11/7/2017

Hemostasis
Yasser Bakr

Learning Outcomes
By the end of this presentation you should be
able to:
• Define Hemostasis.
• Discuss disorders of primary hemostasis
• Describe the clinical picture of disorders of
primary hemostasis
• Explain investigations available to reach diagnosis
• Outline management of ITP
• Discuss disorders of secondary hemostasis

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Hemostasis and Thrombosis

Normal hemostasis is a consequence of tightly regulated processes
that maintain blood in a fluid state in normal vessels, yet also permit
the rapid formation of a hemostatic clot at the site of a vascular
injury.
Thrombosis involves blood clot formation within intact vessels.
Both hemostasis and thrombosis involve three components:
the vascular wall, platelets and the coagulation cascade.

Normal hemostasis occurs as a result of the balance between

procoagulant and anticoagulant factors.

After initial injury there is a brief period of arteriolar vasoconstriction mediated by reflex neurogenic
mechanisms and augmented by the local secretion of factors such as endothelin (a potent endothelium-
derived vasoconstrictor)
The effect is transient, however, and bleeding would resume if not for activation of the platelet and
coagulation systems.

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Endothelial injury exposes highly thrombogenic sub endothelial extracellular matrix (ECM), facilitating platelet
adherence and activation. Activation of platelets results in a dramatic shape change (from small rounded discs
to flat plates with markedly increased surface area), as well as the release of secretory granules. Within
minutes the secreted products recruit additional platelets (aggregation) to form a hemostatic plug; this process
is referred to as primary hemostasis.

Tissue factor is also exposed at the site of injury. Also known as factor III and thromboplastin, tissue factor is
a membrane-bound procoagulant glycoprotein synthesized by endothelial cells. It acts in conjunction with
factor VII as the major in vivo initiator of the coagulation cascade, eventually culminating in thrombin
generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork, and
also induces additional platelet recruitment and activation. This sequence, secondary hemostasis,
consolidates the initial platelet plug.

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Polymerized fibrin and platelet aggregates form a solid, permanent plug to prevent
any further hemorrhage. At this stage, counter-regulatory mechanisms (e.g., tissue
plasminogen activator, t-PA) are set into motion to limit the hemostatic plug to the
site of injury

Clotting factors
involved in PT and
PTT

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Signs and Symptoms of

Disorders of Hemostasis

Disorders of Primary Hemostasis

Definition
• Inability to form an adequate platelet plug due to:
• Disorders of blood vessels
• Disorders of platelets
• Abnormal function
• Abnormal numbers (thrombocytopenia)
• Disorders of vWF

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Classification

Immune Thrombocytopenic Purpura (ITP)

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Epidemiology
• Most common cause of
thrombocytopenia in childhood
• Peak age: 2-6 year, M=F
• Incidence 5:100,000 children Acute (Child-Type)
per year ITP
Etiology
• Caused by autoantibodies that bind
to platelet membranes leading to
splenic uptake and destruction of
platelets

Clinical Presentation
• 50% present 1-3 week after viral illness (URTI,
chicken pox)
• Sudden onset of petechiae, purpura, epistaxis in an
otherwise well child
• Clinically significant bleed in only 3% (severe bleed
more
likely with platelet count <10) with <0.5% risk
of intracranial bleed
• No lymphadenopathy, no hepatosplenomegaly
• Labs: thrombocytopenia with normal RBC, WBC,
reticulocyte count
• Bone marrow aspirate only if atypical presentation (≥1
cell line abnormal, hepatosplenomegaly)
• Differential diagnosis: leukemia, drug-induced
thrombocytopenia, HIV, infection (viral), autoimmune
(SLE, ALPS)

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Management
• Observation vs. pharmacologic intervention highly
debated; spontaneous recovery in >70% of cases within 3
months
• Treatment with IVIg or prednisone if mucosal or internal
bleeding, platelets <10, or at-risk of significant bleeding (surgery,
dental procedure, concomitant vasculitis or coagulopathy)
• Life-threatening bleed: additional platelet transfusion ―
emergency splenectomy
• Persistent (>3-12 months) or chronic (>12 months): re-evaluate;
treat if symptoms persist
• Supportive: avoid contact sports and ASA/NSAIDs

CHRONIC (ADULT-TYPE) ITP

• Most common cause of isolated thrombocytopenia
• Diagnosis of exclusion [i.e. isolated thrombocytopenia (platelets
<100 x 109/L) and the absence of any obvious initiating and/or
underlying cause]
Pathophysiology
• An acquired immune-mediated disorder with:
• Anti-platelet antibodies bind to platelet surface leading to increased splenic
destruction and clearance
• Impaired platelet production
• Helper T-cell and cytotoxic T-cell activation also implicated in platelet
destruction

