“The best index to a person's character is Haemostasis

how he treats people who can't do him &Bleeding disorders

any good or who can't fight back”
back”

— Abigail Van Buren

Dr. Venkatesh M. Shashidhar. MD
Senior Lecturer in Pathology
Fiji School of Medicine

Haemostasis
Haemostasis overview:
Introduction: Road map..
BV Injury
¾Haemostasis – capacity to minimise loss of Contact/
blood following injury to blood vessel. Neural Tissue
Factor
¾Blood vessel – Coagulation – Platelet act.
Blood Vessel Platelet Coagulation
¾Bleeding disorders – Bv, Plt, Coag. Constriction Aggregation Cascade
Primary hemostatic plug
¾Laboratory tests of Haemostasis. Reduced Platelet
Activation Fibrin
¾BT, CT, PT, aPTT, TT, FDP. Blood flow formation

¾Factor analysis, PLT function, PCR, MB Stable Hemostatic Plug

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Haemostasis Haemostasis

Blood Vessels in Hemostasis: Coagulation:

¾Initial phase of hemostasis.
¾Present as petechiae / ecchymoses
¾Simple easy bruising – women
¾Senile purpura – atrophy,
¾Scurvy – vit-C deficiency, collagen def.
¾Steroid induced purpura
¾Henoch-Schonlein – children, viral fevers.
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¾Fibrinogen to Fibrin – Coag. Cascade
¾Several factors – proenzymes-activation.
¾Enzyme amplication –
¾Plasma, Endothelium & Platelets
¾Stable hemostatic plug.
¾Clot lysis – starts soon after clot formation.

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 Haemostasis:
¾ Vasoconstriction – N
¾ Platelet activation
¾ Haemostatic plug
¾ Coagulation
¾ Stable clot formation
¾ Clot dissolution

Coagulation:
¾ Contact activation-
Intrinsic system
¾ Tissue factor activation –
Extrinsic
¾ Common path-
amplification
¾ Fibrin formation
¾ Fibrin lysis.

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 Haemostasis

Coagulation Cascade: Bleeding: Clinical Features

Intrinsic Pathway (Contact) Extrinsic Path
(12,11,9,8)
1. Local - Vs - General, spontaneous . .
Tissue - (7)
(aPTT) 2. Hematoma & Joint bleed - Coagulation
(PT)
(Factor 10)
3. Skin/Mucosal Petechiae & Purpura – PLT
Common
Path (TT) 4. wound / surgical bleeding –
(5,2)
¾ Immediate - (PLT)
(Thrombin)
¾ Delayed - (Coagulation)

Fibrinogen Æ Fibrin (F & FDP)

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Haemostasis
Platelet Coagulation Disorders of Hemostasis
¾Vascular disorders
ƒ Scurvy, easy bruising,

¾Platelet disorders
ƒ Low Number or abnormal function

¾Coagulation disorders
ƒ Factor deficiency.

¾Mixed/Consumption: DIC
Petechiae, Purpura Hematoma, Joint bl.
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Haemostasis Haemostasis
Senile Purpura
Vascular disorders:
¾Petechiae, purpura, ecchymoses
¾senile purpura
¾vitamin C deficiency (scurvy)
¾Connective tissue disorders
¾Infections – Meningococcus
¾Henoch-Schonlein Purpura-Immu

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 Haemostasis Haemostasis

Henoch-Schonlein purpura
¾ Immune disorder
¾ Children
¾ Follows
infection
¾ Petechiae with
Petechiae in edema and
Vasculitis itching.

(Rocky Mountain Spotted Fever)

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Haemostasis Haemostasis

Henoch-Schonlein purpura Disorders of platelets

¾Decreased Number: Thrombocytopenia
ƒ Decreased Production
ƒ Decreased Survival – Immune (ITP)
ƒ Increased utilization - DIC
¾Defective Platelet function:
ƒ Acquired – Drugs – Aspirin, MPS, MDS
ƒ Congenital – Eg. Thrombasthenia.

