Bleeding Disorders 1

MDS: Senior Clerkship Bleeding Disorders.

2001/02

Bleeding Disorders Hemostasis: o Primary: Adhesion to collagen in subendothelium Release of ADP & thromboxane A2

  Aggregation of Plts (Plts plug).

o Secondary: extrinsic + intrinsic + common pathways.

Tests of hemostasis: Platelets: o #: count, estimate. = 150 – 400 X 109/L. o Bleeding time: affected by Plts count, Plts function, blood vessels. o Blood film: if big  new cells. Coagulation: aPTT (activated Partial Thromboplastin Time): o Purpose: measure intrinsic pathway (Factors VIII, IX, XI, XII). o Normal = 25 sec. PT (Prothrombin Time): o Purpose: measure extrinsic pathway (Factors VII; synthesized in liver). o Normal = 12 sec. INR (International Normalized Ratio): o = (PT of pts) / (PT of the normal people). o Purpose: enables doctors to obtain appropriate level of coagulation, independent of lab reagents & to follow published recommendations for intensity of anti-coagulation. o Normal = 1. Others:  Fibrinogen.  FDP (Fibrinogen Degradation Products)  esp. D-dimers.  Specific factor assays.  Tests of physiological inhibitors (anti-thrombins, protein S, protein C, hereditary resistance to Activated Protein C “APC” = Factor V Leiden).  Tests of pathological inhibitors (lupus anti-coagulant).

Khalid A. Yarouf.

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MDS: Senior Clerkship Bleeding Disorders.

2001/02

Signs & symptoms of Disorders of Hemostasis: Primary (Plts)

Secondary (Coagulation)

Surface cuts

Excessive, prolonged.

Normal / slightly prolonged.

Onset after injury

Immediate

Delayed

Typical type & site of bleeding

Superficial:

Deep = Large spreading ecchymotic lesions & hematoma.

Mucosal: 

Nasal  epistaxis.

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Gingival.

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GI tract.

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Uterine  menorrhagia.

Into joints (hemoarthrosis). GU tract. Post-traumatic.

Petechiae. Purpura

Classification of Bleeding Disorders: I. Disorders of Primary Hemostasis: 1. Vascular (Non-thrombocytopenic pupura):  Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu).  Acquired: o Senile purpura: common. o Dysproteinemias. o Henoch-Schönlein purpura (HSP). o Scurvy: due to Vit C deficiency. o Cushing’s synd. o Infections. o Drugs: Steroids. 2. Platelets:  Dysfunction: o Hereditary: von Willebrand’s disease. o Acquired:  Drugs: ASA, EtOH (alcohol), NSAIDs.  Uremia.  Myelo-proliferative disorders.  Dysproteinemias.

Khalid A. Yarouf.

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MDS: Senior Clerkship Bleeding Disorders.

2001/02

N.B. ASA inhibits Thromboxane A2 (strong inducer of Plts aggregation). N.B. Uremia also ↓ RBCs lifespan  hemolysis. 

Thrombocytopenia (usually acquired): o ↓ Production:  Drugs, toxins.  Radiation.  BM infiltrate / failure.  Megaloblastic anemias (Vit B12, folic acid).  Myelodysplasia.  Viral infections (varicella, mumps, HIV, EBV, CMV, parvovirus). o ↑ Destruction:  Drugs (quinidine, sulfas, thiazides, heparin, cephalosporins).  Idiopathic Thrombocytopenic Purpura (ITP).  Allo-Antibodies: e.g. SLE.  Infections: HIV, Sepsis. o ↑ Consumption:  DIC.  Micro-angiopathic (Thrombotic thrombocytopenic purpura = TTP).  Hyper-splenism. o Sequestration  splenomegaly. o Dilutional  massive transfusion with stored blood.

II. Disorders of Secondary Hemostasis: 

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Hereditary: o Factor VIII: Hemophilia A + vWD. o Factor IX: Hemophilia B (Christmas disease). o Factor XI (Rosenthal synd). Acquired: o Liver disease. o DIC. o Vit K deficiency. o Anti-coagulants: Warfarin (Coumadin).

