2 The main adverse effect of DLI is acute or chronic GvHD especially if administered early after SCT. The incidence of these complications has been reduced by the adoption of an escalating dose regimen but increased with MUD SCT. 09-BMT.qxd 10.12.2003 04.22 PM Page 339 Transplantation 339 09-BMT.qxd 10.12.2003 04.22 PM Page 340 Discharge and follow-up Criteria for discharge Blood counts should ideally be: Hb >10.0g/dL (but may require transf u- sion), neutrophils >1.0 109/L, platelets >25 109/L, and patients should be able to maintain a fluid intake of 2 \200\2233L/d, tolerating diet and oral med- ications particul arly in allografts on cyclosporin. Should be apyrexial and no longer losing weight. Counsel patients 1. Possible need for blood/platelets. 2. Adherence to neutropenic diet. 3. Check temperature bd and report immediately if febrile. 4. Fatigue post-transplant in irra diated patients due to the late TBI effect usually 6 \200\22310 weeks post transplant. 5. Risk of HZV (explain the early symptoms). 6. To continue with mouth care. 7. To report a ny new symptoms. Blood tests \200\224initially twice weekly 2 FBC, reticulocytes and blood movie. 2 Biochemi stry including LFTs. 2 CyA levels pre-dose (EDTA sample) \200\224allografts only. 340 Initially once a week 2 Magnesium. 2 CRP. 2 Coagulation screen. 2 CMV screening test e.g DE AFF \200\224allografts and seropositive autograft recipients only. 2 Stool culture \200\224allografts only unless relevant symptoms. Drugs 1. Cyclosporin capsules \200\224allografts only. 2. Acyclovir prophylaxis against HZV 400mg qds PO for minimum of 3 months in non-TBI patients and 6 months in TBI autografts an d all allografts. Allografts may be on 800mg tds if acyclovir chosen for CMV prophylaxis. C onsider low dose 200mg bd maintenance until 1 \200\2232 years post-transplant. Penicillin V 250mg bd PO should be given to all patients. Erythromycin 250mg od PO if penicillin allerg ic. 3. 4. Ciprofloxacin 250mg bd PO if neutrophils <1.0 109/L. 5. Cotrimoxazole 480mg bd PO Mon day, Wednesday, Friday for 1 year minimum and until CD4 count >500. Cotrimoxazole should be started when neutrophils >1.5 109/L and platelets >60 109/L. Until then, use nebulis ed pentamidine 300mg every 3 weeks. Itraconazole \200\224allografts only. 6. 7. Nystatin mouth care. 8. 9. Folic acid 5mg bd until full engraftment. Sanatogen Gold \204 multivitamins 1/d may be adv isable while gaining weight. 10. Antiemetics PRN. 09-BMT.qxd 10.12.2003 04.22 PM Page 341 Transplantation 341 09-BMT.qxd 10.12.2003 04.22 PM Page 342 This page intentionally left blank 342 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 343 Haemostasis and thrombosis 10 Coagulation disorders \200\223 a clinical approach 344 Coagulation disorders \200\223 laboratory approach 346 von Willebrand \200\231s disease (vWD) and vWF-relate d bleeding 348 Hemophilia A and B 352 Other congenital coagula tion deficiencies 356 Vitamin K d eficiency 360 Haemorrhagic disease of the newborn 362 Liver disease 364 Acquired anticoagulants 366 Platele t function tests 370 Hereditary platelet disorders 372 Osler \200\223Weber \200\223Rendu (OWR) syndrome 374 Henoch \200\223Sch nlein purp ura 376 Ac quired disorders of platelet function 378 Numerical abnormalities of platelets \200\223 thrombocytosis 382 Numerical abnormalities of platelets \200\223 thrombocytopenia 384 Investigation of thrombocytopenia 386 Immune thrombocytopenia 388 Other causes of thrombocytopenia 392 Th rombophilia 394 Inherited thrombophilia 396 Acquired thrombophilia 400 Anticoagulation t herapy 402 Anticoagulation in pregnancy and post-partum 404 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 344 Coagulation disorders \200\224a clinical approach Hemophilia is the name given to an increased bleeding tendency. It can be heritable or acqu ired. The commonest heritable bleeding disorder is mild von Willebrand disease, affecting 1 per few hundred of the popula- tion. This heritable disorder is not typically referred to as hemophilia but in the broadest sense of the definition it is a form of hemophilia. \200 \230Classical hemophilia \200\231, also termed \200\230hemophilia A \200\231, is due to fa ctor VIII deficiency and affects only 1 per 10,000 male births. It is therefore encountered infrequently in non-hematological practice. The most common acquired form of hemophilia is that due to oral anticoagulant therapy as 1 per 100 of the population of many countries ar e now taking long-term warfarin or similar anticoagulants. Conversely, thrombophilia is used to describe an increased tendency to thrombosis. This can also be heritable or acquired. Heritable throm- bophilic defects are often insufficient on their own to cause thrombosis and an additional acquired factor, such as surgery, is often the trigger for an acute thrombotic event. Bleeding disorders Causes of bleeding \200\224surgery, trauma, non-accidental injury, coagu lation disorders (including anticoagulant drugs), platelet dysfunction (including aspirin a nd other anti-platelet drugs), vascular disorders. 