Bleeding disorder

Year 5 Group 4

Overview of Hemostasis

Hemostasis
is a process of forming clots in the walls of damaged blood vessels and preventing blood loss while maintaining blood in a fluid state within the vascular system. Maintain a balance between coagulation and anticoagulation

Role of Haemostasis
Stopping bleeding from site of blood vessel injury Prevent extensive clot Breakdown such clot once damage is repaired.

Systems involved in Hemostasis

Vascular system
Injured vessel initiates vasoconstriction

Platelet System
Injured vessel exposes collagen that initiates platelet aggregation and help form plug

Coagulation System
protein factors of intrinsic and extrinsic pathways produce a permanent fibrin plug

5 major components 1. 2. 3. 4. 5. Blood vessels Platelets Coagulation Factors Coagulation inhibitor (anticoagulant) Fibrinolytic system

1. Blood vessels Endothelial cells are arranged closely with each other without gaps in between- Prevents contact of blood with subendothelial layer Vasoconstriction

Function of endothelial cell

2. Platelet

To form primary (10) hemostatic plug Procoagulant activity platelet membrane phospholipid contact factors

HEMOSTASIS
Primary vs. Secondary vs. Tertiary
Primary Hemostasis
Blood vessel contraction Platelet Plug Formation Dependent on normal platelet number & function Initial Manifestation of Clot Formation

Secondary Hemostasis
Activation of Clotting Cascade & Deposition & Stabilization of Fibrin

Tertiary Hemostasis
Dissolution of Fibrin Clot Dependent on Plasminogen Activation

Primary Hemostasis
When a blood vessel is damaged, 1. Vasoconstriction occur to reduces blood flow to injured area. It is trigger by direct injury to vascular smooth muscle and release of endothelin by endothelial cell

release of vasoconstrictors liberated from platelets that adhere to the walls of the damaged vessels eg: serotonin, ADP , Thromboxane A2 2. Platelet plug formation platelet adhere to exposed subendothelium to form temporary plug.

Platelet Adhesion
Platelet ADHERES to exposed collagen. vWF acts as glue to help platelets to stick to vessel wall. lipid mediator plateletactivating factor (PAF) synthesized by endothelial cells promotes the activation of platelets and their adhesion to the endothelial cells

The role of von Willebrand factor (vWF) in platelet adhesion. High flow rates induce conformational changes in vWF allowing interaction of its A3 domain with matrix collagen. This induces a conformational change in the A1 domain, thereby allowing interaction with glycoprotein (GP) platelet receptor Ib-IX-V. This interaction stimulates calcium release, subsequent platelet activation, and subsequent conformational change of the fibrinogen receptor (GPIIb/IIIa), which can interact with fibrinogen and vWF to favor the interaction between platelets (platelet aggregation process). ADP indicates adenosine diphosphate; RGD, Arg-Gly-Asp amino acid sequences

Shape change
Becoming more spherical Form pseudopods Reorganization of internal constituents - forcing granules towards the plasma membrane Facilitating secretion of their contents

Release Reaction

Secretion of its granule contents ADP Serotonin Fibrinogen PDGF Activate arachidonic acid pathway which lead to formation and release of Thromboxane A2

Recruitment and Aggregation

Release ADP and TX2 cause additional platelets to aggregate at the site of vascular injury. Results in formation of large platelet plug (10 hemostatic plug)

Secondary hemostasis

Activation of Clotting Cascade & Deposition & Stabilization of Fibrin

3. Coagulation Factor
Intrinsic pathways Extrinsic pathways Common pathways

(IIa)

(II)

Xa: Prothrombin activator

Vitamin K dependent clotting factors

Fibrin polymer which is formed re enforce the platelet plug. Thus the platelet plug formed becomes more stable.

The fibrin polymer further stabilized and the clot become retracted and solidified.

4. Coagulant inhibitors
Effect of thrombin is limited to the site of injury Tissue factor pathway inhibitor (tFPI) -inactivates complex FXa, FVIIa and TF Protein C and Protein S -inactivate coagulation cofactors, FVIII and V. Antithrombin -inactivates thrombin and other serine protease.

Intrinsic pathway XII

Contact

XIIa

Extrinsic pathway

TFPI
XI
Ca 2+

XIa

Protein C
IXa
Ca 2+ VIII Ca 2+ V

IX

VIIa

TF

VII

X II

Xa
Ca 2+

Protein C
XIII

IIa XIIIa

Antithrombin
Fibrinogen

Fibrin

Tertiary hemostasis
Fibrinolysis - Dissolve the fibrin.
Plasminogen tPA Plasmin Fibrin

Fibrin degradation product (FDP)

Summary of reaction involved in hemostasis

1 hemostasis 2 hemostasis

 Platelet are produced in the bone marrow by fragmentation of the cytoplasm of megakaryocyte. Main function of platelets is the formation of mechanical plugs during the normal haemostatic response to vascular injury The normal platelet count is 150-400x10^9/L Average life span of 7-10 days Platelet disorders typically characterized by bleeding by purpura and bleeding from mucous membrane

 Defined as reduced in the platelet count< 150 x 10^9/L abnormal bleeding, that characterized by spontaneous bleeding and mucosal hemorrhage

