PRIMARY HAEMOSTATIC

DISORDERS
DR C ALEXIS
 REVIEW

• Platelet structure and function

• The mechanism of primary haemostasis- the
role of platelets and von Williebrand factor
 LEARNING OBJECTIVES

By the end of the session you should:

• Know the morphology and function of platelets

• Know the causes of Thrombocytopenia and Platelet
Dysfunction
• Know the causes, clinical features, pathophysiology,
diagnosis and management of ITP
• Know the causes, clinical features, diagnosis and
management of Neonatal alloimmune
thrombocytopenia
 PRIMARY HEMOSTASIS

Platelets
• Interact with injured vessel wall
• Interact with each other
• Produce the primary hemostatic plug

Primary platelet plug

• Fragile
• Can easily be dislodged from the vessel wall
 PLATLET FUNCTION

Platelets function to
• Provide negatively charged surface for factor
X and prothrombin activation
• Release substances that mediate
vasoconstriction, platelet aggregation,
coagulation, and vascular repair
• Provide surface membrane proteins to attach
to other platelets, bind collagen, and
subendothelium
FORMATION OF A STABLE PLUG
 ADHESION
• Damage to
endothelium exposes
blood to the
subepithelial tissue
matrix with adhesive
molecules
• Platelet receptor GPIb
binds to
subendothelium
collagen fibers through
von Willebrand’s
factor (vWF)
• Platelet adherence
stops the initial
bleeding
 SHAPE CHANGE

• Following vessel injury and platelet exposure to

external stimuli, platelets change shape from
circulating discs to spheres with pseudopods
• Shape change is mediated by an increase in cytosolic
calcium
• Exposure of platelet membrane phospholipids promotes
the assembly of vitamin-K dependent factors on the
platelet membrane surface
• Activated platelets adhere to exposed collagen
CHANGE IN PLATLET SHAPE

• Following vessel injury and

platelet exposure to external
stimuli, platelets change
shape from circulating discs
to spheres with pseudopods
• Shape change is mediated by
an increase in cytosolic
calcium
• Exposure of platelet
membrane phospholipids
promotes the assembly of
vitamin-K dependent factors
on the platelet membrane
surface
• Activated platelets adhere to
exposed collagen
 SECRETION

• Secondary aggregation begins with platlet

secretion of dense granules
• Dense granules contain large amounts of ADP
• ADP binds to the platlet membrane triggering
the synthesis and release of TXA2
• The release of large amounts of ADP combined
with TXA2 amplifies the initial aggregation of
platlets into a large platlet mass
FORMATION OF PRIMARY HEMOSTATIC
PLUG
 PLATELETS AND
SECONDARY HEMOSTASIS
Primary platelet plug is
• Unstable and easily dislodged

Secondary hemostasis
• Fibrin formation stabilizes the platelet plug
• Proteins interact to form fibrin assemble on
negatively charged membrane phospholipids
of activated platelets
SUBSTANCES RELEASED BY PLATELETS

• Membrane contains glycoproteins

important for interaction with
subendothelium and other platelets
• Dense tubular system – main site of
Prostaglandin and Thromboxane synthesis
• α-granules – platelet factor 4, platelet-
derived growth factor(stimulates mitosis in
vascular smooth muscle),VWF and
fibrinogen
• Dense granules-ATP, ADP and 5 –
hydroxytryptamine (vasoconstiction)
• Lifespan is 10 days
 PLATELET ACTIVATION

Activation by:

• Stimulation of agonists like thrombin or

• Contact to the subendothelial matrix
• Activation changes shape from disc to sphere with
pseudpods -> secretion of granular contents ->
aggregation
 HAEMOSTATIC RESPONSE OF
PLATELETS TO INJURY
Major function is formation of
the haemostatic plug at damage
sites in the vascular endothelium
A. Disruption of endothelial
lining
B. Platelets attach to and
spread on the
subendothelial matrix
component
C. Platelet secretion initiated
D. Secretions activate more
platelets which aggregate
and form thrombus
 REGULATION OF PLATELET NUMBERS

