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Platelets, blood coagulation and haemostasis

Two Main Aims
1. Keep blood in fluid state
- Endothelium and Natural inhibitors of coagulation
2. Form a thrombus when there is endothelial injury
• Vascular
• Platelets
• Coagulation
• fibrinolytic
• Mostly due to under activity Not due to over activity

Blood flows through intact vessels

 Resting state is designed to keep blood flowing
 Arteries: rapid flow. Injury requires a plug Rapid, localized, controlled. minimize
blood flow compromise
 Veins: slower, intermittent flow Systemic anticoagulant clot dissolving system
Physiology of coagulation
Normal Hemostasis
 Hemostasis is the sequence of events that lead to cessation of bleeding through the
formation of a stable platelet-fibrin hemostatic plug.
 Hemostasis is initiated when the vascular endothelial lining is disrupted
 Complex activating and inhibition system
 4 Components
 Vascular
 Platelets
 Plasma coagulation factors
 Fibrinolysis (clot dissolving)

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Vascular wall injury releases thrombogenic factors:
1. Change in blood flow
2. Release of von-Willebrand factor
3. Release of tissue factor
4. Exposure of thrombogenic subendothelial collagen
5. Decreased endothelial synthesis of antithrombogenic substances

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 Essential cofactor for FVIIa

 FVIIa: inefficient serine protease.
 Complex with TF and oriented to phospholipid membrane
 Phospholipid surface increases the rate of substrate activation (FX, FIX) by 104-107

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Bleeding
Type Vascular Platelets Coagulation
Purpura +ve palpable +ve unpalpable ±very late
Deep muscle -ve -ve + ve
hematoma
Intraarticular + ve early
hemorrhaged
Lab ↑BT – CT ↑BT – CT BT – CT ↑
Lab Platelets count PT
Platelets PTT
function

Approach to bleeding patient

 Screening test ( Bleeding time, PT, PTT, Platelet # are normal)
 Factor XIII deficiency.
 Vascular disorder.
 Fibrinolysis.

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Vascular and platelet abnormalities
 A vessel wall defect, either intrinsic or induced by inflammatory process, can result in
abnormal bleeding despite otherwise normal coagulation system.
 Clinically the patient present with petechiae, palpable purpura or excessive bleeding
after minor trauma or surgery associate with normal platelet number and function.

Causes of vascular purpura

Structural Abnormalities
 Senile purpura: Atrophy of skin and subcutaneous tissues.
 Steroid purpura: Breakdown of collagen.
 Pseudoxanthoma elasticum:
 Due to inherited defect of elastic fibers of the vessel wall.
 Purpura, , severe GIT bleeding, genitourinary and menstrual bleeding and
spontaneous retinal Hge.
 Ehler-Danlos syndrome: skin lack normal resistance to stretch
 Scurvy: Perifollicular bleeding, saddle area.
 Hereditary Hemorrhagic telengectasia.
Vacuities (Palpable purpura)
 Henoch-Schonlein purpura
 Bacterial Sepsis
Dysproteinemia
 Mixed essential cryoglobuinemia.
 Multiple Myloma
 Waldenstom macroglobinemia
Lab Studies
 Normal PT, PTT, PLATELET #

