non-hemophiliac Father

HEMOPHILIA Carrier Mother + Father with Hemophilia

HEMOPHILIA Mother with Hemophilia + Father with Hemophilia

HEMOPHILIA Mother with Hemophilia + Non-hemophiliac Father

 The hallmark of hemophilia is hemarthrosis  Bleeding into the joints may be induced by minor trauma; many are spontaneous.  Life-threatening bleeding in the patient with hemophilia is caused by bleeding into vital structures (CNS, upper airway, GIT, or ilio-psoas hemorrhage)

 PTT prolonged in FVIII or FIX deficiency  Platelet count, bleeding time, prothrombin time, and thrombin time are normal  Specific assay for factors VIII and IX will confirm the diagnosis of hemophilia

Early, appropriate therapy is the hallmark of excellent hemophilia care. 1.Factor VIII or IX concentrate:  When mild to moderate bleeding occurs, levels of FVIII or FIX must be raised to hemostatic levels in the 35–50% range  For life-threatening or major hemorrhages, the dose should aim to achieve levels of 100% activity

2.Intranasal Desmopressin in mild hemophilia A, it is not effective in hemophilia B 3.Prophylaxis treatment: recombinant FVIII or IX products, it was recently started aiming to be the standard of care for most children with severe hemophilia to prevent spontaneous bleeding and early joint deformities

 Advise parents that their child should avoid trauma  Avoid violent contact sports  Early psychosocial intervention helps the family to achieve a balance between overprotection and permissiveness.  Avoid Aspirin and NSAIDs that affect platelet function.  Receive the vaccinations against hepatitis B, even with the use of recombinant products  Patients exposed to plasma-derived products should be screened periodically for hepatitis B and C, HIV, and LFT.

 Long-term complications of hemophilia A and B include: 1.Chronic arthropathy 2.The development of an inhibitor to FVIII or FIX. 3.The risk of transfusion-transmitted infectious diseases.  Education remains crucial in hemophilia care

Case 3  14 year old girl with menorrhagia  History of easy bruising  CBC normal  PTT 32 (2 sec prolonged)  What is diagnosis?  How to diagnose?  Treatment?

Von Willebrand’s Disease  Most frequent inherited bleeding disorder affect 1-2% of general population  less severe than hemophilia  Disease results from a decrease or absence of Von Willebrand factor required for platelet adhesion  Affects primary hemostasis

Clinical features of VWD  Generally mild bleeding - often unrecognized until surgery or injury  epistaxis, menorrhagia, easy bruising, dental and post operative bleeding  Can be severe in certain types  Requires accurate diagnosis  Requires specific treatment

VWD -types  Type I  most frequent, quantitative defect (decreased VWf )  Type II  qualitative defect (abnormal VWf )  Type III  severe, rare, (absence of VWf )

 Long BT and a long PTT  Normal results on screening tests do not exclude the diagnosis of VWD  if the history is suggestive of a muco-cutaneous bleeding disorder, VWD testing should be undertaken

 It is directed toward increasing the plasma level of VWF & FVIII.  Current replacement therapy uses plasma-derived VWF containing concentrates that also contain factor VIII.  Purified or recombinant VWF concentrates (containing no factor VIII) may become available in the near future  Dental extractions and sometimes nosebleeds can be managed with both DDAVP & anti fibrinolytic agent

 Sudden development of a purpuric rash, arthritis, abdominal pain, and renal involvement.  The characteristic rash, consisting of petechae & often palpable purpura, usually lower extremities & buttocks.  Coagulation studies are normal  The pathologic lesions in the skin, intestines, and synovium, inflammatory damage to the endothelium of the capillary mediated by WBC & macrophages (Vasculitis)  The trigger for HSP is unknown. In the kidney, there is focal GN with deposition of immunoglobulin A.

Henoch-Schönlein Purpura

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