Thrombocytopenia
(Quantitative)
Decreased platelet production

Sequestration

Increased destruction

 Usually part of generalized bone marrow failure, ex: cytotoxic drugs, radiotherapy, aplastic anemia, leukaemia, myelodydplastic syndrome, myelofibrosis, marrow infiltration by carcinoma or lymphoma, megaloblastic anaemia

Can also be due to selective megakaryocyte depression cause by drug or chemical toxicity and viral infection

 Caused by splenomegaly Usually, only 1/3 of total platelet are within the spleen When the spleen enlarges, it can retain or sequester up to 80-90% of body platelets and decreased platelets in the peripheral circulation. plt lifespan is normal

 Most common cause of thrombocytopaenia Immune destruction and non-immune destruction

 1) autoimmune idiopathic (ITP)-a diagnosis of exclusion, acute or chronic associated with autoimmune disease or malignancy eg;SLE, CLL, lymphoma 2) drugs-quinidine and heparin, bind to a plasma protein and elicit the production of an IgG antiplatelet antibody. The antibody-coated platelet is then removed by the reticuloendothelial (RE) system. Tx by stop all suspected drugs and transfuse platelet concentrates. 3) infections- immune complexes are absorbed onto the platelet surface, which are then removed by the RE system eg: HIV

 4)alloimmune eg; post transfusion purpura thrombocytopaenia occuring 7-10 days after bld transfusion due to antibody against human plt antigen-1a (HPA-1a)on transfused plt. Antibody also destroys self plt. Bleeding may be severe. Tx: Plasmapheresis, steroid and IVIG.

o Acute ITP o Chronic ITP (starts after the disease has been present for > 6 months). Antiplatelet autoAb(usually IgG) that bind to platelet membrane. The antibody-coated platelets are removed following binding to Fc receptors on macrophage causing their premature destruction by the reticuloendothelial system(spleen) normal lifespan of platelet is 7-10 days but in ITP is reduced to a few hours

Most common autoimmune-mediated thrombocytopenia May divided into

antibody-coated platelets are removed following binding to Fc receptors on macrophage

 Most common in children, the peak age is 2-4 years girls and boys are equally affected self-limiting disorder that resolves spontaneously usually within 2 months Episode follows vaccination or viral infections in the preceding 2-4 weeks. 75% of patients remit spontaneously with 70% achieving platelet count of more than 50x10^9/L by the 4th week of illness In 5-10% of cases, the disease becomes chronic( > 6months)

 Clinical features: Acute onset, with a spectrum of bleeding severity ranging from superficial (petechiae, purpura) to lifethreatening. Hepatosplenomegaly or lymphadenopathy is absent. Diagnosis: clinical diagnosis, (history and PE) full blood count (isolated thrombocytopenia), and examination of the peripheral blood smear (reduce plt num and presence of giant platelet). Bone marrow examination is only indicated in patients not responding to therapy (Normal/ increased megakaryocyte) Additional investigations are done as clinically indicated

 Additional Ix:
ANF and antiDNA antibodies in those progressing into chronic ITP immunoglobulin levels in those with recurrent infections HIV screening for those at risk e.g. parents with HIV infection, intravenous drug users. Coagulation profile is needed for those with suspected non-accidental injury, inherited bleeding disorders or meningococcal infection.

 Tx: Tx as outpatient(observation and monitoring) in platelet count > 20 x10^9/L without bleeding tendencies. Advice for precaution with physical activities, avoidance of contact sports and seeking immediate medical attention if bleeding occurs. Hospitalisation: acute severe life-threatening(ICH) or mucosal bleeds regardless of platelet count or if platelet count is < 20 x109/L without bleeding but with poor access to health care. Tx options include : IVIG 0.8 g/kg as a single dose, or oral prednisolone 2 mg/kg/day for not more than 14 days, or oral prednisolone 4 mg/kg/day for 4 days

 Highest incidence in women aged 15-50 years old. most common cause of thrombocytopenia without anemia/ neutropenia. Plt sensitization with auto abs-IgG: remove by the macrophages of the RES esp spleen prematurely. insidious onset, with no prodromal illness. Total megakaryocytes and plt turnover are increased. Symptoms and signs are highly variable, ranging from the common asymptomatic patient with mild bruising or mucosal bleeding to frank haemorrhage from any site, the most serious of which is intracranial but rare.

 The degree of bleeding is largely dependent on the platelet count and patients with platelet counts below 10x10^9/l (and usually below 5x10^9/l)are at greatest risk of bleeding, including intracranial haemorrhage( rare). Spleen not enlarged unless there is associated dz causing splenomegaly Tend to relapse and remit spontaneously May be seen in a/w SLE, HIV, CLL, hodgkins disease or autoimmune haemolytic anaemia

DIAGNOSIS
Clinical diagnosis Investigations 1) Full blood count Low platelet count Normal Hb and WBC 2) Peripheral smear Reduced platelets num giant platelets (signs of thrombopoietininduced megakaryocyte stimulation ) 3)Bone marrow examination normal or increased megakaryoctes number

4) Coagulation tests Prolong bleeding time, normal PT and aPTT 5) ANF and anti-DNA antibodies: to exclude other autoimmune diseases which may be associated with thrombocytopenia, e.g. systemic lupus erythematosus or antiphospholipid syndrome. 6)HIV antibody testing should also be done in patients with risk factors for HIV infection

