Bleeding disorders

Bleeding

History
• Site of bleed
• Duration of bleed
• Precipitating causes, including
previous surgery or trauma
• Family history
• Drug history
• Age at presentation
• Other medical conditions, e.g. liver disease
Examination
There are two main patterns of bleeding:
1. Mucosal bleeding
Reduced number or function of platelets (e.g. bone marrow failure or aspirin) or von Willebrand factor (e.g.von Willebrand disease)
Skin: petechiae, bruises
Gum and mucous membrane bleeding
Fundal haemorrhage
Post-surgical bleeding
2. Coagulation factor deficiency
(e.g. haemophilia or warfarin)
Bleeding into joints (haemarthrosis) or muscles
Bleeding into soft tissues
Retroperitoneal haemorrhage
Intracranial haemorrhage
Post-surgical bleeding


Vessel wall abnormalities
Vessel wall abnormalities;
congenital, such as hereditary haemorrhagic telangiectasia
• acquired, as in a vasculitis or scurvy
Hereditary haemorrhagic telangiectasia(HHT)
Autosomal dominant .
Telangiectasia and small aneurysms are found on the fingertips, face and tongue, and in the nasal passages,lung and gastrointestinal tract.
Pulmonary arteriovenous malformations (PAVMs) that cause arterial hypoxaemia due to a right-to-left shunt. These predispose to paradoxical embolism, resulting =in stroke or cerebral abscess.
All patients with HHT should be screened for PAVMs; if these are found, ablation by percutaneous embolisation should be considered.

Recurrent bleeds, particularly epistaxis, or with iron deficiency due to occult gastrointestinal bleeding.

TREATMENT

1-Iron replacement for IDA
2-Local cautery or laser therapy may prevent single lesions from bleeding

Platelet function disorders

Primary Hemostasis
Platelet Plug formation
Dependent on normal platelet number & function
Initial manifestation of clot formation
1-Thrombocytopenia
2-Thrombasthenia


Thrombasthenia
Congenital
Deficiency of the membrane glycoproteins
Glanzmann’s thrombasthenia (IIb/IIIa)
Bernard–Soulier disease (Ib)
Defective platelet granules
deficiency of dense (delta) granule
(storage pool disorders)

Macrothrombocytopathies

Alport`s syndrome
Acquired
Iatrogenic;
Aspirin ;cyclo-oxygenase inhibitor
Clopidogrel; adenosine inhibitor
Dipyridamole;phosphodiesterase inhibitor
Abciximab; IIb/IIIa inhibitor

Laboratory Tests for Primary Hemostasis Function

Platelet count
Bleeding time
Platelet Aggregation Studies
clot retraction
Flow cytometric studies for Glycoproteins


Glanzmann thrombasthenia
Background:
Thrombasthenia was first describe in 1918 by Glanzmann when he noted purpuric bleeding in patients with normal platelet counts
Typically, thrombasthenia is diagnosed at an early age
Pathophysiology:
Autosomal recessive trait
The production and assembly of the platelet membrane glycoprotein IIb-IIIa is altered, preventing the aggregation of platelets and subsequent clot formation
Treatment
1-local measure.2-antifibrinolytic agent such as tranexamic acid .3-platelet transfusion.4-Recombinant factor VII

Idiopathic thrombocytopenic purpura

Autoantibodies, most often directed against the platelet
membrane glycoprotein IIb/IIIa, which sensitise the platelet, resulting in premature removal from the circulation by cells of the reticulo-endothelial system.

1-Isolated condition.

2-Association with connective tissue diseases,HIV infection, B cell malignancies, pregnancy and certain drug therapies.

Clinical features

Purpura and haematomas

Mucosal bleeding

Classification of ITP disease phases

ITP phase Definition
Newly diagnosed Within 3 months of diagnosis
Persistent 3 to 12 months from diagnosis
Chronic > 12 months from diagnosis

In adults, ITP usually has an insidious onset, with no preceding illness.

Nearly one-quarter of patients present asymptomatically and
receive a diagnosis of ITP through incidental routine blood
tests
Petechiae or purpura • Unusual or easy bruising (haematoma)• Persistent bleeding symptoms from cuts or other injuries• Mucosal bleeding• Frequent or heavy nose bleeds (epistaxis)
• Haemorrhage from any site (usually gingival or menorrhagia in womenn
Petechie


• Recommended diagnostic approaches for ITP
Patient history
Family history
Physical examination
Complete blood count and reticulocyte count
Peripheral blood smear
Quantitative immunoglobulin level measurement*
Bone marrow examination (in selected patients)
Blood group (rhesus)
Direct antiglobulin test
Helicobacter pylori
Human immunodeficiency virus (HIV)
Hepatitis C virus (HCV)

Bone marrow aspiration

is indicated in older patients (particularly those over 60 years of age to exclude myelodysplastic syndrome),
in those with an atypical presentation (e.g. abnormalities observed on
peripheral blood smear suggestive of other haematological disorders),
in those with a poor response to first-line therapy
and in those being considered for splenectomy..