344 Clinical features \200\224is there a lifelong bleeding history, has the patient been previo usly challenged, is this an isolated symptom? Type of bleeding problem that led to presenta tion e.g. mucocutaneous, easy bruising, spontaneous, post-traumatic. Duration and time of o nset. Menstrual history is important. Absence of obstetric bleeding may be misleading as ha emostatic capacity increases significantly in pregnancy. Systemic enquiry \200\224do symptoms suggest a systemic disorder, bone marrow failure, infe ction, liver disease, renal disease? Past medical history \200\224previous episode, previous known disorder e.g. ITP. Exposure t o trauma, surgery, dental extraction, or pregnancies. Family history \200\224similar bleeding tendency in other family members? Pattern of inheri tance (autosomal dominant, sex-linked). Drugs \200\224thrombocytopenia ((cid:9) p384), platelet dysfunction ((cid:9) p378); not alw ays obvious \200\224aspirin, warfarin. Drug reaction \200\224allergic purpura. Physical examination Signs of systemic disease \200\224anemia, splenomegaly? lymphadenopathy hepato- Assess bleeding site \200\224check palate and fundi. Check size e.g petechiae (pinhead); pu rpura (larger =1cm); bruises (ecchymoses) =1cm \200\224measure them. Joints \200\224swelling or other signs of chronic arthritis, joint destruction or muscle co ntractures from previous bleeds? 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 345 Haemostasis and thrombosis Vascular lesions \200\224purpura e.g. allergic, Henoch \200\223Sch nlein (p376), senile, s teroid-related, hypergammaglobulinaemic, HHT \200\224capillary dilatations (blanches on pre ssure), vasculitic lesions, autoimmune disorders, hyper- sensitivity reactions. Investigation 2 FBC (especially platelet count), movie, biochemistry (especially creati- nine and LFTs), ESR, coagulation tests (PT and APTT). 2 Special tests will be dictated by history. The bleeding time is not a reli- able test and is rarely indicated. von Willebrand \200\231s disease (vWD) often missed beca use PT and APTT and platelet count are normal. If history suggestive of vWD then plasma lev el of von Willebrand factor must be measured. 2 Family studies should be considered to identify other family members at risk of bleeding. Summary Pre-operative history is most important aspect of identifying clinically sig- nific ant bleeding risk. If abnormal bleeding does occur exclude surgical bleeding and take blood for testing before blood transfusion compounds the problem. Decide whether platelet or coa gulation defect or both? Is it hereditary or acquired? 345 Treatment Establish diagnosis and treat as appropriate. Classification of bleeding disorders (cid:9) Inherited von Willebrand \200\231s disease (vWD) Hemophilia A and B Other congenital defici encies p348 p352 p356 Acquired Anticoagulant therapy Heparin Warfarin Thrombolysis Vitamin K deficiency Liver disease DIC Acquired inhibitors Ma ssive blood transfusion p588 p590 p516 p360 p364 p512 p366 p524 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 346 Coagulation disorders \200\224laboratory approach Establish whether bleeding is of recent origin (suggests acquired) or long- standing (conge nital), spontaneous or induced by trauma/surgery, mucocuta- neous (?platelet defect) or gen eralized (?coagulation defect or ?drug induced). Laboratory tests 2 FBC with platelet count, coagulation tests (PT, APTT, fibrinogen). 2 Fil l blood sample tube to the mark to ensure correct anticoagulant concentration. 2 Repeat test if result abnormal before investigating further. 2 Check patient not on antic oagulants. Further investigation Abnormal platelet count 2 Both high and low counts may cause bleeding . 2 If isolated low platelets (cid:9) p384; if platelets high (cid:9) p382. 2 If platelets low and coagulation screen abnormal \200\224could be DIC, liver disease, massive blood transfusion, primary blood disorder (e.g. leukemia). Abnormal coagulation result (cid:2) PT 4 APTT normal Warfarin, vitamin K deficiency, early liver disease, rarely congenital factor VII deficiency. (cid:2) PT 4 APTT 4 Warfarin overdo se, vitamin K deficiency, liver failure, DIC. (cid:2) PT normal APTT 4 Unfractionated hepar in (UFH), hemophilia A or B, lupus anticoagulant, rarely vWD affects APTT, factor VIII inhi bitors are rare but typically prolong APTT. (cid:2) PT normal APTT normal Normal PT and APT T do not exclude a significant bleeding tendency, for example effect of low molecular weigh t heparin, mild factor deficiency, platelet abnormality, or very rare factor deficiency suc h as factor XIII. 346 Further investigation 2 DIC: check blood movie, platelets, thrombin time, fibrinogen, XDPs/ D-dimer. 