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Platelets
 Platelets number 150,000-450,000 /ul
 Diminished Platelets Thrombocytopenia
 Increased Platelets Thromobocytosis
 Abnormal function Thomboasthenia.
 Life span: 9-10 days
Thrombocytopenia
Clinical Picture:
 Peticheal rash
 Bleeding from GIT, nose ……etc
 No Deep Muscle hematoma or Hemoarthrosis
Lab. Studies:
 Pseudothrombocytopenia
 EDTA antibody induced
Diminished production:
 Marrow Damage
 Aplasia
 Drugs
 Malignancy
 Hepatitis
 Congenital defects
 Ineffective production
 Drugs: Thaiazide, estrogen(Diminshed production).
Increased destruction:
Immune:
 Drug Induced (Quindine, Heparin.)
 SLE
 HIV
 Sarcoidosis
 Mononucluosis syndrome
 ITP
Non-Immune:
 DIC
 HUS
 TTP
 HELP
Abnormal distribution
 Splenomegaly. ( Part of systemic disorder(lymphoma).
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ITP
Definition:
 It is an autoimmune disorder characterized by persistent thrombocytopenia
(<I50.000/cmm) due to the presence of autoantibodies binding to the platelet antigen
(s) causing their premature destruction by the reticuloendothelial system (RES) and in
particular the spleen
Clinical types:
1- Childhood ITP:
 It is seen in children, often following viral infection
 Male to female ratio is 1 ; 1
 There is rapid onset of purpura which is usually self limiting and becomes chronic in
only 5-10% of cases
2- Adult ITP :
 It has an insidious onset with no preceding viral illness
 Male to female ratio is 1 : 3
 It affects women of childbearing age
 It is usually idiopathic and,should be differentiated from other causes of immune
thrombocytopenia
 drug induced
 Autoimmune disease as SLE
 chronic lymphatic leukaemia
 viral infections as HIV.
 the disease has a fluctuating course with easy bruising, epistaxis and menorrhagia.
 Major hemorrhage is rare.
 Splenomegaly is not a common finding, however it is reported in 3% of cases and
when reported you have to exclude other diagnoses

Clinical Picture:
Investigations:
 Value of bone marrow examonation: increased number & size of megakaryocytes
with: “defective budding”
Therapy:
 First Line:Corticosteroids, Immunoglobulins, Anti-D
 Second Line: Splenectomy
 Third Line: Imminosuppresive

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Thrombotic thrombocytopenic purpura
 Fever, Low platelets ,(Normal: Pt, PTT and fibrenogen) , platelet thrombi, mechanical
hemolytic anemia, CNS and digital Ischemia.
 Due to deficiency of vWF cleaving factor
 Elevated LDH
 Treatment : Fresh frozen plasma
 Review page 29
HUS
 Clinically related to TTP.
 Absent neurological manifestations.
 Due to E. Coli 0157:H7
 NO vWF cleaving factor deficiency
 Treatment: Plasma exchange and hemodialysis
 Review page 33
Disseminated Intravascular Coagulopathy
 Widespread Inappropriate activation of coagulation system and platelets with
subsequent intravascular deposition of fibrin.
 Due to Intravascular activation of coagulation system (release of procoagulants into
the blood stream)
 Leads to wide spread thrombus formation together with depletion of platelets and
coagulation factors.
 Clinical picture of widespread thombi associated with bleeding
 Wide-spread endothelial damage and collagen exposure( gram-negative sepsis).
 Clinically: Mainly hemorrhage (5-10 % of cases with thrombosis).

Causes of DIC
 Infections
 Gram negative sepsis.
 Other infectious agents.
 Malignancy.
 Mucin secreting tumor.
 Promyelocytic leukemia.
 Obstetric complications.
 Amniotic fluid embolism.
 Septic abortion.
 Wide-spread tissue damage (burns, Trauma).
 Vascular abnormalities (Vascular aneurysms)
 Others (Pancreatitis, LCF, Heat stroke, Hypothermia)

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Laboratory investigations
 Low Platelet count.
 Low fibrinogen concentration.
 Prolonged thrombin time.
 High levels of FDPs.
 Prolonged PT and PTT (usually in acute setting). (Compensated By Liver).
 Fragmented cells( due to fibrin deposition).
Treatment
 Bleeding:
 Fresh frozen plasma.
 Platelet Concentrate (In patients with severe bleeding).
 Cryo-precipitate.
 Thrombosis:
 In patients with thrombotic complications (Dermal Ischemia).
 Fibrinolytic inhibitors--- CONTRAINDICATED---
 Antithrombin concentrate and recombinant human protein C (In PATIENTS WITH
SEPSIS)

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Coagulation defects
(Congenital Vs Acquired Other Classifications)

Congenital
 Associated with significant bleeding tendency
 The X linked hemophilia A and B due to deficiency of factor XIII or IX.
 Clinically significant hematoma and hemoarthrosis.
Hemophilia A
 Factor VIII on X chromosome.
 Cause : Hemophilia is an X-linked recessive disease, and as a rule only males are affect

 Clinical Severity correlated best with factor VIII activity.

