This document discusses bleeding and clotting disorders, including the diagnosis and evaluation of bleeding problems. It describes the principal presentations of bleeding disorders such as easy bruising, bleeding from mucous membranes, and excessive bleeding after trauma. It then covers specific types of bleeding disorders like those affecting platelets or coagulation factors. The document outlines typical screening tests used to evaluate bleeding disorders and describes both inherited and acquired causes of platelet and coagulation abnormalities.

1. BLEEDING AND CLOTTING
DISORDERS
Disorders of platlets and blood vessels and
clotting factors
Dr Anoop.K.R
Asst Prof. Dept of medicine

2. DIAGNOSIS OF BLEEDING PROBLEMS
 Questions to address:
 Is a bleeding tendency present?
 Is the condition familial or acquired?
 Is the disorder one affecting
 Primary hemostasis (platelet or blood vessel wall problems)
 Secondary hemostasis (coagulation problems)
 Is there another disorder present that could be the cause of
or might exacerbate any bleeding tendency?
 Principal Presentations of bleeding disorders
 Easy bruising
 Spontaneous bleeding from mucous membranes
 Menorrhagia – excessive bleeding during menstruation
 Excessive bleeding after trauma

3. MUCOSAL BLEEDING & MENORRHAGIA
 Epistaxis - nosebleed
 History of recurrence
 Gingival bleeding
 Hematuria, hemoptysis, hematemesis
 Relatively uncommon presenting features
 Menorrhagia

4. EXCESSIVE BLEEDING AFTER TRAUMA
 Surgical trauma
 Dental extraction, tonsillectomy
 Delayed wound healing
 Postpartum hemorrhage

5. JOINT AND MUSCLE BLEEDS
 Hemarthroses (bleeding into joints) and spontaneous
muscle hematomas
 Characteristic of severe plasma protein deficiencies
Characteristic of Hemophilias
 Rarely occur in other bleeding disorders
 Except severe von Willebrand disease

6. TYPES OF BLEEDING DISORDERS
 Disorder of
 Primary platlet plug formation
 Fibrin formation
 Premature clot dissolution - fibrinolysis
 Spontaneous skin petechiae
 Usually severe thrombocytopenia
 Spontaneous hemarthrosis
 Usually coagulation factor deficiency

7. SIGNS AND SYMPTOMS OF 1O
HEMOSTASIS PROBLEMS
 Ecchymoses
 Petechiae
 Mucus membrane bleeding
 Hematoma
 Prolonged bleeding after minor surgery

8. TYPICAL SCREENING TESTS FOR
BLEEDING DISORDERS
 Prothrombin Time (PT)
 Activated Partial Thromboplastin Time (APTT)
 Quantitative platelet count
 (+/-) Bleeding Time Test (BTT)
 (+/-) Thrombin Time

9. HEREDITARY VASCULAR
PROBLEMS
 Hereditary (spider) telangiectasis (Osler-Rendu-
Weber): dilated superficial capillaries
 Ehlers-Danlos: collagen disorder
 Marfan syndrome: connective tissue
 Osteogenesis imperfecta

10. ACQUIRED VASCULAR PROBLEMS
 Senile purpura (Bateman’s): altered connective
tissue support
 Cushing syndrome: metabolic
 Scurvy: abnormal collagen
 Allergy: vascular inflammation
 Viral infection

11. BLEEDING TIME
 For vascular and platelet functions
 Duke (1910) on earlobes
 Ivy (1941) on arm with 1mm x 3mm incision
 Mielke (1969) with 1mm x 10mm template
 1980’s: disposable devices (e.g., Simplate,
Surgicutt)

12. Bleeding Time

13. QUANTITATIVE PLATELET
DISORDERS
 Thrombocytopenia
<100,000/µl BT prolonged
≈10,000 Bleeding in trauma or OR
<10,000 Spontaneous, CNS bleeding
 Thrombocytopenia due to destruction
ITP (acute in children, chronic in young
women) with anti-glycoprotein
Drug reaction
Heparin induced thrombocytopenia
DIC and TTP

