Hemorrhagic Diathesis

Immune thrombocytopenic purpura (ITP)

•          Also called idiopathic thrombocytopenic purpura

•          Autoimmune disorder with production of anti-platelet antibody causing destruction of platelet

–        Primary or idiopathic( absence of any known risk factors )

–        Secondary

•          Primary

–        Acute

–        Chronic- more common

•          Secondary

–        Systemic lupus erythematosus  

–        AIDS

–        After viral infection

–        drug therapy

Chronic ITP

•          Adult women younger than age 40 years

•          F:M= 3:1

•          Insidious onset

•          Bleeding into skin and mucosal surfaces

•          Petechiae, ecchymoses

•          H/O nosebleeds, bleeding from gums, hemorrhage into soft tissues from minor trauma

•           May present with melena, hematuria or excessive menstrual flow

•           Subarachnoid hemorrhage and intracerebral hemorrhage: Serious consequences

Pathogenesis

•          Chronic ITP caused by formation of autoantibodies against platelet membrane glycoproteins, most often IIb-IIIa or Ib-IX

•          Antiplatelet antibodies are of the IgG class

•          Opsonized platelets susceptible to phagocytosis by the cells of mononuclear phagocyte system

•          Destruction of platelets

•          Thrombocytopenia

Morphology

•          Spleen: Normal in size

•          Bone marrow

–        Increased number of megakaryocytes

–        Immature with large nonlobulated single nuclei

–        Due to accelerated thrombopoiesis

–        Important to rule out thrombocytopenia resulting from bone marrow failure

Diagnosis

•          Prolonged bleeding time

•          Normal clotting time, PT, APTT

•          Low platelet count

•          Normal or high megakaryocytes in bone marrow

•          Abnormally large platelets (megathrombocytes) in blood smear

•          Diagnosis of ITP should be made only after other causes of platelet deficiencies have been ruled out.

Acute immune thrombocytopenic purpura

•          Disease of childhood occuring with equal frequency in both sexes

•          Caused by antiplatelet antibody

•          Abrupt onset

•          Preceded by viral illness (2 wks)

•          Self limited, usually resolving spontaneously within 6 months

Hemophilia A (Factor VIII deficiency)

Ø  Most common hereditary disease associated with serious bleeding

Ø  Caused by reduction in the amount or activity of factor VIII

Ø  X-linked recessive trait; males affected

Ø  Heterozygous females, presumably as a result of lyonization (inactivation of the normal X chromosome in most of the cells

Clinical severity according to level of factor VIII activity

  <1% of normal activity- Severe disease

  2-5%: Moderate disease

  6-50%: Mild disease

30% new mutation, remaining positive family history

Clinical features

Ø  Easy bruising (discoloured skin caused by injury on blood vessels)

Ø   Massive hemorrhage after trauma or operative procedures

Ø  Spontaneous hemorrhage into joints- Hemarthroses

Ø  Deformities

Ø  Petechiae are characteristically absent

Investigation

•          Normal BT, PT and platelet count

•          Prolonged PTT; Abnormality of intrinsic coagulation pathway

•          Factor VIII assay

•          Treatment involves infusion of factor VIII

Hemophilia B (Christmas disease, Factor IX deficiency)

Ø   Clinically indistinguishable from factor VIII deficiency (hemophilia A)

Ø  Caused by mutation in factor IX

Ø   X-linked recessive

Ø   PTT prolonged

Ø   BT, PT normal

Ø   Factor IX assay

Disseminated intravascular coagulation (DIC)

•          Acute, subacute or chronic thrombohemorrhagic disorders occurring as a secondary complication in a variety of diseases

•          Systemic activation of coagulation pathway

•          Formation of microthrombi through out the microcirculation 

•          Consumption of platelet, fibrin, and clotting factors- “consumption coagulopathy”

•          Activation of fibrinolytic mechanism

•          Microthrombi à  tissue hypoxia and microinfarcts

•           Pathologic activation of fibrinolysis and the depletion of the elements required for hemostasis à Bleeding disorder