 Degree
1. Mild : 50- 150 %
2. 6- 49 %
3. 1-5 %
4. < 1%
Clinically:
Profuse post circumcision bleeding.
1. Prolonged bleeding after dental extraction
2. Joint and soft tissue bleeding
3. Local pressure----------local entrapment
4. Spontaneous hematuria and gastrointestinal bleeding.
5. Hemophilic pseudo tumor (large encapsulated hematoma with progressive cystic

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6. Swelling from repeated hemorrhage).
7. Occurs in facial and muscle planes, and long bones( from repeated subperiosteal
8. hemorrhages with ? Subsequent bone formation and new bone formation.
9. Infection
Laboratory investigations
 Normal bleeding time.
 Prolonged PTT.
 Normal PT.
 Normal Platelet Number.
 Mixing studies:( To detect Inhibitors)
Treatment
 Fresh frozen plasma.
 Recombinant factor VIII.
 DDVAP(Desmopressin)(ADH effect).
 Local supportive measures.
 Treatment of Inhibitors:
 Factor VIIa.
 Activated prothrombin complex.
 Immunosuppressive( delayed effect).
 High dose factor VIII.

Hemophilia B
 Due to deficiency of factor IX.
 Gene on long arm of chromosome X.
Factor VII deficiency is very rare AR.
(Prolonged PT and Normal PTT)
Factor X, V, prothrombin AR
(Prolonged PT, PTT)

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Acquired

Acquired factor VIII Inhibitors:

 SLE.
 Elderly.
 Hemophilia.
Medications
 Heparin
 Oral anti-coagulants
Vitamin K Deficiency:
 Poor Diet.
 Mal-absorption.
 Drugs: Antibiotics.
Liver disease:
 Biliary obstruction.
 Hepatocellular disease.
 Coagulation Vs Haemostatic Vs hematological.
 Obstructive Vs hepatocellular
Others:
 Amyloidosis (Factor x binding).
 Nephrotic syndrome : (Factor IX)

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Thrombosis and Antithrombotic therapy
Antithrombotic Properties of the Endothelium
Anti-platelet properties
 Covers highly thrombogenic basement membrane
 Uninjured endothelium does not bind platelets
 PGI2 (prostacyclin) and NO from uninjured endothelium inhibit platelet binding
 ADPase counters the platelet aggregating effects of ADP
Heparin-like molecules:
 activate anti-thrombin III (inactivates active proteases)
Thrombomodulin:
 changes specificity of thrombin (activates protein C, which inactivates factors Va and
VIIIa).
 Endothelial cells produce tPA which activates fibrinolysis via plasminogen to
plasmin

Prothrombotic Properties of the Endothelium

 Synthesis of von Willebrand factor
 Release of tissue factor
Production of plasminogen activator inhibitors (PAI)

Thrombosis :
 Definition: Solid mass or plugs formed in the circulation from blood constituents.
Arterial or venous.
 Arterial: Mainly platelets.
 Venous: Platelet role is less important.
 Virchow’s triad :
1. Vessel wall damage. (A)
2. Hypercoagulibility. (V)
3. Slowing of circulation. (V)

Vascular wall injury releases thrombogenic factors:

1. Change in blood flow
2. Release of von-Willebrand factor
3. Release of tissue factor
4. Exposure of thrombogenic subendothelial collagen
5. Decreased endothelial synthesis of antithrombogenic substances

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Arterial thrombosis Atherosclerosis :
 Risk factors:
- Positive family history. - Male sex.
- Hyperlipidemia. - DM.
- Gout. - Polythycemia.
- Hyperhomocystenemia. - Cigarette smoking.
- Collagen vascular disease. - Bechcet disease.
- Elevated factor VII. - Elevated fibrinogen.

Venous thrombosis :
Related to coagulation abnormality:

Related to
unknown
cause:
Hereditary:
Hereditary or acquired: Related to
(? Multiple
stasis:
mechanisms).

 Factor V Lieden.  Raised factor VII,VIII,IX or  CHF.  PNH.

 Prothrombin XI.  Stroke .  Age.
G 2010 variant.  Raised plasma  Immobility.  Obesity.
 Protein C deficiency. fibrenogen.  Nephrotic  Bechcet
 Protein S deficiency.  Lupus anticoagulant. syndrome. disease.
 Abnormal fibrinogen.  Estrogen.
 Abnormal  HIT.
plasminogen.  Pregnancy.
 MI.
 Thrombcythemia.