14. ABOUT THROMBOTIC
THROMBOCYTOPENEIC PURPURA
(TTP)
 Disorder of systemic platelet aggregation
in microvasculature
 Stimulus: unusually large vWf
 In children: likely to be deficiency in vWf
metalloproteinase to break down vWf
 In adults: vWf metalloproteinase inhibited
by autoantibodies
 Low PLT count, intravascular hemolysis,
RBC fragmentation, high LDH

15. IDIOPATHIC THROMBOCYTOPENIC
PURPURA (ITP)
 Caused by an autoreactive antibody to the
patient’s platlets
 Young children – acute and usually transient for 1-2
weeks with spontaneous remission
 Adults – chronic and occurs more often in women
 Treatment
 Corticosteroids
 Splenectomy
 Rituximab

16. QUANTITATIVE PLATELET
DISORDERS
 Thrombocytopenia due to decreased production
Aplastic anemia (e.g., Fanconi’s)
Fibrosis
Acute leukemia
Megaloblastic anemia
Hereditary (e.g., May-Hegglin, Wiscott-
Aldrich, Bernard-Soulier)
 Splenic sequestration
 HELLP syndrome (hemolysis, elevated liver
enzyme, low PLT) in pre-eclampsia
 Dilution (massive transfusion)

17. Platelet Satellitosis in EDTA

18. QUANTITATIVE PLATELET
DISORDERS
 Thrombocytosis
 Primary with dysfunctions (e.g., CML, ET)
 Post splenectomy: also see HJ, etc.
 Hemolytic anemia
 Acute hemorrhage and surgery

19. PSEUDO THROMBOCYTOSIS
 Red cell abnormalities
HJ bodies
Clumped Pappenheimer bodies
nRBC
Malaria
Microspherocytes and schistocytes
 White cell abnormalities
Unlysed WBC
WBC fragments and necrobiotic cells

20. AGGREGATION STUDIES
 ADP
reversible 1o
wave
if ADP is released, then 2o
wave
abnormal with aggregation and release
problems
 Epinephrin
similar to ADP
 Collagen
direct release so only one wave of aggregation
 Ristocetin
antibiotic
aggregation only with vWF and GP-Ib

21. Platelet Aggregometry

22. Platelet
Aggregation

23. THROMBOCYTOPENIA
 Platelet count
 <150 x 109
/L
 Usually no ↑ risk of bleeding unless <50 x 109
/L
 Risk of severe and spontaneous bleeding when platelet
count is <10 x 109
/L
 Petechiae
 Bleeding from mucous membranes
 GI, GU tract, etc
 Bleeding into CNS
 BT is related to the platelet count unless there is also a concurrent
platelet dysfunction
 Thrombocytopenia may result from
 Abnormal platlet distribution
 Deficient platlet production
 Increased platlet destruction

24. PLATELET SEQUESTRATION
(DISTRIBUTION DEFECT)
 Normally ~30% of platelets held in spleen
 Splenomegaly/hypersplenism
 Up to 90% sequestered
 May occur in a wide variety of diseases
 Infection
 Inflammation
 Hematologic diseases
 Neoplasias

25. DECREASED PRODUCTION
 Failure of BM to deliver adequate platlets to the
peripheral blood
 Hypoplasia of megakaryocytes
 Drug or radiation therapy for malignant disease
 Generalized marrow suppression
 Acquired aplastic anemia
 Replacement of normal marrow
 Leukemias and lymphomas
 MDS
 Other neoplastic diseases
 Fibrosis or granulomatous inflamm
 Ineffective thrombopoiesis
 Megaloblastic anemia

26. DECREASED PRODUCTION
 Hereditary thrombocytopenias
 Congenital aplastic anemia
 Wiskott-Aldrich Syndrome (WAS)
 X-Linked Thrombocytopenia (XLT)
 Bernard-Soulier syndrome (BSS)
 May-Hegglin anomaly (MHA)
 Congenital amegakaryocytic thrombocytopenia (CAMT)
 Congenital thrombocytopenia with radioulnar synostosis
(CTRUS)
 Thrombocytopenia with absent radii Syndrome (TAR)

27. INCREASED DESTRUCTION
 Immune destruction
 Platelets are destroyed by antibodies
 Platelets with bound antibody are removed by mononuclear
phagocytes in the spleen
 Anti-platlet antibody tests to identify antibodies on platelets are
available

