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CME: Bleeding Disorders - Clinical Features


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CME: Bleeding Disorders - Clinical Features

  2. 2. Bleeding disorders Vascular abnormalities *** Platelet disorders Clotting factor abnormalities DIC
  3. 3. Platelet Disorders - Features: <ul><li>Mucocutaneous bleeding </li></ul><ul><li>Petechiae </li></ul><ul><li>Purpurae </li></ul><ul><li>ecchymosis </li></ul><ul><li>spontaneous bleeding after trauma </li></ul><ul><li>CNS bleeding (severe) </li></ul>
  4. 4. Petechiae PETECHIAE:minute 1-2 mm hges into skin,mucous membranes or serosal surfaces Do not blanch with pressure (typical of platelet disorders)
  5. 5. Petechiae
  6. 6. Purpura :slightly larger 3 mm haemorrhages
  7. 7. Bleeding disorders Platelet disorders ↓ production ↑ destruction Sequestration Hypersplenism Primary/Idiopathic ITP Acute/Chronic Secondary Drugs, HIV
  8. 8. Classification of thrombocytopenia <ul><li>PSEUDO-ARTIFACTUAL THROMBOCYTOPENIA </li></ul><ul><ul><li>Platelet agglutination </li></ul></ul><ul><ul><li>Platelet satellitism </li></ul></ul><ul><ul><li>Giant platelets </li></ul></ul><ul><ul><li>IMPAIRED PLATELET PRODUCTION </li></ul></ul><ul><ul><li>congenital </li></ul></ul><ul><ul><li>autosomal dominant </li></ul></ul>
  9. 9. <ul><li>MYH9 RELATED </li></ul><ul><li>May hegglin,fetchner,epstein,sebastian syndromes </li></ul><ul><ul><li>Mediterranean macrothrombocytopenia </li></ul></ul><ul><ul><li>Familial platelet syndrome with predisoposition to AML </li></ul></ul><ul><ul><li>Thrombocytopenia with linkage to ch 10 </li></ul></ul><ul><ul><li>Paris-trousseau syndrome </li></ul></ul><ul><ul><li>AUTOSOMAL RECESSIVE </li></ul></ul><ul><ul><ul><li>Congenital amegakaryocytic </li></ul></ul></ul><ul><ul><ul><li>TAR syndrome </li></ul></ul></ul><ul><ul><ul><li>Bernard soulier syndrome </li></ul></ul></ul><ul><ul><ul><li>Gray platelet syndrome </li></ul></ul></ul>
  10. 10. <ul><li>X-LINKED </li></ul><ul><ul><li>WISKOTT-ALDRICH syndrome </li></ul></ul><ul><ul><li>WITH DYSERYTHROCYTOSIS </li></ul></ul><ul><ul><li>ACQUIRED </li></ul></ul><ul><ul><li>Marrow infiltration </li></ul></ul><ul><ul><li>Infectious disease-HIV,parvo,CMV </li></ul></ul><ul><ul><li>Radiotherapy n chemotherapy </li></ul></ul><ul><ul><li>Folic acid and vit b12 deficiency </li></ul></ul><ul><ul><li>PNH </li></ul></ul><ul><ul><li>Acquired aplastic anemia </li></ul></ul><ul><ul><li>Myelodysplastic syndromes </li></ul></ul>
  11. 11. ACCELELERATED PLATELET DESTRUCTION <ul><li>IMMUNE MEDIATED </li></ul><ul><li>Autoimmune thrombocytopenic purpura </li></ul><ul><li>Idiopathic </li></ul><ul><li>secondary-infections,pregnancy </li></ul><ul><li>Alloimmune </li></ul><ul><li>neonatal </li></ul><ul><li>posttransfusion purpura </li></ul><ul><li>Autoimmune diseases </li></ul><ul><li>MDS </li></ul><ul><li>Lymphoproliferative disorders </li></ul>
