PRIMARY HAEMOSTASIS,BLEEDING DISORDERS

1. DISORDERS OF PRIMARY
HEMOSTASIS
Disorders of platlets and blood vessels
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.  THANK YOU