28. ALLOIMMUNE THROMBOCYTOPENIAS
 Isoimmune neonatal thrombocytopenia
 Maternal antibodies produced against paternal
antigens on fetal platelets
 Similar to erythroblastosis fetalis
 HPA-1a
 Most serious risk: bleeding into CNS
 Posttransfusion purpura
 More common in females
 Previously sensitized, pregnancy or transfusion
 Thrombocytopenia
 Usually occurs 1 week after transfusion
 Transfused and recipient’s and antigen-negative
platelets are destroyed

29. DRUG-INDUCED
THROMBOCYTOPENIAS
 Many drugs implicated
 Same mechanisms as described for drug induced
destruction of RBCs
 Symptoms of excess bleeding
 Usually appear suddenly and can be severe
 Removal of drug
 Usually halts thrombocytopenia and bleeding
symptoms

30. HEPARIN AND THROMBOCYTOPENIA
 Heparin associated thrombocytopenia (HAT)
 Non-immune mediated mechanism
 Develops early in treatment and is benign
 Heparin causes direct platelet activation
 Thrombocytopenia
 Immune mediated destruction of platelets
 Antibody develops against a platlet factor 4-heparin
complex
 Attaches to platelet surface
 ↑ platelet clearance

31. MISCELLANEOUS IMMUNE
THROMBOCYTOPENIA
 Secondary feature in many diseases
 Collagen diseases
 Other autoimmune disorders (SLE, RA)
 Lymphoproliferative disorders (HD, CLL)
 Infections
 EBV, HIV, CMV, bacterial septicemia

32. NON-IMMUNE MECHANISMS
OF DESTRUCTION
 Disseminated intravascular coagulation (DIC)
 Thrombotic thrombocytopenic purpura (TTP)
 Hemolytic Uremic Syndrome (HUS)
 PNH
 Mechanical destruction – artificial heart valves

33. THROMBOCYTOSIS
 ↑ platelet count above reference range
 Peripheral blood smear
 > 20 platelets per 100 x oil immersion field
 Result of ↑ production by BM (not prolonged lifespan)
 ↑ BM megakaryocytes
 Primary
 Occurs in chronic myeloproliferative disorders and myelodysplasia
 Secondary thrombocytosis
 Reactive thrombocytosis
 ↑ platelets caused by another disease or condition
 Transient thrombocytosis

34. QUALITATIVE PLATELET DISORDERS
 Clinical symptoms vary
 Asymptomatic → mild, easy bruisability → severe, life-
threatening hemorrhaging
 Type of bleeding
 Petechiae
 Easy & spontaneous bruising
 Bleeding from mucous membranes
 Prolonged bleeding from trauma

35. INHERITED QUALITATIVE
PLATELET DISORDERS
 Defects in platelet-vessel wall interaction
 Disorders of adhesion
 von Willebrand disease
 Deficiency or defect in plasma VWF
 Bernard-Soulier syndrome
 Deficiency or defect in GPIb/IX/V
 Defects in collagen receptors
 GP-IcIIa; GPVI
 Defects in platelet-platelet interaction
 Disorders of aggregation
 Congenital afibrinogenemia - Deficiency of plasma fibrinogen
 Glanzmann thrombasthenia
 Deficiency or defect in GPIIb/IIIa

36. QUALITATIVE PLATELET
DISORDERS
 Berhard-Soulier: GP-Ib deficiency,
adhesion problem
 Von Willebrand’s: vWF deficiency,
adhesion problem
 Glanzmann’s thrombasthenia: GP-IIb/IIIa
deficiency, aggregation problem -- cannot
bind vWF and Fib
 Storage pool disease: dense body defect,
secretion problem

37. QUALITATIVE PLATELET
PROBLEMS
 Aspirin: inhibits cyclo-oxygenase (COX),
secretion problem, no TxA2
 Plavix (Clopidogrel) inhibits ADP receptor
 Other medications affect GPIIa/IIIb interaction
with Fib
 Uremia, secretion problem
 Gray platelet syndrome: α-granule defect
 Hypofibrinogenemia

