Bleeding Disorders

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Bleeding Disorders

• Dr. Sabir M. Amin

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Vascular abnormalities

• Causes
• Infections
• Meningococcemia, Rickettsioses , Infective
  endocarditis
• Drug reactions
• Hereditary hemorrhagic telangiectasia
• Cushing syndrome
• Henoch - Schönlein Purpura
• Scurvy
• Amyloidosis

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Platelet disorders

• Thrombocytopenia Reduced platelet number
• Decreased production of platelets
• vitamin B12 or folic acid deficiency
• Decreased platelet survival
• Immunologic or Nonimmunologic etiology
• Sequestration- Hypersplenism
• ameliorated by splenectomy
• Dilutional
• Massive transfusions

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Clinical Features of Bleeding Disorders

• Platelet Coagulation disorders disorders
• Site of bleeding Skin Deep in soft tis.
• Mucous membranes (joints, musc)
• Petechiae Yes No
• Ecchymoses (bruises) Small, superficial Large,
  deep
• Hemarthrosis / muscle bleeding Extremely
  rare Common
• Bleeding after cuts scratches Yes No
• Bleeding after surgery or trauma Immediate, Delaye
  d1-2 d
• usually mild often severe

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Screening tests

• Bleeding time
• 2-9 minutes. Prolonged in thrombocytopenia
• Platelet counts
• 150-450 103/mm3
• Prothrombin time (PT)
• Measures the extrinsic (V, VII, X) and
  common (prothrombin, fibrinogen) coagulation
  pathways. 10-15 secs
• activated Partial thromboplastin time (aPTT)
• Measures the intrinsic (V, VIII, IX, XI,
  VII) and common (prothrombin, fibrinogen)
  coagulation pathways. 30 50 secs
• Thrombin time
• Time for thrombin to convert fibrinogen to
  fibrin
• 9-13 secs

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Platelet Coagulation
Petechiae, Purpura Hematoma, Joint bl.
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Hemarthrosis
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Hematoma
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Purpura 3-10mm
Petechiae lt3mm
Ecchymosis gt10mm
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Causes of thrombocytopenia

• Bone marrow disorders
• Hypoplasia
• Idiopathic
• Drug-induced (cytotoxic, alcohol, thiazides)
• Infiltration
• Tumors (leukemia, myeloma, carcinoma)
• B12/folate deficiency

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Causescont.

• Increased consumption of platelets
• Disseminated intravascular coagulation (DIC)
• Immune thrombocytopenic purpura
• Viral infections (HIV, Epstein-Barr virus)
• Bacterial infections (gram-negative septicemia)
• Hypersplenism
• Primary
• Lymphomas
• Liver disease
• Malaria

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Immune thrombocytopenic purpura (ITP)

• It is due to auto- antibodies directed against
  PLT membrane glycoprotein IIb-IIIa which causes
  premature removal of PLTs by the monocyte
  -macrophage system
• ASSOCIATIONSneoplasm (CLL, lymphoma), infections
  (HIV), autoimmune (SLE)

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ITP
Feature Acute Chronic
Age / Sex Children Adult/Female
Onset Abrupt Gradual
Predisposing Factors Viral infection/ vaccine -
Duration lt2 months gt6mnoths
Peripheral smear ?PLT Giant PLTS Same
Bone marrow Normal or ?Megakaryocytes Same
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ITP
Feature Acute Chronic
Tests Prolonged BT Normal PT PTT Same
Complication (most dangerous) Intracranial bleed Same
Clinical course Spontaneous remission No
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management

• 1. In children usually it is self-limiting, if
  severe purpura or epistaxis, or PLT lt10000 give
  steroids ( prednisolone 2mg/kg/d)
• If pesistent epistaxis GI bleeding, retinal
  hemorrhage give PLT transfusion and IV IgG