2 Vit K deficiency: assay VII and II; give vitamin K and repeat 24h later. 2 Liver disease: check LFTs; will not correct to normal with vitamin K. 2 Isolated factor deficien cy: assay as indicated by PT/APTT results. 2 Inhibitor-specific LA tests: check ACL; other factor-specific assays. 2 Heparin: 4 APTT ratio, PT normal if APTT ratio 1.5 \200\2232.5, T T 4, repti- lase normal. 2 Warfarin: PT prolongation>than APTT, low vitamin K dependent factors. 2 vWD: diagnosis of von Willebrand disease requires measurement of vWF level and function. Note: bleeding time is neither sensitive nor specific for diagnosis or bleeding tendency. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 347 Haemostasis and thrombosis TISSUE INJURY TEST TF \200\223VII TFPI PT TF \200\223VIIa 1. Anticoagulant pathway IX IXa Protein S Factor V APTT VIIIa X Xa APC Va II Thrombin 347 PT and APTT Protein C XI XIa TPA 2. Fibrinolytic pathway Fibrinogen Fibrin Plasmin Plasminogen becomes active activates inhibits FDPs Plasmin inhibitor Blood coagulation network Tissue injury triggers off a cascade of zymogen-to-protease react ions which amplify resulting in thrombin generation and fibrin clot. Natural anticoagulation network Natural anticoagulants: Tissue Factor Pathway Inhibitor (TF PI), Antithrombin and Activated Protein C. Thrombin binds to a receptor, thrombomodulin (TM ) on the surface of endothelial cells. Bound to TM thrombin loses anticoagulant activity an d becomes a potent activator of protein C7Activated PC (APC) with co-factors PS and FV, cle aves and inactivates Factors Va and VIIIa. Fibrinolytic network Tissue plasminogen activators (TPA) activate plasminogen to plasmin; t his breaks down fibrin releasing degradation products (FDPs, or XDPs when cross-linked) int o the circulation. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 348 von Willebrand \200\231s disease (vWD) and vWF-related bleeding Autosomal inherited bleeding disorder due to reduced production of von Willebrand factor (v WF) or production of defective protein, affects both sexes with estimated incidence of 1 pe r few hundred. First described in 1926 in the \205land Islands in the Baltic, it has a wor ldwide distribution. Pathophysiology vWF, produced in endothelial cells and megakaryocytes, is a protein of 250k Da molecular weight. Initial dimerisation and subsequent removal of propeptide allows polym erisation and secretion of large multimers. The higher molecular weight (HMW) multimers, up to 20 x 103 kDa, are par- ticularly haemostatically active. vWF has two main functions: 1. Its primary haemostatic function is to act as a ligand for platelet adhe- sion and it is th is reduced activity that causes bleeding. It has a secondary function as a carrier protein for factor VIII protecting it from degradation. In most patients with vWD the associated mi ld reduction in factor VIII level is not the cause of the haemostatic defect. 2. Many cases of heritable/congenital vWD are currently thought to be caused by genetic mutati ons at the vWF locus but some may be due to defects in other genes, which affect vWF levels . Increasingly vWF is con- sidered a continuous variable with low levels associated with an increased bleeding tendency. 348 Many subtypes but for simplicity the disease is classified into 3 main types: 2 Type 1 \200 \224quantitative deficiency of vWF (autosomal dominant). 2 Type 2 \200\224qualitative defic iency of vWF (autosomal dominant/recessive). 2 Type 3 \200\224complete deficiency of vWF (a utosomal recessive). Clinical features 2 Type 1 is common (70% of cases). 2 Type 2 25%. 2 Type 3 is rare. The clinical picture varies markedly. Symptoms may be intermittent, due to dysfunction of p latelet adhesion e.g. mucocutaneous bleeding, easy bruising, nose bleeds, prolonged bleedin g from cuts, dental extractions, trauma, surgery and menorrhagia. Type 2B causes thrombocytopenia which may present in pregnancy. Usually the picture is cons istent within a family. Laboratory diagnosis 2 vWF is an acute phase protein \200\224increa sing with stress, oestrogens, pregnancy, neoplasm, thyrotoxicosis, etc. vWF levels are dependent on ABO blood group being lower in group O than non-O. 2 In type 1 APTT usually normal as are PT and platelets. VIII may be normal or 5. vWF level and function typically mildly or moderately 5. Bleeding time is ofte n normal and is no longer used in many hemophilia centers. It has been largely replaced by