TREATMENT
Patients with platelet counts exceeding 30 x 10^9/L require no treatment. Treat when symptomatic or when platelet count <30x10^9/L First Line Therapy in Adults Oral corticosteroids are used as first line therapy at 1 mg/kg body weight /day (max 60 mg) for 2-4 weeks tapering off over several weeks Intravenous methylprednisolone (30 mg/kg body weight/day with total maximum daily dose of 1 gram for 3 days) is an alternative to oral prednisolone where more rapid response is required Intravenous immunoglobulin (1g/ kg body weight /day for 2 days or 0.4 g/kg/day for 5 days) is useful in severe ITP who require rapid rise of platelet count. MOA : block Fc receptors on macrophage/ modify autoantibody production

 IVIG is effective in elevating the platelet count Combination of IVIG/ oral prednisolone seemed to be more effective than IV methylprednisolone/ oral prednisolone in adults with severe ITP Adverse effects with intravenous immunoglobulin are common but generally mild including fever, chills, rigors, headache and backache.

Second Line Treatment Patients not responding to steroids or requiring persistently high doses require second line therapy. The choice of therapy must be individualized. The treatment options are: Splenectomy. Danazol Azathioprine Dapsone Eltrombopag ( oral thrombopoietin receptor agonist) intravenous anti-D rituximab (anti-CD20 monoclonal antibody)

 Splenectomy (two thirds of patients achieving a complete remission) --> indicated in : - patients with symptoms and platelet count < 30 x 10^9/L despite 3 months of steroid therapy - require unacceptably high dose steroids to maintain platelet count > 30 x 10^9/L Immunosuppressive drugs - For those do not respond sufficiently to steroid and splenectomy - Ex: azathioprine, cyclophosphamide

Indications for platelet transfusion in ITP Platelet transfusion in ITP is only given in the following situations: 1. life-threatening haemorrhage e.g. intracerebral haemorrhage (ICH) 2. severe thrombocytopenia < 10 x 109/L and patient has to undergo an emergency surgery High dose IV steroids and IVIG must also be given together to raise the platelet counts and to stop the haemorrhage. Platelet survival is increased if the platelets are transfused immediately after IVIG infusion Recommendations : Platelet Transfusion Dosage 6-8 U of platelet concentrate, or 1 U/10 kg body weight 1 U of platelets to increase count of a 70-kg adult by 510 x 109/L and an 18-kg child by 20 x 109/L

Antiplatelet drugs

Uremia

Acquired
Hyperglobulinemia Myeloproliferative and myelodysplastic disorders
GLYCOPROTEIN RECEPTOR ABNORMALITIES Bernard-Soulier disease Glanzmanns thrombasthenia

Platelet dysfunction ( Qualitative)

Hereditary

Storage pool disease

 Aspirin
Aspirin is the most common. Associated with GI haemorrhage. Purpura may not be obvious and produce prolonged bleeding time inhibition of cyclo-oxygenase with impaired thromboxane A2 synthesis. hence, this will impair the release reaction and aggregation. defect after single dose lasts 7-10 days. Tx: withold aspirin ( if pre-op, stop 1 week prior to it)

 Dipyridamole phosphodiesterase inhibitor, lead to increase cAMP level and inhibit platelet aggregation. used as an adjunct to oral anticoagulants Clopidogrel - inhibit ADP binding to platelet receptor, impair platelet aggregation. IV agent (abciximab) a glycoprotein IIb/IIIa receptor antagonist used in pt undergoing PCI with unstable angina and ACS risk of transient thrombocytopenia and need platelet transfusion

 Inhibits plt function by uremic toxins,

Abnormal bleeding is common. Bleeding time is prolonged. Blood vessels in patients with uraemia produce greater quantities of platelet-inhibitory prostaglandin and synthesize less thromboxane A2 Tx: platelet transfusion
dialysis

 a/w multiple myeloma may cause interference with platelet adherence, release and aggregation

COAGULATION DISORDERS
A) Haemophilia A and B B) Anticoagulant (Warfarin and Heparin) C) Acquired Factor VIII Inhibitor

Causes of Coagulation Deficiency and Coagulation Dysfunction

Common Group
Disorder Pathophysiology Mode of Inheritance
XL

Molecular genetics

Approximate incidence
100

Haemophilia A

Factor VIII deficient or defective

Deletions ,inversions, missense, nonsense, insertions, splicing Deletions, missense, nonsense

Von Willebrands disease

Von Willebrand factor deficient or defective

AD or AR

AD : 100 or more AR : 1

Haemophilia B

Factor IX deficient

XL

Deletions ,missense, nonsense , splicing

20

Haemophilia C

Factor XI

AD or R

Missense, nonsense splicing

5 % in Ashkenazi Jews,others rare

XL ,X linked recessive ; AD, autosomal dominant ; AR , autosomal recessive

Rare Group
Disorder Mode Of Inheritance Molecular Genetics Approximate incidence per 106 population
1 1 Missense, Nonsense, deletion, splicing Missense 1

Factor X deficiency Factor V deficiency Factor VII deficiency

AR AR AR

Deletions, Missense

Factor II (prothrombin) deficiency

AR

Factor XIII deficiency Afibrinogenaemia

Dysfibrinogenaemia Factor V plus VIII deficiency

AR AR
AD AR

Missense, deletion

Missense Missense, Nonsense, Deletion, Insertion Missense, Insertion

1 1

Hyperplasminaemia 2antiplasmin deficiency

AR

Very Rare

 Vit K def- Hemorhagic Disease Newborn -Biliary obstruction -drugs- warfarin and heparin (anticoagulant) Liver disease, Renal disease, Malabsorption DIC disseminated intravascular coagulation Inhibitors of coagulation: FVIII inhibitor/antibody to factor VIII eg in autoimmune disease (SLE) Massive transfusion syndrome- massive blood loss due to low factor VIII and factor V due to dilutional effect.