  12. 12. NONIMMUNE THROMBOCYTOPENIA <ul><ul><li>THROMBOTIC MICROANGIOPATHIES </li></ul></ul><ul><ul><li>DIC </li></ul></ul><ul><ul><li>KASSABACHMERIT SYNDROME </li></ul></ul><ul><ul><li>PLATELET DESTRUCTION BY ARTIFICIAL SURFACES </li></ul></ul><ul><ul><li>HEMOPHAGOCYTOSIS </li></ul></ul>
  13. 13. ABNORMAL DISTRIBUTION OR POOLING <ul><li>Splenomegaly </li></ul><ul><li>Hypersplenism </li></ul><ul><li>Hypothermia </li></ul><ul><li>Massive transfusion </li></ul><ul><li>DRUG INDUCED </li></ul><ul><li>HEPARIN INDUCED </li></ul><ul><li>OTHERS </li></ul>
  14. 14. Immune Thrombocytopenic Purpura (ITP) <ul><li>Cause </li></ul><ul><li>1-4 weeks following exposure to a common viral infection, small number of children develop an autoantibody directed against platelet surface. Following binding of the antibody to the platelet surface, circulating antibody coated platelet are recognized by receptor on splenic macrophage, ingested & destroyed. The virus that has been described in association with ITP including EBV,HIV. </li></ul><ul><li>Morphology </li></ul><ul><ul><li>Peripheral Blood </li></ul></ul><ul><ul><ul><li>thrombocytopenia, abnormally large platelets (megathrombocytes or Giant platelets), </li></ul></ul></ul><ul><ul><li>Marrow </li></ul></ul><ul><ul><ul><li>Normal or Increased magakaryocyte </li></ul></ul></ul>
  15. 15. ITP Same Normal or ↑Megakaryocytes Bone marrow Same Thrombocytopenia & Giant PLTS Peripheral smear IgG against Platelet GP - Pathogenesis >6mnoths <2 months Duration - Viral infection/ vaccine Predisposing Factors Gradual Abrupt Onset Adult/Female Children Age / Sex Chronic Acute Feature
  16. 16. <ul><li>Clinical Manifestation:- </li></ul><ul><li>1-the classic presentation of ITP from 1-4 years old who has sudden onset of generalized petechiae & purpura. </li></ul><ul><li>2-often there is bleeding from gums & mucous membrane. </li></ul><ul><li>3- splenomegaly are rare, so also lymphadenopathy or hepatosplenomegaly. </li></ul><ul><li>4-70 to 80% of children who present with acute ITP with have spontaneous resolution of their ITP within 6 months. </li></ul><ul><li>5-less than 1% of cases develop intracranial hemorrhage. </li></ul>
  17. 18. Thrombotic Microangiopathies <ul><li>Thrombotic thrombocytopenic Purpura (TTP) </li></ul><ul><li>Hemolytic-Uremic syndrome (HUS) </li></ul>
  18. 19. TTP  HUS <ul><li>Exist on a continuum </li></ul><ul><li>Diagnosed by a common pentad </li></ul><ul><ul><li>Microangiopathic Hemolytic Anemia : Schistocytes membranes are sheared passing through microthrombi </li></ul></ul><ul><ul><li>Thrombocytopenia : More sever in TTP </li></ul></ul><ul><ul><li>Fever </li></ul></ul><ul><ul><li>Renal Abnormalities : More prominent in HUS: include Renal insufficiency, azotemia, proteinuria, hematuria, and renal failure </li></ul></ul><ul><ul><li>Neurologic Abnormalities : hallmark of TTP 1/3 of HUS: confusion, CN palsies, seizure,coma </li></ul></ul>
  19. 20. Thrombotic Microangiopathies HUS TTP Feature Genetic (vWF metalloprotease- ADAMTS 13 ) deficiency Cause Infection ( E.coli O157 : H7) Adults Age Children Less prominent Acute Renal Failure Prominent Prominent Neurological symptoms Absent