38. INHERITED QUALITATIVE
PLATELET DISORDERS
 Defects of platelet secretion and signal transduction
 Diverse group of disorders with impaired secretion of
granule contents
 Results in abnormal aggregation during platelet activation
 Abnormalities of platelet granules
 Storage pool deficiency
 αSPD (grey platlet syndrome)
 δSPD
 αδSPD
 Defects in platlet coagulant activity
 Decreased Va-Xa binding and VIIIa-IXa binding slows
normal coagulant response

39. INHERITED DISORDERS OF PLATLET FUNCTION

40. VON WILLEBRAND DISESE

41. ACQUIRED QUALITATIVE PLATLET
DISORDERS
 Chronic renal failure
 Platelet defects associated with uremic plasma
 Dialysis corrects abnormal test results
 Cardiopulmonary bypass surgery
 Thrombocytopenia
 Abnormal platelet function
 Correlates with duration of the bypass procedure
 Platelet defect likely due to
 Effects of platelet activation
 Fragmentation in extracorporeal circulation
 Liver disease
 Thrombocytopenis due to splenomegaly from portal hypertension
 Paraproteinemias
 Clinical bleeding and platlet dysfunction are often seen

42. HEMATOLOGIC DISORDERS THAT
AFFECT PLATELET FUNCTION
 Chronic Myeloproliferative Disorders
 Can see either bleeding or thrombosis
 Abnormal platelet function
 Leukemias & Myelodysplastic Syndromes
 Bleeding usually due to thrombocytopenia
 Abnormal platelet function
 Dysproteinemias
 MM and Waldenstrom’s macroglobulinemia
 Thrombocytopenia most likely cause of bleeding

43. CLOTTING DISORDERS
AND DISSEMINATED
INTRAVASCULAR
COAGULATION.

44. COAGULATION
PATHWAYS
 INTRINSIC PATHWAY: activated by contact of
coagulation proteins with negatively charged surfaces.
 EXTRINSIC PATHWAY: activated by contact of factor
VII with tissue factor.
 COMMON PATHWAY: the intrinsic and extrinsic
pathways converge in the common pathway.

45. COAGULATION
PATHWAY

46. PARAMETER
1.SEX
2.FAMILY HISTORY
3.PETECHIE, BLEEDING
GUMS, NOSE BLEEDS,
MELENA
4.SKIN HEMORRHAGES
5.Deep hematomas,
hemarthrosis
6.Delayed bleeding
CLOTTING
DISORDER
S
1. More common in males
2. Often positive
3. Rare
4. Large and few
5. Common
6. Characteristic
BLEEDING
DISORDERS
1. More common in females
2. Often negative
3. Common
4. Small and many
5. Not seen
6. Not seen

47. CLOTTING DISORDERS
 HEREDITARY:
 Autosomal dominant inheritance: Von Willebrand
disease.
 X-Linked recessive inheritance: Hemophilia A,
Hemophilia B.
 Autosomal recessive inheritance.
 ACQUIRED:
 Liver diseases.
 Vitamin K deficiency.
 Disseminated intravascular coagulation.

48. HEREDITAR
Y
DISORDERS

49. FACTOR
VIII
 Synthesized in endoplasmic reticulum and Golgi region of
hepatocytes.
 The gene controlling the production of the factor VIII is
located at the terminal end of the long arm of the X
chromosome.
 Plasma contains some free factor VIII but most is
stabilized by vWf in a 1:1 molar ratio. It is the smaller
component of the factor VIII/vWf complex.

50.  Factor VIII is composed of two distinct, non-covalently
bonded subunits:
 Factor VIII with pro-coagulant activity (VIII:C). It is also
known as the anti-hemophiliac factor and serves as the
cofactor in factor X activation by factor IX.
 The portion that carries the von willebrand factor activity
(VIII:vWf).

51. FACTOR VIII
DEFICIENCY
 Also known as Hemophilia A.
 It is the most common hereditary disease associated with
life-threatening bleeding.
 It is caused by mutations in factor VIII gene, which is an
essential co-factor for factor IX in the coagulation cascade.
 Hemophilia A is inherited as an X-Linked recessive trait
and thus affects mainly males and homozygous females.

52. CLINICAL
PRESENTATIONS
• Clinical severity correlates well with the level of factor VIII
activity:
• Less than 1% of normal levels : severe
• 2% to 5% of normal levels
• 6% to 50% of normal levels
: moderate
: mild
• The varying degrees of factor VIII deficiency are largely
explained by heterogeneity in the causative mutation.