Hereditary disorders of homeostasis :

 Four clues to a hypercoagulable state:
1. Thrombosis at an early age.
2. Recurrent thromboses .
3. Thrombosis at an unusual site .
4. Family history of thrombosis.

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 Five most common inherited hypercoaguable states:
1. Factor V Leiden.
2. Prothrombin Gene Mutation .
3. Protein S deficiency .
4. Protein C deficiency .
5. Antithrombin III deficiency

Factor V Leiden :
 Most common inherited cause of
increased risk for VTE.
 Due to failure of Inactivation of factor V
by protein C system.
 AT deficiency.

 Protein C deficiency.
Warfarin induced skin necrosis.
 Prothrombin G20210 A Due to activation of TAFI with down regulation of fibrinolysis.

Clinical Characteristics of Patients With Inherited hypercoaguable states :

 Venous thromboembolism (90% of cases)
 Deep vein thrombosis of lower limbs (common)
 Pulmonary embolism (common)
 Superficial thrombophlebitis
 Mesenteric vein thrombosis (rare but characteristic)
 Cerebral vein thrombosis (rare but characteristic)
 Frequent family history of thrombosis

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 First thrombosis usually at young age (<40 yr)*
 Frequent recurrences
 Neonatal purpura fulminans (homozygous protein C and protein S deficiency)
*All these features are less evident in patients with activated protein C resistance, who
appear to be less severely affected clinically.

Six acquired hypercoaguable states :

 Estrogen Excess (oral contraceptives, pregnancy).
 Malignancy.
 Antiphospholipid antibodies .
 Hyperhomocysteinemia.
 Inflammatory Bowel Disease .
 Nephrotic syndrome.

Deep venous thrombosis :

 Diagnosis:
A. Clinical suspicion MOST IMPORTANT.
B. Serial compression US.
C. Contrast venography.
D. D-Dimer:
- Good negative test.
- Increased in cancer, after surgery.
 Impedance plethmogaphy (out of date).
 MRI (expensive).

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Pulmonary embolism :
 Clinical suspicion.
 Chest x ray.
 Ventilation perfusion scan.
 CT with pulmonary angiogram.
 MRI angiography.
 Pulmonary angiogram

Probability of PE

Variable Point
 DVT Symptoms and signs 3.0
 PE more likely 3.0
 HR > 100 beats/min 1.5
 Immobilization or surgery 1.5
 Previous DVT or PE 1.5
 Hemoptysis 1.0
 Malignancy 1.0

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 If clinical suspicion is low and D-dimer is negative,no imaging studies are needed
 |f CT is negative/non diagnostic and D-dimer is subsequently negative,and if the clinical suspicion is
also low,no further testing may be necessary. Pulmonary arteriography or a leg study should be
considered if the clinical suspicion is high.
 Although subsegmental emboli cannot be excluded, larger emboli are unlikely. A recent study
suggests CT is only 70% sensitive for acute PE
 lf The V/Q scan is very low probability, no further study is generally needed, If the V/Q is low or
intermediate probability and clinical suspicion is high, additional testing is needed, D-dimer testing
may be considered, especially when suspicion is low

Treatment
 Anticoagulants
o Heparin and LMWH.
o Oral anticoagulants.
o Newer anti coagulants.
 Inferior vena cava filter.
 Fibrinolytic therapy.

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Anti thrombotic
 Anti platelets
 Anticoagulants
 Heparin and LMWH and other ( parenteral)
 Vitamin K antagonist.
 Newer oral anti coagulants..
 Fibrinolytic therapy

A. Antiplatelets
 Aspirin:
 Clopidogrel:
 Abcimab,Epitifibtade, tirofeban:

Aspirin
 Inhibit cyclooxygenase irreversibly leading to diminshed production of platelet TX A2.
 Dose: 75 mg/PO/OD.
 Side effect: Gastritis, tinitus------

Others
 Dipyridamole (persantin):Phosphodiesterase inhibittor.
 Ticlodipine. Side effect neutopenia and thrombocytopenia.
 Clopidogrel: ADP receptor antagonist.
 GP IIa-IIIB antagonist : Abciximab,Epitifibatide, Tirofeban.