Haemophilia A & B

 Factor VIII (antihaemophilic factor) deficiency The most common hereditary clotting factor deficiencies. Sex linked inheritance (recessive). 33% spontaneous mutation and therefore no family history Clinical features: based on severity of the disease.

Coagulation factor activity (%)

Clinical features Severe disease Frequent spontaneous bleeding Joint deformity and crippling if not adequately treated. Moderate disease Post traumatic bleeding Occassional spontaneous episodes Mild disease Post traumatic bleeding

<1

1-5 5-20

Profuse post circumcision bleeding Joint and soft tissue bleeds haemophilic pseudo-tumors. Muscle haematomas-> Compartment Syndrome Painful haemathroses Prolonged bleeding after dental extractions GIT bleeding/hematuria Operative and traumatic bleeding: may be life threatening in both severely and mildly affected pts. Intra cranial bleeding- high mortality.

Right knee haemarthrosis with muscle wasting at the medial sight of thigh

Grade 1
- popliteal soft tissue fullness indicative of synovial thickening and osteopenia of the tibial epiphysis.

Grade 2
-normal cartilage interval, early joint surface erosions, widened epiphyses, and juxta-articular osteopenia.

Grade 3
- medial compartment has surface irregularity, subchondral cysts, reactive sclerosis, and partially narrowed cartilage interval

Grade 4
- complete loss of cartilage interval, extensive surface erosions, a large synovial cyst, tibiofemoral subluxation, and lateral subluxation of the patella.

Muscles hematomas

 Laboratory: Prolonged APTT& corrected APTT by mixing test Immunological: Factor VIII assay DNA study: For diagnosis and carrier detection.

Management
Multidisciplinary team Factor VIII replacement therapy
Factor concentrates

Cryopercipitate from blood donors Porcine factor VIII concentrates Recombinant factor VIII ( therapeutic or prophylactic) DDAVP ( 1- desamino-8-D-arginine-vasopressin) mild hemophilia; Cause increase release of factor VIII from endogenous stores

Supportive care (Resting and prevention from further trauma) joint bleeding Prophylactic treatment: home therapy

Development of Factor VIII antibody/inhibitor Especially in Hemophilia A (5-10%) Poor response to treatment Continue to bleed despite on the replacement Ix: Factor VIII inhibitor assay Mx: APCC activated prothrombin complex concentrates FEIBA- Factor eight inhibitor bypassing agents

Principle of haemostatic tests- APTT and Mixing test

APTT Mixing test: Use to detect factor deficiency or factor inhibitor Prolonged APTT = 67 secs ( 30- 39 secs) Mix normal plasma and patient plasma (1: 1) Do clotting test (repeat APTT) Check APTT result again: i) clotting time: 36 secs (corrected factor deficiency)

ii) Clotting time 60 secs

( not corrected-still prolonged factor inhibitor)

Patient plasma

Normal plasma

Anaemia Chronic haemophilic arthritis pseudotumor hematuria neurology

CNS Spinal cord Peripheral nerves

HIV/AIDS The hemophilic patients get HIV/AIDS from the blood of the HIV/AIDS donor due to the transmission of HIV virus from the donors blood to the recipients blood. Hepatitis Same goes to the hepatitis virus by spreading from the donors blood to the recipients blood. Muscular Damage (eg: muscle atrophy)

 Clinical features are the same with Hem A Factor IX deficiency The two disorders can be distinguished only by factor assay. Lab Ix: - Prolonged APTT -Low in the factor IX levels - Bleeding time and Prothrombin time are normal Rx: Factor IX concentrates (biological long half-life-> infusions do not have to given as frequently) -Recombinant FIX

Most common inherited bleeding disorder Deficiency of vWF (factor) vWF has 2 roles: - promotes platelet adhesion to damage endothelium - Carrier protein for FVIII protecting from premature destruction( in vWD factor VIII level may be reduced)

Types: Type I- partial reduction in vWF Type 2-abnormal vWF Type 3- total lack of vWF AD- varying expression Severity of bleeding is variable.

Bleeding from mucous membrane and skin Excessive bleeding from cuts and abrasions Operative and post traumatic bleeding Haemathroses and muscle haematomas are very rare presentation except in type 3

Lab Investigations:
bleeding time is prolonged Fac VIII levels are low Prolonged APTT vWF/antigen is low (type 1) Platelet count=normal; thrombocytopenia (type2B) Y? abnormally high affinity for platelets

Treatment:
antifibrinolytic agents (tranxenamic acid for mild bleeding) DDAVP- for type I (C/I in type 2B) Immediate-purity factor concentrates contain vWF (Contain both VWF and factor VIII)-> very low VWF levels cryoprecipitates- not recommended nowadays

Anticoagulant-induced coagulation disorder

 Vitamin K antagonist Decreased biological activity of the vitamin K dependent factors II, VII, IX and X. After warfarin is given, factor VII levels fall considerably within 24H but prothrombin has a longer plasma half-life and only falls to 50% of normal at 3days The patient is fully anticoagulated only after this period

 Typical starting regime for warfarin would be 10mg on day 1 5mg on day 2 5mg on third day After this, dosage adjusted according to PT Usual maintenance dose 3-9mg/day Crosses placenta and is teratogenic Continue warfarin for 3-6months for DVT, PE.