  20. 21. PLATELET FUNCTION DISORDERS <ul><li>Inherited </li></ul><ul><li>Acquired </li></ul>
  21. 22. <ul><li>Inherited Disorders: </li></ul><ul><li>1.GLYCOPROTEIN RECEPTOR ABNORMALITIES </li></ul><ul><li>Bernard-Soulier disease </li></ul><ul><li>Glanzmann’s thrombasthenia </li></ul><ul><ul><li>2. ABNORMALITIES OF PLATELET GRANULES </li></ul></ul><ul><ul><li>-D-storage pool deficiency </li></ul></ul><ul><ul><li>-gray platelet syndrome: a-storage pool deficiency </li></ul></ul><ul><ul><li>-PARIS TROUSSEAU/JACOBSON syndrome(giant a granule) </li></ul></ul><ul><ul><li>-QUEBEC platelet factor V disorder </li></ul></ul><ul><ul><li>3.PLATELET COAGULANT ACTIVITY ABNORMALITY </li></ul></ul><ul><ul><li>SCOTT SYNDROME-failure of normal microvesiculation in response to stimuli </li></ul></ul><ul><ul><li>-not primarily mucocutaneous. </li></ul></ul>
  22. 23. Glanzmann Thromasthenia BSS Inheritance Autosomal Recessive Autosomal Recessive, rarely AD Platelet Count Normal Low Size Normal Giant Glycoprotein Deficiency IIb/IIIa aggregation Ib-IX-V adhesion
  23. 24. Platelet functional disorders
  24. 25. Bleeding in glanzmann thrombasthenia <ul><li>Menorrhagia </li></ul><ul><li>Easy bruising,purpura </li></ul><ul><li>Epistaxis </li></ul><ul><li>Gingival bleeding </li></ul><ul><li>GI haemorrhage </li></ul><ul><li>Hematuria </li></ul><ul><li>Hemarthrosis </li></ul><ul><li>Intra cerebral haemorrhage </li></ul><ul><li>Visceral hematoma </li></ul>
  25. 26. Bleeding in Bernard soulier <ul><li>Epistaxis </li></ul><ul><li>Echymoses </li></ul><ul><li>Menometrorrhagia </li></ul><ul><li>Gingival haemorrhage </li></ul><ul><li>GI bleeding </li></ul><ul><li>Post traumatic bleeding </li></ul><ul><li>Hematuria </li></ul><ul><li>Cerebral hge </li></ul><ul><li>Retinal hge </li></ul>
  26. 27. Drugs affecting platelet function <ul><li>NSAIDS </li></ul><ul><li>Theinopyridines </li></ul><ul><li>Gp iib- iii a antagonists </li></ul><ul><li>Antibiotics </li></ul><ul><li>Anticoagulants </li></ul><ul><li>fibrinolytics </li></ul>
  27. 28. Uremia associated abnormal platelet function <ul><li>Renal failure associated anemia </li></ul><ul><li>Reduced fibrinogen binding </li></ul><ul><li>Defective aggregation </li></ul><ul><li>Concurrent medications </li></ul>
  28. 29. Liver Disease and Hemostasis <ul><li>Decreased synthesis of II, VII, IX, X, XI, and fibrinogen </li></ul><ul><li>Dietary Vitamin K deficiency (Inadequate intake or malabsortion) </li></ul><ul><li>Dysfibrinogenemia </li></ul><ul><li>Enhanced fibrinolysis (Decreased alpha-2-antiplasmin) </li></ul><ul><li>DIC </li></ul><ul><li>Thrombocytoepnia and platelet function defects </li></ul>
  29. 30. HIV associated <ul><li>Accelerated destruction because of immune complexes </li></ul><ul><li>Decreased production </li></ul><ul><li>Splenic sequestration </li></ul><ul><li>TTP </li></ul><ul><li>Medications </li></ul><ul><li>Concurrent infections </li></ul>
  31. 32. Platelet Coagulation Petechiae, Purpura Hematoma, Joint bl.
