Disorders of Haemostasis and thrombosis

Dr Raihan Sajid
Assistant professor
Department of pathology
College of medicine
Alfaisal University
 Classification of haemostatic disorders
• Disorders of primary haemostasis
– Vascular
• Inherited (e.g. Ehlers-Danlos Syndrome )
• Acquired (e.g. Henoch-Schönlein purpura, Scurvy)
– Platelet
• Quantitative: thrombocytopenia e.g. ITP
• Qualitative: Platelet function disorders e.g. Glanzmann thrombasthenia and BSS.
• Disorders of secondary haemostasis
– Coagulation
• Congenital - Haemophilia (A, B,C), Von-Willebrands
• Acquired - Vitamin-K deficiency, Liver disease
• Mixed/Consumption: DIC, HIT, APS
 Thrombocytopenia
• Risk of bleeding
– platelet count
• <20,000 spontaneous bleeding
• 20-50,000 post traumatic bleeding
 Clinical manifestations:
– mucosal and skin bleeding e.g.
• epistaxis,
• petechiae (<3 mm),
• purpura (0.3-1 cm)
• ecchymoses > 1 cm
• Others: GI bleeding, intracranial bleeding and menorrhagia.
 Classification of Platelet Disorders
• Quantitative Disorders • Qualitative Disorders

• Decreased production • Inherited disorders (rare)

• Decreased platelet – Defect of adhesion (Bernard Soulier
syndrome)
survival – Defect of aggregation (Glanzmann
• Sequestration thrombasthenia)
• Dilution effect • Acquired disorders
– Medications (aspirin)
– Chronic renal failure (uremia)
– Cardiopulmonary bypass
 Thrombocytopenia
• Causes of thrombocytopenia
– Decreased production
• Drugs, infections (malaria, HIV, Dengue) , B12 and folate deficiency, Aplastic anaemia, leukaemia, MDS
– Decreased platelet survival
• Immune (ITP) acute or chronic
• Secondary…SLE
• Drugs and infections
• DIC, TTP
– Sequestration
• Hypersplenism (Hypersplenism is cytopenia caused by splenomegaly)
– Dilution
• transfusions
 Acquired thrombocytopenia with
shortened platelet survival

• Associated with bleeding • Associated with thrombosis

– Thrombotic thrombocytopenic purpura
– Immune-mediated thrombocytopenia – DIC
(ITP) – Heparin-associated thrombocytopenia
– Most drug-induced thrombocytopenias
– Most other causes
 Acute Immune Thrombocytopenic Purpura

• Children > adults, peak age 2–5 years

• Females = Males
• Seasonal (peak incidence Winter/Spring)

• Self-limiting acute severe thrombocytopenia

– Platelets usually <20 x 109/L
• Occurs abruptly within ~3 weeks of acute viral infection (or immunization)
• In most cases Nonspecific immune complex
• Lasts <6 months
• Bone marrow shows increased megakaryocytes; no splenomegaly

• Spontaneous remission or respond to corticosteroid therapy in 85%

~10–15%  chronic ITP (mirrors adult phenotype)
 Chronic Immune Thrombocytopenic Purpura

• Chronic ITP is caused by auto-antibodies to platelets

– Autoantibodies (IgG), most often directed against platelet membrane glycoproteins IIb-IIIa or Ib-IX, can be
demonstrated in the plasma and bound to the platelet surface in about 80% of patients.
• It can occur in the setting of a variety of predisposing conditions and exposures (secondary)
like SLE, HIV infection & CLL or in the absence of any known risk factors (primary or
idiopathic).