53.  Easy bruising and massive hemorrhage after trauma or
surgery.
 Spontaneous hemorrhages frequently occur in the
regions of the body normally subject to trauma,
particularly the joints. Recurrent bleeding into the joints
leads to progressive deformities that can be crippling.
 Petechiae are characteristically absent.

56. LABORATORY
FINDINGS
 PLATELET TESTS: normal
 COAGULATION FACTOR
TESTS:• PT
• APTT
• Thrombin time
• Factor VIII assay
• vWf:Ag assay
• Factor IX assay
 FIBRINOLYSIS
normal
increased
normal
decrease
d normal
normal
normal

57. TREATMEN
T
 Factor VIII concentrates.
 Recombinant factor VIII.

58. FACTOR
IX
 Factor IX is a vitamin-K dependent serine protease that
functions in the intrinsic pathway of fibrin formation.
 Glycoprotein.
 It is synthesized in hepatocytes.
 The gene is located on the terminal end of the long arm
of the X-chromosome near the gene for factor VIII.

59. FACTOR IX
DEFICIENCY
 Clinical presentation resembles that of factor VIII
deficiency.
 PT will be normal, APTT prolonged . Definitive
diagnosis is possible only by assay of factor levels.
 This disease is treated with infusions of recombinant
factor IX and factor IX concentrates.

60. VON WILLEBRAND
DISEASE
 Von willebrand disease is caused by deficiency of von
willebrand factor.
 Von willebrand factor acts the bridge that, along with the
glycoprotein Ib receptor, helps platelets adhere to
collagen fibers after an injury.

61. VON WILLEBRAND
FACTOR
 Glycoprotein and the larger of the two components of the
factor VIII/von Willebrand complex.
 Gene controlling the production of vWf is located on
chromosome 12.
 Synthesized in endoplasmic reticulum and golgi region of
megakaryocytes and endothelial cells.
 Stored in Weibel-Palade bodies of the endothelial cells
and α-granules of platelets.
 It circulates in the plasma bound to Factor VIII by non-
covalent bond in 1:1 ratio.

62. FUNCTION
S
 Platelet adhesion.
 Prevents degradation of factor VIII in the plasma.
 Fibrin formation.

63. CLINICAL
PRESENTATION
 HETEROZYGOUS:
 Mild.
 Symptoms may not begin until second decade of
life.
 Resemble clinical features of platelet disorder.
 HOMOZYGOUS:
 Severe.
 Symptoms begin early.
 Resemble clinical features of coagulation factor
deficiency.

64. CLINICAL
PRESENTATION
 Symptoms seen most frequently are mucosal and
cutaneous hemorrhages like epistaxis, gingival bleeding,
easy bruising, and hypermenorrhea.
 Excessive bleeding at child-birth is comparatively rare,
because in pregnancy the activity of entire complex
increases.

65. LABORATORY
FINDINGS
 PLATELET TESTS
 Platelet count normal
 Platelet aggregation normal with ADP, collagen,
epinephrine
 COAGULATION FACTOR TESTS
 PT normal
 APTT normal or increased
 Thrombin time normal
 Factor VIII assay decreased
 VWF:Ag assay decreased
 Factor IX assay normal
 FIBRINOLYSIS normal

66. TREATMEN
T
 CRYOPRECIPITATE – which contains all molecular
forms of Von Willebrand factor.
 A modified antidiuretic hormone deamino-D-argenine
vasopressin(DDAVP) is found to induce release of stored
von willebrand factor in endothelium.
 Therapy is given symptomatically and is monitored by the
bleeding time.

67. FACTOR I
DEFICIENCY
Inherited as autosomal recessive trait.
Three forms are seen
AFIBRINOGENEMIA:
 Homozygous
 No antigenically detectable fibrinogen is found
HYPOFIBRINOGENEMIA:
 Heterozygous
 plasma levels of fibrinogen are between 20 and 100
mg/dl
DYSFIBRINOGENEMIA:
 Structural alteration of molecule

68. CLINICAL
FEATURES
 AFIBRINOGENEMIA
 Severe disease.
 At birth, umbilical cord bleeding.
 Post-traumatic and post-surgery bleeds.
 Rarely, joint bleeds.
 HYPOFIBRINOGENEMIA
 Few bleeding symptoms.
 DYSFIBRINOGENEMIA
 Most patients are asymptomatic.
 Rarely mild, post-traumatic bleeding can be
seen.