• Thrombopoietin (TPO) – binds to megakaryocytes and

haematopoietic stem cells -> increase platelet production

• TPO – secreted by the liver

CAUSES OF THROMBOCYTOPENIA
Decreased platelet production
• Congenital or Hereditary Disorders – TAR syndrome
• Marrow infiltration -Myeloproliferative disorders,
Lymphoproliferative disorders, Malignancy
• Marrow failure - Aplasia/hypoplasia
• Ineffective erythropoiesis
• Drugs – chemotherapy, thiazides, alcohol
Increased utilisation/destruction
• Immune – Autoantibody disorders (primary or secondary),
Alloantibody disorders, drug-induced, infections
• Non immune – TTP/HUS, DIC, hemangiomas, massive bleeding,
infections
• Platelet redistribution – splenomegaly, Gaucher’s
 DEFINITIONS OF IMMUNE THROMBOCYTOPENIA:
ITP WORKING GROUP
 Primary ITP (80%)
• Isolated thrombocytopenia
• Platelet count < 100,000/µL
• Absence of other disorders that may be associated with
thrombocytopenia
• Diagnosis of exclusion
• No clinical or laboratory parameters are available to establish
this diagnosis with accuracy
• Main clinical problem is an increased risk of bleeding
• Best diagnostic parameter is response to therapy
 Secondary ITP(20%)
• All forms of immune-mediated thrombocytopenia except
primary ITP
 SECONDARY ITP

 Infections - HCV, HIV, H. pylori

 Autoimmune diseases – SLE
 Malignancy – CLL, Lymphoma,
 Drugs – heparin, gold, sulphonamides, penicillin,
quinine, quinidine (bind to platelet membrane,
antibody formed and only reacts with drug-coted
platelets not normal)
 ESTIMATED FRACTION OF THE
VARIOUS FORMS OF SECONDARY ITP

SLE 5%

APS 2%
CVID 1%

Primary CLL 2%
80% Evan’s 2%
ALPS, post-tx 1%
HIV 1%
Hep C 2%
H. pylori 1%
Postvaccine 1%
Misc systemic
infection 2%
 STAGES OF ITP
• Newly diagnosed ITP - Within 3 months of diagnosis
• Persistent ITP - Within 3-12 months of diagnosis,
includes patients not reaching spontaneous remission or
maintaining complete response off therapy
• Chronic ITP - Lasting for more than 12 months
• Severe ITP
o Presence of bleeding symptoms at presentation sufficient
to mandate treatment
o Occurrence of new bleeding symptoms requiring
additional therapeutic intervention with a different
platelet-enhancing agent or an increased dose
 ITP PATHOPHYSIOLOGY

• Accelerated platelet destruction due to

phagocytosis of antibody coated platelets by the
reticuloendothelial system in spleen, liver, and
bone marrow
• Phagocytosis is mediated by Fc receptors, which
recognize Fc domains of Ig G
THROMBOPOIETIN LEVELS IN ITP
Thrombopoietin – hormone driving megakaryocytes
to make platelets
Healthy volunteers
– Serum TPO: low to normal
Amegakaryocytic thrombocytopenia (AMT) patients
– Serum TPO: high
ITP patients
– Serum TPO: normal
CLINICAL MANIFESTATIONS

Depends on the absolute platelet count

• >50 x109/l – no major symptoms
• 25-50x109/l – petechiae and bruising with minor
trauma
• 10-25x109/l – spontaneous petechiae and bruising
mainly lower limbs, menorragia, epistaxis
• <10x109/l – prominent mucosal bleeding in gums, GI,
GU, nose and increase risk of CNS bleed
 CLINICAL MANIFESTATIONS
Adults
•More chronic course – 15% remit in first year
•Similar symptoms as described previously
•Risk of fatal haemorrhage 1.5-4%, lower risk in <40yrs
compare >60 years
Children
•Peak age 5-6years
•50-60% patients have preceding febrile illness,
•Associated viral infections and immunisations esp MMR
•Fatal haemrrohage rare 0.1-0.5%
•65-70% remit by 6 mths and 15-20% after 1 year
•5-10% - chronic course; older and female
DIAGNOSIS

• History and Clinical examination

• FBC and film – major
• Coagulation screen – to exclude DIC, presence
of lupus anticoagulant
• Bone marrow to rule out malignant cause and
also can prove peripheral destruction
 TESTS TO ESTABLISH CAUSE

Autoantibodies found in 40-80% patients

testing not always helpful but
ITP
• Glycoprotein specific antibody – GPIIb/IIIa (66%
patients); GPIb/Tx (20%)
Secondary causes
• Antiphospholipid antibody
• Antithyroglobulin antibody and TFTs
• ANA
• Viral PCR –parvovirus, CMV, Hepatitis B and C
 What Is a “Safe” Platelet Count?