•          Consumptive coagulopathy

Major disorders associated with DIC

1.       Obstetric complications

a.       Abruptio placentae

b.      Retained dead fetus

c.       Septic abortion

d.      Amniotic fluid embolism

e.      Toxemia

2.       Infections

a.       Gram negative sepsis

b.      Meningococcemia

c.       Histoplasmosis

d.      Aspergillosis

e.      Malaria

3.       Neoplasms

a.       Carcinomas of pancreas, prostate, lung and stomach

b.      Acute promyelocytic leukemia

4.       Massive tissue injury

a.       Traumatic

b.      Burns

c.       Extensive surgery

5.       Miscellaneous: Acute intravascular hemolysis, snake bite, shock

Most important

–        Obstetric complications

–        Malignant neoplasia

–        Sepsis

–        Major trauma

Pathogenesis

•          Two major mechanisms trigger DIC:

–        Release of tissue factor  or thromboplastic substances into circulation

–        Widespread injury to endothelial cells

•          Obstetric complications

–        Tissue thromboplastin released from placental tissue ,dead retained fetus or amniotic fluid enter circulation

–        Endothelial injury caused by hypoxia, acidosis and shock

•          Malignancies

–        Tissue thromboplastin derived from granules of leukemic cells

–        Mucus released from adenoca directly activate factor X independent of factor VII

•          Sepsis

–        Activate both intrinsic and extrinsic pathways

–        Bacterial endotoxin cause activated monocytes to release TNF and IL-1 à Both increase expression of tissue factor on endothelial cells

–        TNF causes endothelial cell inflammation and injury

–        Endotoxin inhibit anticoagulant activity of protein C by supressing thrombomodulin expression on endothelium

•          Widespread endothelial injury produced by

–        Antigen-antibody complexes : SLE

–        Temperature extremes: heat stroke, burn

–        Microorganisms: meningococci, rickettsiae

•          Massive trauma, severe burn, extensive surgery

–        Release of tissue thromboplastin

•          Endothelial injury

–        Release tissue factor

–        Promote platelet aggregation

–        Activate intrinsic coagulation pathway (activation of factor XII by surface contact with collagen or other negatively charged substances)

Consequences of DIC

Widespread deposition of fibrin within microcirculation

1. Tissue ischemia
2. Microangiopathic hemolytic anemia

Hemorrhagic diathesis

3. Consumption of platelet and clotting factors with activation of plasminogen
4. Plasmin cleave fibrin, digest factors V and VIII
5. Fibrinolysis leads to formation of fibrin degradation products, which inhibit platelet aggregation, fibrin polymerization and have antithrombin activity

Causes of DIC

Activation of extrinsic/intrinsic coagulation pathways

                                                Thrombin

Fibrinogen          Fibrin     Fibrin clot

                                                                Plasmin

                                                Fibrin degradation products (FDP)

                                                                                Bleeding

                                               

Morphology

•          Thrombi found in following sites:

–        Brain, heart, lungs, kidneys, adrenals, spleen, and liver

–        Lungs: fibrin thrombi in alveolar capillaries with pulmonary edema and fibrin exudation  creating hyaline membrane

–        Kidney: thrombi in glomeruli that evoke reactive swelling of swelling of endothelial cells; in severe cases-microinfarcts, bilateral renal cortical necrosis

–        In CNS thrombi may cause microinfarct

–        Endocrine glands

•          Microthrombi within microcirculation of adrenal cortex in  meningococcemia- Waterhouse-Friderichsen Syndrome (massive adrenal hemorrhage)

•          Sheehan postpartum pituitary necrosis

Clinical features

•           Two main features of DIC:

–        Bleeding

–        Organ damage due to ischemia

•          Acute DIC associated with obstetric complications, endotoxic shock or major trauma: Bleeding

•          Chronic DIC (carcinoma, retention of dead fetus): Thrombotic complications

•          Abrupt onset of bleeding

•          Microangiopathic hemolytic anemia

•          Dyspnea

•          Cyanosis

•          Respiratory failure

•          Convulsion and coma

•          Oliguria, acute renal failure

•          Progressive circulatory failure, shock

Laboratory findings

1. Thrombocytopenia
2. PT, PTT,BT,CT,TT all prolonged
3. FDP +, D-Dimer +
4. Plasma fibrinogen decreased
5. Thrombin time (TT)  increased
6. P/S- Fragmented RBC

•          Prognosis depends on underlying disorder

•          Remove or treat the underlying cause