69. LABORATORY
FINDINGS
 AFIBRINOGENEMIA:
 PT, APTT, Thrombin time, bleeding time –prolonged.
 Diagnosis is confirmed with antigenic and functional
assay for fibrinogen, which reveal almost no fibrinogen.

70.  HYPOFIBRINOGENEMIA:
 PT, APTT, Thrombin time – prolonged.
 The fibrinogen functional assay is roughly equal to an
antigenic assay, indicating decreased protein as opposed to
abnormal protein.
 Platelet function tests are not affected.

71. TREATMENT
 Fibrinogen in the form of cryoprecipitate and fresh frozen
plasma is used as therapy.

72. FACTOR II
DEFICIENCY
Autosomal recessive disorders.
TYPES
HYPOPROTHROMBINEMIA
 decreased protein synthesis.
DYSPROTHROMBINEMIA
 normal amounts of non-functional
protein.

73. CLINICAL
PRESENTATION
 Clinical symptoms in both dysprothrombinemia and
hypoprothrombinemia are proportional to the level of
functional protein and are present in both heterozygous
and homozygous individuals.
 Homozygotes have severe bleeding after trauma or
surgery, epistaxis, menorrhagia, hematuria and easy
bruising.
 Heterozygous patients have a milder disease, with
epistaxis and bleeding after tooth extraction.

74.  Both the PT and APTT are prolonged since
prothrombin
is a factor in the common pathway
 Treatment:
fresh frozen plasma or stored plasma
prothrombin complex concentrates

75. FACTOR V
DEFICIENCY
 Also known as parahemophilia.
 Homozygous and heterozygous states are identified.
 Only the homozygous individuals are symptomatic.
 Both PT and APTT are prolonged.
 Definitive diagnosis is factor V assay.
 Treatment is with fresh or fresh frozen plasma.

76. FACTOR VII
DEFICIENCY
 CLINICAL PRESENTATION:
 homozygous patients may bleed from the umbilical cord,
the nose, and the GIT.
 Fatal intracranial bleeds occur frequently.
 Hemarthrosis occur in men and severe menstrual
bleeding is seen in women

77. MANAGEMENT
 It is the only plasma coagulation disorder in which the
prothrombin time alone is prolonged.
 Treatment is with fresh frozen plasma or prothrombin
concentrates.

78. FACTOR X
DEFICIENCY
 Also known as Stuart-Prower deficiency.
 Heterozygous patients are clinically asymptomatic and
homozygous patients present with bleeding.
 PT, APTT, Russell’s viper venom tests are prolonged.
Factor X assay is definitive.
 Treatment is with plasma or prothrombin complex
concentrates.

79. FACTOR XI
DEFICIENCY
 Also known as Hemophilia C.
 Only homozygous patients present with symptoms of
bleeding, heterozygous patients are asymptomatic.
 The bleeding symptoms tend to be mild, occurring largely
after traumatic injury, surgery or childbirth.
 Laboratory tests reveal a prolonged APTT. Specific
assay for factor XI is the definitive test.
 Treatment of factor XI deficiency is fresh frozen plasma .

80. FACTOR XII
DEFICIENCY
 Also known as Hageman trait.
 No bleeding symptoms are associated with this disease,
even with severe trauma or during surgery. Paradoxically
increased incidence of thromboembolism is seen.
 Prolonged APTT.
 Because there is no bleeding, no treatment is needed,
but treatment for thrombotic episodes is required.

81. FACTOR XIII
DEFICIENCY
 Clinically, homozygous factor XIII deficiency can be life
threatening. About 90% of patients present with umbilical
cord bleeding. Intracranial bleeding is common and
severe bleeding can develop after trauma or surgery.
• In vitro clot formation is abnormal.
• Treated with plasma.

82. ACQUIRED
DISORDERS

83. LIVER
DISEASES
 Liver disease affects all hemostatic functions
 Most hemostatic proteins, those which are involved in
fibrin formation, fibrinolysis, and inhibitors are synthesized
in the liver.
 The liver macrophages play a major role in removal of
activated factors and products of activation, such as the
fibrinopeptides, fibrin split products, and plasminogen
activators.

