Hemat Haemostasis

“The best index to a person's character is how he treats people who can't do him any good or who can't fight back” back”

Haemostasis &Bleeding disorders

— Abigail Van Buren

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

Haemostasis

Introduction: Road map.. ¾Haemostasis – capacity to minimise loss of blood following injury to blood vessel.

Haemostasis overview: BV Injury Contact/ Tissue Factor

Neural

¾Blood vessel – Coagulation – Platelet act. Blood Vessel Constriction

¾Bleeding disorders – Bv, Plt, Coag.

Platelet Aggregation

Coagulation Cascade

Primary hemostatic plug

¾Laboratory tests of Haemostasis.

Reduced

¾BT, CT, PT, aPTT, TT, FDP.

Platelet Activation

Blood flow

¾Factor analysis, PLT function, PCR, MB

Fibrin formation

Stable Hemostatic Plug 3

Haemostasis

Blood Vessels in Hemostasis:

Haemostasis

Coagulation:

¾Initial phase of hemostasis.

¾Fibrinogen to Fibrin – Coag. Cascade

¾Present as petechiae / ecchymoses

¾Several factors – proenzymes-activation.

¾Simple easy bruising – women

¾Enzyme amplication –

¾Senile purpura – atrophy,

¾Plasma, Endothelium & Platelets

¾Scurvy – vit-C deficiency, collagen def.

¾Stable hemostatic plug.

¾Steroid induced purpura

¾Clot lysis – starts soon after clot formation.

¾Henoch-Schonlein – children, viral fevers. 5

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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 activationIntrinsic system ¾ Tissue factor activation – Extrinsic ¾ Common pathamplification ¾ Fibrin formation ¾ Fibrin lysis.

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Haemostasis

Coagulation Cascade: Intrinsic Pathway (Contact) (12,11,9,8)

Bleeding: Clinical Features

Extrinsic Path Tissue - (7)

(aPTT)

1. Local - Vs - General, spontaneous . . 2. Hematoma & Joint bleed - Coagulation

(PT) (Factor 10) Common Path (5,2)

3. Skin/Mucosal Petechiae & Purpura – PLT 4. wound / surgical bleeding –

(TT)

¾ Immediate - (PLT)

(Thrombin)

Fibrinogen Æ Fibrin

¾ Delayed - (Coagulation) (F & FDP) 14

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. 16

Haemostasis

Senile Purpura

Haemostasis

Vascular disorders: ¾Petechiae, purpura, ecchymoses ¾senile purpura ¾vitamin C deficiency (scurvy) ¾Connective tissue disorders ¾Infections – Meningococcus ¾Henoch-Schonlein Purpura-Immu 17

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Haemostasis

Haemostasis

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

Petechiae in Vasculitis (Rocky Mountain Spotted Fever) 19

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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. 21

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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

Routine Investigations:

Special Investigations:

¾ Bleeding time – BV, PLT

¾Specific Factor Assays

ƒ ivy template method - 3-8min

¾ Clotting time – inaccurate – 10-20min ¾ Prothrombin time –Extrinsic (2,5,10 + 7),

¾Platelet function studies – ƒ Aggregometry, ƒ Adhesion studies ƒ Immuno-fluorescence

ƒ Acquired diseases, liver dis, warfarin therapy

¾ aPTT – Intrinsic (2,5,10 + 8,9,12) ƒ Haemophilia, Congenital.

¾Electrophoresis

¾ Trombin Time: Fibrinogen (common path) ƒ DIC & Heparin therapy.

¾Bone marrow examination – plt

¾ CBC – Plt Count ¾ FDP – Fibrinogen Degradation Products - DIC

¾Molecular Biology – FISH 25

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Haemostasis

Haemostasis

Haemophilia

Coagulation Disorders ¾Laboratory findings:

¾Congenital deficiency -Factor 8 (A) or 9 (B)

¾Normal bleeding time & Platelet count

¾Bleeding – Haematoma, joint etc.

¾Prolonged prothrombin time (PT)

¾Gene on X chromosome.

ƒ deficiencies of II, V, VII, X

ƒ (Carrier females, Males suffer)

¾Prolonged time (aPTT)

¾Prolonged PTT but normal PT.

ƒ all factors except VII, XIII

¾Mixing studies - normal plasma corrects PT or aPTT

¾FFP or Factor replacement – Life long.

