Hereditary hemorrhagic disorders Taking histrory Is an essential

Hereditary hemorrhagic disorders

Taking histrory • Is an essential part of the diagnostic process for detecting disorders of bleeding. It is crucial in determining who should be given laboratory tests and is of importance for the determination of the extent of testing to be used if the screening tests are negative. • A good history also allows the physician to classify the patients in to various groups

Ask for: Taking history • Spontaneous loss of blood (nose bleeds, gingival bleeding, menorrhagia, vaginal loss, hematuria, rectal loss of blood/melanea, hemoptysis) • Bleeding into tissue (bruises, small skin haemorrhages, muscle bleeding, deep hematomas, bleeding into joints) • Reaction to trauma (tooth extraction, tonsillectomy, puerperal bleeding, operations, bleeding from cuts)

Taking history Ask for: • Medication • Onset of complaints • Family history

Spontaneous loss of blood • Is not a specific sign of any special bleeding disorder but is found in general only in the more severe disorders. Nose and gingival bleeding are exceptions to this rule. Bleeding form these sites is observed more often in disturbances of primary hemostasis and may occur in patients with relatively minor hemorrhagic disease. • Hemoptysis is not a sign of a general bleeding disorder.

Bleeding into tissues • Bleeding into joints and muscles is observed in hemophilia and in severe deficiencies of humoral coagulation factors. • Joint bleeding is rare, however, outside hemophilia. • Superficial bleeding, especially petecchiae, is observed in thrombocytopenia and vascular disorders but not, or only seldom, with deficiencies of coagulation factors.

Medication • Several analgetics, especially aspirin, increase the bleeding time. These drugs are often not considered as medication by the patient and their use should be asked specifically • The onset of the symptoms may be important to distinguish between congenital and acquired disorders • A congential disorder may express itself for the first time rather late in life especially when no challenge to the hemostatic mechanism has occured

Taking history • The family history is of eminent importance for the diagnosis of diseases like hemophilia and von Willebrand’s disease

History and demography of hemophlia (with special reference to the situation in Sweeden) • Hemophilia was described s a hereditary disease in the Talmud as early as the fifth century of our era • Modern knowledge and research in hemophilia date from the 19 th century (in 1803 American physician Otto reffered the victims as „bleeders”)congenital bleeding disorder only affecting men and passed on by healthy women

History and demography of hemophlia (with special reference to the situation in Sweeden) • The disease was described as manifesting itself in prolonged coagulation time and an abnormal bleeding tendency which appears early in childhood, the most typical bleeding symptom being joint bleeds • In Germany the disease was given its original designation, Haemorrhaphilia, to denote a disease characterized by ‘love of bleeding’, the name subsequently being shortened to hemophilia.

History and demography of hemophlia (with special reference to the situation in Sweeden) • Hemophilia was formerly thought to be uniform entity, but at the end of 1940 s Pavlovsky in Argentina discovered the coagulation defect in the blood of one hemophiliac could be normalized by infusion of blood from another hemophiliac • In the 1950 s it was fonud that there must be at least two types of hemophilia (deficiency of factor VIIIhemophilia A (typical), deficiency of factor IX – hemophilia B • Hemophilia A and B are comparable in heredity, and are clinically indistinguishable

Degrees of severity in hemophilia Coagulation activity VIII: C (%) Hemophilia A Severe Moderate Mild <1 1 -4 5 -25 100 100 IX: C (%) 100 100 <1 1 -4 5 -25 Joint bleeds +++ + (+)

Occurrence of hemophilia in Sweden (1990) Severe Moderate Mild Hemophilia A 163 71 297 Hemophlia B 38 20 77 Total 201 (30%) 91 (14%) 374 (56%) Total 531 (80%) 135 (20%) 666

Changes in median life span among Swedish hemophiliac 1890 -1990

Heredity in hemophilia Parents Normal women Affected male Gametes Children Trait-carrying Normal Girl boy Trait-carrying Normal girl boy

Heredity in hemophilia Parents Trait carrying women Normal male Gametes Children Normal girl Normal boy Trait-carrying girl Affected boy