84. COMPONENTS OF
HEMOSTASIS
SYNTHESIZED IN THE LIVER
 Factor I, factor II, factor V, factor VII:C, factor IX, factor XI,
factor XII, factor XIII
 Prekallikrein
 HMW kininogen
 Antithrombin III
 Protein C
 Protein S
 α2-macroglobulin
 α2-antiplasmin
 plasminogen

85. CLINICAL
MANIFESTATIONS
 Minimal except in severe liver disease.
 Ecchymoses and epistaxis may occur.
 Bleeding from local lesions in the gastro-intestinal tract
are common.

86. LABORATORY
MANIFESTATION
 PT, APTT, thrombin time –
prolonged.
 Platelet count – decreased.
 Fibrin split products – increased.

87. TREATMENT
 Therapy involves the use of replacement products as
needed.

88. VITAMIN
K
 Source: green leafy vegetables in the diet and through
synthesis by bacteria in the gastro-intestinal tract
 Vitamin K is needed by hepatic cells to complete the
post-translational alterations of factors II, VII, IX, X,
protein C and protein S.
 If the level of functional factors fall below 0.3μm/ml,
bleeding symptoms may result.

89. HEMORRHAGIC DISEASE OF
THE NEW BORN
NEWBORN
 Symptomatic vitamin K deficiency is most often seen in
newborns in the first days of life because:
• Liver is still immature.
• Human milk contains little vitamin K.
• Bacterial colonization of gastro-intestinal tract is
incomplete.
• Those factors that are present at birth are metabolized so
that they may become even lower during the first few
days of life.

90. MANIFESTATION
 Bleeding from the umbilicus or circumcision, generalized
ecchymoses, large intramuscular hemorrhages and
intracranial bleeds.
 PT , APTT – prolonged.
 Specific factor assays for factors II, VII, IX, X markedly
decreased.

91.  Other causes of vitamin K deficiency that may be seen in
adults are:
 Mal-absorptive syndromes such as sprue.
 Obstruction of biliary tract because bile salts are
necessary for adsorption.
 Prolonged broad spectrum antibiotic therapy that
abolishes normal flora of the intestine.

92. DISSEMINATED
INTRAVASCULAR
COAGULATIONCOAGULATIO
N
 Disseminated intravascular coagulation is an acquired
syndrome characterized by the intravascular activation of
coagulation with loss of localization arising from different
causes. It can originate from and cause damage to the
microvasculature, which if sufficiently severe, can
produce organ dysfunction.
 Also known as defibrination syndrome, consumption
coagulopathy.

93. ETIOLOGY
 INFECTIONS: bacteria, virus, fungus, rickettsia, protozoa
 COMPLICATIONS OF PREGNANCY: toxemia, retained
placenta, amniotic fluid embolism, abruption placenta.
 NEOPLASMS: luekemias, carcinoma.
 MASSIVE TISSUE INJURY: burns, traumatic injury,
extensive surgery, extracorporeal circulation.
 VASCULAR INJURY: shock, hypotension, hypoxia,
acidosis.
 MISCELLANEOUS: snake bite, heat stroke, any disease.

94. CLINICAL
PRESENTATION
• TYPES:
• ACUTE:
• More commonly recognized.
• Begins with sudden onset of severe bleeding.
• Hemorrhagic symptoms.

95.  CHRONIC:
 Exists for a long period of time.
 May have either mild or no symptoms.
 Thrombotic symptoms.

96.  Generally bleeding begins abruptly and occurs from at
least three sites at the same time. Sites of bleeding tend
to correspond to the tissue involved in the event.
Hematuria, gastrointestinal bleeding, epistaxis, oozing from
needle puncture sites, ecchymoses and petechiae are
some common manifestations.
 Obstruction of the microvasculature by thrombi causes
tissue anoxia and micro-infarcts of the heart, kidney,
brain, liver and pancreas, all leading to shock. Shock is
also induced because products of complement and kinin
system cause increased vascular permeability and
hypotension.