• Dentistry: ≥ 10 x 109/L
• Extractions: ≥ 30 x 109/L
• Regional dental block: ≥ 30 x 109/L
• Minor surgery: ≥ 50 x 109/L
• Major surgery: ≥ 80 x 109/L
• Epidural: ≥ 50 x 109/L

-4311.
 TREATMENT OF ITP
Approaches
Clinical
•Consider age, bleeding risk, co-morbidities and drug toxicities
•Children – aim to rapidly increase platelet count and maintaining
safe level until spontaneous remission
•Adults – increase platelet to safe level and prevent bleeding with
minimal toxicities; treat underlying cause in 2o ITP

Mechanisms of Drugs used in ITP

• Inhibit reticuloendothelial clearance of antibody-coated
platelets
• Inhibit autoantibody production
• Block T- and B-cell interactions
• Enhance platelet production
 FIRST LINE TREATMENT OF ITP

• Corticosteroids – cheapest option; may be used in

conjunction with IVIg or IV ant-RhD
• Intravenous immunoglobulins (IVIg) – quicker
response
• Intravenous Anti –Rh(D) – used only in Rhesus
positive patients
 CORTICOSTEROIDS FOR ITP
• Prednisone po
o Dose: 1-2 mg/kg/day, then taper
o Clinical responses in 65% to 85%
o Responses in 7-10 days; peak in 2-4 wks
o Only 5% to 30% sustain response after discontinuation
o Toxicity: glucose intolerance, psychosis, osteoporosis, Cushingoid
habitus, weight gain
 Dexamethasone IV/po
o 40 mg/day x 4 days
o 1 or more cycles, every 2 wks
o Response rate 85% with 60-65%
 IV Methylprednisolone
o Used for more rapid response
 INTRAVENOUS IMMUNOGLOBULIN THERAPY
FOR ITP
• Dose - 0.5-2.0 g/kg over 2-5 days
• Mechanisms - Modulation of Fc receptors, Attenuation
of complement mediated damage,Induction of
antiinflammatory cytokines, Anti–cytokine antibodies,
Neutralization of autoantibodies by anti-idiotypes,
Modulation of T-cell activity, Inhibition of lymphocyte
proliferation
• Efficacy - 65% achieve platelet count > 100,000/µL;
85% > 50,000/µL, most responses transient, 30%
become refractory; concomitant use of steroids may
enhance response and decrease infusion reactions
• Toxicity – Headache, Positive DAT, Anaphylaxis in IgA
deficient patients, Thrombosis, infusion reactions
INTRAVENOUS ANTI-RH(D) THERAPY
• Creates RBC hemolysis and Fcγ receptor
blockade
• Initial dose: 50 µg/kg IV over 2-5 mins
• > 70% responders; duration > 21 days in 50%
• All patients drop Hb (0.8 g/dL)
• Not effective in Rh-negative or splenectomized
patients , contraindicated in anaemic patients
• Rare but severe AE: intravascular hemolysis and
DIC
 SECOND LINE TREATMENT

• Elective Splenectomy
• Ritximab – 20% complete response
• Immunosuppressives
 ELECTIVE SPLENECTOMY

• Second line treatment

• Early response rate: 80%, with long term response
66%
• Laparoscopic splenectomy associated with less
morbidity
• No definitive predictors of response
• Preparation
oImmunize with pneumococcal, Hib, meningococcal
vaccine at least 2 weeks prior
oPost splenectomy – penicillin prophylaxis long term,
immediate post op thrombocytosis complication
DURABLE RESPONSE TO RITUXIMAB IN
PATIENTS WITH CHRONIC ITP
• Mechanism – B-cell depletion
• Rituximab-treated ITP patients treated show a complete
response (platelet count > 30,000 cells/µL) for at least 1
year: (32%)
• 63% of those patients maintained the complete response
(platelet count > 30,000 cells/µL) for 5 years
• 20% of patients overall with CR for at least 5 years
• Side effects – infusion reactions, reactivation of
Hepatitis B, progressive multifocal leukoencephalopathy
 THIRD LINE TREATMENT

Usually post splenectomy

• TPO-receptor agonists
 TPO-R AGONISTS FOR ITP
Romiplostim Eltrombopag
Nonpeptide small
Classification Peptibody
molecule