The structure and thrombin activation (thrombin cleavage site of circulating factor VIII A 1 A 2 Circulating form of factor VIII in complex with v. WF C 2 C 1 B Ca++ v. WF A 3 Elimination of B domain Ca++ v. WF Final activation Ca++ v. WF )

Factor VIII and v. WF factor • The concentration of factor VIII in plasma is only 150 ng/ml whereas v. WF is present at large excess, 5 -10 ug/ml • v. WF factor is thus the carrier protein which is required for adequate secretion of factor VIII and also protects the labile factor VIII from proteolytic degradation • Moreover, since farctor VIII is associated with v. WF, it is targeted to the exposed subendothelium and localized at its site of action in sufficient concentrations.

Synthesis of factor VIII, the v Willebrand factor and the factor VIII-v. WF complex Factor VIII Von Willebrand factor X-chromosome Liver sinusoidal cells Endothelial cells Chromosome 12 Hepatocyte Megakarocytes Single chain form of factor VIII transforms into two-chain form Endothelial cells v. WF subunit (Mr ~ 220 k. Da) combines into v. WF protomer Factor VIII, two-chain form, Mr ~280 k. Da Factor VIII-v. WF complex v. WF multimer, Mr ~ 1 -20 MDa

Factor VIII • Synthesized by sinusoid cells in the liver • The gene of factor VIII is is located on the long arm of the X chromosome • Plays a key part in the coagulation process as a cofactor IXa and thereby accelerates the activation of factor X • Is inactivated by activated protein C important regulating mechanism

Factor IX • Is synthesized in the liver, and is a single chain glycoprotein with molecular weight of 56 000 • The plasma concentration is 3 -5 ug/ml • The factor IX gene is located on the long arm of the X chromosome • Together with a factor VIIIa and phospholipid, factor IXa forms an enzyme complex in the presence of calcium ions tenase, then converts the zymogen factor X to the active enzyme factor Xa

von Willebrand factor • The v. WF is a large adhesive glycoprotein present in both plasma, the -granules of platelets, and the vessel wall • It is composed of a series of multimers ranging in molecular mass from 800 k. Da to as much as 20 000 k. Da (single subunit of 220 k. Da) • Plays an important part in the earliest phase of hemostasis by promoting the adhesion of platelets to the subendothelium exposed after vessel injury • Serves as a carrier protein for factor VIII, thereby preventing the rapid removal of factor VIII from the circulation • The high molecular weight multimers of v. WF are the most hemostatically efficient (interaction with platelets and subendothelium)

Bleeding symptoms in hemofilia • Mean age at diagnosis of hemophilia is about nine months in severe cases and 22 months in moderate cases • The commonest symptoms at the onset are: - soft tissue bleedings (41%) - Bleeding in conjunction with puncture, injection or surgery (16%) - Bleedings of the oral cavity (11%) - The bleedings into muscle and joints that are characteristic of the disease are not a rule seen at onset

Bleeding symptoms in hemofilia • After negligible trauma, or even no trauma patients with severe hemophilia are afflicted with profuse and extensive bleeding into the soft tissue and muscles • Its can be extremely painful and could leads to serious pressure defects as neural damage with consequent paresis, and even result in the formation of pseudotumors (blood-filled cysts) • The slightest lesion (e. g. small cut) can result in uncontrolled bleeding that may last for weeks

Bleeding symptoms in hemophilia • The most characteristic symptoms are joint bleeds, which appeared when the child is learning to walk • Acute join bleeds usually develop without any known trauma • Bleeds may affect almost any joint, the most commonly occur in the knees, ankles and elbows • Bleeding into the shoulder or hip joints being more rare • Spinal and wrist joints are very seldom affected, and usually only as a result of trauma

Bleeding symptoms in hemophilia • After bleeds, the joint becomes stiff, swollen, warm and tender • Generally the joint remains slightly flexed, all movement being inhibited by stiffness and pain • Bleeding in the iliopsas muscle is not uncommon and is often misinterpreted as bleeding into the hip joint

Bleeding symptoms in hemophilia • Cerebral hemorrhage has been the commonest single cause of death • It can often be caused by minimal trauma, giving rise to exsanguinating hemorrhage, in time resulting in severe intracranial hemorrhage start prophilactic replacement therapy at the earliest opportunity

Bleeding symptoms in mild hemophilia • Patients do not usually manifest either severe bleedings or joint bleeds • Bleeding episodes occur first and foremost in conjunction with trauma and surgery, and they manifest renal and gastric bleedings • Even in these patients life-threatening bleeding may result from dental extraction !