20y Male, fever, painful symmetric polyarthritis for a day. During the next two days,
edema and palpable purpura developed.
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Haemostasis

Ideopathic T. Purpura - ITP

¾Young female – 20-35y (15-50)
¾Easy bruising, Petechiae, menorrhagia
¾Anti PLT Antibody (IgG) – destruction of plt
¾Low Platelet number.

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 Haemostasis Haemostasis

Routine Investigations: Special Investigations:

¾ Bleeding time – BV, PLT
ƒ ivy template method - 3-8min ¾Specific Factor Assays
¾ Clotting time – inaccurate – 10-20min ¾Platelet function studies –
¾ Prothrombin time –Extrinsic (2,5,10 + 7), ƒ Aggregometry,
ƒ Acquired diseases, liver dis, warfarin therapy ƒ Adhesion studies
¾ aPTT – Intrinsic (2,5,10 + 8,9,12) ƒ Immuno-fluorescence
ƒ Haemophilia, Congenital.
¾ Trombin Time: Fibrinogen (common path) ¾Electrophoresis
ƒ DIC & Heparin therapy. ¾Bone marrow examination – plt
¾ CBC – Plt Count
¾Molecular Biology – FISH
¾ FDP – Fibrinogen Degradation Products - DIC
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Haemostasis Haemostasis

Coagulation Disorders Haemophilia

¾Laboratory findings:
¾Congenital deficiency -Factor 8 (A) or 9 (B)
¾Normal bleeding time & Platelet count
¾Bleeding – Haematoma, joint etc.
¾Prolonged prothrombin time (PT)
ƒ deficiencies of II, V, VII, X
¾Gene on X chromosome.
ƒ (Carrier females, Males suffer)
¾Prolonged time (aPTT)
ƒ all factors except VII, XIII ¾Prolonged PTT but normal PT.

¾Mixing studies - normal plasma corrects ¾FFP or Factor replacement – Life long.
PT or aPTT
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Haemostasis Haemostasis

Factor VIII Deficiency Factor IX Deficiency

¾Christmas disease (Hemophilia B)
¾ Classic hemophilia (hemophilia A)
¾ X-linked disorder (affects 1º males) ¾X-linked recessive disorder
¾ Most common - severe bleeding ¾Indistinguishable from classic
hemophilia (F VIII)
¾ Spontaneous hematomas < 1, 5, 75%
¾ Abnormal aPTT – Intrinsic path.
¾Requires evaluation of factor VIII and IX
activity levels to diagnose
¾ Diagnosis - factor VIII assay
¾Treatment - factor IX concentrate
¾ Treatment - factor VIII concentrate
¾Cryoprecipitate if factor IX unavailable
¾ Cryoprecipitate (less desirable) 29 30

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 Haemostasis Haemostasis

Von-Willebrand Disease:
¾ Von-Willebrand Disease
¾Coagulation + PLT disorder:
¾ vWF: F-VIII & PLT function. ¾Congenital disorder
¾ Defective Platelet Adhesion ¾Deficiency of vWF molecule
¾ Skin Bleeding ¾Part of FVIII,
¾ Prolonged Bleeding time. ¾Mediates platelet adhesion
¾ Low Factor VIII levels. ¾Prolonged Bleeding time
¾Low Factor VIII & long aPTT
¾Mucocutaneous bleeding
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Haemostasis
Secondary Hemostatic
Disorders
Acquired coagulation disorder:
z Vitamin K deficiency
- neonates - decreased intestinal
flora and dietary intake
- oral anticoagulants (coumadin)
- fat malabsorption syndromes
z Required for factors II, VII, IX, X
Haemostasis
Combined Primary and
Secondary Hemostatic Disorders
Severe Liver Disease
z Primary - dysfunctional platelets and/or
thrombocytopenia (↑ BT)
z Secondary - decrease in all coagulation
factors except vWF (↑ PT, aPTT)
z Vitamin K will promote synthesis of