TPO-R binding site Ligand-binding domain Transmembrane domain

eTPO homology None None

Delivery SC Oral
Dosing Once wkly Once daily

Patients with chronic ITP Patients with chronic ITP

who have had an who have had an
insufficient response to insufficient response to
Indication
corticosteroids, corticosteroids,
immunoglobulins, or immunoglobulins, or
splenectomy splenectomy
 ROMIPLOSTIM
FC Carrier Domain Peptide Receptor

• Unique platform peptibody • 4 receptor binding sites

• Fragment crystallizable domain
stablises it in the circulation
• Expressed in E. coli
• Molecular weight = 60,000 D
ELTROMBOPAG
• Small molecule (MW = 546) O OH

• Orally bioavailable
• Once-daily dosing
• Stimulates megakaryocyte
proliferation and differentiation OH

NH

• Increases platelet counts N

O
• Not immunogenic
H C
3

N N

• Does not activate platelets

CH
3

• Binds to transmembrane portion

of TPO receptor CH
3
 TPO-R AGONISTS: ASSOCIATED
TOXICITIES
Eltrombopag
• Hepatotoxicity - Elevated transaminases, Grade 4
toxicity rare
• Cataracts – Develops or worsens, perform baseline eye
exam and monitor closely for symptoms
Romiplostim
• Rebound thrombocytopenia
• Thrombosis
• Bone marrow fibrosis
• Progression of hematologic malignancies: MDS (25%
progression), AML(10%)
 IMMUNOSUPPRESSIVES IN ITP

• Most have shown limited efficacy

• Remission <30%
• Drugs – azathioprine, danazol,
cyclophosphamide, Cyclosporin A
 THROMBOCYTOPENIA IN PREGNANCY

• Gestational thrombocytopenia – 4-8% of pregnancies,

develops in 3rd trimester, severe maternal or neonatal
thrombocytopenia is rare, difficult to distinguish from
ITP

• Mothers with ITP

 ITP IN PREGNANCY
• 1-2/1000 deliveries
• Transplacental passage of maternal autoantibodies
with destruction of fetal platelets
• No non-invasive way to predict neonatal platelet
count
• Risk of neonatal thrombocyopenia 9-15% with
increase risk if previous affected foetus
• Maternal risks – epidural and Caesaran section
adequate counts (see safe platelet counts before)
• Neonatal risk of intracranial haemorrhage (ICH) <1%
 NEONATAL ALLOIMMUNE
THROMBOCYTOPENIA
• Transplacental passage of maternal alloantibodies
against platelet antigens
• Maternal platelet counts may be noermal
• Antibodies include homozygous for HPA-1a, HPA-1b
• Develop in 1-6% babies, ICH in 10-20%,fatal in 1-
5%
• Production of HPA-1a ab is associated with HLA
haplotype DRB30101 (Dw52a)
 MANAGEMENT

Index case occurs without warning and devastating

• Delivery – need to prevent ICH
• Head ultrasound/CT on neonate
• Prevention of neonatal ICH
• Platelets preferred HPA-1a negative (maternal, washed),
random donors
• IV IgG and IV methylprednisolone
 MANAGEMENT OF SUBSEQUENT
PREGNANCIES
• Severe thrombocytopenia in 99% of babies and 40%
foetuses by 24 weeks
• Most severely affected
2 approaches
• Weekly transfusion of maternal or antigen matched
platelets in utero 20-26 weeks
• IV IgG 1-2g/kg/week + prednisolone 0.5-1mg/kg/day
at 20-20 weeks
• Possible Fetal sampling @ 32-36 weeks
 HEREDITARY/CONGENITAL DISORDERS OF
PLATELET FUNCTION
• Disorders of Platelet adhesion
Bernard-Soulier syndrome – AR, deficiency of GP1b-IX-V complex,
thrombocytopenia, increased platelet size, nil or marked decrease aggregation
response to ristocetin, normal response to ADP, epinephrine and collagen,
treatment is platelet transfusion
• Disorders of Platelet Aggregation
Glanzmann thrombasthenia – AR, deficiency of glycoprotein IIb-IIIa deficiency,
absent or markedly reduced aggregation responses, normal aggregation with
ristocetin, transfusion of normal platelets in life-threatening circumstances
• Disorders of Platelet Secretion
Gray Platelet syndrome – α granule deficiency, autosomal inheritance, variable
platelet aggregation
Dense granule deficiency – δ storage pool disese – Wiskott-Aldrick syndrome
TAR syndrome, Hermansy-Pudlak, Chediak-Higashi
• Disorders of Secretion due to abnormal secretory mechanism
• Disorders of platelet procoagulant activity
 ACQUIRED DISORDERS OF
PLATELET DYSFUNCTION
• Uremia
• Liver Failure
• MPD
• MDS
• Medical interventions e.g. Cardiopulmonary
bypass
• Drugs – aspirin, NSAIDs, antihistamines,
expectorants, anticonvulsants, antidepressants
• Herbal supplements – garlic, ginger, vitaminE,
omega-3 fatty acids, gingo biloba
 VASCULAR DISORDERS
• Most vascular diseases
• Are not associated with platelet or plasma defects
• Most common symptom
• Abnormal bleeding into or under the skin due to increased
permeability to blood
• Laboratory tests are used to exclude
• Coagulation or platelet disorders
• Majority of patients
• Hemostatic testing is entirely normal, despite a history or physical
examination that suggests substantial bleeding
 PLATELET DISORDERS
• Quantitative
• Thrombocytopenia
• Thrombocytosis
• Qualitative
• Morphologic abnormalities
• Macrothrombocytes
• Microthrombocytes
• Hypogranular or agranular platelets
 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
 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
 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
 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)
 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
 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
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
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
 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
 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
INHERITED DISORDERS OF PLATLET
FUNCTION
VON WILLEBRAND DISESE
 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
 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
 TEST FOR PLATELET FUNCTION