Treatmentwhen to treat?

If a patient has two relapses,or primary refractory disease, splenectomy is considered. Splenectomy produces complete remission in about 70% of patients and improvement in a further 20–25%, so that,following splenectomy, only 5–10% of patients require further medical therapy.
Second-line therapy with the thrombopoietin analogue romiplostim or the thrombopoietin receptor agonist eltrombopag
Rituximab, ciclosporin and tacrolimus should be consideredin cases where the approaches above are ineffective.

Coagulation disorders

Clinical Features of Bleeding Disorders
Platelet Coagulation disorder disorders

Site of bleeding Skin Deep in soft tissues
Mucous membranes (joints, muscles)
(epistaxis, gum,
vaginal, GI tract)

Petechiae Yes No

Ecchymoses (“bruises”) Small, superficial Large, deep


Hemarthrosis / muscle bleeding Extremely rare Common

Bleeding after cuts & scratches Yes No

Bleeding after surgery or trauma Immediate, Delayed (1-2 days),
Severity usually mild often severe

Only men are affected

Heamophillia A is the classic example of an X-linked recessive trait

Haemophilia A the "ROYAL DISEASE"

Epidemiology:more than 400.000persons affected
About 1 in 10.000 people is born with heamphilia A


A prolonged aPTT: a normal aPTT does not exclude mild hemophilia A because the aPTT may not be sufficiently sensitive to detect slightly reduced levels of FVIII-C in the approximate 20-30% range
Normal PT

Haemophilia A

Clinical features

Treatment

Replacement of missing coagulation factor
Clotting factor replacements Two main Treatment Modalities
Clotting factor concentrates (CFCs) *On -demand
Plasma-derived **Prophylaxis
Recombinant
FVIIa Complication of clotting factor therapy
Cryoprecipitate in developing countries - Infection; HIV, HBV, HCV
Other pharmacologic agents - Anti factor VIII inhibitor in 20 % ,
• Desmopressin (DDAVP) treated by infusion of activated factor
• Anti-fibrinolytic agent VIIa OR factor VIII inhibitor bypass
• Tranexamic acid activity (FEIBA)
• 8-aminocaproic acid (EACA)
Supportive measures
Rest
Ice
Compression
Elevation

Site of haemorrhage

Optimal factor level
Dose (U/Kg BW)
Duration (days)
Joint

30-50

15-25
1-2
• Muscle

30-50

15-25
1-2
• GIT

40-60

30-40
7-10
Oral mucosa
30-50
15-25
Until healing
• Epistaxis


30-50
15-25
• Until healing

Hematuria

30-50
15-25
• Until healing

• CNS

80-100
50
10-21
Retroperitoneal
50-100
30-50
7-14
• Trauma/Surgery

50-100

30-50
• Until healing


*Each unit infused/Kg BW raises serum factor VIII level by 2% of normal activity
Optimal dosage according to the site of Haemorrhag

Haemophilia B (Christmas disease)

Due to deficiency of factor IX .
X-linked
Clinical manifestation indistinguishable from haemophilia A
Treatment ; factor IX concentrate , indication and dosing same as to haemophilia A.
Complication of therapy similar to haemophilia A regarding transmission of infection BUT the incidence of inhibitor is < 1%.

Von Willebrand disease

von Willebrand factor
Synthesis in endothelium and megakaryocytes
Forms large multimer
Carrier of factor VIII
Anchors platelets to subendothelium
Bridge between platelets

Lab Studies:

Screening tests typically include
prothrombin time (PT)
activated partial thromboplastin time (aPTT),
FVIII level
ristocetin cofactor (RCoF) activity
vWF antigen (vWF:Ag).

Laboratory evaluation of von Willebrand disease

Classification
Type 1 Partial quantitative deficiency
Type 2 Qualitative deficiency
Type 3 Total quantitative deficiency
• *Bleeding time ↑
• *aPTT ↑
• vWD type

Assay 1 2 3

vWF antigen ß Normal ßß
vWF activity ß ß ßß
Multimer analysis Normal Abnormal Absent

Disseminated intravascular coagulation (DIC)

DIC is a clinicopathologic syndrome in which widespread intravascular coagulation is induced by procoagulant that are introduce or produce in circulation and overcome the natural anticoagulant mechanisms.
DIC may cause tissue ischemia from occlusive microthrombi as well as bleeding from both consumption of platelet and coagulation factor and anticoagulation effect of product of secondary fibrinolysis

Disseminated Intravascular Coagulation (DIC)Mechanism

Systemic activation
of coagulation
Intravascular
deposition of fibrin

Depletion of platelets

and coagulation factors
Bleeding
Thrombosis of small
and midsize vessels
with organ failure