Target levels for INR

Pulmonary embolism and DVT Aim INR of 2-3; 3.5 if recurrent Atrial fibrillation For stroke prevention: Target INR; 2-3 Prosthetic metallic heart valves For stroke prevention: Target INR; 3-4

Day
1 2 3 (16 hrs)

INR

Dosage
5 or 10 5 or 10

<2.0 2.0-2.1 2.2-2.3 2.4-2.5 2.6-2.7 2.8-2.9 3.0-3.1 3.2-3.3 3.4 3.5 3.6-4.0 >4.0 <2.0 2.0-3.5 3.6-4.0 >4.0

8 5 4.5 4.0 3.5 3.0 2.5 2 1.5 1 0.5 NA 8 Stay -1.0 Omit next days dose then 2.0

Drug Interactions
97% bound to albumin Free fraction enter liver parenchymal cells and is active In liver cells, degraded in microsomes to inactive water-soluble metabolite which is conjugated and excreted in the bile and partially reabsorbed to be also excreted in urine Drug that affect the albumin binding or excretion of warfarin or those that decrease the absorption of vitamin K will interfere with the control of therapy

Management of warfarin overdose

INR>4.5 without bleeding, stopped for 1 or 2 days, then dose adjusted according to INR. The long half-life of warfarin (40H) delays the full impact of dose changes for 4-5days. If INR is very high (>8) without bleeding, oral dose of 0.5-2.5mg vitamin K may be given. Mild bleeding only need INR assessment, drug withdrawal and dosage adjustment.

 Serious bleeding may need cessation of therapy, vitamin K therapy or the infusion of fresh frozen plasma or prothrombin concentrates. Vitamin K is the specific antidote Oral or IV dose of 2.5mg is usually effective Higher doses result in resistance to further warfarin therapy for the 2-3 weeks.

Management of surgery
For minor surgery (eg dental extraction) anticoagulant can be maintained and mouth rinses with tranexamine acid given. For major surgery, warfarin is stopped to get an INR<1.5 and LMWH given when the INR falls to <2.0 (except on the day of surgery) and continued until the INR is >2.0 after restarting warfarin.

 Acidic, unfractionated mucopolysaccharide of average molecular weight (MW) 15000-18000 Inhibitor of blood coagulation Potentiating the activity of antithrombin Must be given by injection Inactivated by the liver and excreted in the urine Effective biological half-life is approximately 1H

Mechanism of Action:
Potentiates the formation of complexes between antithrombin and activated serine protease coagulation factors, thrombin (IIa) and factors IXa, Xa and XIa Inactivates these factors irreversibly Also impairs platelet function LMWH preparation (MW 2000-10000) are produced by enzymatic or chemical depolymerization of unfractionated heparin.

Unfractionated Heparin Mean Molecular weight in kilodaltons (range) Anti-Xa : anti-IIa Inhibits platelet function Bioavailability Half-life -Intravenous -subcutaneous Elimination Monitoring Frequency of heparin-induced thrombocytopenia Osteoporosis 15 (4-30) 1:1 Yes 50% 1H 2H Renal and hepatic APTT High Yes 4.5 (2-10) 2:1 to 4:1 No 100% 2H 4H Renal

LMWH

Xa assay (usually not needed) Low Less frequent

Standard Heparin
Continuous intravenous infusion Smoothest control of heparin therapy Rapid reversal of anticoagulation by protamine sulphate Adult: 30000-40000 u/24H (1000-2000 u/H) Monitor APTT: 2-3 times upper limit of normal value Start warfarin within 2 days of starting heparin Discontinue heparin when INR > 2.0 on 2 successive days

Coagulation profile to be taken before IV bolus and subsequently 6 hourly Results of coagulation profile to be reviewed and acted upon within 2 hours of taking the APTT Loading DOSE: 75u/kg Initial maintenance dose: 13u/kg
APTT <40 40-54 55-95 96-120 >120 Rate of Change Add 200u Add 100u Stay Withhold 30min (-100u) Withhold 60min (-200u) Repeat APTT 6H 6H 6H 6H 6H

Loading DOSE: 5000u Initial maintenance dose: 1000u/hr

aPTT
<35s 35-45s 46-70s 71-90s >90s

IV Heparin dose modification

5000u bolus and add 200u/hr 2500u bolus and add 100u/hr No change Reduce by 100u/h Withhold infusion for 1 hour and reduce by 200u/hr

LMWH
Given by subcutaneous injection Longer half-life, given once a day More predictable dose-response which avoids the need for routine monitoring Less risk of thrombocytopenia or osteoporosis Typical treatment regimes: 200 anti-Xa units/kg OD or 100 anti Xa units/kg BD LMWH is preferred for DVT & PE.