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Haemostasis

Haemostasis

Factor VIII Deficiency

Factor IX Deficiency ¾Christmas disease (Hemophilia B)

¾ Classic hemophilia (hemophilia A)

¾X-linked recessive disorder

¾ X-linked disorder (affects 1º males)

¾Indistinguishable from classic hemophilia (F VIII)

¾ Most common - severe bleeding ¾ Spontaneous hematomas < 1, 5, 75%

¾Requires evaluation of factor VIII and IX activity levels to diagnose

¾ Abnormal aPTT – Intrinsic path. ¾ Diagnosis - factor VIII assay

¾Treatment - factor IX concentrate

¾ Treatment - factor VIII concentrate ¾ Cryoprecipitate (less desirable)

Haemostasis

¾Cryoprecipitate if factor IX unavailable 29

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Haemostasis

Haemostasis

Von-Willebrand Disease: ¾ Von-Willebrand Disease

¾Coagulation + PLT disorder: ¾Congenital disorder ¾Deficiency of vWF molecule ¾Part of FVIII, ¾Mediates platelet adhesion ¾Prolonged Bleeding time ¾Low Factor VIII & long aPTT ¾Mucocutaneous bleeding

¾ vWF: F-VIII & PLT function. ¾ Defective Platelet Adhesion ¾ Skin Bleeding ¾ Prolonged Bleeding time. ¾ Low Factor VIII levels.

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Secondary Hemostatic Disorders

Haemostasis

z z

Haemostasis

Combined Primary and Secondary Hemostatic Disorders

Acquired coagulation disorder: z

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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 factors II, VII, IX, X

Vitamin K deficiency - neonates - decreased intestinal flora and dietary intake - oral anticoagulants (coumadin) - fat malabsorption syndromes Required for factors II, VII, IX, X Prolonged PT and aPTT 33

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Haemostasis

Nail bed - Hematoma

Clinical Cases

•Red •Blue/Gr •Brown

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Haemostasis

Contusion - Hematoma

Haemostasis

Megaloblastic Anemia •Macrocyte •Lymphocyte

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Haemostasis

Leukemia (AML-M4) Platelet Myeloid Blasts Auer Rod

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Haemostasis

Petechiae & Echymoses -↓Plt

Haemostasis

Petechiae & Echymoses -↓Plt

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Haemostasis

Bleeding-Coagulation disorder

Haemostasis

Sub Conjuctival Haemorrhage Low PLT

•Deep bleeding •Haematoma •Joint bleeds •Haemophilia

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Haemostasis

Dengue – Hemorrhagic fever ↓Plt

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Haemostasis overview: BV Injury

Lab Tests •CBC-Plt •BT,(CT) •PT, PTT,TT Contact/ •Special tests Tissue Factor

Neural

Blood Vessel Constriction

Platelet Aggregation

Coagulation Cascade

Primary hemostatic plug Platelet Activation

Reduced Blood flow

Fibrin formation

Bl. Disorders: Stable Hemostatic Plug 45

Haemostasis

Summary Hemostatic Disorders -↑

-

-

-

PLT Disorder

-↑

-↓

-

-

Factor 8/9 *Congenital

-

-

-

↑

Vit K / Liver *Acquired

-

-

↑

-↑

Combined (DIC)

↑

↓

-↑

↑

Haemostasis

Disorders of Hemostasis ¾Vascular disorders –

BT Plt PT PTT Vascular Dis

Cong/Acqured BV, Coag, PLT

ƒ Scurvy, easy bruising, Henoch-Schonlein purpura.

¾Platelet disorders ƒ Quantitative - Thrombocytopenia ƒ Qualitative - Platelet function disorders – Glanzmans

¾Coagulation disorders ƒ Congenital - Haemophilia (A, B), Von-Willebrands ƒ Acquired - Vitamin-K deficiency, Liver disease

¾Mixed/Consumption: DIC 47

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Haemostasis

Haemostasis

Approach to thrombocytopenia

¾idiopathic autoimmune platelet destruction

THROMBOCYTOPENIA

¾#1 cause of isolated thrombocytopenia in otherwise healthy young persons

rule out pseudothrombocytopenia SEQUESTRATION

È PRODUCTION

look for splenomegaly

bone marrow investigation review meds

Causes of splenomegaly • infection • inflammation • congestion • maligancy • red cell disorders • storage diseases