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B. Anticoagulants

Heparin
 Acidic unfractionated poly-saccaride.
 Dramatically potentiates action between AT and active factor IIa (thromin), IXa, Xa, XIa
irreversabily.
 Inhibit platelet function.

Administration and lab control

Administration
 Intravenous (Continous intravenous infusion)
 (loading 5000 unit followed by 1000 unit/hour).
 When rapid anti-coagulation is required.
 Sub- cutaenous (5000 u/ SC/8 hours.
 Start oral anticoagulants.
 NOT IM

Laboratory control
 APTT (2-3times).

Complications
 Bleeding.
 Osteoporosis.
 Heparin induced thrmbocytopenia
Heparin Induced Thrmbocytopenia
Mechanism: Platelet factor 4 (PF4) is released from a granules and forms a complex on
the platelet surface with heparin. Immunoglobulin G antibodies (usually IgG) develop
against this complex and once bound can activate the platelet through the platelet
immunoglobulin receptor Fc-RII This leads to platelet stimulation, further release of PF4
and the platelet release reaction with consequent thrombocytopenia and thrombus
development.
 With unfractionated Heparin.
 Diagnosis: 50% of the initial platelets.
 Treatment: Direct thrombin inhibitors

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Bleeding during heprin therapy
 Half life of heparin less than 1 hour.
 Protamine sulphate
 1 mg neutralize 100 u
 Paradoxical anti coagulant.
LMWH

Administration and lab control

Administration
 Sub-cutaenous
 NOT IM
Laboratory control
Anti Xa activity.

Warfarin—Indications
 Prophylaxis and/or treatment of:
o Venous thrombosis and its extension
o Pulmonary embolism
 Thromboembolic complications associated with AF and/or cardiac valve replacement
 Reduce risk of death, recurrent MI, and thromboembolic events such as stroke or
systemic embolization after MI

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Optimal Therapeutic Range for the INR in Various Indications
Indication for Warfarin Therapy Therapeutic INR Range Duration
Venous thromboembolism treatment 2.0–3.0
Venous thromboembolism prevention 1.5-2.5
Atrial fibrillation 2.0–3.0
Valvular heart disease 2.0–3.0
Heart valves
Tissue valves 2.0–2.5
Mechanical valves
Bileaflet aortic position 2.0–3.0
High-risk valve 3.4–4.0
Acute myocardial infarction
Prevention of embolism 2.0–3.0
Prevention of reinfarction 3.5–4.5

Warfarin Contraindications
 Risk of hemorrhage is greater than benefits of therapy
 Pregnancy
 Hemorrhagic tendencies or blood dyscrasias
 Traumatic surgery with large open areas, recent or contemplated surgery of CNS or
eye
 Bleeding tendencies with active ulceration or overt bleeding
 Senility, alcoholism, psychosis or other lack of patient cooperation
 Spinal puncture and procedures with potential for uncontrollable bleeding
 Inadequate laboratory facilities

Warfarin—Adverse Effects
 Fatal or non-fatal hemorrhage from any tissue or organ
 Necrosis of skin and other tissues
 Other adverse reactions reported less frequently include:
 Systemic cholesterol microembolization
 Alopecia

INCREASED ANTICOAGULANT EFFECT

 Aspirin  NSAIDs
 Cimetidine  Omeprazole
 Fibrates  Simvastatin

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 Sulphonamides  penicillins?
 Thyroxine  Erythromycin
 Amiodarone  Ciprofloxacin
 Quinidine  broad spectrum antibacterial agents
 hormone antagonists.  imidazole/triazole antifungal agents

DECREASED ANTICOAGULANT EFFECT

 Rifampicin  Carbamazepine
 Phenytoin  Cholestyramine
 Barbiturates  vitamin K
 griseofulvi  oral contraceptives
Elimination Half-Lives of Vitamin K-Dependent Proteins
 Warfarin induced skin necrosis
Protein Half-Life
Factor VII 4–6 hours
Factor IX 24 hours
Factor II 60 hours
Factor X 48–72 hours
Protein C 8 hours
Protein S 30 hours

