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Bleeding disorders

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									Randa Al-Harizy
Prof of Internal Medicine
Much information may be obtained from the history and physical examination:
Is there a generalized haemostatic defect?
 Bleeding from multiple sites, spontaneous bleeding, and excessive bleeding after
    injury.
Is the defect inherited or acquired?
 A family history of a bleeding disorder
 Severe inherited defects usually become apparent in infancy, while mild inherited
    defects may only come to attention later in life. Some defects are revealed by
    routine coagulation screens which are performed before surgical procedures.
Is the bleeding suggestive of a vascular/platelet defect or a coagulation defect?
 Vascular/platelet bleeding is characterized by easy bruising and spontaneous
    bleeding from small vessels. There is often bleeding into the skin. The term
    purpura includes both petechiae, which are small skin haemorrhages varying
    from pinpoint size to a few millimetres in diameter and which do not blanch on
    pressure, and ecchymoses, which are larger areas of bleeding into the skin.
    Bleeding also occurs from mucous membranes especially the nose and mouth.
 Coagulation disorders are typically associated with haemarthroses and muscle
    haematomas, and bleeding after injury or surgery. There is often a short delay
    between the precipitating event and overt haemorrhage or haematoma
    formation.
   Blood count and film show the number and morphology of platelets and any blood disorder such
    as leukaemia or lymphoma. The normal range for the platelet count is 150-400 × 109/L.
   Bleeding time measures platelet plug formation in vivo. It is normally between 3 and 10 minutes.
    Prolonged bleeding times are found in patients with platelet function defects, and there is a
    progressive prolongation with platelet counts less than 80 × 109/L. The bleeding time should not
    be performed at low platelet counts.
   Coagulation tests are performed using blood collected into citrate, which neutralizes calcium
    ions and prevents clotting.
   The prothrombin time (PT) is measured by adding tissue thromboplastin in the form of animal
    brain extract, or a recombinant equivalent, and calcium to the patient's plasma ('extrinsic'
    system). The normal PT is 16-18 s, and it is prolonged with abnormalities of factors VII, X, V, II or I,
    liver disease, or if the patient is on warfarin.
   The activated partial thromboplastin time (APTT) is also sometimes known as the PTT with
    kaolin (PTTK). It is performed by adding a surface activator (such as kaolin), phospholipid (as
    platelet substitute) and calcium to the patient's plasma ('intrinsic' system). The normal APTT is
    30-50 s depending on the exact methodology, and it is prolonged with deficiencies or inhibitors of
    one or more of the following factors: XII, XI, IX, VIII, X, V, II or I (but not factor VII) .
   The thrombin time (TT) is performed by adding thrombin to the patient's plasma. The normal TT
    is about 12 s, and it is prolonged with fibrinogen deficiency, dysfibrinogenaemia (normal level of
    fibrinogen but abnormal function) or inhibitors such as heparin or FDPs.
 Correction tests can be used to differentiate prolonged times in
  the PT, APTT and TT due to various coagulation factor deficiencies
  and inhibitors of coagulation. Prolonged PT, APTT or TT because
  of coagulation factor deficiencies are corrected by addition of
  normal plasma to the patient's plasma; no correction of an
  abnormal result after the addition of normal plasma is suggestive
  of the presence of an inhibitor of coagulation.
 Factor assays are used to confirm coagulation defects, especially
  where a single inherited disorder is suspected.
 Special tests of coagulation will often be required to confirm the
  precise haemostatic defect. Such tests include estimation of
  fibrinogen and FDPs, platelet function tests such as platelet
  aggregation and tests of the fibrinolytic pathway.
   Results in spontaneous bleedings mostly
    affecting the skin resulting in purpuric
    eruptions and ecchymosis and also affecting
    the mucus membranes with gingival,
    conjunctival and orificial bleeds. Prolonged
    bleeding after trauma is also common.
    Intracerebral and intraabdominal bleedings
    can also occur.
   Where platelets are normal in count and
    function. They include hereditary
    hemorrhagic telangiectasia. An autosomal
    dominant trait affecting the mucous
    membranes and skin resulting in
    gastrointestinal bleedings and chronic iron
    deficiency.
The causes of vascular bleeding disorders also include:
 Simple easy bruising: occuring in healthy women
 Senile purpura: due to atrophy of the supporting tissues of blood
  vessels and affects the dorsum of the hands and forearms
 Purpura associated with infections e.g. infective endocarditis
 Vasculitis: characterized by palpable purpura e.g. Henoch-
  Schonlein purpura: immune complex reaction with hematuria,
  abdominal pains and joint affection. Usually self limited though
  can progress to severe renal involvement.