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management

• 2. In adults prednisolone 1 mg/kg/d for 3-4 wk
  then gradually tapered over 6-8 wk. If platelet
  count did not increase after 4 weeks of
  treatment, consider splenectomy
• PLT transfusion and IVIg 1 g/kg/d 12 days,
  indicated in life-threatening bleeding. If the pt
  has two relapses , splenectomy is indicated,
  which is curative in 70 of patients, in the
  remainder the aim is to keep the patient free of
  symptoms rather than to raise level of PLT( e.g
  5mg/d of prednisolone may be sufficient)

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management

• In severe cases iv methylpredinsolone 1gIV
  dailyX3 days. with or without IVIg may be given
• If still not controlled give immunosuppressive
  drugs e.g vincristine, cyclophosphamide

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Clotting factor abnormalities

• Congenital disorders
• Von Willebrand disease
• Factor VIII Deficiency - Hemophilia A or Classic
  Type
• Factor IX Deficiency Hemophilia B
• Acquired disorders
• Vit. K deficiency Due to deficient carboxylation
  of factors II, VII, IX X
• Oral anti-coagulants
• warfarin inhibit Vit. K factors
• Liver diseases ? synthesis of factors

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Hemophilia A

• Factor VIII is synthesized mainly by liver , but
  also by spleen, kidney, and placenta, carried by
  vWF, half-life in plasma is 12hr.
• It is X-linked recessive and affects about
  1/10000, thus all daughters of hemophiliacs are
  carriers and 50 of sisters are carriers. If a
  carrier has a son, he has 50 chance of having
  hemophilia and a daughter has 50 chance of being
  a carrier

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Hemophilia A

• C/F
• At around 6 m. child develop bruises and
  hemarthrosis as he starts to move around.
• Normal level of factor VIII is 50-150, and
  severity is measured according to this level

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Severity of hemophilia depends on level of
factor VIII
Factor VIII levels lt 1 1 - 5 5 - 25
Type Severe hemophilia Moderate hemophilia Mild hemophilia
Symptoms Severe hemorrhage, deep tissue bleeding. Present within first year of life. Bleeding after mild trauma. Present during childhood. Bleeding after severe trauma and surgery. Present during adulthood.
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Hemophilia A

• Joints commonly affected include knees, elbows,
  ankles, and hips.
• They look hot, swollen, and very painful and
  tender. With recurrent bleeding there will be
  synovial hypertrophy, destruction of cartilage
  and secondary osteoarthritis,
• In muscles calf, psoas bleeding lead to
  ischemia, necrosis, fibrosis which will lead to
  contracture shortening of tendons e.g. Achilles
  tendon making walking difficult.

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Shortening of Achilles tendon
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Dosing guidelines for hemophilia A

• Mild bleeding
• Target 30 dosing q8-12h 1-2 days (15U/kg)
• Hemarthrosis, oropharyngeal or dental, epistaxis,
  hematuria
• Major bleeding
• Target 80-100 q8-12h 7-14 days (50U/kg)
• CNS trauma, hemorrhage, lumbar puncture
• Surgery
• Retroperitoneal hemorrhage
• GI bleeding
• Adjunctive therapy
• ?-aminocaproic acid or DDAVP (for mild disease
  only)

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von Willebrands disease

• Usually it is a mild bleeding disorder of many
  types, the commonest being type I which is
  autosomal dominant.
• vWF is synthesized by endothelial cells and
  megakaryocytes and has two functions
• 1. carrier for F VIII
• 2. form bridges between PLT and subendothelial
  collagen

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vW Dis.

• C/F
• Bruising, epistaxis, menorrhagia, GI bleeding
• LAB
• Decreased level of vWF, increased bleeding
  time, increased PTT

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Treatment

• Cryoprecipitate
  
• Source of fibrinogen, factor VIII and VWF
  
• DDAVP (deamino-8-arginine vasopressin)
  
• ? plasma VWF levels by stimulating
  secretion from endothelium
  
  
• Factor VIII concentrate
  
• Virally inactivated product
  

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Acquired bleeding disorders

• Liver disease
• Vitamin K deficiency
• Disseminated intravascular coagulation (DIC)
• Infection

