Bruising (and bleeding conditions)

CoMEP

14th & 27th April 2010

Specific Learning Objectives Understand basics of physiological haemostasis

Recognise and differentiate ‘normal’ and pathological bruising patterns and likely underlying aetiologies

Be able to take a bleeding history with the aim of differentiating acquired & congenital and platelet/vascular & coagulation factor disorders

Understand the appropriate investigative strategies [and interpretation of their results] for bruising/bleeding patients

Specific Learning Objectives Understand & recognise the common causes of

acquired bleeding disorders [drugs and co-morbid disease]

Understand the basics of the more common congenital bleeding disorders – prevalence, inheritance pattern, clinical and laboratory diagnostic features and treatment

What physiological mechanisms come into play when a blood vessel is

damaged?

von Willebrand factor in Primary Haemostasis

Defective Primary Haemostasis

Thrombocytopenia Dysfunctional platelets [anti-platelet agents]

Defective platelet - vessel wall interaction Vessel wall disorder severe VWD

Prolonged Bleeding Time

Petechiaeand

Purpura

Vasculitic Purpura

Senile Purpura

Bleeding Disorder Symptoms

Immediate bleeding Delayed bleedingcontrolled by pressure not controlled by pressure

Purpura & petechiae Muscle & joint bleeds

Mucosal bleeding Large ecchymosesEpistaxis, menorrhagia Haematuria

Bleed after venepunctureBleed after im injection

Post-traumatic bleeds Post-traumatic bleeds

GI & CNS bleeds GI & CNS bleeds

Platelet / Vascular Defects Clotting Factor Defects

FibrinFibrinogen

Extrinsic Activation Intrinsic Activation

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

XIa

XIIa

XI

XII

Collagen, HMWK, PK

Common Pathway

Coagulation Pathways

FibrinFibrinogen

Extrinsic Activation Intrinsic Activation

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

XIa

XIIa

XI

XII

Collagen, HMWK, PK

Common Pathway

Coagulation Pathways

FibrinFibrinogen

Extrinsic Activation Intrinsic Activation

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

XIa

XIIa

XI

XII

Collagen, HMWK, PK

Common Pathway

Coagulation Pathways – lab assays

APTT

TCT

PT

Ca2+ and phospholipidalso required

Current & New Anticoagulant Agents

Adapted from Weitz JI et al. J Thromb Haemost. 2005;3:1843-1853.

FibrinFibrinogen

Indirect Xa inhibitors FondaparinuxDanaparoid

LMWH, UFH

Xa Inhibitors:RivaroxabanApixaban

IIa InhibitorsXimelagatranDabigatran

ORAL PARENTERAL

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

Antithrombin

Indirect IIa inhibitors

UFH, [LMWH]

Warfarin

FDPs, D-dimer

Antithrombin

Plasmin

Bleeding Disorder Symptoms

Immediate bleeding Delayed bleedingcontrolled by pressure not controlled by pressure

Purpura & petechiae Muscle & joint bleeds

Mucosal bleeding Large ecchymosesEpistaxis, menorrhagia Haematuria

Bleed after venepunctureBleed after im injection

Post-traumatic bleeds Post-traumatic bleeds

GI & CNS bleeds GI & CNS bleeds

Platelet / Vascular Defects Clotting Factor Defects

Key aspects of bleeding history

Type, location & size of bruising

Precipitating factors Length of bleeding

following lacerations & shaving cuts

Post-op bleeding

Epistaxis Gum bleeding Dental

extractions GI bleeding Menorrhagia

Is the bleeding history only recent or is it life long

Coagulation Pathway Disorders

Congenital– Haemophilia A Factor VIII deficiency

– Haemophilia B Factor IX deficiency

– von Willebrands disease Deficient or abnormal vWF

Acquired– Heparins– Warfarin (and new oral anticoagulants)

– Liver disease

FibrinFibrinogen

Extrinsic Activation Intrinsic Activation

Xa

IIa

TF/VIIa

X IXIX

IXaIXaVIIIaVIIIa

Va

II

XIa

XIIa

XI

XII

Collagen, HMWK, PK

Common Pathway

Coagulation Pathways – Haemophilia

APTT

TCT

PT

Isolated deficiency of Factors VIII, IX, XI or XII

[intrinsic pathway]causes prolonged APTT

with normal PT

Case 1 35y male Attends A&E following altercation in pub

– Has received punches to face and kicks to right leg

– O/E no bleeding or bruising– No fractures on X-rays

Informs staff he has haemophilia B

What would you do next?