  32. 33. Bleeding disorders Vascular abnormalities Platelet disorders Clotting factor abnormalities DIC
  33. 34. Clotting factor abnormalities <ul><li>Congenital disorders </li></ul><ul><ul><li>Factor VIII Deficiency - Hemophilia A or Classic Type </li></ul></ul><ul><ul><li>Factor IX Deficiency – Hemophilia B </li></ul></ul><ul><li>Acquired disorders </li></ul><ul><ul><li>Vit. K deficiency =Due to deficient carboxylation of factors II, VII, IX &X or liver disease </li></ul></ul><ul><ul><li>Accelerated catabolism or thrombolytic therapy </li></ul></ul><ul><ul><li>Antibody mediated neutralisation </li></ul></ul><ul><ul><li>Accelerated clearance </li></ul></ul>
  34. 35. 1/50,000 1/10,000 males Incidence X-linkedrecessive X-linkedrecessive Inheritance Factor IX Factor VIII factor deficiency Hemophilia B Hemophilia A
  35. 36. Hge secondary to trauma or surgery Rare spontaneous hge. 6-30% Mild Hge secondary to trauma or surgery Occasional spontaneous hemarthroses 1-5% Moderate Spontaneous he from early infancy Frequent spontaneous hemarthroses <1% Severe Clinical features Levels Classificat ion
  36. 37. Hemophilias <ul><li>Clinical manifestations (hemophilia A & B are indistinguishable) </li></ul>
  37. 38. Clinical features <ul><li>Excessive bleeding into various parts of the body </li></ul><ul><ul><li>hemarthroses </li></ul></ul><ul><ul><li>hematomas </li></ul></ul><ul><ul><li>hematuria </li></ul></ul><ul><ul><li>hemorrhage into the central nervous system </li></ul></ul><ul><ul><li>mucous membrane hemorrhage </li></ul></ul><ul><ul><li>pseudotumors (blood cysts) </li></ul></ul><ul><ul><li>dental and surgical bleeding </li></ul></ul>
  38. 39. Ecchymosis
  39. 40. Ecchymoses (typical of coagulation factor disorders)
  40. 41. Hemarthroses <ul><li>Bleeding into joints accounts for about 75% of bleeding episodes in severely affected patients </li></ul><ul><li>The joints most frequently involved: knees, elbows, ankles, shoulders , wrists and hips </li></ul><ul><li>Repeated hemarthroses results in destruction of articular cartilage, synovial hypertrophy and inflammation </li></ul><ul><li>The major complication of repeated bleeding is joint deformity complicated by muscle atrophy and soft tissue contractures </li></ul><ul><li>Target joint </li></ul>
  41. 42. Hemarthrosis (acute)
  42. 43. Hemarthrosis
  43. 44. hematomas <ul><li>Subcutaneous </li></ul><ul><li>Retro peritoneal </li></ul><ul><li>Retro pharyngeal </li></ul><ul><li>Iliopsoas muscle </li></ul>
  44. 45. CT scan showing large hematoma of right psoas muscle
  45. 46. Neurologic complications <ul><li>Hemorrhage into the central nervous system is the most dangerous event in hemophilic patients </li></ul><ul><li>Intracranial bleeding may be spontaneous or follows trauma, which may be trivial. </li></ul><ul><li>SUBDURAL OR EPIDURAL HEMATOMA </li></ul><ul><li>Hemorrhage into the spinal canal can result in paraplegia </li></ul><ul><li>Peripheral nerve compression is a frequent complication of muscle hematomas, particularly in the extremities </li></ul>
  46. 47. <ul><li>HAEMOPHILIA C </li></ul><ul><li>Factor XI deficiency, autosomal recessive </li></ul><ul><li>The only type of haemophilia that can occur in girls. </li></ul><ul><li>PARAHAEMOPHILIA </li></ul><ul><li>Factor V deficiency. </li></ul><ul><li>Combined factor V – VIII deficiencies-mutations in ERGIC 53, MCFD 2 </li></ul>
  47. 48. Von Willebrand Disease <ul><li>Coagulation + PLT disorder </li></ul><ul><li>vWF: F-VIII & PLT function </li></ul><ul><ul><li>von Willebrand factor </li></ul></ul><ul><ul><ul><li>Synthesis in endothelium and megakaryocytes </li></ul></ul></ul><ul><ul><ul><li>Forms large multimer </li></ul></ul></ul><ul><ul><ul><li>Carrier of factor VIII </li></ul></ul></ul><ul><ul><ul><li>Anchors platelets to subendothelium </li></ul></ul></ul><ul><ul><ul><li>Bridge between platelets </li></ul></ul></ul><ul><li>. </li></ul>