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Clinical Presentation
• Can present with no symptoms, minimal bruising
to a serious bleed (including GI bleed, skin and
mucosal hemorrhage or intracranial hemorrhage),
lethargy, fatigue

Investigations
• CBC and reticulocyte count: thrombocytopenia (request Retics
count if not an isolated thrombocytopenia)
• Bleeding Time is prolonged, but PT and aPTT are normal
• Peripheral blood film: decreased platelets, giant platelets
• HIV, HCV (if risk factors are present)
• Bone marrow aspirate and biopsy: increased number
of megakaryocytes
• Recommended in patients >60 years of age, pre-splenectomy or have failed
multiple lines of ITP treatment, those with systemic symptoms, an abnormal
blood film and/or abnormal signs to rule out other causes of
thrombocytopenia (e.g. myelodysplasia)

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Treatment
• Rarely indicated if platelets
>30 x 109/L unless active
bleeding, trauma or surgery

Treatment
A. Emergency Treatment (active bleeding (CNS, GI or GU) or in need of
emergency surgery)
• General measures: stop drugs reducing platelet function, control blood pressure,
minimize trauma
• Corticosteroids: prednisone (1 mg/kg) or methylprednisolone (1 g/day x 3 days) or
dexamethasone (40 mg PO x 4 days)
• Antifibrinolytic: tranexamic acid (1 g PO tid or 1 g IV q6h) if refractory bleeding
• IVIg 1 g/kg/d x 2 doses, or 2 g/kg over 5 d
• Platelet transfusion: for life-threatening bleeding
• Emergency splenectomy: may be considered, vaccinations prior (Pneumococcus,
Meningococcus, H. influenza B)
• Management of intracranial bleeding: IV steroids, IVIG, platelets, emergency
splenectomy, and then craniotomy; maintain Platelets >100 for at least 7 weeks
post intracranial hemorrhage

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Treatment
B. Non-Urgent Treatment (platelet count <20-30 x 109/L and no bleeding
OR significant bleeding symptoms with platelet count <50 x 109)
• platelet transfusion does not work
• First Line
• Corticosteroids (dexamethasone 40 mg/d x 4 weeks or prednisone 1 mg/kg/d)
• IVIg
• Second Line
• Splenectomy (need vaccinations prior to splenectomy: pneumococcus,
meningococcus, H.influenzae B)
• Immunosuppressants (azathioprine, cyclophosphamide)
• Rituximab
• Danazol, Vincristine
• Thrombopoietin (TPO) receptor agonists (romiplostim, eltrombopag)

MAHA
TTP-HUS
Thrombotic-thrombocytopenic purpura

Hemolytic Uremic Syndrome

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Von Willebrand Disease

(vWD) Classification
• Type 1: mild quantitative defect
(decreased amount of vWF
and proportional decrease in
vWF activity) – 75% of cases
• Type 2: qualitative defect (vWF
activity disproportionally lower
than quantity) – 20-25% of
cases
• Type 3: severe total quantitative
defect (no vWF produced) –
rare

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Investigations

Treatment
• Desmopressin (DDAVP) is treatment of choice for type 1 vWD
• Causes release of vWF and Factor VIII from endothelial cells
• Variable efficacy depending on disease type; tachyphylaxis occurs
• Need good response before using with further bleeding
• Caution in children due to hyponatremia
• Tranexamic acid (Cyklokapron, antifibrinolytic) to stabilize
clot formation
• High-purity Factor VIII concentrate containing vWF (Hemate P®)
in select cases and type
• Frozen plasma (FP) is not useful
• Need to monitor vWF and factor VIII levels (very high factor VIII level
can cause thrombosis)
• Conjugated estrogens (increase vWF levels)

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Disorders
of
Secondary
Hemostasis

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Disorders of Secondary Hemostasis

Definition
• Inability to form an adequate fibrin clot
• Disorders of clotting factors or co-factors
• Disorders of proteins associated with fibrinolysis
• Characterized by delayed bleeding, deep muscular
bleeding, spontaneous joint bleeding

Classification of Secondary
Hemostasis Disorders

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Hemophilia A (Factor VIII Deficiency)

Pathophysiology
• X-linked recessive, 1/5,000 males
• Mild (>5% of normal factor level), moderate (1-5%), severe (<1%)
Clinical features
• Older patients may also have HIV or HCV from contaminated
blood products
Investigations
• Prolonged aPTT, normal INR (PT)
• Decreased factor VIII (<40% of normal)
• vWF usually normal or increased

