Blood Coagulation and Haemostasis

Dr. Ahlam AL-Buhairan Basic clinical haematology (241 CLS)

Haemostatic System
Definition:

A physiological mechanism whereby bleeding is stopped from sites of vessel injury.

Maintains a balance between procoagulant and anticoagulant processes.

Haemostatic System
Five major components are involved in this mechanism:
1.Platelets 2.Coagulation Factors 3.Coagulation Inhibitors 4.Fibrinolysis 5.Blood vessels

Platelets
Plts are produced in the B.M.
The precursor megakaryoblast. cells are the

The megakaryocytes mature by endomitotic synchronous nuclear replication.

Platelets
Each megakaryocyte production of ~4000 plts. results in

Plts production takes ~ 10 days

Plts production
Plts production is regulated mainly by Thrombopoietin. It is produced by the liver and kidney and its level is high in thrombocytopenia. Another factor is interleukin-11.

Plts production
The 150normal plts 400X109/l. count range is

Plts life span is 7-10 days.

~30% of plts may be trapped in the spleen at any one time of their production.

Plts function

1. 2. 3. 4.

The main function is the formation of mechanical plug during vascular injury. This is achieved through: Plts adhesion Plts release reaction Plts aggregation Plts procoagulant activity

Blood coagulation cascade

This involves a cascade of circulating precursor proteins called coagulation factors.
They form what is known as intrinsic and extrinsic pathways.

Blood coagulation cascade

They result in the generation of thrombin which converts plasma fibrinogen into fibrin leading to a firm and stable haemostatic plug.

Inherited Bleeding Disorders

Abnormal bleeding result from vascular disorders, thrombocytopenia, plt dysfunction, or defective coagulation

Thrombocytopenia
Occurs when plts are lost from the circulation faster than they can be replaced by the B.M.
This result from a failure of plts production, an increased rate of removal from the circulation or a combination of both mechanisms.

The Blood Platelets

Abnormal bleeding associated with thrombocytopenia is characterized by spontaneous skin purpura, haemorrhage and prolonged bleeding after trauma. Causes of thrombocytopenia can be classified under 2 main categories; defective plt production and diminished plt survival.

Causes of thrombocytopenia
Failure of plt production:
Part of general B.M failure e.g aplastic anaemia, leukaemia, M.A, cytotoxic drugs. Selective megakaryocyte depression chemicals, viral infections and drugs. e.g

Causes of thrombocytopenia
Increased consumption of plts:
Immune e.g autoimmune, SLE, CLL, infections (HIV, malaria..) Disseminated intravascular coagulation (DIC) Thrombotic thrombocytopenic purpura.

Chronic autoimmune thrombocytopenic pupura (ITP)

The commonest cause of thrombocytopenia without anaemia or neutropenia. The highest incidence in women aged 1550 years. Idiopathic and may be associated with SLE, HIV, CLL.etc.

Chronic autoimmune thrombocytopenic pupura (ITP)

Plt sensitization with auto-antibodies (IGg) leads to premature removal from the circulation by the macrophages in the spleen and liver.
The normal lifespan of plts is reduced to only few hours.

Clinical features
Petechial haemorrhage, easy bruising and menorrhagia.
Mucosal bleeding in severe cases.

The spleen is not palpable.

Diagnosis
Plt count is 10-50X109 . Hb is normal. WBC is normal. Blood film shows reduced plts (large). B.M shows normal or increased plts. Sensitive tests will demonstrate antiplatelet IgG on the platelet surface or in the serum in most patients.

Treatment
Aim: reducing the level of autoantibody
and reducing the destruction rate of sensitized plts. Steroids. Splenectomy.

Inherited Bleeding Disorders

Recent advances in protein chemistry and recombinant DNA technology have produced a comprehensive account both of normal coagulation and of the molecular genetics of some bleeding disorders.

Haemophilia A
Occurs due to FVIII being deficient or defective. Almost all patients are male. An X-linked recessive disorder. The gene for FVIII is localized near the tip of the long arm of the X chromosome.

Haemophilia A
The cDNA for FVIII has been cloned. This lead to the identification of many genetic defects including gene deletions and point mutations.

Clinical features
The patients suffer mainly from recurrent painful haemarthroses and muscle haematomas with progressive crippling. Prolonged bleeding is frequent after dental extractions. Haematuria. Operative and post traumatic haemorrhage are life-threatening in affected patients.

Clinical features
Spontaneous intracerebral haemorrhage (a cause of death in many severe haemophilics). Haemophilic pseudotumours in the long bones, pelvis and fingers may occur Infections e.g hepatitis B, C, HIV ..etc..due to infusions of blood products. In general the severity correlates with FVIII level.

Disease severity and FVIII activity

FVIII activity (%) Clinical manifstations

<1 1-5 5-20

Severe disease (frequent bleeding episodes early in life, joint deformity and crippling. Moderate disease (post traumatic bleeding, occasional bleeding episodes). Mild disease (post-traumatic bleeding).

Lab findings
B.T is normal. P.T is normal. Platelet count is normal. Ristocetin-induced platelet. APTT is prolonged. FVIII is low.

Treatment
Specialized haemophilia centers.
Bleeding episodes are treated with FVIII replacement therapy (FVIII concentrates) or desmopressin (DDAVP).

Factor IX deficiency (Haemophilia B)

Also called Christmas disease. FIX is coded by a gene near the tip of the long arm of the X chromosome. The inheritance and clinical picture are identical to those of haemophilia A. They can be distinguished by specific coagulation factor assays.

Lab findings
B.T is normal. P.T is normal. APTT is prolonged. FIX clotting assay is low.

Treatment
Similar to the approach of haemophilia A.
FIX concentrates (has longer half- life than FVIII).

von Willebrand disease

von Willebrand disease (VWD) is the most frequent inherited human bleeding disorder. It occurs due to a deficiency and/or abnormality of von Willebrand factor (VWF). The inheritance is autosomal dominant.

VWD
Patients who have reduced or abnormal VWF suffer mainly from mucosal bleeding (epistaxis, menorrhagia), operative and posttraumatic haemorrhage and excessive blood loss from superficial cuts.

VWD types
VWD is a very heterogeneous disorder that has been classified into : Type 1 VWD (partial deficiency of VWF)
Type 2 VWD (qualitative abnormality) Type 3 VWD (total deficiency of VWF)

VWF function
VWF performs two essential functions in primary haemostasis: 1.Binds to and stabilises blood clotting factor VIII in the circulation 2. Mediates the adhesion of platelets at sites of vascular damage

Lab findings
P.T is normal. Plt count is normal. Prolonged B.T. APTT is normal or prolonged. FVIII:C is low (FVIII activity). VWF level is low. Ristocetin- induced plt aggregation is defective. VWF:RCo is low (VWF activity).

Treatment
Bleeding episodes are managed by intermediate- purity FVIII concentrates (contain both FVIII and VWF) or
DDAVP.