Complication
Risk of complication reduced by 50% by the use of LMWH a)Bleeding during heparin therapy -Protamine able to inactivate heparin immediately -Severe bleeding 1mg/100u-heparin b) Heparin-induced thrombocytopenia

c) Osteoporosis -occurs with long-term (>2months) heparin therapy -the drug complexes minerals from the bone

Heparin-induced thrombocytopenia
Mild platelet lowering in first 24H as a result of platelet clumping, no clinical consequence HIT type 1 HIT type II, may occur in 5% of patients with standard heparin. Binding of heparin to platelets heparin-platelet factor 4 (PF4) complex Generation of IgG to PF4 complex platelet activation. Presentation: Fall of >50% of platelet count, 5 days or more after starting heparin treatment and thrombosis. Heparin must be discontinued. Thrombin inhibitors such as hirudin or lepirudin or argatroban and heparinoid danaparoid as alternatives.

 Acquired hemophilia A; has no known genetic inheritance pattern Rare bleeding diathesis caused by autoantibodies directed against clotting factor VIII and associated with an increased morbidity and mortality The incidence of acquired hemophilia A increases with age, being a very uncommon condition in children. The age distribution of autoantibodies is typically biphasic with a small peak between 20 and 30 years, due to postpartum inhibitors and a major peak in patients aged 68 to 80 years. The incidence in men and women is similar except in the age range 20 to 40 years, when the effect of pregnancy results in a preponderance in women.

 Type 1 inhibitors develop in patients with congenital hemophilia A and are generally alloantibodies that show complete neutralization of FVIII activity. Acquired inhibitors to FVIII show type 2 kinetics, with a rapid neutralization phase, followed by an equilibrium in which residual FVIII activity can be detected in vitro. Although the type 2 inhibitors usually do not totally inactivate factor VIII in vitro, the measurable factor activity offers little or no protection against hemorrhage in vivo.

Conditions associated with acquired hemophilia A

Diagnosis
Based on: (1) the initial detection of an isolated prolongation of activated partial thromboplastin time (APTT), which cannot be corrected by incubating for 2 hours at 37C equal volumes of patient plasma and normal plasma (mixing study); and (2) subsequent identification of a reduced FVIII level with evidence of FVIII inhibitor activity (titrated using the Bethesda assay or its Nijmegen modification)

Clinical Features
Hemarthroses are the hallmark of congenital hemophilia, but they seldom occur in acquired hemophilia. Classically presents with purpura or soft tissue bleeding. Severe muscle bleeding, hematuria, epistaxis, gastrointestinal bleeding and even intracerebral bleeds are seen more frequently. Inhibitor development in congenital hemophilia no longer appears to increase mortality, whereas patients with acquired hemophilia continue to exhibit an increased mortality Manifest more dramatically by excessive bleeding following trauma or surgery

Treatment

Treatment of acute bleeding episodes and the long-term eradication of the autoantibody

A) Treatment of Acute Haemorrhages

Bypassing Treatment First-line treatment Both the recombinant activated factor VII (rFVIIa) and the activated prothrombin complex concentrate (aPCC) factor 8 inhibitor bypassing activity (FEIBA)= EFFECTIVE Treatment of Raise Circulating FVIII To achieve hemostatic levels in situations Eg: Porcine FVIII concentrates, Human FVIII concentrates, Desmopressin

B) Long-term Eradication of the Autoantibody (Inhibitor) Immunosuppressive agents (steroids, cytotoxic drugs such as cyclophosphamide, azathioprine and vincristine, cyclosporine, and rituximab [Immunosuppressive agents]) High-dose intravenous immunoglobulin (IVIG), immunoadsorption Immune tolerance

Thank You for your attention

Bleeding rose and Heart

BLEEDING DUE TO BOTH PLATELET AND CLOTTING FACTOR DISORDER.

In what condition they co-exist?

A) Disseminated intravascular coagulation (DIC) B) Liver disease C) Massive blood transfusion D) von Willebrand disease (vWD)

DIC
Disseminated Intravascular Coagulation

Systemic activation of the blood coagulation system

result in the generation and deposition of fibrin

Micro-vascular thrombi in various organs

development of multi-organ failure

ongoing activation of the coagulation system

Consumption of coagulation protein and platelets

induce severe bleeding complication

DIC
ACUTE
CHRONIC

Acute DIC
clinically is life threatening, need to recognize/diagnose fast and manage as haematologic emergency need to treat the primary disorder and give blood transfusion support
develops when sudden exposure of blood to procoagulants (eg, tissue factor [TF], or tissue thromboplastin) generates intravascular coagulation. Compensatory hemostatic mechanisms are quickly overwhelmed, and, as a consequence, a severe consumptive coagulopathy leading to hemorrhage develops. Abnormalities of blood coagulation parameters are readily identified, and organ failure frequently results.

Chronic DIC
not critical possible conversion to acute DIC as a result of haemostatic decompensation need to treat the cause/ primary disorder but usually blood transfusion is not indicated reflects a compensated state that develops when blood is continuously or intermittently exposed to small amounts of TF. Compensatory mechanisms in the liver and bone marrow are not overwhelmed, and there may be little obvious clinical or laboratory indication of the presence of DIC. more frequently observed in solid tumors and in large aortic aneurysms.