automated in vitro platelet function analysis at high shear rate (PFA-100). When mild, the 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 349 Haemostasis and thrombosis condition may be difficult to diagnose as many of the tests are normal, including the VIII and variably the vWF level. Repeat testing is neces- sary. Family testing is useful. Classification of von Willebrand \200\231s disease Type VIII vWF Ag vWF RIPA low dose multimer 5/N 5/N 5/N 4 HMW activity 5 5 N/5 N/5 N/5 N/5 5 55 5 N/5 N/5 N/5 1 N 5 2A 5 2M N 5 5 2B 2N N 55 N 55 N 55 N 3 Usually undetectable 349 vWF activity measured as ristocetin cofactor activity (Ricof) or collagen binding activity (CBA), which is measured in plasma and is not the same as RIPA (see below) which is ability of ristocetin to agglutinate platelet rich plasma. The main subtypes of type 2 are 2A and 2M. In 2A there is a qualitative defect with absent HMW multimers and in 2M there is a qualitative defect but with HMW multimers present. RIPA is ristocetin-induced platelet agglutination performed on a patient \200\231s platelet rich plasma. Only value of RIPA test is for detection of type 2B when RIPA is increased du e to high affinity variant vWF which produces thrombocytopenia and reduced circulating leve l of VWF Factor VIII is seldom low enough to cause the joint bleeds seen in hemophilia except in Typ e 3 which is a severe bleeding disorder. Type 2N is rare autosomal recessive variant in which the VIII:C carrier function of vWF is reduced. May be misdiagnosed as hemophilia A but clue is that females are affected as well as males and autosomal recessive inheritance. Management 2 Avoid aspirin and NSAIDs. 2 Mild bleeding symptoms \200\224easy bruising, blee ding from cuts may settle with local pressure. 2 Tranexamic acid (TXA) is a useful antifibrinolytic drug (15mg/kg PO tds). 2 TXA mouthwash 5% is useful for dental work. 2 Moderate disease and minor surgery \200\223 DDAVP (0.3mg/kg SC or by slow IV injection/infusion). Fewer side effects with SC route. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 350 \200\223 Most responders have type 1 vWD but may work in some type 2 patients. Avoid in type 2B (may reduce platelets). 2 Major surgery, bleeding symptoms or se vere disease. \200\223 If DDAVP insufficient use vWF rich factor VIII concentrate e.g. intermediate puri ty VIII concentrate, e.g. Alphanate, BPL 8Y, Haemate P. \200\223 Monitor treatment with VWF:Ricof or VWF:Ag. Bleeding time or PFA-100 (see below) may not correct despite good clinical response. Treat post-op for 7 \200\22310 days. 2 Pregnancy \200\224VIII and VWF rise in pregnancy so rarely presents a problem for type 1. Post-partum vWF falls so watch out for PPH in mod/severely affected wom en. Give DDAVP or vWF concentrate to maintain levels >30% if clinical problem. In Type 2B a bnormal HMW multimers can cause platelet aggregation and thrombocytopenia in pregnancy. Avo id TXA in pregnancy/type 2B as there may be risk of thrombosis. 2 Menorrhagia \200\224may be major problem. TXA for first 3 days of the menstrual period helps some patients. Combined oral contraceptive pill is useful. Mirena (h ormone impregnated) coil very effective in some patients. Complications Vaccination against HBV and HAV recommended for all patients. Inhibitors infr equent \200\224usually type 3 disease. 350 Natural history Majority of patients will have type 1 disease which rarely causes life- thr eatening bleeds; may have little impact on quality of life/life expectancy. Management with vWF rich factor VIII concentrates as for severe hemophilia should enable patients with sev ere vWD to have good quality of life. Sadler, J.E. (2003) Von Willebrand disease type 1: a diagnosis in search of a disease. Bloo d, 101, 2089 \200\2232093. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 351 Haemostasis and thrombosis 351 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 352 Hemophilia A and B Congenital bleeding disorders caused by defective production of factor VIII (hemophilia A) or IX (hemophilia B); sex-linked recessive inheri- tance. Females carriers are rarely sympt omatic. Queen Victoria passed the disease on to her great-grandson, Alexis, son of the Tsar , contributing to the fall of Tsarist Russia. Pathophysiology Factor VIII activated by thrombin, and IX activated by the TF/factor VIIa c omplex, together activate factor X, leading to thrombin generation and conversion of solubl e fibrinogen to insoluble fibrin (px). Hemophilia A and B are disorders characterized by in ability to generate cell surface- associated factor Xa. Genetic abnormalities include: inve rsions within intron 22 of factor VIII gene in 50%, point mutations and deletions. Gross ge ne alterations common in