  48. 50. Classification of von Willebrand disease <ul><li>Type 1 vWD- the most common variant </li></ul><ul><ul><li>autosomal dominant in inheritance </li></ul></ul><ul><ul><li>normal vWF in structure and function but decrease in quantity- range 25-50% of normal </li></ul></ul><ul><li>Type 2 vWD ( 2A, 2B, 2M, 2N) </li></ul><ul><ul><li>autosomal dominant in inheritance </li></ul></ul><ul><ul><li>vWF is abnormal in structure and/or function </li></ul></ul><ul><li>Type 3 vWD </li></ul><ul><ul><li>autosomal recessive in inheritance </li></ul></ul><ul><ul><li>the most severe form characterized by very low or undetectable level of vWF </li></ul></ul>
  49. 51. Mutations in vWF precluding binding of FVIII.- autosomal haemophilia 2N Dysfn of vWF molecule 2M Inc.spontaneous binding of vWF to platelets 2B Inc.susceptibility to cleavage by ADAMTS 13-loss of high n intermediate multimers 2A Defect Type
  50. 52. Clinical symptoms <ul><li>Mucocutaneous bleeding- the most common symptom </li></ul><ul><ul><li>epistaxis </li></ul></ul><ul><ul><li>easy bruising and hematomas </li></ul></ul><ul><ul><li>menorrhagia </li></ul></ul><ul><ul><li>gingival bleeding </li></ul></ul><ul><ul><li>gastrointestinal bleeding </li></ul></ul><ul><li>spontaneous hemarthroses occur almost exclusively in patients with type 3 vWD </li></ul>
  51. 53. Pseudo/platelet type vwb disease <ul><li>Due to enhanced interaction between an abnormal platelet GP Ib-IX receptor n normal vwb disease. </li></ul><ul><li>Mild to moderate mucocutaneous hge. </li></ul><ul><li>ACQUIRED VWD </li></ul><ul><li>lymphoproliferative disorders-MGUS,multiple myeloma, waldenstrom’s </li></ul><ul><li>HEYDE’s syndrome. </li></ul>
  52. 54. Hemophilia A Hemophilia B Von Willebrand Disease Inheritance X linked X linked Autosomal dominant Factor deficiency VIII IX VWF Bleeding site(s) Muscle,joint Surgical Muscle ,joint Mucous Skin Prothrombin time Normal Normal Normal Activated PTT Prolonged Prolonged Prolonged Bleeding time Normal Normal Prolonged or normal Platelet aggregation Normal Normal Normal
  53. 55. Bleeding disorders Vascular abnormalities Platelet disorders Clotting factor abnormalities DIC
  54. 56. Vascular abnormalities <ul><li>Causes </li></ul><ul><ul><li>Infections </li></ul></ul><ul><ul><ul><li>Meningococcemia, Rickettsioses , Infective endocarditis </li></ul></ul></ul><ul><ul><li>Drug reactions </li></ul></ul><ul><ul><li>Hereditary hemorrhagic telangiectasia </li></ul></ul><ul><ul><ul><li>Autosomal dominant </li></ul></ul></ul><ul><ul><li>Cushing syndrome </li></ul></ul><ul><ul><li>Henoch - Schönlein Purpura </li></ul></ul><ul><ul><ul><li>systemic hypersensitivity disease of unknown cause </li></ul></ul></ul><ul><ul><ul><li>polyarthralgia, and acute Glomerulonephritis </li></ul></ul></ul><ul><ul><ul><li>Palpable purpuric rash, colicky abdominal pain </li></ul></ul></ul><ul><ul><li>Scurvy and the Ehlers-Danlos syndrome </li></ul></ul><ul><ul><li>Amyloid infiltration of blood vessels </li></ul></ul>
  55. 57. HEREDITARY HAEMORRHAGIC TELENGIECTASIA - CURACAO CRITERIA <ul><li>Epistaxis -spontaneous and recurrent </li></ul><ul><li>Telengiectasias -multiple at characteristic sites-lips,oral cavity,fingers,nose </li></ul><ul><li>Visceral lesions-with or without bleeding(GI,pulmonary,cerebral and hepatic) </li></ul><ul><li>Positive family h/o </li></ul>
  56. 58. <ul><li>Henoch-Sch ő nlein Purpura (Vaculitis) </li></ul><ul><li>Definition:- </li></ul><ul><li>It is hypersensitivity vasculitis involving the small blood vessels of skin ,joints,gut & kidneys. Etiology:- </li></ul><ul><li>in most cases there is history of preceding upper respiratory tract infection. Hypersensitivity vasculitis may be due to virus-antigen/antibody reaction. </li></ul><ul><li>Age:- </li></ul><ul><li>It can occur at any age , it is more common in children than in adult. Most commonly between 2-8 years , boys are affected twice as often as girls. </li></ul>