Other anticoagulants

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Factor Xa Inhibitors:
 Fondaparunix: Synthetic analogue of the AT binding site of heparin.
 Fondaparinux (Arixtra®)-Synthetic sulphated pentasaccharide; active moiety of
heparin
 Irreversible inhibition to factor Xa.
 Only inhibits factor Xa
 No Need for lab monitoring.
 Bioavailability virtually 100%, can be given QD
 No thrombocytopenia seen in trials (does not bind to platelet factor IV)
 Data clearly shows it to be superior to LMWH when given postoperatively, & probably
superior to LMWH given preoperatively

FONDAPARINUJX
 Offers possibility of post-op prophylaxis against DVT with same or better efficacy as
preop administration of LMWH
 Small but real incidence of wound hematomas (nil if given >6 hrs post-op); bleeding
risk otherwise Similar to LMWH
 Avoids problems with administration of drug during regional anesthes1a, since can be
given after the epidural catheter is pulled
 Approved for treatment of VTE
 Longer prophylactic treatment better than shorter

Direct thrombin inhibitors:

 Hirudin,Argatroban.
 Efficacy and safety have been recently questioned
Lepirudin (Refludan®)
 Hirudin derivative
 Half life 30-40 minutes
 Problematic in renal disease Not reversible
 Approved for Heparin-Induced Thrombocytopenia and Thrombosis
Argatroban ®
 Small molecule active site blocker of thrombin
 Half life 30-40 minutes
 Problematic in liver disease
 Not reversible
 Approved for Heparin-Induced Thrombocytopenia and Thrombosis & for Acute
Coronary Syndromes

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Bivalirudin (Angiomax®)
 Hirudin derivative
 Short-acting
 Not reversible
 Approved for unstable angina/angioplasty

Fibrinolysis
Inhibitors of fibrinolysis
 Plasminogen activator inhibitors (PAIs)
 α2-antiplasmin (serpin)

C. Fibrinolytic therapy

 Agents that are able to lyse fresh thrombi

 Systematically to patients with STEMI, Ilofemoral DVT , Pulmonary embolism (with
homodynamic instability).
 Locally acute PVD.
 Streptokinase.
 t-PA.
 APSAC Acylated plasminogen steptokinase activator complex

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Absolute contraindications
 Active GIT bleeding.
 Aortic dissection.
 Neurosurgery in the past 2 months
 Intracranial neoplasm or vascular malformation.
 Proliferate diabetic retinopathy.
 Sever hypertension (180/110).

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Thrombotic micro- angiopathy
 Thrombotic microangiopathy (TMA) refers to a diverse range of pathological
syndromes leading to endothelial and red cell injury, platelet aggregation, and
thrombus formation in the microcirculation, with resultant thrombocytopenia,
hemolytic anemia, thrombosis, and tissue ischemia in various organs and tissues.

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 Pathological features:
1. Vessel wall thickening
2. Swelling and detachment of the endothelial cell from the basement membrane.
3. Intraluminal platelet thrombosis
4. Microangiopathic hemolytic anemia
5. Partial or complete vessel luminal obstruction and fragmentation of red blood cells

Thrombotic Thrombocytopenic Purpura (TTP):

 Epidemiology:
- more common in females age 10-39 yrs
- highest incidence is seen in fourth decade
- annual incidence 3.7 cases per 1,000,0001
 Clinical Presentation:
- Classic "Pentad" of symptoms:
1. microangiopathic hemolytic anemia 2. thrombocytopaenia
3. neurological symptoms 4. renal damage 5. Fever
 Plasma exchange improves symptoms; now standard treatment for TTP

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Hemolysis
1. Elevated reticulocyte count
2. Elevated serum lactate dehydrogenase (LDH),
3. Increased total and unconjugated bilirubin,
4. Undetectable serum haptoglobin
5. Presence of fragmented red cells (schistocytes).
6. Autoantibody testing (to rule out presence of autoimmune hemolytic anemia) is
often negative.