 SLE, polyarteritis nodosa
 Vitamin C deficiency: where the purpuric eruptions are around hair
  follicles
 Hereditary connective tissue disorders with abnormal collagen as
  in Ehlers-Danols syndrome and pseudoxanthoma elasticum
A- Quantitative platelet abnormalities
-Thrombocytopenia:
 Quantitative reduction of platelets can results
  from a defective production from the
  marrow, an increased consumption or
  abnormal distribution and rarely from a
  dilutional effect
Failure of platelet production by the bone marrow
 Selective depression of megakaryocytes as with drugs,
  chemicals or infections
 Part of generalized bone marrow failure as in aplastic,
  dysplastic marrow or with bone marrow infiltration
Increased consumption of the platelets:
 Immune mediated reactions as in autoimmune and
  idiopathic, drug-induced including heparin, infections and
  neonatal
 Consumption as in disseminated intravascular
  coagulation, thrombotic thrombocytopenic purpura,
  hemolytic uremic syndrome
 Hypersplenism
Dilutional as in cases of massive transfusion of stored blood
Thrombocytopenia is due to immune destruction of platelets. The antibody
coated platelets are removed following binding to Fc receptors on macrophages.
ITP in children
 The condition is usually acute but self-limiting and may follow a viral infection or
   immunization.
 Bone marrow examination is not usually performed unless treatment becomes
   necessary on clinical grounds.
ITP in adults
 The presentation is usually less acute than in children.
 Adult ITP is characteristically seen in women and may be associated with other
   autoimmune disorders such as SLE, thyroid disease and autoimmune haemolytic
   anaemia (Evans' syndrome), in patients with chronic lymphocytic leukaemia and
   solid tumours, and after infections with viruses such as HIV.
 Platelet autoantibodies are detected in about 60-70% of patients, and are
   presumed to be present, although not detectable, in the remaining patients; the
   antibodies often have specificity for platelet membrane glycoproteins IIb/IIIa
   and/or Ib.
 Clinical features: Major haemorrhage is rare and is seen only in patients with
   severe thrombocytopenia. Easy bruising, purpura, epistaxis and menorrhagia are
   common. Physical examination is normal except for evidence of bleeding.
   Splenomegaly is rare.
Investigation :
 The only blood count abnormality is thrombocytopenia.
 Normal or increased numbers of megakaryocytes are found in the bone marrow
 The detection of platelet autoantibodies is not essential for confirmation of the
   diagnosis.
Treatment:
 Children do not usually require treatment. Where this is necessary on clinical
   grounds, high-dose prednisolone is effective, given for a very short course.
   Intravenous immunoglobulin (i.v. IgG) should be reserved for very serious
   bleeding or urgent surgery.
 Adults:
 Patients with platelet counts greater than 30 × 109/L require no treatment unless
   they are about to undergo a surgical procedure.
 First-line therapy consists of oral corticosteroids 1 mg/kg body weight but i.v. IgG
   is useful where a rapid rise in platelet count is desired, especially before surgery.
   There are also advocates for high-dose corticosteroids as initial therapy.
 Second-line therapy involves splenectomy, to which the majority of patients
   respond, but a wide range of treatments is available in chronic ITP. These include
   high-dose corticosteroids, high-dose i.v. IgG, intravenous anti-D, vinca alkaloids,
   danazol, immunosuppressive agents such as azathioprine, ciclosporine and
   dapsone. There is also interest in the use of specific monoclonal antibodies such
   as rituximab, as well as recombinant thrombopoietin.
 Platelet transfusions are reserved for intracranial or other extreme haemorrhage,
   where emergency splenectomy may be justified.
 TTP-HUS results from factors leading to platelet
  aggregation and formation of microvascular thrombi.
  These factors include toxins, drugs or defeciency of von
  Willebrand cleaving protease
 Red cells are sheared leading to microangiopathic
  hemolytic anemia and the consumption of the platelets
  leads to a paradox of ischemia of the involved organs and
  bleeding thrombocytopenia
 Hemolytic anemia, thrombocytopenia, fever, neurological
  and renal impairement constitute the syndrome
 Treatment: Plasma exchange should be initiated promptly
  and carried out daily till LDH and platelet count are
  normalized. Steroids, immunosuppression and
  splenectomy are used in refractory cases
   May be congenital as Glanzman’s
    thrombasthenia and von Willibrand’s disease
   Acquired: as seen with drugs such as aspirin,
    clopidogrel, NSAIDS, and many antibiotics.
    They are also seen in myelodysplastic
    syndrome and renal failure
Common causes of abnormal coagulation tests
   Prolonged PTT          Prolonged PT              Prolonged PT/PTT
   LA                     LA                        LA
   Heparin                Warfarin                  Liver disease
   Deficiency of factor   Vitamin K deficiency      Warfarin
   VIII, IX, XI, XII
   Hypofibrinogenemia     Deficiency or             Deficiency of factor II,
                          inhibitors to II, VII,X   V, X
                          Hypofibrinogenemia        DIC


                                                    Hypofibrinogenemia
   Congenital coagulation factor deficiencies
    result in bleeding. Characteristically, the
    bleeding occurs in response to trauma.

   Haemarthrosis, muscle hematoma,
    retroperitoneal and intracranial collections,
    postoperative bleeding and hematuria are
    usually the presenting features.