Hemophilic arthropathy • Isolated joint bleeding episodes are relatively innocuous blood has been reabsorbed and the swelling has diminished, normal joint mobility and function are restored • Repeated bleeding episodes damage of various joint components— arthropathy affecting both the joint capsule and cartilage as well as the adjacent bones and soft tissue fibrosis of the joint capsule and surrounding soft tissue, with markedly reduced joint mobility

Hemophilic arthropathy • The joint cartilage degenerates and is eroded after repeated bleedings by the action of aggressive proteolytic enzymes and collagenases reduced cartilage stability • Parallel with the cartilage degeneration, the underlying subchondral bone undergoes changes, becoming by turns osteoporotic (bone resorption) and sclerotic (ossification) • Clinically, joint function is impaired, both extension and flexion being diminished, and the joint can become deformed by widening and various forms of malalignment. • The surrounding musculature is affected atrophy

Replacement therapy in hemophilia A • Recent years have witnessed the development of several high purity preparations (i. e. Containing > 10 IU of factor VIII/mg protein) and several super-pure preparations (i. e. With a final specific activity of 1000 -4000 IU VIII; C/mg protein) • All preparations are virus-inactivated with methods that exclude the risk of HIV transmission • Preparations purified with monoclonal antibodies, and these exposed to wet heat and steam treatment or chemical inactivation, also manifest a high degree of safety with regard to hepatitis C transmission • In contrast to low or intermediate purity concentrates, the superpure concentrates have been found to have no immunosupressive effect

Factor VIII concentrates Preparation Octanativ – M (Pharmacia) Hemate P (Behring) Recombinate (Baxter) Kogenete (Bayer) Manufacturing Virus procedure inactivation Affinity purified with Solvent detergent monoclonal antibodies technique against factor VIII Cryoprecipitate+Al(OH)3 Wet heat adsorption+PEG+Glycine treatment at 60 C for 10 h DNA technology

Properties of factor VIII concentrates VIII: C Preparation Octanativ – M (Pharmacia) Hemate P (Behring) v. WF: Ag IU/ml Fibringogen Fibronectin ug/IU VIII: C Specific activity IU VIII: C/mg protein 96 1, 6 <0. 001 37 28 71 0. 09 0. 07 5. 7 Recombinate (Baxter) 50 <0. 001 5. 2 Kogenete (Bayer) 169 < 0. 001 <0. 001 42

Factor IX concentrates available Preparation Prothromplex TIM 4 (Immuno) Nanotiv (Pharmacia) Manufacturing procedure DEAE Sephadex Virus inactivation Steam treatment at 60 C for 10 h Chromatographic purification Immunine (Immuno) „ Mononine (Armour) Affinity purified with monoclonal factor IX antibodies Solvent detergent technique Steam treatment at 60 C for 10 h Sodium thiocyanate

Biochemical properties of factor IX concentrates Preparation IX: C II Prothromplex TIM 4 (Immuno) 55 Nanotiv (Pharmacia) 115 Immunine (Immuno) Mononine (Armour) 86 VII 3. 9 X PC PS Specific activity IU IX: C/mg protein 44 2. 3 7 1. 9 0. 05 <0. 01 0. 03 0. 17 0. 74 278 110 0. 98 <0. 05 0. 21 0. 002 0. 04 195 98 0. 25 0. 02 0. 06 236 0. 03 0. 14