  57. 59. <ul><li>Clinical Manifestation:- </li></ul><ul><li>1- Skin rash (100% of cases) </li></ul><ul><li>Appear in lower extremities and buttocks. </li></ul><ul><li>The classic lesion begins as a small maculopapular lesion initially blanch on pressure but later loses this feature & generally become petechial or purpuric rash. There is erythemia multiform & angioedema involving the scalp, eyelid , lips,ears, dorsum of hand & feet. </li></ul><ul><li>2- Arthritis( 65% of cases) </li></ul><ul><li>Occur in 2/3 of affected children,large joints-particularly the knee & ankles-,joint may be swollen,tender , painful on motion. When present effusion reveal serious fluid ,they are not hemorrhagic. It resolves after a few days without residual deformity or damage </li></ul>
  58. 60. Henoch-Schonlein purpura
  59. 61. <ul><li>3- Abdominal Manifestation(65 % of cases) </li></ul><ul><li>There is severe colicky pain ,vomiting is common & may be associated with hematemesis, malena or occult blood in stool may be present,the most important complication in intussusception. </li></ul><ul><li>4- Renal Manifestation(20 % of cases) </li></ul><ul><li>There is hematuria </li></ul><ul><li>Nephrotic syndrome ,hypertension, oliguria may occasionally occur. </li></ul><ul><li>5- C.N.S. (not common </li></ul><ul><li>convulsion,paresis & coma. </li></ul>
  60. 62. Henoch-Schonlein purpura
  61. 63. Bleeding disorders Vascular abnormalities Platelet disorders Clotting factor abnormalities DIC
  62. 64. Disseminated Intravascular Coagulation (DIC) Mechanism Systemic activation of coagulation Intravascular deposition of fibrin Depletion of platelets and coagulation factors Bleeding Thrombosis of small and midsize vessels with organ failure
  63. 65. Trigger Thrombin Generation Fibrinemia Consumption of platelet &coagulation factor Microvascular thrombosis Preservation of fibrin Proteolysis of fibrin Hemorrhagic diathesis Organ damage D.I.C.
  64. 66. Common clinical conditions <ul><li>Sepsis </li></ul><ul><li>Trauma </li></ul><ul><ul><li>Head injury </li></ul></ul><ul><ul><li>Fat embolism </li></ul></ul><ul><li>Malignancy </li></ul><ul><li>DRUGS </li></ul><ul><li>LIVER DISEASE </li></ul><ul><li>Obstetrical complications </li></ul><ul><ul><li>Amniotic fluid embolism </li></ul></ul><ul><ul><li>Abruptio placentae </li></ul></ul><ul><li>Vascular disorders </li></ul><ul><li>Reaction to toxin (e.g. snake venom, drugs) </li></ul><ul><li>Immunologic disorders </li></ul><ul><ul><li>Severe allergic reaction </li></ul></ul><ul><ul><li>Transplant rejection </li></ul></ul>
  65. 67. <ul><li>Clinical Manifestations:- </li></ul><ul><li>-- bleeding first occur from site of venipuncture or surgical incision with associated petechiae & ecchymoses. </li></ul><ul><li>-- anemia caused by hemolysis may develop rapidly. </li></ul><ul><li>- Minimal to profound shock, renal failure, dyspnea, cyanosis, convulsions, and coma </li></ul><ul><li>- Hypotension is characteristic </li></ul>
  66. 68. <ul><ul><li>Kidney = microinfarcts in the renal cortex </li></ul></ul><ul><ul><ul><li>In severe cases = bilateral renal cortical necrosis </li></ul></ul></ul><ul><ul><li>Adrenals = bilateral adrenal hemorrhage </li></ul></ul><ul><ul><ul><li>resembles waterhouse - Friderichsen syndrome </li></ul></ul></ul><ul><ul><li>Brain= Microinfarcts surrounded by foci of hemorrhage </li></ul></ul><ul><ul><li>Heart and anterior pituitary= show Similar changes </li></ul></ul>Organ damage due to Micro thrombi
  67. 70. THANK YOU