hemophilia A but infrequent in hemophilia B. This may account for low frequency of inhibitors in hemophilia B. Third of hemophilia B patients have dysfunctio nal molecule. Carrier detection and antenatal diagnosis now possible in many cases by direct gene mutatio n detection. Affected family member usually required. Linkage analysis no longer recommende d as first line method. Epidemiology Hemophilia A occurs in 1:10,000 9 in the UK, in 1 \201\2043 cases no family h istory as new mutation; 5 more frequent than hemophilia B; no striking racial distributio n. 352 Clinical presentation Hemophilia A and B \200\224clinically indistinguishable. Symptoms dep end on the factor level. Severe disease (plasma level <1%) Usually presents in the first years of life with easy bruising and bleeding out of proporti on to injury Moderate disease (1 \200\2235% factor level) Intermediate & variable severity Mild disease (>5%) May only present after trauma/surgery in later life General features Haemarthrosis; spontaneous bleeding into joints (knees>elbows>ankles>hips>wrists) produce l ocal tingling, pain; later \200\224swelling, limitation of movement, warmth, redness, sever e pain Bleeds into muscles, spontaneous bleeding into arms, legs, iliopsoas, or any site \200\224m ay lead to nerve compression, compartment syndrome, muscle contractures \200\224look for th ese. Haematuria is common; retroperi- toneal and CNS bleeds are life threatening. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 353 Haemostasis and thrombosis Diagnosis Assess duration, type of bleeding, exposure to previous trauma/surgery and family history. Look for bruising, petechial hemorrhages, early signs of joint damage. Exclude ac quired bleeding disorders. Laboratory tests PT normal, APTT 4 depending on degree of deficiency (note: a normal APTT d oes not exclude mild disease). Assay VIII first, then IX. Exclude vWD. Radiology Acute bleed \200\224USS or CT scan if in doubt. In established disease \200\224ch ronic synovitis, arthropathy and other pathological changes seen. Complications Chronic arthropathy Repeated joint bleeds preventable but older patients ofte n have arthropathy. Development of factor VIII inhibitors Suggested by 5 response to concentrates; occurs in 15 \200\22325% hemophilia A patients following treatment (IX inhibitors are uncommon; <2%). 353 Transmission of HBV, HCV and HIV Transmission high prior to the introduction of viral inact ivation of concen- trates (1985 in the UK). HIV management Prophylaxis against infections and retroviral inhibition have significantly improved prognosis. HCV HCV infection of most hemophiliacs treated with pooled human factor concentrates before 1985. Approximately 20% have chronic liver disease. HCV PCR is used to identify patients a t higher risk of progressive liver disease. Liver biopsy is not contraindicated if hemophil ia management at time of biopsy is optimal. Combined antiviral therapy superior to inter- f eron alone. Variant CJD There is no evidence as yet of transmission of vCJD by pooled human blood produ cts. Hemophilia management General regular medical and hemophilia review and lifelong support ar e essential. At presentation establish blood group, liver function and base- line viral sta tus (HIV, HCV, HBV, HAV). Vaccinate against HBV and HAV if not immune. Regularly check inhi bitor status, LFTs, FBC. Avoid aspirin, anti-platelet drugs, and IM injections. Early treat ment of bleeding episodes is essential. Prophylaxis is preferable to demand treatment for m any patients with severe hemophilia. Prophylaxis started in first year or two of life can p revent most if not all joint damage and almost eliminate signif- 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 354 icant bleeding. Portacath may be required to deliver prophylaxis. Factor concentrate needs to be administered every 2 or 3 days. If not on prophylaxis home demand treatment is prefer able to hospital demand treatment. Hemophilia A-specific treatment Mild disease 2 Minor bleeds may stop without factor concent rate therapy. 2 Tranexamic acid (15 \200\22325mg/kg tds oral) \200\224useful for cuts or de ntal extraction. Do not use when haematuria. 2 DDAVP (desmopressin) for minor surgery and bleeds that fail to settle (0.3 g/kg SC or sl ow IVI/20 min); may also be given by nasal spray. 30 min later take blood sample to check r esponse (if required); plasma level increased 3 \200\2234 fold. Reduced response with repea ted exposure sometimes observed. 2 Cryoprecipitate no longer recommended. Severe disease 2 Factor VIII concentrates are cornerstone of management for severe disease and life-threatening situations. Products 2 Recombinant products are treatment of choice. Second generation recombinants do not contain any human material in product. Human donor-derived products are now subjected to double viral inactivation (solvent-detergent and heat treatment, e.g. 80 C for 72h); good record of viral safety. 