Haemophilia A

Classical haemophilia Factor VIII deficiency

– severe 1iu/dl– moderate 2 - 5 iu/dl– mild 6 - 40 iu/dl

Incidence 1/20,000 [1/10,000 males]

X-linked inheritance Prolonged APTT

Treatment of coagulation factor deficiency

Education- patients and doctor Desmopressin [DDAVP]

Replacement therapy– FFP / Cryoprecipitate– plasma derived factor concentrate– recombinant produced factor concentrate

Gene therapy

Case 2

Case 2 48y female

– pyrexia + rigors– ? acute abdomen– paracolic abscess at laparotomy

Post-op -> ICU Haematology Results

– Hb 94 g/l PT 21s (NR 11-15)

– WBC 16.0 x109/l APTT 41s (NR 26-37)

– Platelets 78 x109/l D-dimer 4200 (NR <500)

Disseminated Intravascular Coagulation

Systemic activation of coagulation

Intravascular deposition of fibrin

Depletion of platelets and coagulation factors

Thrombosis of small and midsize vessels and

organ failure

Bleeding

DIC - Laboratory Investigations

LOOK FOR UNDERLYING CAUSE– sepsis, trauma, cancer, obstetric disaster

Coagulation PT, APTT, Fibrinogen D-dimers FBC + film platelets, RBC fragments Coag Factors ?

DIC - Treatment TREAT UNDERLYING CAUSE

FFP +/- platelets if bleeding or high risk for bleeding

? Heparin 300-500u/h if thrombotic phenotype ? AT III concentrate (reduces mortality 56% -> 44%)

? Protein C concentrate (meningococcal sepsis)

? Activated Protein C

Case 3 - Confused lady in A&E

80y female found behind door of ground floor sheltered housing

GCS = 9 right sided weakness with dysphasia irregular pulse urinalysis clear

Sent for CT head

Case 3 FBC

– Hb 11.8 g/dl– WBC 12.7 x109/l– Plts 191 x109/l

Coagulation– PT 97s (INR 7.6)

– APTT72s (APTTr 1.9)

– TCT 12s (NR 9-12s)

Bleeding complications with warfarin

fatal haemorrhage 0.25 - 0.64% per year

major haemorrhage 1.1 - 2.7% per yearAchieved INR major bleeds (% per year) minor bleeds

< 2 1.5 112 - 3 2.5 123 - 4 2.5 154 - 5 4 205 - 6 5 34 6 9 96

van der Meer et al., Arch Int Med 1993

What can we do when INR is too high?

Stop warfarin or reduce dose

Give Vitamin K1 (oral or iv)

Give coagulation factors (II, VII, IX, X)

Decline of INRafter warfarin cessation when INR >6

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7

Days

% INR> 4

Hylek et al. 2000

Warfarin - Life threatening bleeding

Stop warfarin

5mg intravenous Vit K1

Intravenous factor concentrate– Prothrombin Complex Concentrate

(Beriplex or Octaplex)

Irrespective of INR

Case 4 – 64y male 4 days after commencing warfarin for PE

Case 5

24y female attends GP having noted petechial rash on legs– Suffered a short epistaxis previous week– also gum bleeding after brushing teeth

PMH– ? Recent viral URTI– uncomplicated tonsillectomy age 12y

DH – C-OCP

What lab test would you do next?

Case 5 – blood results

FBC– Hb 98 g/L– WBC 18.7 x109/l– Plts 25 x109/l

Coagulation– PT 14s (INR 1.2)

– APTT 32s (NR 25-35s)

– TCT 12s (NR 9-12s)

What most likely diagnosis? Any other tests?

Case 5 – blood results

FBC– Hb 98 g/L– WBC 18.7 x109/l– Plts 25 x109/l

Coagulation– PT 14s (INR 1.2)

– APTT 32s (NR 25-35s)

– TCT 12s (NR 9-12s)

What most likely diagnosis? Any other tests?

Case 6

44y male brought to A&E confused and tremulous– He is icteric and admits to alcohol intake >60 units/week for

some years– He has many medium sized bruises on limbs and trunk– Abdominal examination reveals hepatosplenomegaly [liver

5cm bcm, spleen 3cm bcm] PMH

– Several previous similar admissions– Stabbing age 21y and # fibula age 24y without excessive

bleeding DH – nil

What lab test would you do next?

Case 6 – blood results FBC

– Hb 110 g/L– WBC 4.0 x109/l– Plts 55 x109/l

Coagulation– PT 23s (=INR 1.2)

– APTT 43s (NR 25-35s)

– TCT 12s (NR 9-12s)

What are the possible mechanisms for this patients coagulopathy?

U&E– Na 127 umol/L– K 4.0 umol/L– Urea 2.7 umol/L– Creat 91 umol/L

LFTs– bili 76 u/L– Alt 143 u/L– Ast 100 u/L

Case 6 – Coagulopathy in liver disease

Poor coagulation factor synthesis in liver If Vit K deficient (poor diet +/- obstructive component to

jaundice)

Poor clearance of activated coagulation factors DIC Hypersplenism ( low WBC and Plts)

Reduced thrombopoietin synthesis ( low Plts)

Summary

Establish type, duration and distribution of bruising & bleeding

Is it platelet/vascular of coagulation factor deficiency pattern?

Determine if acquired or congenital Establish drug history and co-morbid disease What is the pattern of coagulation screen

abnormality?