Aetiology of DIC

Acute Infection/sepsis Obstetric complications Trauma-severe Transfusion of ABO incompatible blood

Chronic Malignancy Retained dead fetus severe localised intravascular coagulation Hematologic disorders Autoimmune diseases

PATHOPHYSIOLOGY
Triggered by the entry of procoagulant material into the circulation Widespread endothelial damage and collagen exposure

Involves 2 steps

First step
abnormal activation of coagulation by triggering mechanism Result in thrombin generation

 Activation of thrombin leads to:

Conversion of fibrinogen to fibrin Activation of platelets Activation of factors: FV and FVIII Activation of endothelial cells Activation of fibrinolysis

Disseminated micro/macrothrombosis

Second step
Consumption of coagulation factors, and platelets Activation of fibrinolysis Generation of plasmin Locally dissolves the microthrombus production of Fibrin/fibrinogen degradation products (FDPs).

Bleeding

FDP
(Fibrin Degradation Product)

combine with circulating fibrin monomers soluble fibrin monomer (sFM). Inhibit thrombin action interferes with fibrin monomer polymerization impair hemostasis Bind to platelet membranesPlatelet function defect biodegrades factor V,VIII,IX,XI and others

Trigger factor

Activation of coagulation cascade

Vessel wall damage

Platelet activation
Distored and fragmented RBC Intravascular hemolysis

Fibrin-platelet thrombosis

End organ damage

Coagulation factor deficiency

Low platelet count

Fibrinolysis activation FDPs generated

Hypotension, Shock

Generalized bleeding tendency

Interfere fibrin monomer polymerization

Inhibit thrombin

Bind to platelet membrane

biodegrades factor V,VIII,IX,XI and others

Clinical Features
(acute)

Thrombosis

Haemorrhage

Cytokine and Kinin generation

1) Thrombosis
Renal failure Coma Liver failure Respiratory failure (Chest pain and
dyspnea, hemoptysis, and cough)

Skin necrosis/gangrene Venous thromboembolism :

i) Pain, redness, warmth, and swelling in the lower leg ii) Headaches, speech changes, paralysis ,dizziness, and trouble speaking and understanding

2) Hemorrhage
Persistent bleeding/oozing at the venipuncture/surgical sites Spontaneous bruising Petechiae GIT bleeding Resp tract bleeding ICB

 Meningococcemia ( purpura fulminans ) bleeding from GI tract, gingival bleeding, epistaxis, pulmonary haemorrhage, hematuria

 Circulatory signs :
-Signs of spontaneous and lifethreatening hemorrhage -Signs of subacute bleeding -Signs of diffuse or localized thrombosis -Bleeding into serous cavities

Cardiovascular signs : -Hypotension -Tachycardia -Circulatory collapse

Respiratory signs : -Pleural friction rub -Signs of acute respiratory distress syndrome (ARDS)

Central nervous system signs :

-Nonspecific altered consciousness or stupor -Transient focal or neurologic deficits

 GI signs :
-Hematemesis -Hematochezia

Dermatologic signs :
-Petechiae -Jaundice (liver dysfunction or hemolysis) -Purpura -Hemorrhagic bullae -Acral cyanosis -Skin necrosis of lower limbs (purpura fulminans) -Localized infarction and gangrene -Wound bleeding and deep subcutaneous hematomas -Thrombosis

Genitourinary signs :
-Signs of azotemia and renal failure -Acidosis -Hematuria -Oliguria -Metrorrhagia -Uterine hemorrhage

3) Cytokine and kinin generation

Tachycardia Shock Hypotension Oedema

Clinical finding of Chronic DIC

Compensated Few or no clinical signs Non-obvious multiple small microthrombosis No or few bleeding Risk of decompensation

Cont.
superficial and extensive ecchymosis of extremities without petechiae which may be intermittent or can persist. recurrent episodes of epistaxis or internal mucosal bleeding. impairment of renal function, confusion, repeated episodes of cerebral thrombosis

Diagnosis
Laboratory tests:
No single test for confirmation Panel of tests needed in coagulation study Screening tests More Specific tests

Screening tests
PT aPTT Platelet count Thrombin time Fibrinogen level Acute phase protein Coagulation factor assay

More specific assay

To suggest the presence of abnormally high concentration Thrombin FDPs Fibrin monomer D-Dimer

Acute
PT/PTT Prolonged

Chronic
Normal

Platelets
Fibrinogen Fibrin monomer FDP D-Dimer TT Factor assay Antithrombin

Decreased
Decreased Positive Positive Positive Prolonged Usually decreased FV & FVIII Usually low

Normal
Normal Positive Positive ( concentration) Positive Often normal

Usually normal

Morphological findings in DIC

Schistocytes are red cell fragnents seen in 50% of patient with DIC Absence of red blood cell fragments does not rule out diagnosis of DIC -mild reticulocytosis -mild leucocytosis -(L) shift

Management
Supportive measures and removal of triggering mechanism are the key to successful management.

Outcome depends primarily on the ability to deal with the trigger and not on direct attempts to correct the coagulation deficit.

Replacement therapy
Indicated only in patients with active bleeding and in those requiring an invasive procedures or otherwise at risk for bleeding complication Should not instituted on the basis of laboratory results alone!

Goals
Platelet count > 50microliter Fibrinogen concentration > 1g / L Prothrombin values less than double the normal range.