354 \200\223 High and intermediate purity human donor-derived products avail- able for patient s not receiving recombinant therapy. No particular advantage for high purity over intermedi ate except possibly useful in patients with allergic reactions to intermediate purity. High purity previously recommended for HIV +ve patients. \200\223 Principle of treatment: rais e factor VIII to haemostatic level (15 \200\22350u/dL for spontaneous bleeds, 40u/dL minor ops; 100u/dL major surgery or life- threatening bleeds). Formula 1u/kg body weight raises plasma concentration by about 2u/dL. t1/2 6 \200\22312h. S pontaneous bleeds usually settle with single treatment if treated early. In major surgery p rovide cover for up to 10d. Hemophilia B 2 General approach: as for hemophilia A \200\224DDAVP typically of no value. 2 Products \200\224recombinant factor IX treatment of choice. If not recombi- nant then hig h purity factor IX preferable to intermediate (also known as prothrombin complex concentrat e) as high risk of thrombosis with intermediate purity product. Formula 1u/kg body wt raises plasma concentration 1u/dL; t1/2 12 \200\22324h. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 355 Haemostasis and thrombosis Special considerations Antenatal diagnosis Carriers can be identified be genetic mutation a nalysis. Factor VIII: vWF ratio is unreliable. Antenatal diagnosis in carriers with 9 fetus ideally per- formed by chorionic villus sample DNA analysis at 10 weeks gestation to allo w termination of pregnancy; rarer nowadays because of improved treatment and prognosis. Iss ue is complex and counseling/testing should be at comprehensive care center. Home treatment has transformed the life of the hemophiliac. Parents, the local GP, the boy himself from age 6 \200\2237 onwards, can be trained to give IV factor concentrates at home . Treatment usually starts in first year or two of life and portacath may be needed until a ge 4 or more. Prophylaxis \200\224e.g. 3 weekly injections of concentrate (average dose 15 \200\22325u /kg) given at home. Specialist support \200\224physiotherapy plays key role in preservation of muscle and joint function in patients with haemarthroses. Combined clinics with orthopedic surgeons, dental surgeons, hepatologists, pediatricians, HIV physicians, and geneticists are required to gi ve comprehensive care. 355 ii Do not give IM injections when factor is low. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 356 Other congenital coagulation deficiencies Pathophysiology Deficiency of other coagulation factors is described but with a prevalence of 1 \200\2232 per million is rare cf. vWD and hemophilia A and B. Autosomal recessive inhe ritance, the deficiency either due to reduced synthesis (type 1) or production of a variant protein (type 2). All coagulation factors are produced in the liver and their interaction in the coagulation cascade is shown. 2 The t1/2 of the factors vary and will determine the frequency and ease of treatment. 2 Factor concentrates should be considered when available, e.g. factor XI, factor XIII. 2 Recombinant VIIa for factor VII deficiency. The use of recombinant factor VIIa is increasing and it is increasingly used to treat a variety of factor deficien cies and severe platelet function disorders. 2 FFP can be used and virally-inactivated plasma should be used when available. FFP is a so urce of all coagulation factors but large volumes may be required and even with viral inact ivation there is risk of disease transmission. 356 Diagnosis Conditions rarely produce haemarthrosis, except factor XIII deficiency, and may o nly present at time of surgery. Clinical and laboratory features of the different condition s are listed. Treatment Many patients with inherited coagulation deficiencies will not bleed unless expos ed to surgery or trauma, and may seldom require treatment. When bleeding arises or cover fo r surgery is needed, the aim is to achieve a plasma factor concentration at least as high a s the minimal haemostatic value and make sure it does not drop below this until haemostasis is secure. Specific conditions Factor XI Deficiency more common in certain ethnic groups such as Ashkenazi Jews. Clinicall y of variable severity, often mild; even low factor levels may not produce symptoms whilst significant bleeding can occur with mild defi- ciency. Diagnosis PT normal, APTT normal unless factor XI <40u/dL. Therefore necessary to measure f actor XI level to make diagnosis in many cases. Treatment Tranexamic acid and DDAVP for oral and dental surgery. Factor XI con- centrates s ometimes available. Otherwise, use virally-inactivated FFP. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 357 Haemostasis and thrombosis Fibrinogen Normal range 2.0 \200\2234.0g/L. Produced by liver, it is an acute phase protein , raised in inflammatory reactions, pregnancy, stress, etc. Converted into fibrin by the ac tion of thrombin and is a key component of a clot. Abnormalities of fibrinogen are more oft en acquired than inherited. Inherited defects are usually quantitative and include heterozy gous hypofibrinogenaemia or homozygous afibrinogenaemia. Qualitative defects \200\224the dy sfibrinogenaemias \200\224are inherited as incomplete auto- somal dominant traits with >200 reported fibrinogen variants; defective fibrin polymerisation or fibrinopeptide release ma y occur. Most patients are heterozygous. Clinical presentation Symptoms of bruising, bleeding usually after trauma or operations wil l depend on the concentration and are more severe when <0.5g/L. Afibrinogenaemia (fibrinoge n <0.2g/L) is a severe disorder with sponta- neous bleeding, cerebral and gastrointestinal hemorrhage and haemarthrosis. It may present as hemorrhage in the newborn. Recurrent miscar riages occur. Most patients with dysfibrinogenaemia are heterozy- gous and bleeding symptom s are usually minor; arterial and venous thrombosis is described with some variants. 357 Diagnosis 4 PT, APTT and thrombin time; in afibrinogenaemia, the blood may be unclottable. Fibrinogen level measured by Clauss assay. Acquired hypofib- rinogenaemia needs to be exclu ded (DIC, liver disease) and family studies are necessary. Dysfibrinogenaemia 4 PT and APTT. Variable abnormalities of thrombin time and reptilase tim e; fibrinogen-dependent platelet function may be defective. Confirm diagnosis by demonstrat ing normal chemical/immunological fibrinogen concentrations with reduced functional propert ies. Treatment Fibrinogen has a long t 1/2 (3 \200\2235d), severe deficiency managed by repeated (twice weekly) prophylactic injections with fibrinogen concentrates, FFP or cryoprecipitat e. Fibrinogen levels should be raised to 0.5 \200\2231.0g/L to achieve haemostasis. Factor VII Vitamin K dependent factor playing a pivotal role in initiating coagulation is s hort (4 \200\2236h). In severe deficiency, but low level required. The t1/2 bleeding sympto ms (similar to hemophilia) occur and spontaneous intracerebral hemorrhage at a young age ha s been reported. Diagnosis 4 PT and normal APTT. Assay factor VII to assess severity. 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 358 Treatment Use factor VII concentrate 1u/kg body wt to elevate plasma conc 20u/dL or recomb inant factor VIIa. For cerebral bleed give a >50u/dL rise and continue treatment for 10d. V ery short t1/2 makes management difficult, requiring IV replacement 3 \200\2234 /24h. If using FFP, give initial IV injection (15mL/kg) and check response. Other deficiencies Factor II, V, X deficiencies very rare. Bleeding less severe with factor V deficiency than with factor X or prothrombin deficiency. Factor XIII (fibrin stabilizing factor) Clinical Characteristically produces delayed post-o perative bleeding (6 \200\22324h later). Neonatal umbilical stump bleeding more common than with other defi- ciencies. High risk of cerebral hemorrhage. Diagnosis APTT and PT both normal so will be missed in a bleeding investigation unless spec ifically looked for by screening test (clot formed with thrombin and stability in acetic ac id is measured). Treatment Only very low levels required for haemostasis; t1/2 is very long. Severe defi- ci ency should be treated with once-monthly prophylaxis with factor XIII concentrate. 358 Multiple defects Rare familial coagulation factor deficiencies described; may be consan- fa ctor involves guineous parents. Often (V>IX>VII). Other combinations seen. factor VIII and another 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 359 Haemostasis and thrombosis 359 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 360 Vitamin K deficiency Pathophysiology Vitamin K (vit K) is a fat-soluble vitamin obtained either by dietary intak e (vit K1) from vegetables and liver, and absorbed in the small gut or pro- duced by bacter ial synthesis in the gut and absorbed in the colon (vit K2). Its essential role in coagulat ion is as cofactor for the gamma carboxylation of the precursor proteins for factors II, VI I, IX, X, protein C and S, all of which are produced in the liver. Until the routine prophy lactic administra- tion of vit K, deficiency was common in the neonate, almost exclusively a disease of breast-fed babies because 5 vit K in human breast milk cf. formula feeds, and 5 synthesis in the neonatal gut. Clinical features 2 Dietary deficiency may arise within a few weeks in patients who are not eating well since body stores are limited and the t1/2 of the vitamin is short (days). Coagulopathy due to deficiency common in ITU patients unless vitamin K administered. 