ITP

Ç DESTRUCTION

¾a diagnosis of exclusion

look for underlying disorders review meds

• immune • aplasia auto-immune (ITP, SLE • infiltration drugs • ineffective megakaryopoiesis infections eg. MDS • selective impairment of platelet allo-immune • non-immune production sepsis DIC, TTP, HUS hypertensive disorders of pregnancy 49

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Haemostasis

Haemostasis

ITP: Clinical features

ITP: Laboratory features

¾occurs in any age or sex, but typically young female

¾ITP IS A DIAGNOSIS OF EXCLUSION 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 51

ITP: Treatment Patient is not bleeding

Haemostasis

¾ plt > 50: Rx not indicated

¾ plt 20-50: Rx usually not needed, monitor closely

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ITP: Treatment Patient is bleeding

Haemostasis

¾For serious bleeding (eg. CNS, retroperitoneal, GI) ƒ Prednisone and IVIG

¾ plt < 20: Rx indicated with one or more of: ƒ prednisone

ƒ Transfuse platelets

ƒ IVIG

ƒ consider urgent splenectomy

ƒ anti-D if Rh pos

ƒ Provide other supportive/resuscitative care as needed

ƒ splenectomy if relapsing severe ITP (No role for prophylactic platelet transfusion, even if plt = 0) 53

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Haemostasis

ITP: Prognosis ¾Children: usually permanent remission

Haemostasis

Disseminated Intravascular Coagulation (DIC)

¾DIC is characterized by

ƒ the systemic activation of the coagulation system followed by activation of fibrinolytic system

¾Adults: usually relapsing (chronic ITP), but 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. 55

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Haemostasis

Haemostasis

Causes of DIC ¾ Infection

Pathophysiology of DIC PATHOPHYSIOLOGIC EVENTS

- bacterial sepsis, viral infections

LABORATORY MANIFESTATIONS

CLINICAL MANIFESTATIONS

underlying disorder

¾ Neoplasm

- AML, adenocarcinoma tissue factor release

¾ Obstetrical disorders - retained dead fetus, abruption, etc

depletion of clotting factors prolonged PT, PTT thromboctyopenia (consumption)

activation of intrinsic pathway of coagulation (systemic thrombin generation)

¾ Trauma/surgery

- brain injury, crush, burns, etc.

¾ Others

- acute hemolytic transfusion reaction, etc.

hemorrhage depletion of physiologic anticoagulants decreased fibrinogen

generalized intravascular fibrin deposition

microangiopathic hemolytic anemia

activation of fibrinolytic system (systemic plasmin generation)

increased FDP and D-dimer

thrombosis/infarction

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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 player presents to your office with a three day history of increased bruising and petechiae. Her only medications are naproxen and an oral contraceptive. Physical exam shows petchiae on the legs and several small bruises on the extensor surfaces.

¾ replacement therapy ƒ cryoprecipitate ƒ FFP ƒ platelet concentrate ƒ packed red cells

Leukocytes (x 109/L) Hemoglobin (g/L) MCV (fL) Platelet count (x 109/L) MPV (fL)

¾ consider additional pharmacologic therapy ƒ controversial or investigational agents • AT, APC, PC concentrate, heparin, antifibrinolytic agents. 59

6.8 130 87 11 12.5

[4.0 - 11.0] [120-160] [80 - 100] [150 - 450] [7.4 -10.4] 60

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Haemostasis

Thrombocytopenia: Case 1

Haemostasis

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?

How you manage this patient and what do you advise her about her activities and medications?

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Leukocytes (x 109/L) Hemoglobin (g/L) MCV (fL) Platelet count (x 109/L) MPV (fL) Reticulocytes (x 109/L)

3.6 127 101.5 56 8.1 86

[4.0 - 11.0] [140 - 180] [80 - 100] [150 - 450] [7.4 -10.4] [18 - 94]

Neutrophils (x 109/L) Lymphocytes (x 109/L) Monocytes (x 109/L) Eosinophils (x 109/L) Basophils (x 109/L)

1.3 1.6 0.7 0 0

[2-7.5.0] [1.5-4.0] [0.2-0.8] [0-0.7] [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. 63

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