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Vitamin K deficiency

• Source of vitamin K Green vegetables
  intestinal flora
• Required for synthesis Factors II, VII, IX
  ,X
• Causes of deficiency
• Inadequate intake Biliary
  obstruction Malabsorption Antibiotic
  therapy

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Common clinical conditions associated with DIC

• Activation of both coagulation and fibrinolysis
• Triggered by

• Sepsis (E. coli, N. meningitidis, malaria)
• Trauma Head injury, Fat embolism
• Malignancy lung, prostate, pancreatic

• Obstetrical disorders
• Amniotic fluid embolism
• Abruptio placentae
• Vascular disorders
• Reaction to toxin (e.g. snake venom, drugs)
• Immunologic disorders
• Severe allergic reaction
• Transplant rejection

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Pathophysiology

• damage to endothelium ?release of tissue factor ?
  massive activation of
• coagulation cascade ? intravascular coagulation
  and depletion of clotting factors

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Features

• microangiopathic hemolytic anemia,
  thrombocytopenia, bleeding, thrombosis, ischemia.
  ?INR, ? PTT, ? fibrinogen (although it can be
  normal or even elevated), ? factor VIII (in
  contrast to liver diseases, which have normal
  factor VIII). Schistocytes on peripheral smear

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Treatment

• treat underlying cause and complications
  (hypoxia, dehydration, acidosis, acute renal
  failure). Replete coagulation factors if bleeding
  (FFP 2 U, cryoprecipitate 10 U). Anticoagulation
  if thrombosis (consider IV heparin)

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Management of Hemostatic Defects in Liver Disease

• Treatment for prolonged PT/PT
• Vitamin K 10 mg x 3 days - usually ineffective
• FFP infusion (1200-1500 ml)
• immediate but temporary effect
• Treatment for low fibrinogen
  
• Cryoprecipitate (1 unit/10kg body weight)
• Treatment for DIC
• Replacement therapy

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Venous thrombosis

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Venous thrombosis

• VT arise either because of damage to, or
  pressure on veins (e.g. varicose veins or pelvic
  tumor) , or as a result of changes in plasma or
  cellular elements of blood.
• The familial thrombophilic disorders include
  factor V Leiden, prothrombin 20210A and
  deficiencies of protein C, protein S, and
  antithrombin.

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Venous thrombosis

• The incidence of factor V Leiden, is 3-5, and
  that of the prothrombin 20210A allele is 2-3
• These are thus the commonest causes of an
  inherited predisposition to venous thrombosis
  (thrombophilia). All the hereditary thrombophilic
  conditions are autosomally dominantly inherited
  and are present in up to 50 of cases of venous
  thrombosis, particularly when recurrent,
  familial, or at a young age.

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Predisposing factors

• 1. Patient a) age gt40
  
• b) obesity
  c)
  varicose veins
  d) previous DVT
  e)
  OCP
  f) pregnancy/puerperium
  g)
  dehydration
• h) immobility
• 2. Surgical
  a) if gt30 min
  duration
  b) abdominal or pelvic
  c) orthopedic to lower limb

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Pred. fact.

• 3. Medical a) MI/HF
  b) IBD c) malignancy d)
  Nephrotic syn e) pneumonia
• 4. Hematological a) PV b) ET c) PNH d)
  myelofibrosis
• 5. Anticoagulant deficiency a) antithrombin b)
  protein C c) protein S d) factor V Leiden e)
  prothrombin mutations
• 6. Antiphospholipid syndrome a) lupus
  anticoagulant b) anticardiolipin Ab

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C/F of familial thrombophilic conditions

• Family history of venous thromboembolism
• First episode at early age
• Recurrent venous thromboembolism
• Unusual site of thrombosiseg cerebral,
  mesenteric
• Thrombosis during pregnancy or puerperium
• Spontaneous venous thrombosis without
  environmental or acquired risk factor
• Recurrent superficial thrombophlebitis

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Special Investigations of DVT