Screening
oBleeding time –inter-operator variable, poor
reproducibility, inability to predict clinical bleeding ,
unsuitable in young children
oPlatelet function analyser (PFA-100) – more widely
available but abnormal in thrombocytopenia or on certain
medications; not very sensitive used for screening
Platelet Aggregation studies –most specific; citrated blood
or platelet rich plasma is tested with different concentration
of agonists: ADP, epinepherine, collagen, arachidonic acid
and ristocetin – evaluates using light transmission, pattern
distinguishes different diseases; expensive
 TESTS FOR PLATELET
DYSFUNCTION
Should be reserved for patients with convincing
bleeding history in whom evaluation for
bleeding disorders are negative
Technically demanding, time consuming and
poorly standardised
VON WILLEBRAND DISEASE
 VWD
VWF is made by endothelial cells and
megakaryocytes
Functions:
• Primary haemostasis -Promotes platelet attachment
and interacts with GPIIb/IIIa -> platelet aggregation
• Secondary function is a carrier for Factor VIII and
prolongs the half life of FVIII

• Most common inherited bleeding disorder

• Prevalence 0.8-2%
• Majority are AD with varying expression
• Qualitative or quantitative defect in VWF
 TYPES OF VWD

• Type 1 – most common, 70-80% 0f cases, quantitative

decrease
• Type 2 – associated thrombocytopenia (20%)
• Type 2A - most common qualitative abnormality
• Type 2B – loss of large VWF multimers
• Type 3 – severe, rare, inherited dyfunctional gene from both
parents -> complete absence of vWF

Majority of the patients are heterozygous

 CLINICAL FEATURES

Bleeding due to diminished platelet adhesion and FVIII

deficiency
Mucosal bleeding
• Epistaxis
• Bleeding after dental extractions
• Menorrhagia
• GI bleeding
• Post op bleeding
Skin bleeding
• in Type 2 B(thrombocytopenia)
 LABORATORY TESTING
Screening
• prolonged aPTT and prolonged bleeding time
Initial
• Qualitative test: VWF:Rco(ristocetin cofactor) – measure
platelet adhesion ;VWF:CB (collagen binding)– subendothelial
binding, FVIII:C – carrier function on VWF
• Quantitative Tests: VWF:Ag - concentration

Specialised –
• RIPA ( ristocetin-induced platelet agglutination) – measures
VWF affinity for VWF platelet membrane receptor GP1b
• multimer gel electrophoresis – qualitative, detects abnormal
structure
 TREATMENT

Replacement
•DDAVP- Desmopressin - Vasopressin analogue – releases
VWF/VIII from storage in the endothelial cells, IV or intranasal,
Useful in type 1 or 2
•Cryoprecipitate
•VWF concentrates - Factor VIII concentrate that contains VWF
Clot stabilisation
•Antifibrinolytics – amicar, tranexamic acid, thrombin with
gelfoam
•Can monitor treatment with vWF:Rco and vWF:Ag assay