Blood products
Packed red cells Plt concentrate FFP Cryoprecipitate AT concentrates Factor concentrates

 Fresh Frozen Plasma ( FFP ) - 0.7- 1.0 U/ml of factors II,V,VII,VIII,X,XI, XII, XIII and 2.5mg/ml fibrinogen Dosage : 15ml/kg Cryoprecipitate - Fibrinogen 150mg/bag , factor VIII 80-120 units/bag , factor XIII & vWB Dosage : 1 bag/ 5kg bw

 Random donor platelets ( RDP) : - 5.5x10^10 platelets Dosage : 1 unit/10kg Single donor platelets: 3x10^ 11 platelets Fresh blood : Indicated in severe trauma to replace acute massive blood loss.

Anticoagulation therapy
Heparin and other anticoagulant therapy to inhibit thrombin. Indicated in patients with clinically overt thromboembolism, chronic DIC and extensive fibrin deposition. Dosage : weight < 30kg 10U/kg/hr weight > 30kg 4U/kg/hr

Liver disease

 Can present with diffuse bleeding from minor trauma -Multiple coagulation defects due todecreased factor synthesis -thrombocytopenia related to hypersplenism associated with portal hypertension

 Biliary obstruction results in impaired vitamin K absorption decreased factor II,VII, IX, X Severe hepatocellular disease reduced factor V and fibrinogen and increased plasminogen activator Dysfibrinogenaemia is found in many patient

Thrombocytopenia due to decreased thrombopoietin production Hypersplenism a/w portal HPT.

Tests:
FBP: low platelet LFT APTT and PT-prolonged Low in fibrinogen

Therapy:
FFP Platelet concentrate Cryoprecipitate

Approach to bleeding disorder

APPROACH TO BLEEDING DISORDER

History
Physical Examination Investigation

HISTORY
Age Gender Site of bleeding Early or late onset Male is predominant in haemophilia -multiple sites -mucosal bleeding (epistaxis, gum bleeding, menorrhagia) -skin bruises -hemarthrosis -spontaneous bleeding -excessive bleeding after trauma/surgery -liver disease -malignancies -renal disease -poor nutrition (vit k and c deficiency)

Duration and precipitating causes Medical history Drug history

-aspirin -anticoagulant -alcohol -anticancer -traditional medicine Genetic causes (haemophilia,vWf disease) -menorrhagia -post partum haemorrhage

Family history Obstetric/menstual history

Clinical differences between diseases of platelets/vessel walls or coagulation factors

Finding
Mucosal bleeding Petechiae Deep hematomas Bleeding from skin cuts Sex of patient

Platelet/vessel wall
Common Common Rare Persistent Equal

Coagulation
Rare Rare Characteristic Minimal >80% male

Physical finding
Pallor Skin: petechiae (<3 mm) / purpura (3-1cm) / ecchymoses (>1cm or larger) Gum hypertrophy and mucous membrane bleeding Fundal haemorrhage Joint swelling Lymphadenopathy, hepatosplenomegaly

Petechiae

Purpura

Ecchymoses

Haemarthrosis

Clinical effects cause by different levels of platelet count

Platelet count(x10^9/L) >500 500-100 100-50 Clinical defect Thrombosis No clinical effect Moderate hemorrhage after injury

50-20

Purpura may occur Hemorrhage after injury

Purpura common Spontaneous hemorrhage from mucous membrane Intracranial hemorrhage

<20

Investigations
FBP Bleeding time Coagulation profile (PT, aPTT, TT)

FBP
( blood indices + histogram + peripheral smear)

Thrombocytopenia -platelet count and morphology Anaemia

Bleeding time
To detect abnormal platelet function and abnormal blood vessel In ivy template method, after the application of 40 mmhg pressure to the upper arm with a BP cuff, two 1-mm deep, 1 cm long incisions are made in the flexor surface of forearm skin Bleeding stops normally in 3-8 min. Prolonged BT: thrombocytopenia, platelet dysfunction, von willebrand disease, vascular abnormalities

Prothrombin time
Measures factors VII, X, V, prothrombin and fibrinogen Tissue thromboplastin + calcium added to citrated plasma Normal time 10-14 s Prolonged PT: deficiency of the above coagulation factors,warfarin,liver disease, DIC

aPTT
Measures factors VIII, IX, XI, XII, X, V, prothrombin and fibrinogen Phospholipid + a surface activator (kaolin) + calcium added to citrated plasma Normal time 30-40 s Prolonged APTT: deficiency of above coagulation factors, heparin, liver disease

Thrombin time
Sensitive to a deficiency of fibrinogen or inhibition of thrombin Diluted thrombin added to citrated plasma Normal time 14-16 s Prolonged TT; hypofibrinogenaemia or dysfibrinogenaemia, heparin, fibrin degradation products

Special tests
Coagulation factors assays Estimation of fibrin, FDPs and d-dimer vW factor assay Tests for fibrinolytic pathway; euglobulin clot lysis time (ELT), assays of plasminogen, t-PA, PAI-1

Summary of bleeding disorder

Vascular disease Platelet disorder Factor VIII/IX deficiency (congenital) Vitamin K/ liver disease (acqiured) Combined (DIC) BT N/ N/ N Platelet N N/ N PT N N N aPTT N N

N/

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