2 Systemic illness, parenteral nutrition, hepatic or renal failure, hypo- albuminaemia, ant ibiotics (e.g. cephalosporins) are compounding factors. 2 Haemorrhagic disorder of the newborn. Prematurity and maternal intake of anticonvulsants increase the incidence. Usually presents in first few days of life with bleeding (e.g. umbi lical stump). Cerebral hemorrhage is rare. A late form seen 3 \200\2236 months after birth is rare may be due to liver disease, intestinal malabsorption. 360 Malabsorption 2 Disease of the small gut (e.g. coeliac disease) may lead to clinically manifest vit K deficiency. 2 Obstruction of bile flow, either extrahepatic (gallstones, Ca pancreas, or bile ducts) or intrahepatic (liver disease, liver fibrosis) may be asso- ciated with overt bleeding or no ted on routine coagulation laboratory testing. Laboratory diagnosis 2 Clotting screen shows 4 PT and APTT. 2 Thrombin time and platelet co unt are normal. 2 PT is more prolonged than APTT, and corrects with normal plasma. 2 Furthe r investigation (factor assays, PIVKA levels, vit K concentration) rarely required. A thera peutic trial of vit K will confirm diagnosis, with rapid ( 24h) PT correction. Treatment Asymptomatic patients \200\224adult dose vit K 10mg IV; repeat as necessary; can be given by mouth in dietary deficiency. Neonate prophylaxis \200\2241mg IM 1 \200\2233 mg PO. Bleeding patients \200\224in addition to vit K as above, give FFP (10 \200\22320mL/kg body wt) for immediate replacement of the clotting factors. PCC 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 361 Haemostasis and thrombosis (concentrate containing factors II, VII, IX and X) can be used in life- threatening situati ons. Natural history Response to treatment is good but treatment of the underlying condition is necessary to prevent recurrence. 361 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 362 Haemorrhagic disease of the newborn Haemorrhagic disease of the newborn is caused by deficiency of the vitamin K dependent fact ors and is a significant cause of bleeding in the neonatal period unless prevented by vitam in K. Two forms described; an early classical and a late form with different etiology Pathophysiology Classical haemorrhagic disease of the newborn is almost exclusively a disea se of breast fed babies; incidence may be as high as 1/2500 deliveries in the UK. This is a true deficiency; human milk has less vitamin K than formula milk and there is less bacteri al synthesis of vitamin K due to the sterile gut of the newborn. Immaturity of the liver an d impaired produc- tion of the vitamin K factors may be a contributing factor. The late for m 40 \200\223100/million live births also is seen in breast fed babies but is mainly due t o malabsorption of vitamin K, secondary to cholestasis, or GIT pathology. Clinical features 2 Early haemorrhagic disease of the newborn presents in the first week of life with bleeding \200\224umbilical cord, the skin, post circumcision bleeding is commo n; ICH is rare. Presents <24h in haemorrhagic disease of the newborn 2 to maternal drug i ngestion (anti-epileptic, anti-TB). 362 2 Late haemorrhagic disease of the newborn has a peak incidence at 2 \200\2236 weeks but ca n occur up to 6 months of age. Underlying cholestatic disease is often present, biliary atr esia, cystic fibrosis, a-1 antitrypsin deficiency and diarrhea are documented causes. About half of cases present with ICH. Diagnosis \200\224laboratory findings 2 PT/APTT \200\224may be markedly prolonged (normal T T, fibrinogen, D- dimer/FDPs low cf. DIC). 2 Factor assay (II, VII, IX, X) if in doubt. High PIVKA and low vit K \200\224not routinely available tests. 2 Correction of coagulation abnormality in 24h with parenteral vitamin K confirms diagnosis. Differential diagnosis 2 Exclude other causes of bleeding in the neonatal period. 2 Thrombo cytopenia \200\224platelets are normal in haemorrhagic disease of the newborn. 2 DIC \200\224see below. 2 Congenital disorders e.g. hemophilia. 2 Radiologica l \200\224scan for ICH/internal bleeding as required. Management Treatment \200\224general support as indicated by clinical presentation. FFP for immediate correction of bleeding. Vitamin K1 1mg IV will correct PT/APTT to normal for age \200\224ta kes 24 h. Prophylaxis \200\2241mg at birth will prevent all early and most delayed vit K deficiency i n neonate 10-Haemostasis.qxd 10.12.2003 04.26 PM Page 363 Haemostasis and thrombosis