z Prolonged PT and aPTT factors II, VII, IX, X

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Haemostasis

Nail bed - Hematoma

•Red
•Blue/Gr
Clinical Cases •Brown

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 Haemostasis Haemostasis

Contusion - Hematoma Megaloblastic Anemia

•Macrocyte
•Lymphocyte

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Haemostasis

Leukemia (AML-M4)
Platelet

Myeloid
Blasts

Auer Rod

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Haemostasis Haemostasis

Petechiae & Echymoses -↓Plt Petechiae & Echymoses -↓Plt

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 Haemostasis Haemostasis

Bleeding-Coagulation disorder Sub Conjuctival Haemorrhage

Low PLT
•Deep bleeding
•Haematoma
•Joint bleeds
•Haemophilia

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Haemostasis
Haemostasis overview: Lab Tests
Dengue – Hemorrhagic fever ↓Plt •CBC-Plt
•BT,(CT)
BV Injury
•PT, PTT,TT
Contact/ •Special tests
Neural Tissue
Factor

Blood Vessel Platelet Coagulation

Constriction Aggregation Cascade
Primary hemostatic plug

Reduced Platelet
Activation Fibrin
Blood flow formation

Bl. Disorders:
Stable Hemostatic Plug Cong/Acqured
BV, Coag, PLT
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Haemostasis Haemostasis

Summary Hemostatic Disorders Disorders of Hemostasis

BT Plt PT PTT ¾Vascular disorders –
ƒ Scurvy, easy bruising, Henoch-Schonlein purpura.
Vascular Dis -↑ - - -
¾Platelet disorders
PLT Disorder -↑ -↓ - -
ƒ Quantitative - Thrombocytopenia
Factor 8/9 ƒ Qualitative - Platelet function disorders – Glanzmans
*Congenital - - - ↑
¾Coagulation disorders
Vit K / Liver ƒ Congenital - Haemophilia (A, B), Von-Willebrands
*Acquired - - ↑ -↑
ƒ Acquired - Vitamin-K deficiency, Liver disease
Combined (DIC) ↑ ↓ -↑ ↑
¾Mixed/Consumption: DIC
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 Haemostasis Haemostasis

Approach to thrombocytopenia ITP

¾idiopathic autoimmune platelet destruction
THROMBOCYTOPENIA

rule out pseudothrombocytopenia

¾#1 cause of isolated thrombocytopenia in
otherwise healthy young persons
SEQUESTRATION È PRODUCTION Ç DESTRUCTION
look for splenomegaly bone marrow investigation look for underlying disorders ¾a diagnosis of exclusion
review meds review meds
Causes of splenomegaly • aplasia • immune
• infection • infiltration auto-immune (ITP, SLE
• inflammation • ineffective megakaryopoiesis drugs
• congestion eg. MDS infections
• maligancy • selective impairment of platelet allo-immune
• red cell disorders production • non-immune
• storage diseases sepsis
DIC, TTP, HUS
hypertensive disorders of pregnancy
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Haemostasis Haemostasis

ITP: Clinical features ITP: Laboratory features

¾occurs in any age or sex, but typically ¾ITP IS A DIAGNOSIS OF EXCLUSION
young female
¾no sensitive and specific test for ITP
¾can be preceeded by viral infection
¾isolated thrombocytopenia
¾signs and symptoms depend on platelet
count ¾increased MPV

¾onset usually insidious ¾normal PT, PTT

¾bone marrow investigation not essential in
straightforward cases
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Haemostasis Haemostasis
ITP: Treatment ITP: Treatment
Patient is not bleeding Patient is bleeding
¾ plt > 50: Rx not indicated ¾For serious bleeding (eg. CNS,
¾ plt 20-50: Rx usually not needed, monitor closely retroperitoneal, GI)
¾ plt < 20: Rx indicated with one or more of: ƒ Prednisone and IVIG
ƒ prednisone ƒ Transfuse platelets
ƒ IVIG ƒ consider urgent splenectomy
ƒ anti-D if Rh pos
ƒ Provide other supportive/resuscitative care as
ƒ splenectomy if relapsing severe ITP
needed