Diagnosis of primary chronic ITP is made only after secondary causes are excluded.
 Chronic (adult) ITP
• Insidious onset, may be abrupt (skin or mucosal bleeding)
• Generally no preceding illness, not seasonal
• Young/middle age adults (15–40 years)
• Commoner in women of child-bearing age 3:1
• Platelets usually 30-80 x 109/L
• In many cases IgG antibodies against GPIIb-IIIa or Ib
• Usually lasts >6 months, generally long history of easy bruising, epistaxis, bleeding gums or
soft tissue haemorrhage from relatively minor trauma
• Spontaneous remissions 2%
• Problems: bruising and mucous membrane bleeding
 ITP
Feature Acute Chronic
Age / Sex Children Adult/Female
Onset Abrupt Gradual
Predisposing Factors Viral infection/ -
vaccine
Duration <2 months >6months
Pathogenesis Non specific IgG against Platelet
GP
Peripheral smear Thrombocytopenia & Same
Giant PLTS
Bone marrow Normal or Same
↑Megakaryocytes
 Pathogenesis of ITP

• Poorly understood
• Platelets are coated with autoantibody or immune complexes  destruction by RES (spleen)
• In BM megakaryocytes are often increased
• Bleeding can happen when platelets <20 x 109/L
• Labs:
– low platelets: peripheral smear show absence or  platelet count and may be
megathrombocytes or giant platelets
– Normal PT/APTT, BT prolonged
– Bone marrow shows increased megakaryocytes
• Spleen is normal in size but histologically hyperactive and congested.
 ITP: treatment
• Corticosteroids
• IVIG
• Rituximab (CD20 antibody): 50% response rates
• Thrombopoietin-receptor agonists: Romiplostim[s/c] (fusion protein analog of
thrombopoietin) and eltrombopag [oral](agonist of the c-mpl (TpoR) receptor, which is the
physiological target of the hormone thrombopoietin).They stimulate thrombopiesis and are used in
patients refractory to steroids.
• Splenectomy: (removes the primary source of antibody production
and platelet destruction)
Inherited Platelet Functions
Disorders
 Qualitative platelet disorders
• Bernard Soulier syndrome
– GP1b deficiency
– Platelet adhesion is impaired
– Low platelets. Giant platelets
– Increased bleeding time, abnormal aggregation studies
• Glanzmann thrombasthenia
– GP IIb IIIa deficiency
– Platelet aggregation is impaired
– Normal platelet count
– Increased bleeding time, abnormal aggregation studies Abnormal Platelet aggregation in Glanzmann
 Von Willebrand disease
• Most common inherited bleeding disorder
• Qualitative defects/ quantitative defects
• Autosomal dominant (could be recessive)
• vW factor decreased (or abnormal)
• Variable severity
• Mucosal bleeding (epistaxis, Menorrhagia) in most patients
• Deep joint bleeding in severe cases
 What is vWF
• Huge multimeric protein
• Made by megakaryocytes and endothelial cells
• Glues platelets to endothelium
• Carries factor VIII (that’s why FVIII is low in VWD)
• Decreased or abnormal in vW disease
• Labs
• Bleeding time / PFA100: prolonged
• APTT: prolonged
• PT: normal
• Other investigations include Factor VIII levels, VWF Ag, and VWF High MW Multimer
analysis
 Treatment of vWF
• DDAVP (raises VIII and vWF levels by releasing vWF from
Weibel-Palade bodies of endothelial cells)…effective in type 1
• Cryoprecipitate (contains vWF and VIII)
• Plasma derived Factor VIII/VWF concentrates
 Coagulation factor disorders

• Primary (Inherited bleeding disorders)

– Hemophilia A and B
– von Willebrand disease
– Other factor deficiencies

Defect can be qualitative or quantitative

• Secondary (Acquired bleeding
disorders)
– Liver disease
– Vitamin K deficiency/warfarin
overdose
–
 Hemophilia
Clinical manifestations (hemophilia A & B are indistinguishable)
Hemarthrosis (most common)
Fixed joints
Soft tissue hematomas (e.g., muscle)
Muscle atrophy
Shortened tendons
Other sites of bleeding
Urinary tract
CNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dental extractions
Lab tests: APTT prolonged, Factor level low,
• Severity related to factor level
• <1% - Severe - spontaneous bleeding
• 1-5% - Moderate - bleeding with mild injury
• 5-25% - Mild - bleeding with surgery or trauma
• Hemophilia A • Hemophilia B
• Factor VIII deficiency • Factor IX deficiency
• X-linked recessive • X-linked recessive
• Clinical severity: mild, moderate and • Clinical severity: mild, moderate and
severe severe
• Labs: APTT increased. PT normal • Labs: APTT increased. PT normal
• Normal platelet count and bleeding • Normal platelet count and bleeding
time time
• Treatment: factor VIII concentrates • Treatment: factor IX concentrates
 Haemophili
a