97. LABORATORY
FINDINGS


PLATELET COUNT
PROTHROMBIN TIME
: decreased
: increased
• APTT : increased
 THROMBIN TIME : increased
 FIBRINOGEN : decreased
 PROTAMINE SULFATE TEST : positive
 FIBRIN SPLIT PRODUCTS : positive
 CIRCULATING FIBRINOPEPTIDE A : increased
 PLASMINOGEN : decreased
 ANTITHROMBIN III : decreased
 BLOOD SMEAR : schistocytes

98. TREATMENT
 Treatment for DIC is to first eliminate the primary
condition, if possible.
 ACUTE FORM: disease is often self limited and will
disappear when the fibrin is completely lysed.
Replacement therapy using platelets, red cells or plasma
are used when indicated.
 CHRONIC FORM: Heparin therapy sometimes may be
useful if thrombosis is life threatening.

99. ANTICOAGULANT
THERAPY
 Patients with thrombotic diseases are treated with drugs that
either inhibit the formation of blood clots or remove the clots
that have formed. The use of them is called anticoagulant
therapy or thrombolytic therapy.
 The drugs interfere with normal hemostasis and can
potentially cause serious hemorrhage if given in excess. If
the dose isn’t high enough, however, the drug will be
ineffective. Because of individual response to these drugs,
there is no standard dosage that is both safe and effective in
all patients. The most clinically effective dose is established
by trial or error, using in vitro laboratory test results as a
guide.

100. APPROACHES TO ANTICOAGULANT
therapy
 Prevention of extension of venous thrombosis: heparin,
oral anticoagulants.
 Antiplatelet drugs: aspirin, dipyridamale, sulfinpyrazole,
ditran, clofibrate, prostaglandins, phenolthiazine,
antihistamine.
 Thrombolytic agents: streptokianase, urokianase.

101. HEPARIN
 Treatment of thromboembolic disorders.
 DVT.
 Pulmonary embolism.
 Prophylaxis of the thromboembolic disorders.
 Treatment of arterial thrombosis or embolism.
 Treatment of DIC in some patients.
 Prevention of clots in extracorporeal circulation and renal
dialysis.
 As an anticoagulant for blood sampling for selected
laboratory tests.

102. HEPARIN THERAPY
MONITORING
 The APTT, which uses plasma, has become most popular
because it is already available in most laboratories as a
screening test for coagulation abnormalities, and because it
provides adequate information.
 With continuous therapy and with intermittent injections, the
APTT is performed daily and the next dose is adjusted
accordingly until the desired effect is achieved. With
intermittent therapy, the test is usually timed 1 hour before
administration of the next dose.
 It is standard practice to adjust the dose of heparin so that
the APTT is about 1.5 to 2 times the patient baseline value
before treatment. This corresponds to a heparin
concentration of 0.3 to 0.5 units/Ml.

103. DISADVANTA
GE
 Disadvantages of using the APTT for monitoring heparin
therapy lie in the wide variety of instruments and
reagent systems in use in clinical laboratory. Each
laboratory uses its own combination of instruments and
reagents, making standardization between laboratories
difficult.

104. ORAL
ANTICOAGULAN
T
 Oral anticoagulants inhibit carboxylation of vitamin K
dependent factors and make these factors inactive.
 PT is the standard test for monitoring treatment with oral
anticoagulants

105. INR
 Various types of thromboplastin reagents obtained from
different sources are available for PT test. These differ in
their responsiveness to deficiency of vitamin K
dependent factors. Technique of PT is also different in
different laboratories. For standardization and to obtain
comparable results, it is recommended to report PT in the
form of an International Normalized Ratio i.e, ratio of PT
of patient to PT of control.
 International Sensitivity Index of a particular tissue
thromboplastin is derived by comparing it with a
reference thromboplastin of known ISI.

106.  INR should be maintained in the therapeutic range for the
particular indication.
 INR 2.0-3.0 for prophylaxis and treatment of DVT
 INR 2.5-3.5 for mechanical heart valves
 Therapeutic range provides adequate anticoagulation for
prevention of thrombosis and also checks excess
dosage, which will cause bleeding.

107. REFERENCES
 ROBBINS AND COTRAN, PATHOLOGIC BASIS
OF
DISEASE, 8TH EDITION.
 MACKENZIE TEXT BOOK OF HEMATOLOGY, 2ND
EDITION.

108.  THANK YOU