(No role for prophylactic platelet transfusion, even if plt =

0)
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 Haemostasis Haemostasis
Disseminated Intravascular
ITP: Prognosis
Coagulation (DIC)
¾Children: usually permanent remission ¾DIC is characterized by
ƒ the systemic activation of the coagulation
system followed by activation of fibrinolytic
¾Adults: usually relapsing (chronic ITP), but system
course is relatively benign. ƒ high thrombin and plasmin generation

¾DIC is not a disease itself, but is a

manifestation of a serious underlying
disorder.
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Haemostasis Haemostasis

Causes of DIC Pathophysiology of DIC

PATHOPHYSIOLOGIC LABORATORY CLINICAL
¾ Infection - bacterial sepsis, viral infections EVENTS MANIFESTATIONS MANIFESTATIONS
underlying disorder

¾ Neoplasm - AML, adenocarcinoma depletion of clotting factors

prolonged PT, PTT
tissue factor release

¾ Obstetrical disorders - retained dead fetus, abruption, etc activation of intrinsic

thromboctyopenia (consumption)
hemorrhage
pathway of coagulation

¾ Trauma/surgery
(systemic thrombin depletion of physiologic anticoagulants
- brain injury, crush, burns, etc. generation)
decreased fibrinogen

¾ Others - acute hemolytic transfusion reaction, etc. generalized intravascular

fibrin deposition microangiopathic hemolytic anemia

thrombosis/infarction
activation of
fibrinolytic system
increased FDP and D-dimer
(systemic plasmin
generation)

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Haemostasis Haemostasis

Treatment of DIC Thrombocytopenia: Case 1

¾ treat the underlying disease
A previously healthy 23 year old female competitive lacrosse
¾ replacement therapy player presents to your office with a three day history of increased
ƒ cryoprecipitate bruising and petechiae. Her only medications are naproxen and an
ƒ FFP oral contraceptive. Physical exam shows petchiae on the legs and
several small bruises on the extensor surfaces.
ƒ platelet concentrate
ƒ packed red cells Leukocytes (x 109/L) 6.8 [4.0 - 11.0]
Hemoglobin (g/L) 130 [120-160]
¾ consider additional pharmacologic therapy MCV (fL) 87 [80 - 100]
ƒ controversial or investigational agents Platelet count (x 109/L) 11 [150 - 450]
• AT, APC, PC concentrate, heparin, antifibrinolytic MPV (fL) 12.5 [7.4 -10.4]
agents.
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 Haemostasis Haemostasis

Thrombocytopenia: Case 1 Thrombocytopenia: Case 2

A CBC comes back on a 75 year old man who is new to your practice.
How do you approach this problem diagnostically?
Leukocytes (x 109/L) 3.6 [4.0 - 11.0]
Hemoglobin (g/L) 127 [140 - 180]
MCV (fL) 101.5 [80 - 100]
Platelet count (x 109/L) 56 [150 - 450]
MPV (fL) 8.1 [7.4 -10.4]
How you manage this patient and what do you advise her Reticulocytes (x 109/L) 86 [18 - 94]
about her activities and medications? Neutrophils (x 109/L) 1.3 [2-7.5.0]
Lymphocytes (x 109/L) 1.6 [1.5-4.0]
Monocytes (x 109/L) 0.7 [0.2-0.8]
Eosinophils (x 109/L) 0 [0-0.7]
Basophils (x 109/L) 0 [0-0.1]

No platelet clumps are seen on the peripheral blood film.

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Haemostasis

Thrombocytopenia: Case 2
What is the differential diagnosis?

B12, folate deficiency

hypersplenism
alcohol
medications
myelodysplasia
other bone marrow pathology

How do you sort this out?

Obtain a history and examine the patient.

Ultrasound of the abdomen (spleen size).
Serum B12, RBC folate
bone marrow investigation.
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