Test Advantages Disadvantages
Contrast Gold standard Invasive
Venography Sensitivity 100 Requires specialized equipment
 
MRI Highly accurate Expensive
  Safe during pregnancy Not readily available
  Non-invasive  
   


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Special investigations
CT Non-invasive Limited data
  Can diagnose pelvic DVT  
  Concurrently exclude PE  
Ultrasonography Highly accurate Not accurate for calf or pelvic DVT
  Non-invasive Complete study is time consuming
D-dimer Rapid laboratory study Only used to rule-out DVT
   
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Management of thromboembolism

• Indications for anticoagulation
• Heparin
• 1. Treatment prevention of DVT
• 2. Pulmonary embolism
• 3. post-thrombolysis for MI
• 4. unstable angina
• 5. acute peripheral arterial occlusion

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Indications of warfarin Rx

• prophylaxis against DVT
• treatment of DVT PE
• arterial embolism
• AF with stroke risk factors
• mobile mural thrombus on echo post-MI
• extensive anterior MI( all these INR 2.5)
• recurrent DVT
• mechanical prosth heart valves( latter two
  INR3.5)

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Contraindications to anticoagulation

• 1. Recent surgery( esp. to eye or CNS)
• 2. pre-existing hemorrhagic condition( e.g. liver
  disease, RF, hemophilia, thrombocytopenia)
• 3. Peptic ulcer
• 4. Recent cerebral hemorrhage
• 5. Uncontrolled HT
• 6. Dementia and frequent falls in old age

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Heparin

• Standard (unfractionated) heparin (SH)
  potentiate the activity of antithrombin which
  inhibits the procoagulant enzymic activity of
  factors IIa, VIIa, IXa, Xa, and XIa.
• Low-molecular weight heparin ( LMWH) augments
  antithrombin activity preferentially against
  factor Xa. LMWH does not prolong PTT( unlike SH),
  and injections need only be given once daily SC
  and no monitoring is required, many pts can be
  treated at home.

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Heparincont.

• SH is reserved for treating pts with very severe,
  life-threatening TE e.g. major PE giving rise to
  hypoxia or hypotension.
• Dose loading dose of 5000 U i.v, followed by a
  continuous infusion of 20U/kg/hr initially. PTT
  done after 6 hr, and if satisfactory daily
  thereafter. The aim is to keep PTT 1.5-2.5 times
  the control time.

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Heparincont.

• Half-life of heparin is 1 hr, and if pt bleeds,
  it is sufficient just to discontinue the
  infusion however, if bleeding is severe , the
  excess can be neutralised with i.v protamine.
  Treatment with either SH or LMWH should continue
  for 6-8 days, and it is appropriate to start
  warfarin therapy at the same time as heparin, and
  heparin should be continued until INR is gt2.0 for
  2 consecutive days.

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Warfarin

• inhibits vit. K-dependent synthesis of FII, VII,
  IX and X
• Dose
• loading 10 mg orally on the first day, and
  subsequent daily doses depending on the INR. If
  single DVT it is given for 3-6 m, if two or more
  it should be continued for life.
• Bleeding is the most common side effect of
  warfarin 1.0/yr. If INR is above therapeutic
  level stop warfarin and give a small dose of
  vit.k e.g. 5 mg orally or 2 mg by slow i.v. If
  the pt bleeds, give vit. K¹ 1-5 mg slowly i.v. If
  bleeding is serious , give coagulation
  concentrate containing factors II, VII, IX and X
  (50U/kg)or, if unavailable, FFP

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Prevention of venous thrombosis

• Full-length graduated compression stockings
• SH or LMWH
• It should be started preop and continued until
  the pt is fully mobile
• Conditions A) moderate risk of DVT 1. major
  surgery in pts gt40yr or with other risk factors,
  2. major medical illness e.g HF, chest
  infection, malignancy, IBD
• B) High risk of DVT 1. hip or knee surgery, 2.
  major abdominal or pelvic surgery( for malignancy
  or with Hx of DVT or known thrombophilia)