   Factor VIII deficiency is X-linked, resulting in bleeding
    with prolonged PTT.
   Desmopressin (synthetic vasopressin) are used for
    mild cases.
   Factor VIII concentrate is needed in severe cases or in
    the presence of bleeding.
   In the absence of concentrates, cryoprecipitate can be
    used, though the risks of viral infections are very high
   25% of patients with hemophilia A will develop
    inhibitors to the transfused factor necessitating the
    use of excess human factor to bypass the inhibitor or
    use a prothrombin complex concentrate or more
    recently recombinant activated factor VIIa
Hemophilia B (Christmas disease):
 It is less common and results from factor IX deficiency
von Willebrand disease (vWD):
 It results from quantitative (type 1 and 3) or qualitative
  (type 2) deficiency of von Willebrand factor. vWF is an
  adhesive protein needed for platelet adhesion and
  aggregation and is also carrier of factor VIII. Subsequently
  in vWD, PTT is prolonged because of the lack of
  availability of factor VIII and prolonged bleeding time
  resulting from platelet dysfunction. Desmopressin and
  vWF replacement are usually the lines of therapy
Congenital deficiencies of factor V, VII and XI are less
common
Vitamin K deficiency
 Vitamin K is necessary for the γ-carboxylation of glutamic acid
   residues on coagulation factors II, VII, IX and X and on proteins C
   and S. Without it, these factors cannot bind calcium.
 Deficiency of vitamin K may be due to:
 inadequate stores, as in haemorrhagic disease of the newborn and
   severe malnutrition (especially when combined with antibiotic
   treatment)
 malabsorption of vitamin K, a fat-soluble vitamin, which occurs in
   cholestatic jaundice owing to the lack of intraluminal bile salts
 oral anticoagulant drugs, which are vitamin K antagonists.
 The PT and APTT are prolonged and there may be bruising,
   haematuria and gastrointestinal or cerebral bleeding.
 Minor bleeding is treated with phytomenadione (vitamin K1) 10
   mg intravenously. Some correction of the PT is usual within 6
   hours but it may not return to normal for 2 days.
Liver disease
Liver disease may result in a number of defects in haemostasis:
 Vitamin K deficiency. This occurs owing to intrahepatic or
   extrahepatic cholestasis.
 Reduced synthesis. Reduced synthesis of coagulation factors may
   be the result of severe hepatocellular damage. The use of vitamin
   K does not improve the results of abnormal coagulation tests, but
   it is generally given to ensure that a treatable cause of failure of
   haemostasis has not been missed.
 Thrombocytopenia. This results from hypersplenism due to
   splenomegaly associated with portal hypertension or from folic
   acid deficiency.
 Functional abnormalities. Functional abnormalities of platelets
   and fibrinogen are found in many patients with liver failure.
 Disseminated intravascular coagulation. DIC may occur in acute
   liver failure.
Disseminated intravascular coagulation (DIC)
 There is widespread generation of fibrin within blood vessels, owing to activation
    of coagulation by release of procoagulant material, and by diffuse endothelial
    damage or generalized platelet aggregation. The consequences of these changes
    are a mixture of initial thrombosis followed by a bleeding tendency due to
    consumption of coagulation factors and fibrinolytic activation.
Causes of DIC
 These include: malignant disease, septicaemia (e.g. Gram-negative and
    meningococcal), haemolytic transfusion reactions
 obstetric causes (e.g. abruptio placentae, amniotic fluid embolism), trauma,
    burns, surgery, other infections (e.g. falciparum malaria), liver disease or snake
    bite.
Clinical features
 The underlying disorder is usually obvious. The patient is often acutely ill and
    shocked. The clinical presentation of DIC varies from no bleeding at all to
    profound haemostatic failure with widespread haemorrhage. Bleeding may occur
    from the mouth, nose and venepuncture sites and there may be widespread
    ecchymoses. Thrombotic events may occur as a result of vessel occlusion by
    fibrin and platelets. Any organ may be involved, but the skin, brain and kidneys
    are most often affected.
Disseminated intravascular coagulation (DIC)
Investigations
 The diagnosis is often suggested by the underlying condition of
   the patient. Severe cases with haemorrhage, The PT, APTT and TT
   are usually very prolonged and the fibrinogen level markedly
   reduced. High levels of FDPs, including D-dimer are found owing
   to the intense fibrinolytic activity stimulated by the presence of
   fibrin in the circulation. There is severe thrombocytopenia. The
   blood film may show fragmented red blood cells.
Treatment
 The underlying condition is treated and this may be all that is
   necessary in patients who are not bleeding. Maintenance of blood
   volume and tissue perfusion is essential. Transfusions of platelet
   concentrates, FFP, cryoprecipitate and red cell concentrates is
   indicated in patients who are bleeding. The use of heparin to
   prevent intravascular coagulation is rarely indicated. Inhibitors of
   fibrinolysis such as tranexamic acid should not be used in DIC as
   dangerous fibrin deposition may result. Antithrombin and/or
   activated protein C concentrates have been used in selected cases.

								
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