 Clinical subtypes of TTP:

Congenital
Acquired Acute idiopathic - No identifiable precipitant.
- Low relapse rate.
Secondary - Drugs (OCP, ticlopidine,
cyclosporin).
- B.M transplantation.
- SLE.
- Malignancy.
- Pregnancy.
- Infective-HIV.
Intermittent

 Treatment:
- plasma exchange should be started within 24h of presentation.
- Daily plasma exchange should continue for a minimum of 2d after complete
remission.
- Steroid therapy should be given pulsed methylprednisolone 1g IV for 3d is often used.
- Low-dose aspirin 75mg daily should be commenced on platelet recovery (platelet
count >50 × 109/L).
- Ritixumab
- Eculzimab
- Caplacizumab, a humanized anti-von Willebrand factor-directed nanobody that blocks
platelet adhesion and avoids microthrombi formation,

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Underlying Cause of TTP
 Idiopathic, Autoimmune disorder 33%
 Bacterial or viral infection including HIV or hepatitis
 Pregnancy
 Drug induced
 Other autoimmune disorders
 Pancreatitis
 Disseminated malignancy
 Post haematopoietic stem cell transplant

Differential Diagnosis of MAHA and low Platelets:

 Disseminated intravascular coagulation (DIG)
 Severe infection e.g. Meningococcus, pneumococcus
 Pregnancy associated e.g. Haemolysis with elevated liver enzymes and low platelets
(HELLP), Pre-eclampsia
 Autoimmune: Cerebral systemic lupus erythematosus (SLE), Lupus Nephritis, Acute
Scleroderma Renal Crisis
 Malignant Hypertension
 Haemolytic uraemic syndrome
 Catastrophic Antiphospholipid Syndrome
 Autoimmune haemolysis and Immune Thrombocytopenia (Evans Syndrome)

Lab :

FBC & blood film Anaemia fragments and thrombocytopenia

Reticulocyte count Raised
LDH Raised Raised
Haptoglobins Reduced Reduced
ESR If raised consider occult malignancy
DAT Usually negative
Anticardiolipin antibody Consider an underlying autoimmune precipitant
Lupus anticoagulant
Autoimmune profile
 Rheumatoid factor
 ANA
Thyroid Function Tests

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 Blood cultures  Consider an underlying infectious precipitant.

 Hepatitis serology (Hep A, B,C) Also important prior to PEX and Rituximab
 HIV treatment
 Stool for E.Coli  Consider HUS if E coli in stool MC+S
Urinalysis (Pregnancy / Protein) Rule out Pregnancy, HELLP, and PreEclampsia
 Clotting screen  Usuallynormal
 U&E  RenalImpairment (oftenmild)
 LFT  Usually normal
 Calcium  Raised in malignancy, may be reduced withPEX
 Amylase  TTP is rarely associated with pancreatitis
 Blood group & Antibody  For blood product provision
screen
ADAMTS13 assay: protease  Confirmation of diagnosis with low ADAMTS 13
activity+ Inhibitor assay (activity and antibody profile). Do not
- 4 x citrate tubes waitfor result before starting treatment in
- double spin & freeze suspected TTP
 CT brain  If significant neurological disturbance
 CT chest, abdo, pelvis  Consider to exclude underlying malignancy

 Echocardiogram, troponin,  Consider Cardiac involvement- these are high risk

and ECG patients and early Rituximab treatment should be
considered.

Hemolytic uremic syndrome (HUS):

 Epidemiology:
- More commonly seen in children rather than adults
- most common cause of pediatric acute renal failure
- occurs most frequently in children under the age of 5 years
- annual incidence of 6.1 cases per 100,000 children under 5 years
- affects 0.2 - 4.28 people per 100,000 worldwide

 Classification:
A) Typical
- More than 90% of cases in children
- secondary to infection with:
1) Escherichia coli serotypes O157:H7, O111:H8, O103:H2, O123, O26, or
others, which produce Shiga-like toxin (Stx)
2) several other bacteria, such as Streptococcus pneumoniae.
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B) Atypical
- Approximately 10% of cases in children
- not caused by either Stx-producing bacteria or streptococci.
- poor prognosis:
1) death rates as high as 25%
2) progression to end-stage renal disease in half the patients.
- Research has linked to uncontrolled activation of the complement system.
- more commonly associated with extra-renal effects than typical HUS

 Stx-related lesions indistinguishable from atypical form via standard histologic

analysis.

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