Khalid A. Yarouf.

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Page 3 of 6

MDS: Senior Clerkship Bleeding Disorders.

2001/02

Specific diseases Idiopathic Thrombocytopenic Purpura (ITP): Child type (acute): 

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Cause: Antibodies (Abs) that bind to Plt membranes  splenic destruction of Ab-coated Plts. Presentation: • Typically present after viral illness. • Sudden onset of petechiae, purpura, epistaxis in otherwise healthy child. • Negative signs: no lymphadenopathy, no hepatosplenomegaly. • If atypical presentation (> one cell line is abnormal, hepatosplenomegaly)  rule out leukemia  do BM aspiration.

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Self-limited in 80% children, but usually treat because spontaneous recovery takes a few months. DDx: o Leukemia. o Drug-induced thrombocytopenia. o Infection (viral). o SLE. o HIV. Labs: o Thrombocytopenia (Plts < 20 X 109/L). o Normal WBC & RBC. Mx: o IVIg. o Prednisolone  rule out leukemia before using it! o For life threatening bleeding  Splenectomy.

Adult type (chronic):  Commonest cause of isolated thrombocytopenia.  Pathophysiology: IgG auto-Abs. Features Peak age Sex predilection Hx of recent infection Onset of bleed Plt count Khalid A. Yarouf.

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Acute ITP 2-6 yrs None Common Abrupt < 20 X 109/L

Chronic ITP 20-40 yrs >♀ Rare Insidious 30-80 X 109/L Page 4 of 6

MDS: Senior Clerkship Bleeding Disorders.

Duration Weeks Spontaneous remissions > 80%

2001/02

Months – yrs uncommon

Hemorrhagic disease of newborn: 

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Cause: Vit K deficiency  ↓ Factors II, VII, IX, X (mnemonic: 1972), Protein C, Protein S ↑ PT & aPTT. Presents at 2-7 days with bleeding: GI, intracranial, bleeding from circumcision or umbilical stump. Prevention: IM Vit K at birth to all newborns.

Hemophilia: (very important) Hemophilia A:  

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X-linked recessive, >> common than Hemophilia B. Cause: Factor VIII deficiency  delayed formation of Thrombin (important in forming normal functional fibrin clot & solidifying Plt plug at areas of vascular injury). Severity o Depends on:  Level of factor VIII.  Severity of bleeds.  Presence of Abs to factor VIII. o Mild (>5% factor VIII): Bleeding: GI, GU, after significant trauma (e.g. surgery). o Moderate: (1-5% of Factor VIII). o Severe (<1% factor VIII): spontaneous bleeding / bleeding from minor trauma. Hallmark is hemoarthrosis. Lab: o ↑ PTT + Normal INR (PT). o ↓ Factor VII. o vWF: normal. Rx: o Factor VIII replacement: for minor / major trauma, prophylaxis. o DDAVP for mild disease.

Hemophilia B = Christmas disease: Khalid A. Yarouf.

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MDS: Senior Clerkship Bleeding Disorders.

2001/02

o Factor IX deficiency. o XR. o Presentation: same as Hemophilia A. o Rx: Factor IX replacement. von Willebrand disease:  Normal: von Willebrand factor is adhesive protein  o Enhances Plts adhesion to subendothelial collagen. o Protects factor VIII from rapid clearance.  Abnormal: defect in vW factor. o AD (> common, mild) + AR (rare, severe). o Both 1° & 2° hemostasis are affected. o Presentation  Bleeding:

• mucocutaneous, gingival, recurrent epistaxis, ecchymosis, menorrhagia. o Lab: • ↑ Bleeding time & aPTT. MCQ • ↓ Factor VIII. o Rx: DDAVP  for mild disease  ↑ Release of vW factor. • Cryoprecipitate = contains Factor 8, vWF, Firbinogen, Factor 13. •

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Khalid A. Yarouf.

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