Gross swelling of
the knee joint (deep
bleed)

Gross
crippling
Joint Deformity in Hemophilia
Normal knee Knee of patient with hemophilia

Hemophilic arthropathy of knee

 Acquired Coagulation Disorders
• Deficiency of vitamin-K dependent factors
– Haemorrhagic Disease of Newborn
– Biliary obstruction
– Malabsorption of vitamin-K
– Drugs: antibiotics,

• Liver disease
• DIC
• Coagulation Inhibitors
- Specific i. e.g. antibodies against F VIII components
- Non-sp. i. e.g. antibodies in S L E & R A

• Drugs
– Warfarin
– Heparin
– Thrombolytic therapy
 Vitamin K deficiency
• Source of vitamin K Green vegetables
Synthesized by intestinal flora
• Required for synthesis of Factors II, VII, IX ,X

Protein C and S
• Causes of deficiency Malnutrition
Biliary obstruction
Malabsorption
Antibiotic therapy
• Treatment Vitamin K
Fresh frozen plasma
 Thrombotic disorders
• Virchow triad
– Endothelial injury
– Changes in blood flow (stasis or turbulence)
• What is laminar blood flow
– Hypercoagulable state

Examples:
 immobilization
 MI
 Atheroscelorosis
 Protein C or S deficiency
 Factor V leiden
 Factor V Leiden
• Most common inherited cause of hypercoagulable state
• Inherited point mutation in factor V gene (glutamine to arginine
substitution at 506)
• High risk of thrombosis if homozygous
• Discovered in Leiden, Netherlands
• Produces abnormal factor V
• Factor V resistant to cleavage by protein C
 Intrinsic Extrinsic
thrombin
exposed TF TFPI

XI XIa
TF
IX IXa
VIIa VII
VIII VIIIa

X ATIII
protein
C V Va Xa

prothrombin thrombin
fibrinogen fibrin clot
 Factor V Leiden
• Diagnosis
– APTT and INR not helpful
– Need genetic testing
• Treatment
– Don’t! Unless there is a thrombosis.
– Then give oral anticoagulants
 Other disorders
• Protein C deficiency
• Protein S deficiency
• AT III deficiency
• Antiphospholipid syndrome
 Antiphospholipid syndrome(APS)
• Associated with antiphospholipid
antibodies
• Clinical features
– Repeated first trimester abortions
– Arterial and Venous thromboembolism
– Livedo reticularis
– Skin necrosis APS is defined by the presence of two major
components:

– Low platelets ●Presence in the plasma of at least one type of

autoantibody known as an antiphospholipid antibody
(aPL)
●The occurrence of at least one of the following
clinical manifestations: venous or arterial thromboses,
or pregnancy morbidity
 Antiphospholipid syndrome
• Primary or secondary
• Conditions associated with
– SLE
– RA
– Systemic sclerosis
– Sjogren’s syndrome
• The mechanisms by which Antiphospholipid antibodies cause thrombosis are not completely
understood.
• Targets for antiphospholipid antibodies
– Protein C
– Annexin V
– Β2 glycoprotein 1
• Hypercoagulability is because of endothelial injury and platelet and complement activation
Proposed mechanisms for Apls mediated injury leading to thrombosis and fetal loss
 Antiphospholipid syndrome
• Investigations
– Anticardiolipin antibodies
– Lupus anticoagulant test

• Treatment:
– Warfarin
– Heparin (also aspirin) for favourable pregnancy outcome