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Treatment
• Desmopressin (DDAVPR) in mild hemophilia A
• Recombinant factor VIII concentrate for
• Prophylaxis (2-3 times a week at home)
• Minor but not trivial bleeding (e.g. Hemarthroses)
• Major potentially life-threatening bleeding (e.g. Multiple trauma)
• Emicizumab
• Anti-fibrinolytic agents (e.g. Tranexamic acid)
• Gene Therapy

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Hemophilia B
(Factor IX Deficiency)
• Christmas disease
• X-linked recessive, 1/30,000 males
• Clinical and laboratory features
identical to hemophilia A
(except decreased factor IX)
• Treatment: recombinant factor IX
concentrate, anti-fibrinolytic
agents

Liver Disease
Pathophysiology
• Deficient synthesis of all factors except VIII
(made in endothelium)
• Aberrant synthesis of fibrinogen
• Deficient clearance of hemostatic ‘debris’ and
fibrinolytic activators
• Accelerated destruction due to
dysfibrinogenemias: increased fibrinolysis,
DIC
• Miscellaneous: inhibition of secondary
hemostasis by FDPs

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Investigations & Treatment

• Peripheral blood film: target cells
• Primary hemostasis affected
• Thrombocytopenia 2ry to hypersplenism, folate deficiency, alcohol
intoxication, DIC, decreased production of thrombopoietin
• Platelet dysfunction (e.g. Alcohol abuse)
• Secondary hemostasis affected
• Elevated INR (PT), aPTT and TT, low fibrinogen in end-stage liver
disease
Treatment
• Supportive, treat liver disease, blood products if active
bleeding (frozen plasma, platelets, cryoprecipitate)

Vitamin K Deficiency
Etiology
• Drugs
• Oral anticoagulants which inhibit factors II, VII, IX, X,
proteins C and S
• Antibiotics eradicating gut flora, altering vitamin K
uptake
• Poor diet (especially in alcoholics)
• Biliary obstruction
• Chronic liver disease (decreased stores)
• Malabsorption (e.g. Celiac disease)

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Vitamin K Deficiency
Investigations
• INR (PT) is elevated out of proportion to elevation of the aPTT
• Decreased factors II, VII, IX and X (vitamin k-dependent)
Treatment
• Hold anticoagulant
• Vitamin K 1 mg PO for INR between 4.5 and 10 and no active bleeding
• If bleeding, give vitamin K 10 mg IV
• If life-threatening bleeding and vitamin K antagonist use, give frozen plasma
or prothrombin complex concentrate (PCC)
• PCCS are contraindicated if there is a previous history of HIT
• Use FFP if PCC is contraindicated or unavailable
• Note: excessive vitamin K will delay therapeutic warfarin anticoagulation
once re-started

Disseminated Intravascular Coagulation (DIC)

Definition
• Uncontrolled release of plasmin and thrombin leading to
intravascular coagulation and depletion of platelets, coagulation
factors and fibrinogen
• Risk of life-threatening hemorrhage
Etiology
• Occurs as a complication of many other conditions
• Widespread endothelial damage ― extensive inflammatory
cytokine release

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Etiology of DIC

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Clinical Features
• Presence of both hemorrhage and clotting

Investigations
• Primary hemostasis: decreased platelets
• Secondary hemostasis: prolonged INR (PT), aPTT, TT,
decreased fibrinogen and other factors
• Fibrinolysis: increased FDPs or D-dimers, short
euglobulin lysis time (i.e. accelerated
fibrinolysis)
• Extent of fibrin deposition: urine output, urea,
RBC fragmentation

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Treatment
• Recognize early
• Treat underlying disorder
• Individualized critical care support
• In hemorrhage: replacement of hemostatic elements
with platelet transfusion, frozen plasma, cryoprecipitate
• Maintain platelets >50 x109 and hemoglobin >80
g/L
• 4-5 units of FFP if INR >1.5 or aPTT >38 sec
• 10 units of cryoprecipitate if fibrinogen <1 g/L
• 1 adult dose of buffy-coat platelets if <10 x109 (<20
if febrile, <50 before invasive procedure)
• In thrombotic phase: UFH or LMWH in critically ill,
non- bleeding patients

References & Further Readings

• Kumar and Clark's Clinical Medicine, 9th
Edition
• Davidson's Principles and Practice of
Medicine, 22nd Edition
• Oxford Handbook of Clinical Medicine, 10th
Edition
• CURRENT Medical Diagnosis and Treatment
2018 (LANGE CURRENT Series) 57th Edition

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