Proposed therapy for severe bleeds in severe hemophilia A (serious hematoma, retroperitoneal bleeds, gastrointestinal bleeds, intracranial bleeds) Desired postinfusion factor VIII 50 -100% initially, then 20 -40% concentration Duration of treatment Factor VIII dosage 7 -14 days until healing achieved 50 -70 IU/kg body weight at 6 h intervals initially, then approx. 20 IU/kg at 6 -8 h inetrvals

Principles of relpacement therapy as cover for surgery Hemophilia A Major Minor Hemophilia B Major Minor Day of operation - desired level (%) - initial dose (IU/kg) - maintenance dosage(IU/kg) - interval (h) 50 -100 50 -60 25 -30 4 -6 h 40 -50 25 -40 20 -30 4 -8 50 -150 60 -70 30 -40 8 -12 40 -50 30 -40 20 -30 8 -12 Days 2 -7 postoperatively - desired level (%) -maintenance dosage (IU/kg) - interval (h) 40 -60 20 -40 4 -6 h 30 -50 15 -20 6 -12 40 -60 30 -40 12 -24 30 -50 15 -20 24 Day 8 postoperatively - desired level (%) - maintenance dosage(IU/kg) - interval (h) 15 -25 10 -15 12 -24 h 15 -25 10 -20 24 -48

Home infusion treatment • To prevent profuse bleedings by giving treatment immediately in the event of incipient bleeding • To save time and money in terms of transport to and from hospital, waiting times, and days of treatment • To reduce absence from school or work due to sick certification • To render the patients independent so that they can live normal lives

Prophylaxis and home treatment (severe hemophilia patients) Present age (years) 3 -12 13 -20 21 -26 27 -35 Age at start of treatment Joint bleeds/year Total annual dose of FVIII/IX per kg, Ux 103 Orthopedic joint score Annual absence from school/work, days 1 -2 0. 2 2. 5 2. 6 4. 9 5. 6 7. 0 5. 9 0 1. 6 5. 4 1. 2 2. 7 2. 9 0. 4 3. 3 6. 6 0. 9 2. 8 5. 8 Twice a week tretment regimen – 800 -2500 IU/kg body weight annualy 5400 IU factor VIII/IX per kg annually by Port –A-Cath system

Factor VIII/IX antibodies • Inhibitors develop at an early age, and usually after only a few infusions of factor VIII or factor IX • In every case of hemophilia an inhibitor test be carried one or twice a year, and before any form of surgical intervention • In the treatment of hemophilacs with inhibitors, the aim is twofold: - to control severe acute bleeding episodes or to prepare the patient for essential surgery - to induce immune tolerance, or at least to convert a high responder into alow responder, by elimination of the antibodies

Management of acute bleedings in patients with low inhibitors titers (<10 BU) Previous low immune responce (<10 BU) Previuos high immune response (>20 BU) Treatment Effect Factor VIII/IX concentratesincreased doses- Maintained response possible Factor VIII/IX concentrates- Good initial response increased doses. Resistant after 4 -6 days Factor VIII/IX concentrates – increased doses + cyclophosphamide PCC APCC (Autoplex, Feiba) Response 6 -9 days Beneficial effect in 4060% of episodes

Management of acute bleedings in patients with high inhibitors titers (>10 BU) Methods used or proposed Temporary reduction of the inhibitor: - extensive plasma exchange - immunoabsorption Porcine factor VIII Factor VIII inhibitor by-passing agents - PCC or APCC (Feiba, Autoplex) - Recombinant factor VIIa

Desmopressin (DDAVP) treatment management of mild or moderate hemophilia A and v. WD • Intravenous administration - 0, 3 ug/kg , the peak plasma concentrations of VIII: C and v. WF occur after about 30 minutes - the plasma concentration of VIII: C increases about 2 -6 times and that of v. WF about 2 -4 times about the respective baseline levels • Subcutaneous administration 0, 4 ug/kg - the peak plasma concentrations of VIII: C and v. WF occur after about 2 h - the plasma concentration of VIII: C increases about 2 -5 times and that of v. WF about 2 times about the respective baseline levels