Pathogenesis of DIC
Coagulation
Fibrinolysis
Fibrinogen
Fibrin
Monomers
Fibrin
Clot
(intravascular)
Fibrin(ogen)
Degradation
Products

Plasmin

Thrombin
Plasmin

Release of thromboplastic material into

circulation


Consumption of
coagulation factors;

 aPTT

 PT
 TT
 Fibrinogen

Presence of plasmin

 FDP
Intravascular clot
 Platelets
Schistocytes
MAHA

DIC

Treatment

Treatment of underlying disorder


Platelet transfusion (6-10 U plat (ideally rise to more than 50000-100000

Fresh frozen plasma;1-2 unit For coagulation factor depletion

Hypofibrinogenaemia; 8-10 U cryopercipitate
Anticoagulation with heparin; unless there is a clear contraindication

Coagulation inhibitor concentrate (ATIII)

Patients with DIC should not be treated with antifibrinolytic therapy, e.g.tranexamic acid.

Thrombotic thrombocytopenic purpura(TTP)

thrombosis is accompanied by paradoxical thrombocytopenia,
TTP is characterised by a pentad of findings, although few patients have all five components:
• thrombocytopenia
• microangiopathic haemolytic anaemia(MAHA)
• neurological sequelae
• fever
• renal impairment

TTP-Cont.

It is an acute autoimmune disorder mediated by antibodies against ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type-1 motif).
It is a rare disorder (1 in 750 000 per annum), which may occur alone or in association with drugs (ticlopidine, ciclosporin), HIV, shiga toxins and malignancy.
It should be treated by emergency plasma exchange. Corticosteroids, aspirin and rituximab also have a role in management
Untreated mortality rates are 90% in the first 10 days, and even with appropriate therapy, the mortality rate is 20–30% at 6 months


THROMBOTIC DISORDERS
Virchow’s Triad
• Pathogenesis of a Thrombus
• Endothelial injury
• Abnormal blood flow
• Hypercoagulability
• Genetic
• acquired

• Signs & Symptoms

• DVT:
• 50% with no clinical signs
• ?Edematous extremity
• Plethoric,Warm,Painful extremity
• PE:
• Cough, SOB, Hemoptysis
• Tachycardia

Thrombophilia

Physiologic Inhibitors of coagulation
• Antithrombin
• Activated Protein C + protein S
• Inactivates Va and VIIIa (via proteolysis)
• Thrombomodulin
• Binds to thrombin
• activate Protein C

• Hereditary Thrombophilias

• Protein C pathway
• Factor V Leiden
• Protein C deficiency
• Protein S deficiency
Prothrombin G20210A mutation
• Antithrombin deficiency
• Hyperhomocystinemia
• C677T MTHFR mutation

Hereditary Thrombophilias

None of them is strongly associated with arterial thrombosis.


• All are associated with a slightly increased incidence of adverse outcome of pregnancy,including recurrent early fetal loss, but there are no data to indicate that any specific intervention changes that outcome.
• Apart from in antithrombin deficiency and homozygous factor V Leiden, most carriers of these genes will never have an episode of VTE; if they do, it will be associated with the presence of an additional temporary risk factor.
• There is little evidence that detection of these abnormalities predicts recurrence of VTE.
• None of these conditions per se requires treatment with anticoagulants

Antiphospholipid Antibody Syndrome

Autoimmune Acquired Prothrombotic Disorder
Very High Risk for recurrent thromboembolic disease
both venous and arterial
Indefinite duration anticoagulation recommended +/- immunosuppression
Strict Diagnostic Criteria

Antiphospholipid Syndrome

• Clinical criteria (≥1 must be present):
• 1. Vascular thrombosis:
• - ≥ 1clinical episode of, objectively confirmed, arterial, venous, or small vessel thrombosis
• 2. Pregnancy morbidity:
• - ≥ 1 unexplained fetal death @ ≥ 10 weeks EGA
• - ≥ 1 premature birth (≤ 34th week of gestation) due to eclampsia, severe pre-eclampsia, or placental insufficiency
• - ≥ 3 unexplained consecutive spontaneous abortions @ <10 weeks EGA
Revised Sapporo/Sydney Criteria. JTH 2006;4:295-306


Antiphospholipid Syndrome
Laboratory criteria (≥1 must be present):
Lupus anticoagulant {LA} (+) ≥ 2 occasions, at least 12 weeks apart, according to ISTH guidelines:
prolonged aPTT, lack of correction with 1:1 mix, and correction with
Anticardiolipine antibody(ACLA) and/or anti-β2 glycoprotein-I antibody:
medium or high IgG and/or IgM isotype titer ≥ 2 occasions, at least 12 weeks apart
Standardized ELISA assays
Revised Sapporo/Sydney Criteria. JTH 2006;4:295-306